2020 |
Picetti, Roberto; Miller, Lori; Shakur-Still, Haleema; Pepple, Tracey; Beaumont, Danielle; Balogun, Eni; Asonganyi, Etienne; Chaudhri, Rizwana; El-Sheikh, Mohamed; Vwalika, Bellington; Arulkumaran, Sabaratnam; Roberts, Ian; trial collaborators, WOMAN The WOMAN trial: clinical and contextual factors surrounding the deaths of 483 women following post-partum haemorrhage in developing countries. Journal Article BMC Pregnancy and Childbirth, 20 (1), pp. 409, 2020. @article{lshtm4657498, title = {The WOMAN trial: clinical and contextual factors surrounding the deaths of 483 women following post-partum haemorrhage in developing countries.}, author = {Roberto Picetti and Lori Miller and Haleema Shakur-Still and Tracey Pepple and Danielle Beaumont and Eni Balogun and Etienne Asonganyi and Rizwana Chaudhri and Mohamed El-Sheikh and Bellington Vwalika and Sabaratnam Arulkumaran and Ian Roberts and WOMAN trial collaborators}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4657498/}, year = {2020}, date = {2020-07-01}, journal = {BMC Pregnancy and Childbirth}, volume = {20}, number = {1}, pages = {409}, publisher = {Springer Science and Business Media LLC}, abstract = {BACKGROUND: Post-partum haemorrhage (PPH) is a leading cause of maternal death worldwide. The WOMAN trial assessed the effects of tranexamic acid (TXA) on death and surgical morbidity in women with PPH. The trial recorded 483 maternal deaths. We report the circumstances of the women who died. METHODS: The WOMAN trial recruited 20,060 women with a clinical diagnosis of PPH after a vaginal birth or caesarean section. We randomly allocated women to receive TXA or placebo. When a woman died, we asked participating clinicians to report the cause of death and to provide a short narrative of the events surrounding the death. We collated and edited for clarity the narrative data. RESULTS: Case fatality rates were 3.0% in Africa and 1.7% in Asia. Nearly three quarters of deaths were within 3 h of delivery and 91% of these deaths were from bleeding. Women who delivered outside a participating hospital (12%) were three times more likely to die (OR = 3.12, 95%CI 2.55-3.81) than those who delivered in hospital. Blood was often unavailable due to shortages or because relatives could not afford to buy it. Clinicians highlighted late presentation, maternal anaemia and poor infrastructure as key contributory factors. CONCLUSIONS: Although TXA use reduces bleeding deaths by almost one third, mortality rates similar to those in high income countries will not be achieved without tackling late presentation, maternal anaemia, availability of blood for transfusion and poor infrastructure.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Post-partum haemorrhage (PPH) is a leading cause of maternal death worldwide. The WOMAN trial assessed the effects of tranexamic acid (TXA) on death and surgical morbidity in women with PPH. The trial recorded 483 maternal deaths. We report the circumstances of the women who died. METHODS: The WOMAN trial recruited 20,060 women with a clinical diagnosis of PPH after a vaginal birth or caesarean section. We randomly allocated women to receive TXA or placebo. When a woman died, we asked participating clinicians to report the cause of death and to provide a short narrative of the events surrounding the death. We collated and edited for clarity the narrative data. RESULTS: Case fatality rates were 3.0% in Africa and 1.7% in Asia. Nearly three quarters of deaths were within 3 h of delivery and 91% of these deaths were from bleeding. Women who delivered outside a participating hospital (12%) were three times more likely to die (OR = 3.12, 95%CI 2.55-3.81) than those who delivered in hospital. Blood was often unavailable due to shortages or because relatives could not afford to buy it. Clinicians highlighted late presentation, maternal anaemia and poor infrastructure as key contributory factors. CONCLUSIONS: Although TXA use reduces bleeding deaths by almost one third, mortality rates similar to those in high income countries will not be achieved without tackling late presentation, maternal anaemia, availability of blood for transfusion and poor infrastructure. |
Ageron, Francois-Xavier; Gayet-Ageron, Angele; Ker, Katharine; Coats, Timothy J; Shakur-Still, Haleema; Roberts, Ian; Collaboration, Antifibrinolytics Trials BRITISH JOURNAL OF ANAESTHESIA, 124 (6), pp. 676–683, 2020. @article{lshtm4657257, title = {Effect of tranexamic acid by baseline risk of death in acute bleeding patients: a meta-analysis of individual patient-level data from 28 333 patients.}, author = {Francois-Xavier Ageron and Angele Gayet-Ageron and Katharine Ker and Timothy J Coats and Haleema Shakur-Still and Ian Roberts and Antifibrinolytics Trials Collaboration}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4657257/}, year = {2020}, date = {2020-06-01}, journal = {BRITISH JOURNAL OF ANAESTHESIA}, volume = {124}, number = {6}, pages = {676--683}, publisher = {ELSEVIER SCI LTD}, abstract = {BACKGROUND: Early administration of the antifibrinolytic drug tranexamic acid reduces death from bleeding in trauma and postpartum haemorrhage. We examined how the effectiveness and safety of antifibrinolytic drugs varies by the baseline risk of death as a result of bleeding. METHODS: We performed an individual patient-level data meta-analysis of randomised trials including more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials performed between January 1, 1946 and July 5, 2018 (PROSPERO, number 42016052155). RESULTS: Two randomised trials were selected where 28 333 patients received tranexamic acid treatment within 3 h after the onset of acute bleeding. Baseline characteristics to estimate the risk of death as a result of bleeding were divided into four categories: Low (0-5%), intermediate (6-10%), high (11-20%), and very high (>20%). Most patients had a low baseline risk of death as a result of bleeding (23 008 [81%]). Deaths as a result of bleeding occurred in all baseline risk categories with 240 (1%), 202 (8%), 232 (14%), and 357 (30%) deaths in the low-, intermediate-, high-, and very high-risk categories, respectively. The effectiveness of tranexamic acid did not vary by baseline risk when given within 3 h after bleeding onset (P=0.51 for interaction term). There was no increased risk of vascular occlusive events with tranexamic acid and it did not vary by baseline risk categories (P=0.25). CONCLUSIONS: Tranexamic acid appears to be safe and effective regardless of baseline risk of death. Because many deaths are in patients at low and intermediate risk, tranexamic acid use should not be restricted to the most severely injured or bleeding patients.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Early administration of the antifibrinolytic drug tranexamic acid reduces death from bleeding in trauma and postpartum haemorrhage. We examined how the effectiveness and safety of antifibrinolytic drugs varies by the baseline risk of death as a result of bleeding. METHODS: We performed an individual patient-level data meta-analysis of randomised trials including more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials performed between January 1, 1946 and July 5, 2018 (PROSPERO, number 42016052155). RESULTS: Two randomised trials were selected where 28 333 patients received tranexamic acid treatment within 3 h after the onset of acute bleeding. Baseline characteristics to estimate the risk of death as a result of bleeding were divided into four categories: Low (0-5%), intermediate (6-10%), high (11-20%), and very high (>20%). Most patients had a low baseline risk of death as a result of bleeding (23 008 [81%]). Deaths as a result of bleeding occurred in all baseline risk categories with 240 (1%), 202 (8%), 232 (14%), and 357 (30%) deaths in the low-, intermediate-, high-, and very high-risk categories, respectively. The effectiveness of tranexamic acid did not vary by baseline risk when given within 3 h after bleeding onset (P=0.51 for interaction term). There was no increased risk of vascular occlusive events with tranexamic acid and it did not vary by baseline risk categories (P=0.25). CONCLUSIONS: Tranexamic acid appears to be safe and effective regardless of baseline risk of death. Because many deaths are in patients at low and intermediate risk, tranexamic acid use should not be restricted to the most severely injured or bleeding patients. |
Free, Caroline; McCarthy, Ona L; Palmer, Melissa J; Knight, Rosemary; Edwards, Phil; French, Rebecca; Baraitser, Paula; Hickson, Ford Colin Ian; Wellings, Kaye; Roberts, Ian; Bailey, Julia V; Hart, Graham; Michie, Susan; Clayton, Tim; Ploubidis, George B; Carpenter, James R; Turner, Katy ME; Devries, Karen; Potter, Kimberley BMJ OPEN, 10 (3), pp. e031635–, 2020. @article{lshtm4656873, title = {Safetxt: a safer sex intervention delivered by mobile phone messaging on sexually transmitted infections (STI) among young people in the UK - protocol for a randomised controlled trial.}, author = {Caroline Free and Ona L McCarthy and Melissa J Palmer and Rosemary Knight and Phil Edwards and Rebecca French and Paula Baraitser and Ford Colin Ian Hickson and Kaye Wellings and Ian Roberts and Julia V Bailey and Graham Hart and Susan Michie and Tim Clayton and George B Ploubidis and James R Carpenter and Katy ME Turner and Karen Devries and Kimberley Potter}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4656873/}, year = {2020}, date = {2020-03-01}, journal = {BMJ OPEN}, volume = {10}, number = {3}, pages = {e031635--}, publisher = {BMJ PUBLISHING GROUP}, abstract = {INTRODUCTION: Young people aged 16 to 24 have the highest prevalence of genital chlamydia and gonorrhoea compared with other age groups and re-infection rates following treatment are high. Long-term adverse health effects include subfertility and ectopic pregnancy, particularly among those with repeated infections. We developed the safetxt intervention delivered by text message to reduce sexually transmitted infection (STI) by increasing partner notification, condom use and (STI) testing among young people in the UK. METHODS AND ANALYSIS: A single-blind randomised trial to reliably establish the effect of the safetxt intervention on chlamydia and gonorrhoea infection at 1 year. We will recruit 6250 people aged 16 to 24 years who have recently been diagnosed with chlamydia, gonorrhoea or non-specific urethritis from health services in the UK. Participants will be allocated to receive the safetxt intervention (text messages designed to promote safer sexual health behaviours) or to receive the control text messages (monthly messages asking participants about changes in contact details) by an automated remote online randomisation system. The primary outcome will be the cumulative incidence of chlamydia and gonorrhoea infection at 1 year assessed by nucleic acid amplification tests. Secondary outcomes include partner notification, correct treatment of infection, condom use and STI testing prior to sex with new partners. ETHICS AND DISSEMINATION: Ethics approval was obtained from NHS Health Research Authority - London - Riverside Research Ethics Committee (REC reference: 15/LO/1665) and the London School of Hygiene & Tropical Medicine. We will submit the results of the trial for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: International Standard Randomised Controlled Trials Number: ISRCTN64390461. Registered on 17th March 2016. WHO trial registration data set available at: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ISRCTN64390461. TRIAL PROTOCOL VERSION: 12, 19th July 2018.}, keywords = {}, pubstate = {published}, tppubtype = {article} } INTRODUCTION: Young people aged 16 to 24 have the highest prevalence of genital chlamydia and gonorrhoea compared with other age groups and re-infection rates following treatment are high. Long-term adverse health effects include subfertility and ectopic pregnancy, particularly among those with repeated infections. We developed the safetxt intervention delivered by text message to reduce sexually transmitted infection (STI) by increasing partner notification, condom use and (STI) testing among young people in the UK. METHODS AND ANALYSIS: A single-blind randomised trial to reliably establish the effect of the safetxt intervention on chlamydia and gonorrhoea infection at 1 year. We will recruit 6250 people aged 16 to 24 years who have recently been diagnosed with chlamydia, gonorrhoea or non-specific urethritis from health services in the UK. Participants will be allocated to receive the safetxt intervention (text messages designed to promote safer sexual health behaviours) or to receive the control text messages (monthly messages asking participants about changes in contact details) by an automated remote online randomisation system. The primary outcome will be the cumulative incidence of chlamydia and gonorrhoea infection at 1 year assessed by nucleic acid amplification tests. Secondary outcomes include partner notification, correct treatment of infection, condom use and STI testing prior to sex with new partners. ETHICS AND DISSEMINATION: Ethics approval was obtained from NHS Health Research Authority - London - Riverside Research Ethics Committee (REC reference: 15/LO/1665) and the London School of Hygiene & Tropical Medicine. We will submit the results of the trial for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: International Standard Randomised Controlled Trials Number: ISRCTN64390461. Registered on 17th March 2016. WHO trial registration data set available at: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ISRCTN64390461. TRIAL PROTOCOL VERSION: 12, 19th July 2018. |
Mahmood, A; Needham, K; Shakur-Still, Haleema; Davies, D; Belli, A; Jamaluddin, SF; Harris, T; Mohamed, FL; Leech, C; Lotfi, H; Moss, P; Hopkins, P; Wong, D; Kendall, J; Boyle, A; Wilson, M; Darwent, M; Roberts, I Tranexamic acid in traumatic brain injury: an explanatory study nested within the CRASH-3 trial Journal Article European Journal of Trauma and Emergency Surgery, 2020. @article{lshtm4656920, title = {Tranexamic acid in traumatic brain injury: an explanatory study nested within the CRASH-3 trial}, author = {A Mahmood and K Needham and Haleema Shakur-Still and D Davies and A Belli and SF Jamaluddin and T Harris and FL Mohamed and C Leech and H Lotfi and P Moss and P Hopkins and D Wong and J Kendall and A Boyle and M Wilson and M Darwent and I Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4656920/}, year = {2020}, date = {2020-02-01}, journal = {European Journal of Trauma and Emergency Surgery}, publisher = {Springer Science and Business Media LLC}, abstract = {© 2020, The Author(s). Purpose: The CRASH-3 trial is a randomised trial of tranexamic acid (TXA) on death and disability in patients with traumatic brain injury (TBI). It is based on the hypothesis that early TXA treatment can prevent deaths from post-traumatic intracranial bleeding. The results showed that timely TXA treatment reduces head injury deaths in patients with reactive pupils and those with a mild to moderate GCS at baseline. We examined routinely collected CT scans in a sample of 1767 CRASH-3 trial patients to explore if, why, and how patients are affected by TXA. Methods: The CRASH-3 IBMS is an explanatory study nested within the CRASH-3 trial. We measured the volume of intracranial bleeding on CT scans using established methods (e.g. ABC/2). Results: Patients with any un-reactive pupil had a median intracranial bleeding volume of 60 ml (IQR 18–101 ml) and patients with reactive pupils had a median volume of 26 ml (IQR 1–55 ml). Patients with severe GCS had median intracranial bleeding volume of 37 ml (IQR 3–75 ml) and patients with moderate to mild GCS had a median volume of 26 ml (IQR 0.4–50 ml). For every hour increase from injury to the baseline scan, the risk of new bleeding on a further scan decreased by 12% (adjusted RR = 0.88 [95% CI 0.80–0.96], p = 0.0047). Conclusion: Patients with reactive pupils and/or mild to moderate GCS may have benefited from TXA in the CRASH-3 trial because they had less intracranial bleeding at baseline. However, because bleeding occurs soon after injury, treatment delay reduces the benefit of TXA.}, keywords = {}, pubstate = {published}, tppubtype = {article} } © 2020, The Author(s). Purpose: The CRASH-3 trial is a randomised trial of tranexamic acid (TXA) on death and disability in patients with traumatic brain injury (TBI). It is based on the hypothesis that early TXA treatment can prevent deaths from post-traumatic intracranial bleeding. The results showed that timely TXA treatment reduces head injury deaths in patients with reactive pupils and those with a mild to moderate GCS at baseline. We examined routinely collected CT scans in a sample of 1767 CRASH-3 trial patients to explore if, why, and how patients are affected by TXA. Methods: The CRASH-3 IBMS is an explanatory study nested within the CRASH-3 trial. We measured the volume of intracranial bleeding on CT scans using established methods (e.g. ABC/2). Results: Patients with any un-reactive pupil had a median intracranial bleeding volume of 60 ml (IQR 18–101 ml) and patients with reactive pupils had a median volume of 26 ml (IQR 1–55 ml). Patients with severe GCS had median intracranial bleeding volume of 37 ml (IQR 3–75 ml) and patients with moderate to mild GCS had a median volume of 26 ml (IQR 0.4–50 ml). For every hour increase from injury to the baseline scan, the risk of new bleeding on a further scan decreased by 12% (adjusted RR = 0.88 [95% CI 0.80–0.96], p = 0.0047). Conclusion: Patients with reactive pupils and/or mild to moderate GCS may have benefited from TXA in the CRASH-3 trial because they had less intracranial bleeding at baseline. However, because bleeding occurs soon after injury, treatment delay reduces the benefit of TXA. |
2019 |
Mahmood, Abda; Roberts, Ian; Shakur-Still, Haleema Wellcome open research, 3 , pp. 99–, 2019. @article{lshtm4653827, title = {A nested randomised trial of the effect of tranexamic acid on intracranial haemorrhage and infarction in traumatic brain injury (CRASH-3 trial intracranial bleeding mechanistic study): Statistical analysis plan.}, author = {Abda Mahmood and Ian Roberts and Haleema Shakur-Still}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4653827/}, year = {2019}, date = {2019-11-01}, journal = {Wellcome open research}, volume = {3}, pages = {99--}, publisher = {F1000Research}, abstract = {Background: The CRASH-3 trial is a randomised trial on the effect of tranexamic acid (TXA) versus placebo on death and disability in traumatic brain injury (TBI). The CRASH-3 intracranial bleeding mechanistic study (IBMS) is a randomised trial nested within the CRASH-3 trial to examine the effect of TXA versus placebo on intracranial bleeding and infarction. Methods: Patients eligible for the CRASH-3 trial, with a GCS of 12 or less or intracranial bleeding on a pre-randomisation CT scan are eligible for the IBMS. The occurrence of intracranial bleeding, infarction, haemorrhagic oedematous lesions, mass effect and haemorrhage evacuation is examined within 28 days of randomisation using routinely collected brain scans. The primary outcome is the volume of intra-parenchymal bleeding in patients randomised within three hours of injury (adjusted for prognostic covariates). Secondary outcomes include a composite "poor" outcome, progressive and new intracranial bleeding, intracranial bleeding after neurosurgery and cerebral infarcts seen up to 28 days post-randomisation. All outcomes will be compared between treatment groups. Statistical analyses: The primary outcome will be analysed using a covariate adjusted linear mixed model. The same analysis will be done separately for patients who undergo haemorrhage evacuation post-randomisation. We will express the effect of TXA on the composite outcome, new and progressive bleeding using relative risks and 95% CIs, and on cerebral infarcts using hazard ratios and 95% CIs. We will conduct sensitivity analyses assuming missing data are MCAR or MNAR. Conclusion: The IBMS will provide information on the mechanism of action of TXA in TBI. This pre-specified statistical analysis plan is a technical extension of the published protocol. Trial registration: The CRASH-3 trial was prospectively registered at the International Standard Randomised Controlled Trials registry (19 July 2011) and ClinicalTrials.gov (25 July 2011). The registries were updated with details for the IBMS on 20 December 2016.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: The CRASH-3 trial is a randomised trial on the effect of tranexamic acid (TXA) versus placebo on death and disability in traumatic brain injury (TBI). The CRASH-3 intracranial bleeding mechanistic study (IBMS) is a randomised trial nested within the CRASH-3 trial to examine the effect of TXA versus placebo on intracranial bleeding and infarction. Methods: Patients eligible for the CRASH-3 trial, with a GCS of 12 or less or intracranial bleeding on a pre-randomisation CT scan are eligible for the IBMS. The occurrence of intracranial bleeding, infarction, haemorrhagic oedematous lesions, mass effect and haemorrhage evacuation is examined within 28 days of randomisation using routinely collected brain scans. The primary outcome is the volume of intra-parenchymal bleeding in patients randomised within three hours of injury (adjusted for prognostic covariates). Secondary outcomes include a composite "poor" outcome, progressive and new intracranial bleeding, intracranial bleeding after neurosurgery and cerebral infarcts seen up to 28 days post-randomisation. All outcomes will be compared between treatment groups. Statistical analyses: The primary outcome will be analysed using a covariate adjusted linear mixed model. The same analysis will be done separately for patients who undergo haemorrhage evacuation post-randomisation. We will express the effect of TXA on the composite outcome, new and progressive bleeding using relative risks and 95% CIs, and on cerebral infarcts using hazard ratios and 95% CIs. We will conduct sensitivity analyses assuming missing data are MCAR or MNAR. Conclusion: The IBMS will provide information on the mechanism of action of TXA in TBI. This pre-specified statistical analysis plan is a technical extension of the published protocol. Trial registration: The CRASH-3 trial was prospectively registered at the International Standard Randomised Controlled Trials registry (19 July 2011) and ClinicalTrials.gov (25 July 2011). The registries were updated with details for the IBMS on 20 December 2016. |
Tillin, Therese; Tuson, Claire; Sowa, Barbara; Chattopadhyay, Kaushik; Sattar, Naveed; Welsh, Paul; Roberts, Ian; Ebrahim, Shah; Kinra, Sanjay; Hughes, A; Chaturvedi, Nishi BMJ open, 9 (11), pp. e030119–, 2019. @article{lshtm4655112, title = {Yoga and Cardiovascular Health Trial (YACHT): a UK-based randomised mechanistic study of a yoga intervention plus usual care versus usual care alone following an acute coronary event.}, author = {Therese Tillin and Claire Tuson and Barbara Sowa and Kaushik Chattopadhyay and Naveed Sattar and Paul Welsh and Ian Roberts and Shah Ebrahim and Sanjay Kinra and A Hughes and Nishi Chaturvedi}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4655112/}, year = {2019}, date = {2019-11-01}, journal = {BMJ open}, volume = {9}, number = {11}, pages = {e030119--}, publisher = {BMJ}, abstract = {OBJECTIVE: To determine the effects of yoga practice on subclinical cardiovascular measures, risk factors and neuro-endocrine pathways in patients undergoing cardiac rehabilitation (CR) following acute coronary events. DESIGN: 3-month, two-arm (yoga +usual care vs usual care alone) parallel randomised mechanistic study. SETTING: One general hospital and two primary care CR centres in London. Assessments were conducted at Imperial College London. PARTICIPANTS: 80 participants, aged 35-80 years (68% men, 60% South Asian) referred to CR programmes 2012-2014. INTERVENTION: A certified yoga teacher conducted yoga classes which included exercises in stretching, breathing, healing imagery and deep relaxation. It was pre-specified that at least 18 yoga classes were attended for inclusion in analysis. Participants and partners in both groups were invited to attend weekly a 6- to 12-week local standard UK National Health Service CR programme. MAIN OUTCOME MEASURES: (i) Estimated left ventricular filling pressure (E/e'), (ii) distance walked, fatigue and breathlessness in a 6 min walk test, (iii) blood pressure, heart rate and estimated peak VO2 following a 3 min step-test. Effects on the hypothalamus-pituitary-adrenal axis, autonomic function, body fat, blood lipids and glucose, stress and general health were also explored. RESULTS: 25 participants in the yoga + usual care group and 35 participants in the usual care group completed the study. Following the 3-month intervention period, E/e' was not improved by yoga (E/e': between-group difference: yoga minus usual care:-0.40 (-1.38, 0.58). Exercise testing and secondary outcomes also showed no benefits of yoga. CONCLUSIONS: In this small UK-based randomised mechanistic study, with 60 completing participants (of whom 25 were in the yoga + usual care group), we found no discernible improvement associated with the addition of a structured 3-month yoga intervention to usual CR care in key cardiovascular and neuroendocrine measures shown to be responsive to yoga in previous mechanistic studies. TRIAL REGISTRATION NUMBER: NCT01597960; Pre-results.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: To determine the effects of yoga practice on subclinical cardiovascular measures, risk factors and neuro-endocrine pathways in patients undergoing cardiac rehabilitation (CR) following acute coronary events. DESIGN: 3-month, two-arm (yoga +usual care vs usual care alone) parallel randomised mechanistic study. SETTING: One general hospital and two primary care CR centres in London. Assessments were conducted at Imperial College London. PARTICIPANTS: 80 participants, aged 35-80 years (68% men, 60% South Asian) referred to CR programmes 2012-2014. INTERVENTION: A certified yoga teacher conducted yoga classes which included exercises in stretching, breathing, healing imagery and deep relaxation. It was pre-specified that at least 18 yoga classes were attended for inclusion in analysis. Participants and partners in both groups were invited to attend weekly a 6- to 12-week local standard UK National Health Service CR programme. MAIN OUTCOME MEASURES: (i) Estimated left ventricular filling pressure (E/e'), (ii) distance walked, fatigue and breathlessness in a 6 min walk test, (iii) blood pressure, heart rate and estimated peak VO2 following a 3 min step-test. Effects on the hypothalamus-pituitary-adrenal axis, autonomic function, body fat, blood lipids and glucose, stress and general health were also explored. RESULTS: 25 participants in the yoga + usual care group and 35 participants in the usual care group completed the study. Following the 3-month intervention period, E/e' was not improved by yoga (E/e': between-group difference: yoga minus usual care:-0.40 (-1.38, 0.58). Exercise testing and secondary outcomes also showed no benefits of yoga. CONCLUSIONS: In this small UK-based randomised mechanistic study, with 60 completing participants (of whom 25 were in the yoga + usual care group), we found no discernible improvement associated with the addition of a structured 3-month yoga intervention to usual CR care in key cardiovascular and neuroendocrine measures shown to be responsive to yoga in previous mechanistic studies. TRIAL REGISTRATION NUMBER: NCT01597960; Pre-results. |
Cornelissen, Laura; Woodd, Susannah; Shakur-Still, Haleema; Fawole, Bukola; Noor, Shehla; Etuk, Saturday; Akintan, Adesina Lawrence; Chaudhri, Rizwana; Roberts, Ian Secondary analysis of the WOMAN trial to explore the risk of sepsis after invasive treatments for postpartum hemorrhage. Journal Article International journal of gynaecology and obstetrics, 146 (2), pp. 231–237, 2019. @article{lshtm4653583, title = {Secondary analysis of the WOMAN trial to explore the risk of sepsis after invasive treatments for postpartum hemorrhage.}, author = {Laura Cornelissen and Susannah Woodd and Haleema Shakur-Still and Bukola Fawole and Shehla Noor and Saturday Etuk and Adesina Lawrence Akintan and Rizwana Chaudhri and Ian Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4653583/}, year = {2019}, date = {2019-08-01}, journal = {International journal of gynaecology and obstetrics}, volume = {146}, number = {2}, pages = {231--237}, publisher = {Wiley}, abstract = {OBJECTIVE: To examine the association between the use of invasive treatments for postpartum hemorrhage and the risk of sepsis and severe sepsis. METHODS: Secondary data analysis of the WOMAN randomized controlled trial, including 20 060 women with postpartum hemorrhage in 21 countries. Logistic regression with random effects was used. RESULTS: The cumulative incidence was 1.8% for sepsis and 0.5% for severe sepsis. All-cause mortality was 40.4% in women with severe sepsis versus 2.2% for women without. After adjusting for bleeding severity and other confounders, intrauterine tamponade, hysterectomy, and laparotomy increased the risk of sepsis (aOR 1.77 [95% CI 1.21-2.59], P=0.004; aOR 1.97 [95% CI 1.49-2.65], P<0.001; and aOR 6.63 [95% CI 4.29-10.24], P<0.001, respectively) and severe sepsis (aOR 2.60 [95% CI 1.47-4.59], P=0.002; aOR 1.97 [95% CI 0.83-2.46], P=0.033; and aOR 5.35 [95% CI 2.61-10.98], P<0.001, respectively). CONCLUSION: In this secondary data analysis, certain invasive treatments for postpartum hemorrhage appear to increase the risk of sepsis. Further research is needed to confirm this finding and investigate the role of prophylactic antibiotics during these procedures. The harms and benefits of such interventions must be carefully weighed, both in treatment guidelines and during individual patient management. TRIAL REGISTRATION: ISRCTN76912190.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: To examine the association between the use of invasive treatments for postpartum hemorrhage and the risk of sepsis and severe sepsis. METHODS: Secondary data analysis of the WOMAN randomized controlled trial, including 20 060 women with postpartum hemorrhage in 21 countries. Logistic regression with random effects was used. RESULTS: The cumulative incidence was 1.8% for sepsis and 0.5% for severe sepsis. All-cause mortality was 40.4% in women with severe sepsis versus 2.2% for women without. After adjusting for bleeding severity and other confounders, intrauterine tamponade, hysterectomy, and laparotomy increased the risk of sepsis (aOR 1.77 [95% CI 1.21-2.59], P=0.004; aOR 1.97 [95% CI 1.49-2.65], P<0.001; and aOR 6.63 [95% CI 4.29-10.24], P<0.001, respectively) and severe sepsis (aOR 2.60 [95% CI 1.47-4.59], P=0.002; aOR 1.97 [95% CI 0.83-2.46], P=0.033; and aOR 5.35 [95% CI 2.61-10.98], P<0.001, respectively). CONCLUSION: In this secondary data analysis, certain invasive treatments for postpartum hemorrhage appear to increase the risk of sepsis. Further research is needed to confirm this finding and investigate the role of prophylactic antibiotics during these procedures. The harms and benefits of such interventions must be carefully weighed, both in treatment guidelines and during individual patient management. TRIAL REGISTRATION: ISRCTN76912190. |
Brenner, Amy; Afolabi, Adefemi; Ahmad, Syed Masroor; Arribas, Monica; Chaudhri, Rizwana; Coats, Timothy; Cuzick, Jack; Gilmore, Ian; Hawkey, Christopher; Jairath, Vipul; Javaid, Kiran; Kayani, Aasia; Mutti, Muttiullah; Nadeem, Muhammad Arif; Shakur-Still, Haleema; Stanworth, Simon; Veitch, Andrew; Roberts, Ian; Collaborators, HALT-IT Trial Trials, 20 (1), pp. 467–, 2019. @article{lshtm4653872, title = {Tranexamic acid for acute gastrointestinal bleeding (the HALT-IT trial): statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial.}, author = {Amy Brenner and Adefemi Afolabi and Syed Masroor Ahmad and Monica Arribas and Rizwana Chaudhri and Timothy Coats and Jack Cuzick and Ian Gilmore and Christopher Hawkey and Vipul Jairath and Kiran Javaid and Aasia Kayani and Muttiullah Mutti and Muhammad Arif Nadeem and Haleema Shakur-Still and Simon Stanworth and Andrew Veitch and Ian Roberts and HALT-IT Trial Collaborators}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4653872/}, year = {2019}, date = {2019-07-01}, journal = {Trials}, volume = {20}, number = {1}, pages = {467--}, publisher = {Springer Science and Business Media LLC}, abstract = {BACKGROUND: Acute gastrointestinal (GI) bleeding is an important cause of mortality worldwide. Bleeding can occur from the upper or lower GI tract, with upper GI bleeding accounting for most cases. The main causes include peptic ulcer/erosive mucosal disease, oesophageal varices and malignancy. The case fatality rate is around 10% for upper GI bleeding and 3% for lower GI bleeding. Rebleeding affects 5-40% of patients and is associated with a four-fold increased risk of death. Tranexamic acid (TXA) decreases bleeding and the need for blood transfusion in surgery and reduces death due to bleeding in patients with trauma and postpartum haemorrhage. It reduces bleeding by inhibiting the breakdown of fibrin clots by plasmin. Due to the methodological weaknesses and small size of the existing trials, the effectiveness and safety of TXA in GI bleeding is uncertain. The Haemorrhage ALleviation with Tranexamic acid - Intestinal system (HALT-IT) trial aims to provide reliable evidence about the effects of TXA in acute upper and lower GI bleeding. METHODS: The HALT-IT trial is an international, randomised, double-blind, placebo-controlled trial of tranexamic acid in 12,000 adults (increased from 8000) with acute upper or lower GI bleeding. Eligible patients are randomly allocated to receive TXA (1-g loading dose followed by 3-g maintenance dose over 24 h) or matching placebo. The main analysis will compare those randomised to TXA with those randomised to placebo on an intention-to-treat basis, presenting the results as effect estimates (relative risks) and confidence intervals. The primary outcome is death due to bleeding within 5 days of randomisation and secondary outcomes are: rebleeding; all-cause and cause-specific mortality; thromboembolic events; complications; endoscopic, radiological and surgical interventions; blood transfusion requirements; disability (defined by a measure of patient's self-care capacity); and number of days spent in intensive care or high-dependency units. Subgroup analyses for the primary outcome will consider time to treatment, location of bleeding, cause of bleed and clinical Rockall score. DISCUSSION: We present the statistical analysis of the HALT-IT trial. This plan was published before the treatment allocation was unblinded. TRIAL REGISTRATION: Current Controlled Trials, ID: ISRCTN11225767. Registered on 3 July 2012; Clinicaltrials.gov, ID: NCT01658124. Registered on 26 July 2012.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Acute gastrointestinal (GI) bleeding is an important cause of mortality worldwide. Bleeding can occur from the upper or lower GI tract, with upper GI bleeding accounting for most cases. The main causes include peptic ulcer/erosive mucosal disease, oesophageal varices and malignancy. The case fatality rate is around 10% for upper GI bleeding and 3% for lower GI bleeding. Rebleeding affects 5-40% of patients and is associated with a four-fold increased risk of death. Tranexamic acid (TXA) decreases bleeding and the need for blood transfusion in surgery and reduces death due to bleeding in patients with trauma and postpartum haemorrhage. It reduces bleeding by inhibiting the breakdown of fibrin clots by plasmin. Due to the methodological weaknesses and small size of the existing trials, the effectiveness and safety of TXA in GI bleeding is uncertain. The Haemorrhage ALleviation with Tranexamic acid - Intestinal system (HALT-IT) trial aims to provide reliable evidence about the effects of TXA in acute upper and lower GI bleeding. METHODS: The HALT-IT trial is an international, randomised, double-blind, placebo-controlled trial of tranexamic acid in 12,000 adults (increased from 8000) with acute upper or lower GI bleeding. Eligible patients are randomly allocated to receive TXA (1-g loading dose followed by 3-g maintenance dose over 24 h) or matching placebo. The main analysis will compare those randomised to TXA with those randomised to placebo on an intention-to-treat basis, presenting the results as effect estimates (relative risks) and confidence intervals. The primary outcome is death due to bleeding within 5 days of randomisation and secondary outcomes are: rebleeding; all-cause and cause-specific mortality; thromboembolic events; complications; endoscopic, radiological and surgical interventions; blood transfusion requirements; disability (defined by a measure of patient's self-care capacity); and number of days spent in intensive care or high-dependency units. Subgroup analyses for the primary outcome will consider time to treatment, location of bleeding, cause of bleed and clinical Rockall score. DISCUSSION: We present the statistical analysis of the HALT-IT trial. This plan was published before the treatment allocation was unblinded. TRIAL REGISTRATION: Current Controlled Trials, ID: ISRCTN11225767. Registered on 3 July 2012; Clinicaltrials.gov, ID: NCT01658124. Registered on 26 July 2012. |
Sprigg, Nikola; Flaherty, Katie; Appleton, Jason P; Salman, Rustam Al-Shahi; Bereczki, Daniel; Beridze, Maia; Ciccone, Alfonso; Collins, Ronan; Dineen, Robert A; Duley, Lelia; José, Juan; England, Timothy J; Karlinski, Michal; Krishnan, Kailash; Laska, Ann Charlotte; Law, Zhe Kang; Ovesen, Christian; Ozturk, Serefnur; Pocock, Stuart J; Roberts, Ian; Robinson, Thompson G; Roffe, Christine; Peters, Nils; Scutt, Polly; Thanabalan, Jegan; Werring, David; Whynes, David; Woodhouse, Lisa; Bath, Philip M Tranexamic acid to improve functional status in adults with spontaneous intracerebral haemorrhage: the TICH-2 RCT. Journal Article Health technology assessment, 23 (35), pp. 1–48, 2019. @article{lshtm4653745, title = {Tranexamic acid to improve functional status in adults with spontaneous intracerebral haemorrhage: the TICH-2 RCT.}, author = {Nikola Sprigg and Katie Flaherty and Jason P Appleton and Rustam Al-Shahi Salman and Daniel Bereczki and Maia Beridze and Alfonso Ciccone and Ronan Collins and Robert A Dineen and Lelia Duley and Juan José and Timothy J England and Michal Karlinski and Kailash Krishnan and Ann Charlotte Laska and Zhe Kang Law and Christian Ovesen and Serefnur Ozturk and Stuart J Pocock and Ian Roberts and Thompson G Robinson and Christine Roffe and Nils Peters and Polly Scutt and Jegan Thanabalan and David Werring and David Whynes and Lisa Woodhouse and Philip M Bath}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4653745/}, year = {2019}, date = {2019-07-01}, journal = {Health technology assessment}, volume = {23}, number = {35}, pages = {1--48}, publisher = {National Institute for Health Research}, abstract = {BACKGROUND: Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage. OBJECTIVE: The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH). DESIGN: The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial. SETTING: Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK). PARTICIPANTS: Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset. EXCLUSION CRITERIA: Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy < 3 months; and a Glasgow Coma Scale score of < 5. INTERVENTIONS: Participants, allocated by randomisation, received 1 g of an intravenous tranexamic acid bolus followed by an 8-hour 1-g infusion or matching placebo (i.e. 0.9% saline). MAIN OUTCOME MEASURE: The primary outcome was functional status (death or dependency) at day 90, which was measured by the shift in the mRS score, using ordinal logistic regression, with adjustment for stratification and minimisation criteria. RESULTS: A total of 2325 participants (tranexamic acid, n = 1161; placebo, n = 1164) were recruited from 124 hospitals in 12 countries between 2013 and 2017. Treatment groups were well balanced at baseline. The primary outcome was determined for 2307 participants (tranexamic acid, n = 1152; placebo, n = 1155). There was no statistically significant difference between the treatment groups for the primary outcome of functional status at day 90 [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.76 to 1.03; p = 0.11]. Although there were fewer deaths by day 7 in the tranexamic acid group (aOR 0.73, 95% CI 0.53 to 0.99; p = 0.041), there was no difference in case fatality at 90 days (adjusted hazard ratio 0.92, 95% CI 0.77 to 1.10; p = 0.37). Fewer patients experienced serious adverse events (SAEs) after treatment with tranexamic acid than with placebo by days 2 (p = 0.027), 7 (p = 0.020) and 90 (p = 0.039). There was no increase in thromboembolic events or seizures. LIMITATIONS: Despite attempts to enrol patients rapidly, the majority of participants were enrolled and treated > 4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK. CONCLUSIONS: Tranexamic acid did not affect a patient's functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events. FUTURE WORK: Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN93732214. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage. OBJECTIVE: The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH). DESIGN: The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial. SETTING: Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK). PARTICIPANTS: Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset. EXCLUSION CRITERIA: Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy < 3 months; and a Glasgow Coma Scale score of < 5. INTERVENTIONS: Participants, allocated by randomisation, received 1 g of an intravenous tranexamic acid bolus followed by an 8-hour 1-g infusion or matching placebo (i.e. 0.9% saline). MAIN OUTCOME MEASURE: The primary outcome was functional status (death or dependency) at day 90, which was measured by the shift in the mRS score, using ordinal logistic regression, with adjustment for stratification and minimisation criteria. RESULTS: A total of 2325 participants (tranexamic acid, n = 1161; placebo, n = 1164) were recruited from 124 hospitals in 12 countries between 2013 and 2017. Treatment groups were well balanced at baseline. The primary outcome was determined for 2307 participants (tranexamic acid, n = 1152; placebo, n = 1155). There was no statistically significant difference between the treatment groups for the primary outcome of functional status at day 90 [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.76 to 1.03; p = 0.11]. Although there were fewer deaths by day 7 in the tranexamic acid group (aOR 0.73, 95% CI 0.53 to 0.99; p = 0.041), there was no difference in case fatality at 90 days (adjusted hazard ratio 0.92, 95% CI 0.77 to 1.10; p = 0.37). Fewer patients experienced serious adverse events (SAEs) after treatment with tranexamic acid than with placebo by days 2 (p = 0.027), 7 (p = 0.020) and 90 (p = 0.039). There was no increase in thromboembolic events or seizures. LIMITATIONS: Despite attempts to enrol patients rapidly, the majority of participants were enrolled and treated > 4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK. CONCLUSIONS: Tranexamic acid did not affect a patient's functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events. FUTURE WORK: Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN93732214. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland. |
Beaumont, Danielle; Arribas, Monica; Frimley, Lauren; Balogun, Eni; Roberts, Ian; Shakur-Still, Haleema Trial management: we need a cadre of high-class triallists to deliver the answers that patients need. Journal Article Trials, 20 (1), pp. 354–, 2019. @article{lshtm4653451, title = {Trial management: we need a cadre of high-class triallists to deliver the answers that patients need.}, author = {Danielle Beaumont and Monica Arribas and Lauren Frimley and Eni Balogun and Ian Roberts and Haleema Shakur-Still}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4653451/}, year = {2019}, date = {2019-06-01}, journal = {Trials}, volume = {20}, number = {1}, pages = {354--}, publisher = {BMC}, abstract = {Expert trial managers with the training and experience to overcome operational challenges are often the difference between the success and failure of a clinical trial. Considerable importance is given to the beginning and the end of the clinical trial process, with those responsible for writing a protocol, obtaining funding and analysing the data all being rewarded when the results are published. Yet, trial managers are often overlooked in terms of recognition, value and status. This article highlights some of the key barriers to achieving this and makes suggestions on how they can be addressed within clinical trials units registered with the UK Clinical Research Collaboration.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Expert trial managers with the training and experience to overcome operational challenges are often the difference between the success and failure of a clinical trial. Considerable importance is given to the beginning and the end of the clinical trial process, with those responsible for writing a protocol, obtaining funding and analysing the data all being rewarded when the results are published. Yet, trial managers are often overlooked in terms of recognition, value and status. This article highlights some of the key barriers to achieving this and makes suggestions on how they can be addressed within clinical trials units registered with the UK Clinical Research Collaboration. |
Ker, Katharine; Prieto-Merino, David; Sprigg, Nikola; Mahmood, Abda; Bath, Philip; Law, Zhe Kang; Flaherty, Katie; Roberts, Ian Wellcome Open Research, 2 , pp. 120–120, 2019. @article{lshtm4653445, title = {The effectiveness and safety of anti-fibrinolytics in patients with acute intracranial haemorrhage: statistical analysis plan for an individual patient data meta-analysis}, author = {Katharine Ker and David Prieto-Merino and Nikola Sprigg and Abda Mahmood and Philip Bath and Zhe Kang Law and Katie Flaherty and Ian Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4653445/}, year = {2019}, date = {2019-06-01}, journal = {Wellcome Open Research}, volume = {2}, pages = {120--120}, publisher = {F1000 ( Faculty of 1000 Ltd)}, abstract = {Introduction: The Anti-fibrinolytics Trialists Collaboration aims to increase knowledge about the effectiveness and safety of anti-fibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of anti-fibrinolytics for acute intracranial haemorrhage. Methods: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42019128260). We will conduct an individual patient data meta-analysis of randomised controlled trials with 500 patients or more assessing the effects of anti-fibrinolytics in acute intracranial haemorrhage. The primary outcomes will be 1) death from stroke or head injury within 30 days of randomisation, and 2) death from stroke or head injury, or dependency within 90 days of randomisation. The primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of anti-fibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of anti-fibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. Conclusions: This IPD meta-analysis will examine important clinical questions about the effects of anti-fibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Introduction: The Anti-fibrinolytics Trialists Collaboration aims to increase knowledge about the effectiveness and safety of anti-fibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of anti-fibrinolytics for acute intracranial haemorrhage. Methods: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42019128260). We will conduct an individual patient data meta-analysis of randomised controlled trials with 500 patients or more assessing the effects of anti-fibrinolytics in acute intracranial haemorrhage. The primary outcomes will be 1) death from stroke or head injury within 30 days of randomisation, and 2) death from stroke or head injury, or dependency within 90 days of randomisation. The primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of anti-fibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of anti-fibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. Conclusions: This IPD meta-analysis will examine important clinical questions about the effects of anti-fibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice. |
Ageron, Francois-Xavier; Gayet-Ageron, Angele; Steyerberg, Ewout; Bouzat, Pierre; Roberts, Ian Prognostic model for traumatic death due to bleeding: cross-sectional international study. Journal Article BMJ Open, 9 (5), pp. e026823–, 2019. @article{lshtm4653443, title = {Prognostic model for traumatic death due to bleeding: cross-sectional international study.}, author = {Francois-Xavier Ageron and Angele Gayet-Ageron and Ewout Steyerberg and Pierre Bouzat and Ian Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4653443/}, year = {2019}, date = {2019-05-01}, journal = {BMJ Open}, volume = {9}, number = {5}, pages = {e026823--}, publisher = {BMJ}, abstract = {OBJECTIVE: To develop and validate a prognostic model and a simple model to predict death due to bleeding in trauma patients. DESIGN: Cross-sectional study with multivariable logistic regression using data from two large trauma cohorts. SETTING: 274 hospitals from 40 countries in the Clinical Randomisation of Anti-fibrinolytic in Significant Haemorrhage (CRASH-2) trial and 24 hospitals in the Northern French Alps Trauma registry. PARTICIPANTS: 13 485 trauma patients in the CRASH-2 trial and 9945 patients in the Northern French Alps Trauma registry who were admitted to hospital within 3 hours of injury. MAIN OUTCOME MEASURE: In-hospital death due to bleeding within 28 days. RESULTS: There were 815 (6%) deaths from bleeding in the CRASH-2 trial and 102 (1%) in the Northern French Alps Trauma registry. The full model included age, systolic blood pressure (SBP), Glasgow Coma Scale (GCS), heart rate, respiratory rate and type of injury (penetrating). The simple model included age, SBP and GCS. In a cross-validation procedure by country, discrimination and calibration were adequate (pooled C-statistic 0.85 (95% CI 0.81 to 0.88) for the full model and 0.84 (95% CI 0.80 to 0.88) for the simple model). CONCLUSION: This prognostic model can identify trauma patients at risk of death due to bleeding in a wide range of settings and can support prehospital triage and trauma audit, including audit of tranexamic acid use.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: To develop and validate a prognostic model and a simple model to predict death due to bleeding in trauma patients. DESIGN: Cross-sectional study with multivariable logistic regression using data from two large trauma cohorts. SETTING: 274 hospitals from 40 countries in the Clinical Randomisation of Anti-fibrinolytic in Significant Haemorrhage (CRASH-2) trial and 24 hospitals in the Northern French Alps Trauma registry. PARTICIPANTS: 13 485 trauma patients in the CRASH-2 trial and 9945 patients in the Northern French Alps Trauma registry who were admitted to hospital within 3 hours of injury. MAIN OUTCOME MEASURE: In-hospital death due to bleeding within 28 days. RESULTS: There were 815 (6%) deaths from bleeding in the CRASH-2 trial and 102 (1%) in the Northern French Alps Trauma registry. The full model included age, systolic blood pressure (SBP), Glasgow Coma Scale (GCS), heart rate, respiratory rate and type of injury (penetrating). The simple model included age, SBP and GCS. In a cross-validation procedure by country, discrimination and calibration were adequate (pooled C-statistic 0.85 (95% CI 0.81 to 0.88) for the full model and 0.84 (95% CI 0.80 to 0.88) for the simple model). CONCLUSION: This prognostic model can identify trauma patients at risk of death due to bleeding in a wide range of settings and can support prehospital triage and trauma audit, including audit of tranexamic acid use. |
Brenner, Amy; Ker, Katharine; Shakur-Still, Haleema; Roberts, Ian Tranexamic acid for post-partum haemorrhage: What, who and when. Journal Article Best Practice & Research Clinical Obstetrics & Gynaecology, 61 , pp. 66–74, 2019. @article{lshtm4653135, title = {Tranexamic acid for post-partum haemorrhage: What, who and when.}, author = {Amy Brenner and Katharine Ker and Haleema Shakur-Still and Ian Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4653135/}, year = {2019}, date = {2019-04-01}, journal = {Best Practice & Research Clinical Obstetrics & Gynaecology}, volume = {61}, pages = {66--74}, publisher = {Elsevier BV}, abstract = {Tranexamic acid reduces bleeding by inhibiting the breakdown of blood clots. It is cost-effective and heat-stable with a long shelf life. In the WOMAN trial, tranexamic acid reduced deaths due to bleeding with no increase in thromboembolic events. The effect was greatest when women received tranexamic acid within 3 h of childbirth (RR = 0.69, 95% CI 0.52-0.91). The WHO recommends that women with post-partum haemorrhage receive 1 g tranexamic acid intravenously as soon as possible after giving birth, followed by a second dose if bleeding continues after 30 min or restarts within 24 h since the first dose. Urgent treatment is critical because women with post-partum haemorrhage bleed to death quickly, and tranexamic acid is most effective when given early. Evidence suggests there is no benefit when the drug is given more than 3 h after bleeding onset. Alternative routes of administration and use of tranexamic acid in the prevention of post-partum haemorrhage are research priorities.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Tranexamic acid reduces bleeding by inhibiting the breakdown of blood clots. It is cost-effective and heat-stable with a long shelf life. In the WOMAN trial, tranexamic acid reduced deaths due to bleeding with no increase in thromboembolic events. The effect was greatest when women received tranexamic acid within 3 h of childbirth (RR = 0.69, 95% CI 0.52-0.91). The WHO recommends that women with post-partum haemorrhage receive 1 g tranexamic acid intravenously as soon as possible after giving birth, followed by a second dose if bleeding continues after 30 min or restarts within 24 h since the first dose. Urgent treatment is critical because women with post-partum haemorrhage bleed to death quickly, and tranexamic acid is most effective when given early. Evidence suggests there is no benefit when the drug is given more than 3 h after bleeding onset. Alternative routes of administration and use of tranexamic acid in the prevention of post-partum haemorrhage are research priorities. |
Dallaku, Kastriot; Shakur-Still, Haleema; Beaumont, Danielle; Roberts, Ian; Huque, Sumaya; Delius, Maria; Holdenrieder, Stefan; Gliozheni, Orion; Mansmann, Ulrich Wellcome Open Research, 4 , pp. 21–, 2019. @article{lshtm4651670, title = {No effect of tranexamic acid on platelet function and thrombin generation (ETAPlaT) in postpartum haemorrhage: a randomised placebo-controlled trial.}, author = {Kastriot Dallaku and Haleema Shakur-Still and Danielle Beaumont and Ian Roberts and Sumaya Huque and Maria Delius and Stefan Holdenrieder and Orion Gliozheni and Ulrich Mansmann}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4651670/}, year = {2019}, date = {2019-02-01}, journal = {Wellcome Open Research}, volume = {4}, pages = {21--}, publisher = {F1000 ( Faculty of 1000 Ltd)}, abstract = {Background: Postpartum hemorrhage (PPH) is a leading cause of maternal mortality and morbidity. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. To determine whether TXA has pro-thrombotic effects in women with PPH, we measured endogenous thrombin potential (ETP), coagulation factors V, VIII, von Willebrand (vW), fibrinogen, D-Dimers and platelet function. Methods: We conducted a sub-study within the WOMAN trial, an international randomized, parallel-group, double blind, placebo-controlled trial. Women with primary PPH were randomly allocated to receive 1 gram of tranexamic acid or matching placebo. Baseline blood samples were collected just prior to the first dose and a follow up sample was collected 30±15 minutes afterwards. We compared before and after changes in coagulation parameters between treatment groups using repeated measurement ANOVA. Change in ETP was the primary outcome. We did an intention-to-treat analysis using ANCOVA with adjustment for baseline and the time interval between the blood samples. Findings: A total of 187 patients were randomized to receive TXA (n=93) or matching placebo (n=94). Six patients were excluded due to incomplete data. The reduction in ETP from baseline to follow up was 43.2 nM*min (95%CI, -16.6 to 103.1) in the TXA group and 4.6 nM*min (95%CI, -51.4 to 60.6) in the placebo group. The difference was not statistically significant (95%CI, -42.9 to 120). There were no significant effects of TXA treatment on any other parameters (ADPtest, TRAPtest, coagulation factors activity, fibrinogen levels, D-Dimer level). Conclusion: We found no evidence that tranexamic acid treatment for PPH has substantial pro-coagulant effects. However, larger studies are needed to confirm or refute more modest effects. Trial registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAPlat included on 28/10/2013) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAPlat included on 28/10/2013).}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Postpartum hemorrhage (PPH) is a leading cause of maternal mortality and morbidity. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. To determine whether TXA has pro-thrombotic effects in women with PPH, we measured endogenous thrombin potential (ETP), coagulation factors V, VIII, von Willebrand (vW), fibrinogen, D-Dimers and platelet function. Methods: We conducted a sub-study within the WOMAN trial, an international randomized, parallel-group, double blind, placebo-controlled trial. Women with primary PPH were randomly allocated to receive 1 gram of tranexamic acid or matching placebo. Baseline blood samples were collected just prior to the first dose and a follow up sample was collected 30±15 minutes afterwards. We compared before and after changes in coagulation parameters between treatment groups using repeated measurement ANOVA. Change in ETP was the primary outcome. We did an intention-to-treat analysis using ANCOVA with adjustment for baseline and the time interval between the blood samples. Findings: A total of 187 patients were randomized to receive TXA (n=93) or matching placebo (n=94). Six patients were excluded due to incomplete data. The reduction in ETP from baseline to follow up was 43.2 nM*min (95%CI, -16.6 to 103.1) in the TXA group and 4.6 nM*min (95%CI, -51.4 to 60.6) in the placebo group. The difference was not statistically significant (95%CI, -42.9 to 120). There were no significant effects of TXA treatment on any other parameters (ADPtest, TRAPtest, coagulation factors activity, fibrinogen levels, D-Dimer level). Conclusion: We found no evidence that tranexamic acid treatment for PPH has substantial pro-coagulant effects. However, larger studies are needed to confirm or refute more modest effects. Trial registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAPlat included on 28/10/2013) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAPlat included on 28/10/2013). |
Dallaku, Kastriot; Shakur-Still, Haleema; Beaumont, Danielle; Roberts, Ian; Huque, Sumaya; Delius, Maria; Holdenrieder, Stefan; Gliozheni, Orion; Mansmann, Ulrich Wellcome open research, 4 , pp. 21–, 2019. @article{lshtm4653521, title = {No effect of tranexamic acid on platelet function and thrombin generation (ETAPlaT) in postpartum haemorrhage: a randomised placebo-controlled trial.}, author = {Kastriot Dallaku and Haleema Shakur-Still and Danielle Beaumont and Ian Roberts and Sumaya Huque and Maria Delius and Stefan Holdenrieder and Orion Gliozheni and Ulrich Mansmann}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4653521/}, year = {2019}, date = {2019-02-01}, journal = {Wellcome open research}, volume = {4}, pages = {21--}, publisher = {F1000Research}, abstract = {Background: Postpartum hemorrhage (PPH) is a leading cause of maternal mortality and morbidity. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. To determine whether TXA has pro-thrombotic effects in women with PPH, we measured endogenous thrombin potential (ETP), coagulation factors V, VIII, von Willebrand (vW), fibrinogen, D-Dimers and platelet function. Methods: We conducted a sub-study within the WOMAN trial, an international randomized, parallel-group, double blind, placebo-controlled trial. Women with primary PPH were randomly allocated to receive 1 gram of tranexamic acid or matching placebo. Baseline blood samples were collected just prior to the first dose and a follow up sample was collected 30±15 minutes afterwards. We compared before and after changes in coagulation parameters between treatment groups using repeated measurement ANOVA. Change in ETP was the primary outcome. We did an intention-to-treat analysis using ANCOVA with adjustment for baseline and the time interval between the blood samples. Findings: A total of 187 patients were randomized to receive TXA (n=93) or matching placebo (n=94). Six patients were excluded due to incomplete data. The reduction in ETP from baseline to follow up was 43.2 nM*min (95%CI, -16.6 to 103.1) in the TXA group and 4.6 nM*min (95%CI, -51.4 to 60.6) in the placebo group. The difference was not statistically significant (95%CI, -42.9 to 120). There were no significant effects of TXA treatment on any other parameters (ADPtest, TRAPtest, coagulation factors activity, fibrinogen levels, D-Dimer level). Conclusion: We found no evidence that tranexamic acid treatment for PPH has substantial pro-coagulant effects. However, larger studies are needed to confirm or refute more modest effects. Trial registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAPlat included on 28/10/2013) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAPlat included on 28/10/2013).}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Postpartum hemorrhage (PPH) is a leading cause of maternal mortality and morbidity. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. To determine whether TXA has pro-thrombotic effects in women with PPH, we measured endogenous thrombin potential (ETP), coagulation factors V, VIII, von Willebrand (vW), fibrinogen, D-Dimers and platelet function. Methods: We conducted a sub-study within the WOMAN trial, an international randomized, parallel-group, double blind, placebo-controlled trial. Women with primary PPH were randomly allocated to receive 1 gram of tranexamic acid or matching placebo. Baseline blood samples were collected just prior to the first dose and a follow up sample was collected 30±15 minutes afterwards. We compared before and after changes in coagulation parameters between treatment groups using repeated measurement ANOVA. Change in ETP was the primary outcome. We did an intention-to-treat analysis using ANCOVA with adjustment for baseline and the time interval between the blood samples. Findings: A total of 187 patients were randomized to receive TXA (n=93) or matching placebo (n=94). Six patients were excluded due to incomplete data. The reduction in ETP from baseline to follow up was 43.2 nM*min (95%CI, -16.6 to 103.1) in the TXA group and 4.6 nM*min (95%CI, -51.4 to 60.6) in the placebo group. The difference was not statistically significant (95%CI, -42.9 to 120). There were no significant effects of TXA treatment on any other parameters (ADPtest, TRAPtest, coagulation factors activity, fibrinogen levels, D-Dimer level). Conclusion: We found no evidence that tranexamic acid treatment for PPH has substantial pro-coagulant effects. However, larger studies are needed to confirm or refute more modest effects. Trial registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAPlat included on 28/10/2013) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAPlat included on 28/10/2013). |
2018 |
Ker, Katharine; Roberts, Ian; Chaudhri, Rizwana; Fawole, Bukola; Beaumont, Danielle; Balogun, Eni; Prowse, Danielle; Pepple, Tracey; Javaid, Kiran; Kayani, Aasia; Arulkumaran, Sabaratnam; Bates, Imelda; Shakur-Still, Haleema; trial collaborators, WOMAN-2 Trials, 19 (1), pp. 712–, 2018. @article{lshtm4650850, title = {Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: study protocol for an international, randomised, double-blind, placebo-controlled trial.}, author = {Katharine Ker and Ian Roberts and Rizwana Chaudhri and Bukola Fawole and Danielle Beaumont and Eni Balogun and Danielle Prowse and Tracey Pepple and Kiran Javaid and Aasia Kayani and Sabaratnam Arulkumaran and Imelda Bates and Haleema Shakur-Still and WOMAN-2 trial collaborators}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4650850/}, year = {2018}, date = {2018-12-01}, journal = {Trials}, volume = {19}, number = {1}, pages = {712--}, publisher = {Springer Nature}, abstract = {BACKGROUND: Postpartum haemorrhage (PPH) is responsible for about 100,000 maternal deaths every year, most of which occur in low- and middle-income countries. Tranexamic acid (TXA) reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. TXA decreases blood loss in surgery and reduces death due to bleeding after trauma. When given within 3 h of birth, TXA reduces deaths due to bleeding in women with PPH. However, for many women, treatment of PPH is too late to prevent death. Over one third of pregnant women in the world are anaemic and many are severely anaemic. These women have an increased risk of PPH and suffer more severe outcomes if PPH occurs. There is an urgent need to identify a safe and effective way to reduce postpartum bleeding in anaemic women. METHODS/DESIGN: The WOMAN-2 trial is an international, multicentre, randomised, double-blind, placebo-controlled trial to quantify the effects of TXA on postpartum bleeding in women with moderate or severe anaemia. Ten thousand women with moderate or severe anaemia who have given birth vaginally will be randomised to receive 1 g of TXA or matching placebo by intravenous injection immediately (within 15 min) after the umbilical cord is cut or clamped. The primary outcome is the proportion of women with a clinical diagnosis of primary PPH. The cause of PPH will be described. Data on maternal health and wellbeing, maternal blood loss and its consequences, and other health outcomes will be collected as secondary outcomes. The main analyses will be on an 'intention-to-treat' basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses will be based on the severity of anaemia (moderate versus severe) and type of labour (induced or augmented versus spontaneous). A study with 10,000 patients will have over 90% power to detect a 25% relative reduction from 10 to 7.5% in PPH. The trial will be conducted in hospitals in Africa and Asia. DISCUSSION: The WOMAN-2 trial should provide reliable evidence for the effects of TXA for preventing postpartum bleeding in women with anaemia. TRIAL REGISTRATION: ISRCTN, ISRCTN62396133 . Registered on 7 December 2017; ClincalTrials.gov, ID: NCT03475342 . Registered on 23 March 2018.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Postpartum haemorrhage (PPH) is responsible for about 100,000 maternal deaths every year, most of which occur in low- and middle-income countries. Tranexamic acid (TXA) reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. TXA decreases blood loss in surgery and reduces death due to bleeding after trauma. When given within 3 h of birth, TXA reduces deaths due to bleeding in women with PPH. However, for many women, treatment of PPH is too late to prevent death. Over one third of pregnant women in the world are anaemic and many are severely anaemic. These women have an increased risk of PPH and suffer more severe outcomes if PPH occurs. There is an urgent need to identify a safe and effective way to reduce postpartum bleeding in anaemic women. METHODS/DESIGN: The WOMAN-2 trial is an international, multicentre, randomised, double-blind, placebo-controlled trial to quantify the effects of TXA on postpartum bleeding in women with moderate or severe anaemia. Ten thousand women with moderate or severe anaemia who have given birth vaginally will be randomised to receive 1 g of TXA or matching placebo by intravenous injection immediately (within 15 min) after the umbilical cord is cut or clamped. The primary outcome is the proportion of women with a clinical diagnosis of primary PPH. The cause of PPH will be described. Data on maternal health and wellbeing, maternal blood loss and its consequences, and other health outcomes will be collected as secondary outcomes. The main analyses will be on an 'intention-to-treat' basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses will be based on the severity of anaemia (moderate versus severe) and type of labour (induced or augmented versus spontaneous). A study with 10,000 patients will have over 90% power to detect a 25% relative reduction from 10 to 7.5% in PPH. The trial will be conducted in hospitals in Africa and Asia. DISCUSSION: The WOMAN-2 trial should provide reliable evidence for the effects of TXA for preventing postpartum bleeding in women with anaemia. TRIAL REGISTRATION: ISRCTN, ISRCTN62396133 . Registered on 7 December 2017; ClincalTrials.gov, ID: NCT03475342 . Registered on 23 March 2018. |
Picetti, Roberto; Shakur-Still, Haleema; Medcalf, Robert L; Standing, Joseph F; Roberts, Ian What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies. Journal Article Blood coagulation & fibrinolysis, 30 (1), pp. 1–10, 2018. @article{lshtm4650981, title = {What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies.}, author = {Roberto Picetti and Haleema Shakur-Still and Robert L Medcalf and Joseph F Standing and Ian Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4650981/}, year = {2018}, date = {2018-12-01}, journal = {Blood coagulation & fibrinolysis}, volume = {30}, number = {1}, pages = {1--10}, publisher = {Ovid Technologies (Wolters Kluwer Health)}, abstract = {Intravenous tranexamic acid (TXA) reduces death because of bleeding in patients with trauma and postpartum haemorrhage. However, in some settings intravenous injection is not feasible. To find different routes of administration, we first need to determine the minimal concentration of TXA in the blood that is required to inhibit fibrinolysis.We conducted a systematic review of in-vitro and in-vivo pharmacodynamics studies. We searched MEDLINE, EMBASE, OviSP, and ISI Web of Science from database inception to November 2017 for all in-vitro (including simulated clotting models) or in-vivo studies reporting the relationship between the TXA concentration in blood or plasma and any reliable measure of fibrinolysis.We found 21 studies of which 20 were in vitro and one was in vivo. Most in-vitro studies stimulated fibrinolysis with tissue plasminogen activator and measured fibrinolysis using viscoelastic, optical density, or immunological assays. TXA concentrations between 10 and 15 mg/l resulted in substantial inhibition of fibrinolysis, although concentrations between 5 and 10 mg/l were partly inhibitory.TXA concentrations of 10-15 mg/l may be suitable targets for pharmacokinetic studies, although TXA concentrations above 5 mg/l may also be effective.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Intravenous tranexamic acid (TXA) reduces death because of bleeding in patients with trauma and postpartum haemorrhage. However, in some settings intravenous injection is not feasible. To find different routes of administration, we first need to determine the minimal concentration of TXA in the blood that is required to inhibit fibrinolysis.We conducted a systematic review of in-vitro and in-vivo pharmacodynamics studies. We searched MEDLINE, EMBASE, OviSP, and ISI Web of Science from database inception to November 2017 for all in-vitro (including simulated clotting models) or in-vivo studies reporting the relationship between the TXA concentration in blood or plasma and any reliable measure of fibrinolysis.We found 21 studies of which 20 were in vitro and one was in vivo. Most in-vitro studies stimulated fibrinolysis with tissue plasminogen activator and measured fibrinolysis using viscoelastic, optical density, or immunological assays. TXA concentrations between 10 and 15 mg/l resulted in substantial inhibition of fibrinolysis, although concentrations between 5 and 10 mg/l were partly inhibitory.TXA concentrations of 10-15 mg/l may be suitable targets for pharmacokinetic studies, although TXA concentrations above 5 mg/l may also be effective. |
Nishijima, Daniel K; VanBuren, John; Hewes, Hilary A; Myers, Sage R; Stanley, Rachel M; Adelson, David P; Barnhard, Sarah E; Bobinski, Matthew; Ghetti, Simona; Holmes, James F; Roberts, Ian; Schalick, Walton O; Tran, Nam K; Tzimenatos, Leah S; Dean, Michael J; Kuppermann, Nathan; of the Re, TIC-TOC Collaborators Pediatric Emergency Care Applied Traumatic injury clinical trial evaluating tranexamic acid in children (TIC-TOC): study protocol for a pilot randomized controlled trial. Journal Article Trials, 19 (1), pp. 593–, 2018. @article{lshtm4649943, title = {Traumatic injury clinical trial evaluating tranexamic acid in children (TIC-TOC): study protocol for a pilot randomized controlled trial.}, author = {Daniel K Nishijima and John VanBuren and Hilary A Hewes and Sage R Myers and Rachel M Stanley and David P Adelson and Sarah E Barnhard and Matthew Bobinski and Simona Ghetti and James F Holmes and Ian Roberts and Walton O Schalick and Nam K Tran and Leah S Tzimenatos and Michael J Dean and Nathan Kuppermann and TIC-TOC Collaborators of the Pediatric Emergency Care Applied Re}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4649943/}, year = {2018}, date = {2018-10-01}, journal = {Trials}, volume = {19}, number = {1}, pages = {593--}, publisher = {BMC}, abstract = {BACKGROUND: Trauma is the leading cause of morbidity and mortality in children in the United States. The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage, however, the drug has not been evaluated in a clinical trial in severely injured children. We designed the Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC) trial to evaluate the feasibility of conducting a confirmatory clinical trial that evaluates the effects of TXA in children with severe trauma and hemorrhagic injuries. METHODS: Children with severe trauma and evidence of hemorrhagic torso or brain injuries will be randomized to one of three arms: (1) TXA dose A (15 mg/kg bolus dose over 20 min, followed by 2 mg/kg/hr infusion over 8 h), (2) TXA dose B (30 mg/kg bolus dose over 20 min, followed by 4 mg/kg/hr infusion over 8 h), or (3) placebo. We will use permuted-block randomization by injury type: hemorrhagic brain injury, hemorrhagic torso injury, and combined hemorrhagic brain and torso injury. The trial will be conducted at four pediatric Level I trauma centers. We will collect the following outcome measures: global functioning as measured by the Pediatric Quality of Life (PedsQL) and Pediatric Glasgow Outcome Scale Extended (GOS-E Peds), working memory (digit span test), total amount of blood products transfused in the initial 48 h, intracranial hemorrhage progression at 24 h, coagulation biomarkers, and adverse events (specifically thromboembolic events and seizures). DISCUSSION: This multicenter trial will provide important preliminary data and assess the feasibility of conducting a confirmatory clinical trial that evaluates the benefits of TXA in children with severe trauma and hemorrhagic injuries to the torso and/or brain. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT02840097 . Registered on 14 July 2016.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Trauma is the leading cause of morbidity and mortality in children in the United States. The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage, however, the drug has not been evaluated in a clinical trial in severely injured children. We designed the Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC) trial to evaluate the feasibility of conducting a confirmatory clinical trial that evaluates the effects of TXA in children with severe trauma and hemorrhagic injuries. METHODS: Children with severe trauma and evidence of hemorrhagic torso or brain injuries will be randomized to one of three arms: (1) TXA dose A (15 mg/kg bolus dose over 20 min, followed by 2 mg/kg/hr infusion over 8 h), (2) TXA dose B (30 mg/kg bolus dose over 20 min, followed by 4 mg/kg/hr infusion over 8 h), or (3) placebo. We will use permuted-block randomization by injury type: hemorrhagic brain injury, hemorrhagic torso injury, and combined hemorrhagic brain and torso injury. The trial will be conducted at four pediatric Level I trauma centers. We will collect the following outcome measures: global functioning as measured by the Pediatric Quality of Life (PedsQL) and Pediatric Glasgow Outcome Scale Extended (GOS-E Peds), working memory (digit span test), total amount of blood products transfused in the initial 48 h, intracranial hemorrhage progression at 24 h, coagulation biomarkers, and adverse events (specifically thromboembolic events and seizures). DISCUSSION: This multicenter trial will provide important preliminary data and assess the feasibility of conducting a confirmatory clinical trial that evaluates the benefits of TXA in children with severe trauma and hemorrhagic injuries to the torso and/or brain. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT02840097 . Registered on 14 July 2016. |
Brenner, Amy; Arribas, Monica; Cuzick, Jack; Jairath, Vipul; Stanworth, Simon; Ker, Katharine; Shakur-Still, Haleema; Roberts, Ian Outcome measures in clinical trials of treatments for acute severe haemorrhage. Journal Article Trials, 19 (1), pp. 533–, 2018. @article{lshtm4649587, title = {Outcome measures in clinical trials of treatments for acute severe haemorrhage.}, author = {Amy Brenner and Monica Arribas and Jack Cuzick and Vipul Jairath and Simon Stanworth and Katharine Ker and Haleema Shakur-Still and Ian Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4649587/}, year = {2018}, date = {2018-10-01}, journal = {Trials}, volume = {19}, number = {1}, pages = {533--}, publisher = {BMC}, abstract = {BACKGROUND: Acute severe haemorrhage is a common complication of injury, childbirth, surgery, gastrointestinal pathologies and other medical conditions. Bleeding is a major cause of death, but patients also die from non-bleeding causes, the frequency of which varies by the site of haemorrhage and between populations. Because patients can bleed to death within hours, established interventions inevitably take priority over randomisation into a trial. These circumstances raise challenges in selecting appropriate outcome measures for clinical trials of haemostatic interventions. MAIN BODY: We use data from three large randomised controlled trials in acute severe haemorrhage (CRASH-2, WOMAN and HALT-IT) to explore the strengths and limitations of outcome measures commonly used in trials of haemostatic treatments, including all-cause and cause-specific mortality, blood transfusion and surgical interventions. Many deaths following acute severe haemorrhage are due to patient comorbidities or complications rather than bleeding. If non-bleeding deaths are unaffected by a haemostatic intervention, even large trials will have low power to detect an effect on all-cause mortality. Due to the dilution from deaths unaffected or reduced by the trial treatment, all-cause mortality can also obscure important harmful effects. Additionally, because the relative contributions of different causes of death vary within and between patient populations, all-cause mortality is not generalisable. Different causes of death occur at different time intervals from bleeding onset, with bleeding deaths generally occurring early. Time-specific mortality can therefore be used as a proxy for cause in un-blinded trials where bias is a concern or in situations where cause of death cannot be assessed. Urgent treatment is critical, and so post-randomisation blood transfusion and surgery are often planned before or at the time of randomisation and therefore cannot be influenced by the trial treatment. CONCLUSIONS: All-cause mortality has low power, lacks generalisability and can obscure harmful effects. Cause-specific mortality, such as death due to bleeding or thrombosis, avoids these drawbacks. In certain scenarios, time-specific mortality can be used as a proxy for cause-specific mortality. Blood transfusion and surgical procedures have limited utility as outcome measures in trials of haemostatic treatments.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Acute severe haemorrhage is a common complication of injury, childbirth, surgery, gastrointestinal pathologies and other medical conditions. Bleeding is a major cause of death, but patients also die from non-bleeding causes, the frequency of which varies by the site of haemorrhage and between populations. Because patients can bleed to death within hours, established interventions inevitably take priority over randomisation into a trial. These circumstances raise challenges in selecting appropriate outcome measures for clinical trials of haemostatic interventions. MAIN BODY: We use data from three large randomised controlled trials in acute severe haemorrhage (CRASH-2, WOMAN and HALT-IT) to explore the strengths and limitations of outcome measures commonly used in trials of haemostatic treatments, including all-cause and cause-specific mortality, blood transfusion and surgical interventions. Many deaths following acute severe haemorrhage are due to patient comorbidities or complications rather than bleeding. If non-bleeding deaths are unaffected by a haemostatic intervention, even large trials will have low power to detect an effect on all-cause mortality. Due to the dilution from deaths unaffected or reduced by the trial treatment, all-cause mortality can also obscure important harmful effects. Additionally, because the relative contributions of different causes of death vary within and between patient populations, all-cause mortality is not generalisable. Different causes of death occur at different time intervals from bleeding onset, with bleeding deaths generally occurring early. Time-specific mortality can therefore be used as a proxy for cause in un-blinded trials where bias is a concern or in situations where cause of death cannot be assessed. Urgent treatment is critical, and so post-randomisation blood transfusion and surgery are often planned before or at the time of randomisation and therefore cannot be influenced by the trial treatment. CONCLUSIONS: All-cause mortality has low power, lacks generalisability and can obscure harmful effects. Cause-specific mortality, such as death due to bleeding or thrombosis, avoids these drawbacks. In certain scenarios, time-specific mortality can be used as a proxy for cause-specific mortality. Blood transfusion and surgical procedures have limited utility as outcome measures in trials of haemostatic treatments. |
Roberts, Ian; Belli, Antonio; Brenner, Amy; Chaudhri, Rizwana; Fawole, Bukola; Harris, Tim; Jooma, Rashid; Mahmood, Abda; Shokunbi, Temitayo; Shakur, Haleema Wellcome Open Research, 3 , pp. 86–86, 2018. @article{lshtm4650977, title = {Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial}, author = {Ian Roberts and Antonio Belli and Amy Brenner and Rizwana Chaudhri and Bukola Fawole and Tim Harris and Rashid Jooma and Abda Mahmood and Temitayo Shokunbi and Haleema Shakur}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4650977/}, year = {2018}, date = {2018-09-01}, journal = {Wellcome Open Research}, volume = {3}, pages = {86--86}, publisher = {F1000 Research, Ltd.}, abstract = {Background: Worldwide, traumatic brain injury (TBI) kills or hospitalises over 10 million people each year. Early intracranial bleeding is common after TBI, increasing the risk of death and disability. Tranexamic acid reduces blood loss in surgery and death due to bleeding in trauma patients with extra-cranial injury. Early administration of tranexamic acid in TBI patients might limit intracranial bleeding, reducing death and disability. The CRASH-3 trial aims to provide evidence on the effect of tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients (approximately 10,000 within 3 hours of injury) to an intravenous infusion of tranexamic acid or matching placebo in addition to usual care. This paper presents a protocol update (version 2.1) and statistical analysis plan for the CRASH-3 trial. Results: The primary outcome is head injury death in hospital within 28 days of injury for patients treated within 3 hours of injury (deaths in patients treated after 3 hours will also be reported). Because there are reasons to expect that tranexamic acid will be most effective in patients treated immediately after injury and less effective with increasing delay, the effect in patients treated within one hour of injury is of particular interest. Secondary outcomes are all-cause and cause-specific mortality, vascular occlusive events, disability based on the Disability Rating Scale and measures suggested by patient representatives, seizures, neurosurgical intervention, neurosurgical blood loss, days in intensive care and adverse events. Sub-group analyses will examine the effect of tranexamic acid on head injury death stratified by time to treatment, severity of TBI and baseline risk. Conclusion: The CRASH-3 trial will provide reliable evidence of the effectiveness and safety of tranexamic acid in patients with acute TBI. Registration: International Standard Randomised Controlled Trials registry ( ISRCTN15088122) 19/07/2011, and ClinicalTrials.gov ( NCT01402882) 25/07/2011.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Worldwide, traumatic brain injury (TBI) kills or hospitalises over 10 million people each year. Early intracranial bleeding is common after TBI, increasing the risk of death and disability. Tranexamic acid reduces blood loss in surgery and death due to bleeding in trauma patients with extra-cranial injury. Early administration of tranexamic acid in TBI patients might limit intracranial bleeding, reducing death and disability. The CRASH-3 trial aims to provide evidence on the effect of tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients (approximately 10,000 within 3 hours of injury) to an intravenous infusion of tranexamic acid or matching placebo in addition to usual care. This paper presents a protocol update (version 2.1) and statistical analysis plan for the CRASH-3 trial. Results: The primary outcome is head injury death in hospital within 28 days of injury for patients treated within 3 hours of injury (deaths in patients treated after 3 hours will also be reported). Because there are reasons to expect that tranexamic acid will be most effective in patients treated immediately after injury and less effective with increasing delay, the effect in patients treated within one hour of injury is of particular interest. Secondary outcomes are all-cause and cause-specific mortality, vascular occlusive events, disability based on the Disability Rating Scale and measures suggested by patient representatives, seizures, neurosurgical intervention, neurosurgical blood loss, days in intensive care and adverse events. Sub-group analyses will examine the effect of tranexamic acid on head injury death stratified by time to treatment, severity of TBI and baseline risk. Conclusion: The CRASH-3 trial will provide reliable evidence of the effectiveness and safety of tranexamic acid in patients with acute TBI. Registration: International Standard Randomised Controlled Trials registry ( ISRCTN15088122) 19/07/2011, and ClinicalTrials.gov ( NCT01402882) 25/07/2011. |
Shakur-Still, Haleema; Roberts, Ian; Fawole, Bukola; Kuti, Modupe; Olayemi, Oladapo O; Bello, Adenike; Huque, Sumaya; Ogunbode, Olayinka; Kotila, Taiwo; Aimakhu, Chris; Okunade, Olujide A; Olutogun, Tolulase; Adetayo, Cecilia O; Dallaku, Kastriot; Mansmann, Ulrich; Hunt, Beverley J; Pepple, Tracey; Balogun, Eni Wellcome open research, 3 , pp. 100–, 2018. @article{lshtm4649883, title = {Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): a single-centre, randomised, double-blind, placebo-controlled trial.}, author = {Haleema Shakur-Still and Ian Roberts and Bukola Fawole and Modupe Kuti and Oladapo O Olayemi and Adenike Bello and Sumaya Huque and Olayinka Ogunbode and Taiwo Kotila and Chris Aimakhu and Olujide A Okunade and Tolulase Olutogun and Cecilia O Adetayo and Kastriot Dallaku and Ulrich Mansmann and Beverley J Hunt and Tracey Pepple and Eni Balogun}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4649883/}, year = {2018}, date = {2018-08-01}, journal = {Wellcome open research}, volume = {3}, pages = {100--}, publisher = {F1000Research}, abstract = {Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. We evaluated the effect of TXA on fibrinolysis and coagulation in a sample of WOMAN trial participants. Methods: Adult women with a clinical diagnosis of PPH were randomised to receive 1 g TXA or matching placebo in the WOMAN trial. Participants in the WOMAN trial at University College Hospital (Ibadan, Nigeria) also had venous blood taken just before administration of the first dose of trial treatment and again 30 (±15) min after the first dose (the ETAC study). We aimed to determine the effects of TXA on fibrinolysis (D-dimer and rotational thromboelastometry maximum clot lysis (ML)) and coagulation (international normalized ratio and clot amplitude at 5 min). We compared outcomes in women receiving TXA and placebo using linear regression, adjusting for baseline measurements. Results: Women (n=167) were randomised to receive TXA (n=83) or matching placebo (n=84). Due to missing data, seven women were excluded from analysis. The mean (SD) D-dimer concentration was 7.1 (7.0) mg/l in TXA-treated women and 9.6 (8.6) mg/l in placebo-treated women (p=0.09). After adjusting for baseline, the D-dimer concentration was 2.16 mg/l lower in TXA-treated women (-2.16, 95% CI -4.31 to 0.00, p=0.05). There was no significant difference in ML between TXA- and placebo-treated women (12.3% (18.4) and 10.7% (12.6), respectively; p=0.52) and no significant difference after adjusting for baseline ML (1.02, 95% CI -3.72 to 5.77, p=0.67). There were no significant effects of TXA on any other parameters. Conclusion: TXA treatment was associated with reduced D-dimer levels but had no apparent effects on thromboelastometry parameters or coagulation tests. Registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAC included on 22/03/2012) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAC included on 22/03/2012).}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. We evaluated the effect of TXA on fibrinolysis and coagulation in a sample of WOMAN trial participants. Methods: Adult women with a clinical diagnosis of PPH were randomised to receive 1 g TXA or matching placebo in the WOMAN trial. Participants in the WOMAN trial at University College Hospital (Ibadan, Nigeria) also had venous blood taken just before administration of the first dose of trial treatment and again 30 (±15) min after the first dose (the ETAC study). We aimed to determine the effects of TXA on fibrinolysis (D-dimer and rotational thromboelastometry maximum clot lysis (ML)) and coagulation (international normalized ratio and clot amplitude at 5 min). We compared outcomes in women receiving TXA and placebo using linear regression, adjusting for baseline measurements. Results: Women (n=167) were randomised to receive TXA (n=83) or matching placebo (n=84). Due to missing data, seven women were excluded from analysis. The mean (SD) D-dimer concentration was 7.1 (7.0) mg/l in TXA-treated women and 9.6 (8.6) mg/l in placebo-treated women (p=0.09). After adjusting for baseline, the D-dimer concentration was 2.16 mg/l lower in TXA-treated women (-2.16, 95% CI -4.31 to 0.00, p=0.05). There was no significant difference in ML between TXA- and placebo-treated women (12.3% (18.4) and 10.7% (12.6), respectively; p=0.52) and no significant difference after adjusting for baseline ML (1.02, 95% CI -3.72 to 5.77, p=0.67). There were no significant effects of TXA on any other parameters. Conclusion: TXA treatment was associated with reduced D-dimer levels but had no apparent effects on thromboelastometry parameters or coagulation tests. Registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAC included on 22/03/2012) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAC included on 22/03/2012). |
Shakur-Still, Haleema; Roberts, Ian; Fawole, Bukola; Kuti, Modupe; Olayemi, Oladapo; Bello, Adenike; Huque, Sumaya; Ogunbode, Olayinka; Kotila, Taiwo; Aimakhu, Chris; Okunade, Olujide; Olutogun, Tolulase; Adetayo, Cecilia; Dallaku, Kastriot; Mansmann, Ulrich; Hunt, Beverley; Pepple, Tracey; Balogun, Eni Wellcome Open Research, 3 (100), pp. 14722–, 2018. @article{lshtm4650078, title = {Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): a single-centre, randomised, double-blind, placebo-controlled trial}, author = {Haleema Shakur-Still and Ian Roberts and Bukola Fawole and Modupe Kuti and Oladapo Olayemi and Adenike Bello and Sumaya Huque and Olayinka Ogunbode and Taiwo Kotila and Chris Aimakhu and Olujide Okunade and Tolulase Olutogun and Cecilia Adetayo and Kastriot Dallaku and Ulrich Mansmann and Beverley Hunt and Tracey Pepple and Eni Balogun}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4650078/}, year = {2018}, date = {2018-08-01}, journal = {Wellcome Open Research}, volume = {3}, number = {100}, pages = {14722--}, publisher = {F1000Research}, abstract = {Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. We evaluated the effect of TXA on fibrinolysis and coagulation in a sample of WOMAN trial participants. Methods: Adult women with a clinical diagnosis of PPH were randomised to receive 1 g TXA or matching placebo in the WOMAN trial. Participants in the WOMAN trial at University College Hospital (Ibadan, Nigeria) also had venous blood taken just before administration of the first dose of trial treatment and again 30 (±15) min after the first dose (the ETAC study). We aimed to determine the effects of TXA on fibrinolysis (D-dimer and rotational thromboelastometry maximum clot lysis (ML)) and coagulation (international normalized ratio and clot amplitude at 5 min). We compared outcomes in women receiving TXA and placebo using linear regression, adjusting for baseline measurements. Results: Women (n=167) were randomised to receive TXA (n=83) or matching placebo (n=84). Due to missing data, seven women were excluded from analysis. The mean (SD) D-dimer concentration was 7.1 (7.0) mg/l in TXA-treated women and 9.6 (8.6) mg/l in placebo-treated women (p=0.09). After adjusting for baseline, the D-dimer concentration was 2.16 mg/l lower in TXA-treated women (-2.16, 95% CI -4.31 to 0.00, p=0.05). There was no significant difference in ML between TXA- and placebo-treated women (12.3% (18.4) and 10.7% (12.6), respectively; p=0.52) and no significant difference after adjusting for baseline ML (1.02, 95% CI -3.72 to 5.77, p=0.67). There were no significant effects of TXA on any other parameters. Conclusion: TXA treatment was associated with reduced D-dimer levels but had no apparent effects on thromboelastometry parameters or coagulation tests. Registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAC included on 22/03/2012) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAC included on 22/03/2012).}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. We evaluated the effect of TXA on fibrinolysis and coagulation in a sample of WOMAN trial participants. Methods: Adult women with a clinical diagnosis of PPH were randomised to receive 1 g TXA or matching placebo in the WOMAN trial. Participants in the WOMAN trial at University College Hospital (Ibadan, Nigeria) also had venous blood taken just before administration of the first dose of trial treatment and again 30 (±15) min after the first dose (the ETAC study). We aimed to determine the effects of TXA on fibrinolysis (D-dimer and rotational thromboelastometry maximum clot lysis (ML)) and coagulation (international normalized ratio and clot amplitude at 5 min). We compared outcomes in women receiving TXA and placebo using linear regression, adjusting for baseline measurements. Results: Women (n=167) were randomised to receive TXA (n=83) or matching placebo (n=84). Due to missing data, seven women were excluded from analysis. The mean (SD) D-dimer concentration was 7.1 (7.0) mg/l in TXA-treated women and 9.6 (8.6) mg/l in placebo-treated women (p=0.09). After adjusting for baseline, the D-dimer concentration was 2.16 mg/l lower in TXA-treated women (-2.16, 95% CI -4.31 to 0.00, p=0.05). There was no significant difference in ML between TXA- and placebo-treated women (12.3% (18.4) and 10.7% (12.6), respectively; p=0.52) and no significant difference after adjusting for baseline ML (1.02, 95% CI -3.72 to 5.77, p=0.67). There were no significant effects of TXA on any other parameters. Conclusion: TXA treatment was associated with reduced D-dimer levels but had no apparent effects on thromboelastometry parameters or coagulation tests. Registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAC included on 22/03/2012) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAC included on 22/03/2012). |
Roberts, Ian; Belli, Antonio; Brenner, Amy; Chaudhri, Rizwana; Fawole, Bukola; Harris, Tim; Jooma, Rashid; Mahmood, Abda; Shokunbi, Temitayo; Shakur-Still, Haleema Wellcome Open Research, 3 , pp. 86–86, 2018. @article{lshtm4650215, title = {Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial}, author = {Ian Roberts and Antonio Belli and Amy Brenner and Rizwana Chaudhri and Bukola Fawole and Tim Harris and Rashid Jooma and Abda Mahmood and Temitayo Shokunbi and Haleema Shakur-Still}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4650215/}, year = {2018}, date = {2018-07-01}, journal = {Wellcome Open Research}, volume = {3}, pages = {86--86}, publisher = {F1000 Research, Ltd.}, abstract = {Background: Worldwide, traumatic brain injury (TBI) kills or hospitalises over 10 million people each year. Early intracranial bleeding is common after TBI, increasing the risk of death and disability. Tranexamic acid reduces blood loss in surgery and death due to bleeding in trauma patients with extra-cranial injury. Early administration of tranexamic acid in TBI patients might limit intracranial bleeding, reducing death and disability. The CRASH-3 trial aims to provide reliable evidence on the effect of tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients to an intravenous infusion of tranexamic acid or matching placebo in addition to usual care. This paper presents a protocol update (version 2.1) and statistical analysis plan for the CRASH-3 trial. Results: The primary outcome is head injury death in hospital within 28 days of injury for patients treated within 3 hours of injury (deaths in patients treated after 3 hours will also be reported). Because there are strong scientific reasons to expect that tranexamic acid will be most effective in patients treated immediately after injury and less effective with increasing delay, the effect in patients treated within one hour of injury is of particular interest. Secondary outcomes are all-cause and cause-specific mortality, vascular occlusive events (myocardial infarction, pulmonary embolism, deep vein thrombosis, stroke), disability based on the Disability Rating Scale and measures suggested by patient representatives, seizures, neurosurgical intervention, neurosurgical blood loss, days in intensive care and adverse events. Sub-group analyses will examine the effect of tranexamic acid on head injury death stratified by time to treatment, severity of TBI and baseline risk. Conclusion: The CRASH-3 trial will provide reliable evidence of the effectiveness and safety of tranexamic acid in patients with acute TBI. Registration: International Standard Randomised Controlled Trials registry (ISRCTN15088122) 19/07/2011, and ClinicalTrials.gov (NCT01402882) 25/07/2011.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Worldwide, traumatic brain injury (TBI) kills or hospitalises over 10 million people each year. Early intracranial bleeding is common after TBI, increasing the risk of death and disability. Tranexamic acid reduces blood loss in surgery and death due to bleeding in trauma patients with extra-cranial injury. Early administration of tranexamic acid in TBI patients might limit intracranial bleeding, reducing death and disability. The CRASH-3 trial aims to provide reliable evidence on the effect of tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients to an intravenous infusion of tranexamic acid or matching placebo in addition to usual care. This paper presents a protocol update (version 2.1) and statistical analysis plan for the CRASH-3 trial. Results: The primary outcome is head injury death in hospital within 28 days of injury for patients treated within 3 hours of injury (deaths in patients treated after 3 hours will also be reported). Because there are strong scientific reasons to expect that tranexamic acid will be most effective in patients treated immediately after injury and less effective with increasing delay, the effect in patients treated within one hour of injury is of particular interest. Secondary outcomes are all-cause and cause-specific mortality, vascular occlusive events (myocardial infarction, pulmonary embolism, deep vein thrombosis, stroke), disability based on the Disability Rating Scale and measures suggested by patient representatives, seizures, neurosurgical intervention, neurosurgical blood loss, days in intensive care and adverse events. Sub-group analyses will examine the effect of tranexamic acid on head injury death stratified by time to treatment, severity of TBI and baseline risk. Conclusion: The CRASH-3 trial will provide reliable evidence of the effectiveness and safety of tranexamic acid in patients with acute TBI. Registration: International Standard Randomised Controlled Trials registry (ISRCTN15088122) 19/07/2011, and ClinicalTrials.gov (NCT01402882) 25/07/2011. |
Roberts, Ian; Belli, Antonio; Brenner, Amy; Chaudhri, Rizwana; Fawole, Bukola; Harris, Tim; Jooma, Rashid; Mahmood, Abda; Shokunbi, Temitayo; Shakur-Still, Haleema; trial collaborators, CRASH-3 Wellcome open research, 3 , pp. 86–, 2018. @article{lshtm4649519, title = {Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial.}, author = {Ian Roberts and Antonio Belli and Amy Brenner and Rizwana Chaudhri and Bukola Fawole and Tim Harris and Rashid Jooma and Abda Mahmood and Temitayo Shokunbi and Haleema Shakur-Still and CRASH-3 trial collaborators}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4649519/}, year = {2018}, date = {2018-07-01}, journal = {Wellcome open research}, volume = {3}, pages = {86--}, publisher = {F1000Research}, abstract = {Background: Worldwide, traumatic brain injury (TBI) kills or hospitalises over 10 million people each year. Early intracranial bleeding is common after TBI, increasing the risk of death and disability. Tranexamic acid reduces blood loss in surgery and death due to bleeding in trauma patients with extra-cranial injury. Early administration of tranexamic acid in TBI patients might limit intracranial bleeding, reducing death and disability. The CRASH-3 trial aims to provide evidence on the effect of tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients (approximately 10,000 within 3 hours of injury) to an intravenous infusion of tranexamic acid or matching placebo in addition to usual care. This paper presents a protocol update (version 2.1) and statistical analysis plan for the CRASH-3 trial. Results: The primary outcome is head injury death in hospital within 28 days of injury for patients treated within 3 hours of injury (deaths in patients treated after 3 hours will also be reported). Because there are reasons to expect that tranexamic acid will be most effective in patients treated immediately after injury and less effective with increasing delay, the effect in patients treated within one hour of injury is of particular interest. Secondary outcomes are all-cause and cause-specific mortality, vascular occlusive events, disability based on the Disability Rating Scale and measures suggested by patient representatives, seizures, neurosurgical intervention, neurosurgical blood loss, days in intensive care and adverse events. Sub-group analyses will examine the effect of tranexamic acid on head injury death stratified by time to treatment, severity of TBI and baseline risk. Conclusion: The CRASH-3 trial will provide reliable evidence of the effectiveness and safety of tranexamic acid in patients with acute TBI. Registration: International Standard Randomised Controlled Trials registry ( ISRCTN15088122) 19/07/2011, and ClinicalTrials.gov ( NCT01402882) 25/07/2011.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Worldwide, traumatic brain injury (TBI) kills or hospitalises over 10 million people each year. Early intracranial bleeding is common after TBI, increasing the risk of death and disability. Tranexamic acid reduces blood loss in surgery and death due to bleeding in trauma patients with extra-cranial injury. Early administration of tranexamic acid in TBI patients might limit intracranial bleeding, reducing death and disability. The CRASH-3 trial aims to provide evidence on the effect of tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients (approximately 10,000 within 3 hours of injury) to an intravenous infusion of tranexamic acid or matching placebo in addition to usual care. This paper presents a protocol update (version 2.1) and statistical analysis plan for the CRASH-3 trial. Results: The primary outcome is head injury death in hospital within 28 days of injury for patients treated within 3 hours of injury (deaths in patients treated after 3 hours will also be reported). Because there are reasons to expect that tranexamic acid will be most effective in patients treated immediately after injury and less effective with increasing delay, the effect in patients treated within one hour of injury is of particular interest. Secondary outcomes are all-cause and cause-specific mortality, vascular occlusive events, disability based on the Disability Rating Scale and measures suggested by patient representatives, seizures, neurosurgical intervention, neurosurgical blood loss, days in intensive care and adverse events. Sub-group analyses will examine the effect of tranexamic acid on head injury death stratified by time to treatment, severity of TBI and baseline risk. Conclusion: The CRASH-3 trial will provide reliable evidence of the effectiveness and safety of tranexamic acid in patients with acute TBI. Registration: International Standard Randomised Controlled Trials registry ( ISRCTN15088122) 19/07/2011, and ClinicalTrials.gov ( NCT01402882) 25/07/2011. |
Houghton, G; Kingdon, C; Dower, M; Shakur-Still, Haleema; Alfirevic, Z BJOG, 125 (13), pp. 1744–1753, 2018. @article{lshtm4648287, title = {What women think about consent to research at the time of an obstetric emergency: a qualitative study of the views of a cohort of World Maternal Antifibrinolytic Trial participants.}, author = {G Houghton and C Kingdon and M Dower and Haleema Shakur-Still and Z Alfirevic}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4648287/}, year = {2018}, date = {2018-06-01}, journal = {BJOG}, volume = {125}, number = {13}, pages = {1744--1753}, publisher = {Wiley}, abstract = {OBJECTIVE: The World Maternal Antifibrinolytic (WOMAN) Trial was the first in the UK to use the option of waiver of informed consent at the time of an obstetric emergency. This qualitative study aimed to investigate participants' views of the acceptability of the recruitment methods used. DESIGN: Qualitative study using in-depth interviews with women who did and did not give consent at the time of their recruitment to the WOMAN Trial. SETTING: Highest UK recruitment site for the WOMAN Trial (129/569). Interviews were conducted in participants' homes. POPULATION: About 40 of the 129 women who were recruited to the WOMAN Trial at one UK site were invited to take part, 15 women were interviewed. METHODS: Qualitative, interview study. MAIN OUTCOME MEASURES: Facilitators and barriers to successful recruitment during obstetric emergencies. Guidance for future researchers. RESULTS: Findings revealed that what is important is not so much the consent process used or a signature on a form, but the way in which consent is obtained. Clinicians who successfully negotiate consent to research during childbirth emergencies engage in a 'humane choreography' of words and actions. This emphasises the importance of prompt decision-making and treatment, while respecting the woman's personal situation and experience. CONCLUSIONS: Our findings do not support a single pathway to consent in the context of an obstetric emergency. Women understand that consent to research in an emergency is complex. Clinicians' skills in considering the clinical, ethical, and emotional aspects within the context of the clinical emergency can hamper or promote women's satisfaction. TWEETABLE ABSTRACT: Study reports on women's views of consent to research in an obstetric emergency. PLAIN LANGUAGE SUMMARY: Why and how was the study carried out? We undertook this study to find out what women thought about being included in a research study called the WOMAN Trial at the time they were being treated for heavy bleeding after giving birth. Some women had been asked if they wanted to be a part of the research at the time they were bleeding. Others were asked later, after they had recovered. We conducted interviews with 15 women who had been involved and asked what they thought about the way they had been asked, their preferences and ideas for improvements in future similar studies What were the main findings? Women understood how difficult it was for their doctors and midwives to ask them about the research study. They were pleased to have been included in the research and were mostly happy with the way they gave consent. Women's views were similar whether they were asked about the research at the time of the bleeding or after they had recovered. The most important thing was that doctors and midwives carefully thought about the situation the woman found herself in and how this might make her feel, so they could tailor their approach accordingly. What are the limitations of the work? This study only involved women from one hospital. The WOMAN Trial included women from many areas of the UK and other countries around the world. We do not know how their experiences or views may differ. What is the implication for professionals? Careful use of actions and words by birth attendants was the difference between a good or bad experience for the woman and her family. This is an important skill that could be developed as part of professional training.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: The World Maternal Antifibrinolytic (WOMAN) Trial was the first in the UK to use the option of waiver of informed consent at the time of an obstetric emergency. This qualitative study aimed to investigate participants' views of the acceptability of the recruitment methods used. DESIGN: Qualitative study using in-depth interviews with women who did and did not give consent at the time of their recruitment to the WOMAN Trial. SETTING: Highest UK recruitment site for the WOMAN Trial (129/569). Interviews were conducted in participants' homes. POPULATION: About 40 of the 129 women who were recruited to the WOMAN Trial at one UK site were invited to take part, 15 women were interviewed. METHODS: Qualitative, interview study. MAIN OUTCOME MEASURES: Facilitators and barriers to successful recruitment during obstetric emergencies. Guidance for future researchers. RESULTS: Findings revealed that what is important is not so much the consent process used or a signature on a form, but the way in which consent is obtained. Clinicians who successfully negotiate consent to research during childbirth emergencies engage in a 'humane choreography' of words and actions. This emphasises the importance of prompt decision-making and treatment, while respecting the woman's personal situation and experience. CONCLUSIONS: Our findings do not support a single pathway to consent in the context of an obstetric emergency. Women understand that consent to research in an emergency is complex. Clinicians' skills in considering the clinical, ethical, and emotional aspects within the context of the clinical emergency can hamper or promote women's satisfaction. TWEETABLE ABSTRACT: Study reports on women's views of consent to research in an obstetric emergency. PLAIN LANGUAGE SUMMARY: Why and how was the study carried out? We undertook this study to find out what women thought about being included in a research study called the WOMAN Trial at the time they were being treated for heavy bleeding after giving birth. Some women had been asked if they wanted to be a part of the research at the time they were bleeding. Others were asked later, after they had recovered. We conducted interviews with 15 women who had been involved and asked what they thought about the way they had been asked, their preferences and ideas for improvements in future similar studies What were the main findings? Women understood how difficult it was for their doctors and midwives to ask them about the research study. They were pleased to have been included in the research and were mostly happy with the way they gave consent. Women's views were similar whether they were asked about the research at the time of the bleeding or after they had recovered. The most important thing was that doctors and midwives carefully thought about the situation the woman found herself in and how this might make her feel, so they could tailor their approach accordingly. What are the limitations of the work? This study only involved women from one hospital. The WOMAN Trial included women from many areas of the UK and other countries around the world. We do not know how their experiences or views may differ. What is the implication for professionals? Careful use of actions and words by birth attendants was the difference between a good or bad experience for the woman and her family. This is an important skill that could be developed as part of professional training. |
Houghton, G; Kingdon, C; Dower, M; Shakur-Still, Haleema; Alfirevic, Z BJOG, 125 (13), pp. 1744–1753, 2018. @article{lshtm4648287b, title = {What women think about consent to research at the time of an obstetric emergency: a qualitative study of the views of a cohort of World Maternal Antifibrinolytic Trial participants.}, author = {G Houghton and C Kingdon and M Dower and Haleema Shakur-Still and Z Alfirevic}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4648287/}, year = {2018}, date = {2018-06-01}, journal = {BJOG}, volume = {125}, number = {13}, pages = {1744--1753}, publisher = {Wiley}, abstract = {OBJECTIVE: The World Maternal Antifibrinolytic (WOMAN) Trial was the first in the UK to use the option of waiver of informed consent at the time of an obstetric emergency. This qualitative study aimed to investigate participants' views of the acceptability of the recruitment methods used. DESIGN: Qualitative study using in-depth interviews with women who did and did not give consent at the time of their recruitment to the WOMAN Trial. SETTING: Highest UK recruitment site for the WOMAN Trial (129/569). Interviews were conducted in participants' homes. POPULATION: About 40 of the 129 women who were recruited to the WOMAN Trial at one UK site were invited to take part, 15 women were interviewed. METHODS: Qualitative, interview study. MAIN OUTCOME MEASURES: Facilitators and barriers to successful recruitment during obstetric emergencies. Guidance for future researchers. RESULTS: Findings revealed that what is important is not so much the consent process used or a signature on a form, but the way in which consent is obtained. Clinicians who successfully negotiate consent to research during childbirth emergencies engage in a 'humane choreography' of words and actions. This emphasises the importance of prompt decision-making and treatment, while respecting the woman's personal situation and experience. CONCLUSIONS: Our findings do not support a single pathway to consent in the context of an obstetric emergency. Women understand that consent to research in an emergency is complex. Clinicians' skills in considering the clinical, ethical, and emotional aspects within the context of the clinical emergency can hamper or promote women's satisfaction. TWEETABLE ABSTRACT: Study reports on women's views of consent to research in an obstetric emergency. PLAIN LANGUAGE SUMMARY: Why and how was the study carried out? We undertook this study to find out what women thought about being included in a research study called the WOMAN Trial at the time they were being treated for heavy bleeding after giving birth. Some women had been asked if they wanted to be a part of the research at the time they were bleeding. Others were asked later, after they had recovered. We conducted interviews with 15 women who had been involved and asked what they thought about the way they had been asked, their preferences and ideas for improvements in future similar studies What were the main findings? Women understood how difficult it was for their doctors and midwives to ask them about the research study. They were pleased to have been included in the research and were mostly happy with the way they gave consent. Women's views were similar whether they were asked about the research at the time of the bleeding or after they had recovered. The most important thing was that doctors and midwives carefully thought about the situation the woman found herself in and how this might make her feel, so they could tailor their approach accordingly. What are the limitations of the work? This study only involved women from one hospital. The WOMAN Trial included women from many areas of the UK and other countries around the world. We do not know how their experiences or views may differ. What is the implication for professionals? Careful use of actions and words by birth attendants was the difference between a good or bad experience for the woman and her family. This is an important skill that could be developed as part of professional training.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: The World Maternal Antifibrinolytic (WOMAN) Trial was the first in the UK to use the option of waiver of informed consent at the time of an obstetric emergency. This qualitative study aimed to investigate participants' views of the acceptability of the recruitment methods used. DESIGN: Qualitative study using in-depth interviews with women who did and did not give consent at the time of their recruitment to the WOMAN Trial. SETTING: Highest UK recruitment site for the WOMAN Trial (129/569). Interviews were conducted in participants' homes. POPULATION: About 40 of the 129 women who were recruited to the WOMAN Trial at one UK site were invited to take part, 15 women were interviewed. METHODS: Qualitative, interview study. MAIN OUTCOME MEASURES: Facilitators and barriers to successful recruitment during obstetric emergencies. Guidance for future researchers. RESULTS: Findings revealed that what is important is not so much the consent process used or a signature on a form, but the way in which consent is obtained. Clinicians who successfully negotiate consent to research during childbirth emergencies engage in a 'humane choreography' of words and actions. This emphasises the importance of prompt decision-making and treatment, while respecting the woman's personal situation and experience. CONCLUSIONS: Our findings do not support a single pathway to consent in the context of an obstetric emergency. Women understand that consent to research in an emergency is complex. Clinicians' skills in considering the clinical, ethical, and emotional aspects within the context of the clinical emergency can hamper or promote women's satisfaction. TWEETABLE ABSTRACT: Study reports on women's views of consent to research in an obstetric emergency. PLAIN LANGUAGE SUMMARY: Why and how was the study carried out? We undertook this study to find out what women thought about being included in a research study called the WOMAN Trial at the time they were being treated for heavy bleeding after giving birth. Some women had been asked if they wanted to be a part of the research at the time they were bleeding. Others were asked later, after they had recovered. We conducted interviews with 15 women who had been involved and asked what they thought about the way they had been asked, their preferences and ideas for improvements in future similar studies What were the main findings? Women understood how difficult it was for their doctors and midwives to ask them about the research study. They were pleased to have been included in the research and were mostly happy with the way they gave consent. Women's views were similar whether they were asked about the research at the time of the bleeding or after they had recovered. The most important thing was that doctors and midwives carefully thought about the situation the woman found herself in and how this might make her feel, so they could tailor their approach accordingly. What are the limitations of the work? This study only involved women from one hospital. The WOMAN Trial included women from many areas of the UK and other countries around the world. We do not know how their experiences or views may differ. What is the implication for professionals? Careful use of actions and words by birth attendants was the difference between a good or bad experience for the woman and her family. This is an important skill that could be developed as part of professional training. |
Roberts, Ian Women's work in UK clinical trials is undervalued. Journal Article Lancet, 392 (10149), pp. 732–, 2018. @article{lshtm4649307, title = {Women's work in UK clinical trials is undervalued.}, author = {Ian Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4649307/}, year = {2018}, date = {2018-06-01}, journal = {Lancet}, volume = {392}, number = {10149}, pages = {732--}, publisher = {Elsevier}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Brenner, Amy; Shakur-Still, Haleema; Chaudhri, Rizwana; Fawole, Bukola; Arulkumaran, Sabaratnam; Roberts, Ian; Collaborators, WOMAN Trial BMC pregnancy and childbirth, 18 (1), pp. 215–, 2018. @article{lshtm4648095, title = {The impact of early outcome events on the effect of tranexamic acid in post-partum haemorrhage: an exploratory subgroup analysis of the WOMAN trial.}, author = {Amy Brenner and Haleema Shakur-Still and Rizwana Chaudhri and Bukola Fawole and Sabaratnam Arulkumaran and Ian Roberts and WOMAN Trial Collaborators}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4648095/}, year = {2018}, date = {2018-06-01}, journal = {BMC pregnancy and childbirth}, volume = {18}, number = {1}, pages = {215--}, publisher = {BMC}, abstract = {BACKGROUND: In severe post-partum haemorrhage, death can occur within hours of bleeding onset so interventions to control the bleeding must be given immediately. In clinical trials of treatments for life-threatening bleeding, established treatments are given priority and the trial treatment is usually given last. However, enrolling patients in whom severe maternal morbidity or death is imminent or inevitable at the time of randomisation may dilute the effects of a trial treatment. METHODS: We conducted an exploratory analysis of data from the WOMAN trial, an international, randomised placebo-controlled trial of the effects of tranexamic acid on death and surgical intervention in 20,060 women with post-partum haemorrhage. We assessed the impact of early maternal death or hysterectomy due to exsanguination on the effect of tranexamic acid on each of these respective outcomes. We conducted repeated analyses excluding patients with these outcomes at increasing intervals from the time of randomisation. We quantified treatment effects using risk ratios (RR) and 99% confidence intervals (CI) and prepared cumulative failure plots. RESULTS: Among 14,923 women randomised within 3 h of delivery (7518 tranexamic acid and 7405 placebo), there were 216 bleeding deaths (1.5%) and 383 hysterectomies due to bleeding (2.8%). After excluding deaths from exsanguination at increasing time intervals following randomization, there was a significant reduction in the risk of death due to bleeding with tranexamic acid (RR = 0.41; 99% CI 0.19-0.89). However, after excluding hysterectomies at increasing time intervals post-randomization, there was no reduction in the risk of hysterectomy due to bleeding with tranexamic acid (RR = 0.79; 99% CI 0.33-1.86). CONCLUSIONS: Findings from this analysis provide further evidence that tranexamic acid reduces the risk of death from exsanguination in women who experience postpartum haemorrhage. It is uncertain whether tranexamic acid reduces the risk of hysterectomy for bleeding after excluding early hysterectomies. TRIAL REGISTRATION: ISRCTN trial registration number ISRCTN76912190, 8 Dec 2008; ClinicalTrials.gov number NCT00872469, 30 March 2009; PACTR number PACTR201007000192283, 9 Feb 2010; EudraCT number 2008-008441-38, 8 Dec 2010 (retrospectively registered).}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: In severe post-partum haemorrhage, death can occur within hours of bleeding onset so interventions to control the bleeding must be given immediately. In clinical trials of treatments for life-threatening bleeding, established treatments are given priority and the trial treatment is usually given last. However, enrolling patients in whom severe maternal morbidity or death is imminent or inevitable at the time of randomisation may dilute the effects of a trial treatment. METHODS: We conducted an exploratory analysis of data from the WOMAN trial, an international, randomised placebo-controlled trial of the effects of tranexamic acid on death and surgical intervention in 20,060 women with post-partum haemorrhage. We assessed the impact of early maternal death or hysterectomy due to exsanguination on the effect of tranexamic acid on each of these respective outcomes. We conducted repeated analyses excluding patients with these outcomes at increasing intervals from the time of randomisation. We quantified treatment effects using risk ratios (RR) and 99% confidence intervals (CI) and prepared cumulative failure plots. RESULTS: Among 14,923 women randomised within 3 h of delivery (7518 tranexamic acid and 7405 placebo), there were 216 bleeding deaths (1.5%) and 383 hysterectomies due to bleeding (2.8%). After excluding deaths from exsanguination at increasing time intervals following randomization, there was a significant reduction in the risk of death due to bleeding with tranexamic acid (RR = 0.41; 99% CI 0.19-0.89). However, after excluding hysterectomies at increasing time intervals post-randomization, there was no reduction in the risk of hysterectomy due to bleeding with tranexamic acid (RR = 0.79; 99% CI 0.33-1.86). CONCLUSIONS: Findings from this analysis provide further evidence that tranexamic acid reduces the risk of death from exsanguination in women who experience postpartum haemorrhage. It is uncertain whether tranexamic acid reduces the risk of hysterectomy for bleeding after excluding early hysterectomies. TRIAL REGISTRATION: ISRCTN trial registration number ISRCTN76912190, 8 Dec 2008; ClinicalTrials.gov number NCT00872469, 30 March 2009; PACTR number PACTR201007000192283, 9 Feb 2010; EudraCT number 2008-008441-38, 8 Dec 2010 (retrospectively registered). |
Huque, Sumaya; Roberts, Ian; Fawole, Bukola; Chaudhri, Rizwana; Arulkumaran, Sabaratnam; Shakur-Still, Haleema Risk factors for peripartum hysterectomy among women with postpartum haemorrhage: analysis of data from the WOMAN trial. Journal Article BMC pregnancy and childbirth, 18 (1), pp. 186–, 2018. @article{lshtm4647906, title = {Risk factors for peripartum hysterectomy among women with postpartum haemorrhage: analysis of data from the WOMAN trial.}, author = {Sumaya Huque and Ian Roberts and Bukola Fawole and Rizwana Chaudhri and Sabaratnam Arulkumaran and Haleema Shakur-Still}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4647906/}, year = {2018}, date = {2018-05-01}, journal = {BMC pregnancy and childbirth}, volume = {18}, number = {1}, pages = {186--}, publisher = {BMC}, abstract = {BACKGROUND: Peripartum hysterectomy can cause significant morbidity and mortality. Most studies of peripartum hysterectomy are from high income countries. This cohort study examined risk factors for peripartum hysterectomy using data from Africa, Asia, Europe and the Americas. METHODS: We used data from the World Maternal Antifibrinolytic (WOMAN) trial carried out in 193 hospitals in 21 countries. Peripartum hysterectomy was defined as hysterectomy within 6 weeks of delivery as a complication of postpartum haemorrhage. Univariable and multivariable random effects logistic regression models were used to analyse risk factors. A hierarchical conceptual framework guided our multivariable analysis. RESULTS: Five percent of women had a hysterectomy (1020/20,017). Haemorrhage from placenta praevia/accreta carried a higher risk of hysterectomy (17%) than surgical trauma/tears (5%) and uterine atony (3%). The adjusted odds ratio (AOR) for hysterectomy in women with placenta praevia/accreta was 3.2 (95% CI: 2.7-3.8), compared to uterine atony. The risk of hysterectomy increased with maternal age. Caesarean section was associated with fourfold higher odds of hysterectomy than vaginal delivery (AOR 4.3, 95% CI: 3.6-5.0). Mothers in Asia had a higher hysterectomy incidence (7%) than mothers in Africa (5%) (AOR: 1.2, 95% CI: 0.9-1.7). CONCLUSIONS: Placenta praevia/accreta is associated with a higher risk of peripartum hysterectomy. Other risk factors for hysterectomy are advanced maternal age, caesarean section and giving birth in Asia.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Peripartum hysterectomy can cause significant morbidity and mortality. Most studies of peripartum hysterectomy are from high income countries. This cohort study examined risk factors for peripartum hysterectomy using data from Africa, Asia, Europe and the Americas. METHODS: We used data from the World Maternal Antifibrinolytic (WOMAN) trial carried out in 193 hospitals in 21 countries. Peripartum hysterectomy was defined as hysterectomy within 6 weeks of delivery as a complication of postpartum haemorrhage. Univariable and multivariable random effects logistic regression models were used to analyse risk factors. A hierarchical conceptual framework guided our multivariable analysis. RESULTS: Five percent of women had a hysterectomy (1020/20,017). Haemorrhage from placenta praevia/accreta carried a higher risk of hysterectomy (17%) than surgical trauma/tears (5%) and uterine atony (3%). The adjusted odds ratio (AOR) for hysterectomy in women with placenta praevia/accreta was 3.2 (95% CI: 2.7-3.8), compared to uterine atony. The risk of hysterectomy increased with maternal age. Caesarean section was associated with fourfold higher odds of hysterectomy than vaginal delivery (AOR 4.3, 95% CI: 3.6-5.0). Mothers in Asia had a higher hysterectomy incidence (7%) than mothers in Africa (5%) (AOR: 1.2, 95% CI: 0.9-1.7). CONCLUSIONS: Placenta praevia/accreta is associated with a higher risk of peripartum hysterectomy. Other risk factors for hysterectomy are advanced maternal age, caesarean section and giving birth in Asia. |
Roberts, Ian; Shakur-Still, Haleema; Bellomo, Rinaldo; Bion, Julian; Finfer, Simon; Hunt, Beverley; Myburgh, John; Perner, Anders; Reinhart, Konrad Should hydroxyethyl starch be banned? - Authors' reply. Journal Article Lancet, 392 (10142), pp. 119–, 2018. @article{lshtm4648601, title = {Should hydroxyethyl starch be banned? - Authors' reply.}, author = {Ian Roberts and Haleema Shakur-Still and Rinaldo Bellomo and Julian Bion and Simon Finfer and Beverley Hunt and John Myburgh and Anders Perner and Konrad Reinhart}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4648601/}, year = {2018}, date = {2018-05-01}, journal = {Lancet}, volume = {392}, number = {10142}, pages = {119--}, publisher = {Elsevier}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Sprigg, Nikola; Flaherty, Katie; Appleton, Jason P; Salman, Rustam Al-Shahi; Bereczki, Daniel; Beridze, Maia; Christensen, Hanne; Ciccone, Alfonso; Collins, Ronan; Czlonkowska, Anna; Dineen, Robert A; Duley, Lelia; Egea-Guerrero, Juan Jose; England, Timothy J; Krishnan, Kailash; Laska, Ann Charlotte; Law, Zhe Kang; Ozturk, Serefnur; Pocock, Stuart J; Roberts, Ian; Robinson, Thompson G; Roffe, Christine; Seiffge, David; Scutt, Polly; Thanabalan, Jegan; Werring, David; Whynes, David; Bath, Philip M; Investigators, TICH-2 Lancet, 391 (10135), pp. 2107–2115, 2018. @article{lshtm4647837, title = {Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial.}, author = {Nikola Sprigg and Katie Flaherty and Jason P Appleton and Rustam Al-Shahi Salman and Daniel Bereczki and Maia Beridze and Hanne Christensen and Alfonso Ciccone and Ronan Collins and Anna Czlonkowska and Robert A Dineen and Lelia Duley and Juan Jose Egea-Guerrero and Timothy J England and Kailash Krishnan and Ann Charlotte Laska and Zhe Kang Law and Serefnur Ozturk and Stuart J Pocock and Ian Roberts and Thompson G Robinson and Christine Roffe and David Seiffge and Polly Scutt and Jegan Thanabalan and David Werring and David Whynes and Philip M Bath and TICH-2 Investigators}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4647837/}, year = {2018}, date = {2018-05-01}, journal = {Lancet}, volume = {391}, number = {10135}, pages = {2107--2115}, publisher = {Elsevier}, abstract = {BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage. METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214. FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]). INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect. FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage. METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214. FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]). INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect. FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation. |
Roberts, Ian; Shakur-Still, Haleema; Fawole, Bukola; Kuti, Modupe; Olayemi, Oladapo; Bello, Adenike; Ogunbode, Olayinka; Kotila, Taiwo; Aimakhu, Chris O; Olutogun, Tolulase; Hunt, Beverley J; Huque, Sumaya Haematological and fibrinolytic status of Nigerian women with post-partum haemorrhage. Journal Article BMC pregnancy and childbirth, 18 (1), pp. 143–, 2018. @article{lshtm4647691, title = {Haematological and fibrinolytic status of Nigerian women with post-partum haemorrhage.}, author = {Ian Roberts and Haleema Shakur-Still and Bukola Fawole and Modupe Kuti and Oladapo Olayemi and Adenike Bello and Olayinka Ogunbode and Taiwo Kotila and Chris O Aimakhu and Tolulase Olutogun and Beverley J Hunt and Sumaya Huque}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4647691/}, year = {2018}, date = {2018-05-01}, journal = {BMC pregnancy and childbirth}, volume = {18}, number = {1}, pages = {143--}, publisher = {BMC}, abstract = {BACKGROUND: Early treatment with tranexamic acid reduces deaths due to bleeding after post-partum haemorrhage. We report the prevalence of haematological, coagulation and fibrinolytic abnormalities in Nigerian women with postpartum haemorrhage. METHODS: We performed a secondary analysis of the WOMAN trial to assess laboratory data and rotational thromboelastometry (ROTEM) parameters in 167 women with postpartum haemorrhage treated at University College Hospital, Ibadan, Nigeria. We defined hyper-fibrinolysis as EXTEM maximum lysis (ML) > 15% on ROTEM. We defined coagulopathy as EXTEM clot amplitude at 5 min (A5) < 40 mm or prothrombin ratio > 1.5. RESULTS: Among the study cohort, 53 (40%) women had severe anaemia (haemoglobin< 70 g/L) and 17 (13%) women had severe thrombocytopenia (platelet count < 50 × 109/L). Thirty-five women (23%) had ROTEM evidence of hyper-fibrinolysis. Based on prothrombin ratio criteria, 16 (12%) had coagulopathy. Based on EXTEM A5 criteria, 49 (34%) had coagulopathy. CONCLUSION: Our findings suggest that, based on a convenience sample of women from a large teaching hospital in Nigeria, hyper-fibrinolysis may commonly occur in postpartum haemorrhage. Further mechanistic studies are needed to examine hyper-fibrinolysis associated with postpartum haemorrhage. Findings from such studies may optimize treatment approaches for postpartum haemorrhage. TRIAL REGISTRATION: The Woman trial was registered: NCT00872469; ISRCTN76912190 (Registration date: 22/03/2012).}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Early treatment with tranexamic acid reduces deaths due to bleeding after post-partum haemorrhage. We report the prevalence of haematological, coagulation and fibrinolytic abnormalities in Nigerian women with postpartum haemorrhage. METHODS: We performed a secondary analysis of the WOMAN trial to assess laboratory data and rotational thromboelastometry (ROTEM) parameters in 167 women with postpartum haemorrhage treated at University College Hospital, Ibadan, Nigeria. We defined hyper-fibrinolysis as EXTEM maximum lysis (ML) > 15% on ROTEM. We defined coagulopathy as EXTEM clot amplitude at 5 min (A5) < 40 mm or prothrombin ratio > 1.5. RESULTS: Among the study cohort, 53 (40%) women had severe anaemia (haemoglobin< 70 g/L) and 17 (13%) women had severe thrombocytopenia (platelet count < 50 × 109/L). Thirty-five women (23%) had ROTEM evidence of hyper-fibrinolysis. Based on prothrombin ratio criteria, 16 (12%) had coagulopathy. Based on EXTEM A5 criteria, 49 (34%) had coagulopathy. CONCLUSION: Our findings suggest that, based on a convenience sample of women from a large teaching hospital in Nigeria, hyper-fibrinolysis may commonly occur in postpartum haemorrhage. Further mechanistic studies are needed to examine hyper-fibrinolysis associated with postpartum haemorrhage. Findings from such studies may optimize treatment approaches for postpartum haemorrhage. TRIAL REGISTRATION: The Woman trial was registered: NCT00872469; ISRCTN76912190 (Registration date: 22/03/2012). |
Kiriya, Junko; Edwards, Phil; Roberts, Ian BMJ open, 8 (4), pp. e019419–, 2018. @article{lshtm4647304, title = {Effect of emotional content on online video sharing among health care professionals and researchers (DIFFUSION): results and lessons learnt from a randomised controlled trial.}, author = {Junko Kiriya and Phil Edwards and Ian Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4647304/}, year = {2018}, date = {2018-04-01}, journal = {BMJ open}, volume = {8}, number = {4}, pages = {e019419--}, publisher = {BMJ Publishing Group}, abstract = {OBJECTIVES: We assessed the effect of emotional content on the extent to which online videos are shared among health professionals. SETTING: We conducted a two-arm randomised controlled trial. We sent a link to one of two videos by email to participants asking them to watch the video and forward it to their colleagues. PARTICIPANTS: Health professionals and researchers (obstetrics, gynaecology and midwifery) with an email address apart from those in countries where access to YouTube is banned. We estimated that 7000 participants were required. INTERVENTIONS: We compared two online videos providing background information about the WOMAN trial. The videos were the same length and had the same content. However, the intervention video had more emotional impact than the control video. OUTCOME MEASURES: The primary outcome was video sharing and the secondary outcome was views generated by participants. We conducted a χ2 test for the primary outcome and t-test for the secondary outcome. RESULTS: We randomly allocated 8353 email addresses, 4178 to the intervention video and 4175 to the control. Of these, 221 (5.3%) watched the intervention video and 215 (5.1%) watched the control. In the intervention group, 44 (1.1%) forwarded the video compared with 37 (0.9%) in the control group (risk ratio 1.2 [95% CI 0.8 to 1.8], p=0.44). Mean number of views generated by participants allocated to the intervention video was 0.04 and the control video was 0.03 (mean difference 0.01 [95% CI -0.02 to 0.04], p=0.53). CONCLUSIONS: We found no evidence that emotional content increased forwarding. The trial had low power due to the low video watching rate and the small number of outcome events. A key challenge for online dissemination is ensuring recipients watch the video. TRIAL REGISTRATION NUMBER: NCT02109159.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVES: We assessed the effect of emotional content on the extent to which online videos are shared among health professionals. SETTING: We conducted a two-arm randomised controlled trial. We sent a link to one of two videos by email to participants asking them to watch the video and forward it to their colleagues. PARTICIPANTS: Health professionals and researchers (obstetrics, gynaecology and midwifery) with an email address apart from those in countries where access to YouTube is banned. We estimated that 7000 participants were required. INTERVENTIONS: We compared two online videos providing background information about the WOMAN trial. The videos were the same length and had the same content. However, the intervention video had more emotional impact than the control video. OUTCOME MEASURES: The primary outcome was video sharing and the secondary outcome was views generated by participants. We conducted a χ2 test for the primary outcome and t-test for the secondary outcome. RESULTS: We randomly allocated 8353 email addresses, 4178 to the intervention video and 4175 to the control. Of these, 221 (5.3%) watched the intervention video and 215 (5.1%) watched the control. In the intervention group, 44 (1.1%) forwarded the video compared with 37 (0.9%) in the control group (risk ratio 1.2 [95% CI 0.8 to 1.8], p=0.44). Mean number of views generated by participants allocated to the intervention video was 0.04 and the control video was 0.03 (mean difference 0.01 [95% CI -0.02 to 0.04], p=0.53). CONCLUSIONS: We found no evidence that emotional content increased forwarding. The trial had low power due to the low video watching rate and the small number of outcome events. A key challenge for online dissemination is ensuring recipients watch the video. TRIAL REGISTRATION NUMBER: NCT02109159. |
Shakur-Still, Haleema; Beaumont, Danielle; Pavord, Sue; Gayet-Ageron, Angele; Ker, Katharine; Mousa, Hatem A Antifibrinolytic drugs for treating primary postpartum haemorrhage. Journal Article The Cochrane database of systematic reviews, 2 (2), pp. CD012964–, 2018. @article{lshtm4646707, title = {Antifibrinolytic drugs for treating primary postpartum haemorrhage.}, author = {Haleema Shakur-Still and Danielle Beaumont and Sue Pavord and Angele Gayet-Ageron and Katharine Ker and Hatem A Mousa}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4646707/}, year = {2018}, date = {2018-02-01}, journal = {The Cochrane database of systematic reviews}, volume = {2}, number = {2}, pages = {CD012964--}, publisher = {Cochrane Collaboration}, abstract = {BACKGROUND: Postpartum haemorrhage (PPH) - heaving bleeding within the first 24 hours after giving birth - is one of the main causes of death of women after childbirth. Antifibrinolytics, primarily tranexamic acid (TXA), have been shown to reduce bleeding in surgery and safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events.An earlier Cochrane review on treatments for primary PPH covered all the various available treatments - that review has now been split by types of treatment. This new review concentrates only on the use of antifibrinolytic drugs for treating primary PPH. OBJECTIVES: To determine the effectiveness and safety of antifibrinolytic drugs for treating primary PPH. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (28 May 2017) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), including cluster-randomised trials of antifibrinolytic drugs (aprotinin, TXA, epsilon-aminocaproic acid (EACA) and aminomethylbenzoic acid, administered by whatever route) for primary PPH in women.Participants in the trials were women after birth following a pregnancy of at least 24 weeks' gestation with a diagnosis of PPH, regardless of mode of birth (vaginal or caesarean section) or other aspects of third stage management.We have not included quasi-randomised trials, or cross-over studies. Studies reported as abstracts have not been included if there was insufficient information to allow assessment of risk of bias.In this review we only identified studies looking at TXA. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each study using an agreed form. We entered data into Review Manager software and checked for accuracy.For key review outcomes, we rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach. MAIN RESULTS: Three trials (20,412 women) met our inclusion criteria. Two trials (20,212 women) compared intravenous (IV) TXA with placebo or standard care and were conducted in acute hospital settings (labour ward, emergency department) (in high-, middle- and low-income countries).One other trial (involving 200 women) was conducted in Iran and compared IV TXA with rectal misoprostol, but did not report on any of this review's primary or GRADE outcomes. There were no trials that assessed EACA, aprotinin or aminomethylbenzoic acid.Standard care plus IV TXA for the treatment of primary PPH compared with placebo or standard care aloneTwo trials (20,212 women) assessed the effect of TXA for the treatment of primary PPH compared with placebo or standard care alone. The larger of these (The WOMAN trial) contributed over 99% of the data and was assessed as being at low risk of bias. The quality of the evidence varied for different outcomes, Overall, evidence was mainly graded as moderate to high quality.The data show that IV TXA reduces the risk of maternal death due to bleeding (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.65 to 1.00; two trials, 20,172 women; quality of evidence: moderate). The quality of evidence was rated as moderate due to imprecision of effect estimate. The effect was more evident in women given treatment between one and three hours after giving birth with no apparent reduction when given after three hours (< one hour = RR 0.80, 95% CI 0.55 to 1.16; one to three hours = RR 0.60, 95% CI 0.41 to 0.88; > three hours = RR 1.07, 95% 0.76 to 1.51; test for subgroup differences: Chi² = 4.90, df = 2 (P = 0.09), I² = 59.2%). There was no heterogeneity in the effect by mode of birth (test for subgroup differences: Chi² = 0.01, df = 1 (P = 0.91), I² = 0%). There were fewer deaths from all causes in women receiving TXA, although the 95% CI for the effect estimate crosses the line of no effect (RR 0.88, 95% CI 0.74 to 1.05; two trials, 20,172 women, quality of evidence: moderate). Results from one trial with 151 women suggest that blood loss of ≥ 500 mL after randomisation may be reduced (RR 0.50, 95% CI 0.27 to 0.93; one trial, 151 women; quality of evidence: low). TXA did not reduce the risk of serious maternal morbidity (RR 0.99, 95% CI 0.83 to 1.19; one trial, 20,015 women; quality of evidence: high), hysterectomy to control bleeding (RR 0.95, 95% CI 0.81 to 1.12; one trial, 20,017 women; quality of evidence: high) receipt of blood transfusion (any) (RR 1.00, 95% CI 0.97 to 1.03; two trials, 20,167 women; quality of evidence: moderate) or maternal vascular occlusive events (any), although results were imprecise for this latter outcome (RR 0.88, 95% CI 0.54 to 1.43; one trial, 20,018 women; quality of evidence: moderate). There was an increase in the use of brace sutures in the TXA group (RR 1.19, 95% CI 1.01, 1.41) and a reduction in the need for laparotomy for bleeding (RR 0.64, 95% CI 0.49, 0.85). AUTHORS' CONCLUSIONS: TXA when administered intravenously reduces mortality due to bleeding in women with primary PPH, irrespective of mode of birth, and without increasing the risk of thromboembolic events. Taken together with the reliable evidence of the effect of TXA in trauma patients, the evidence suggests that TXA is effective if given as early as possible.Facilities for IV administration may not be available in non-hospital settings therefore, alternative routes to IV administration need to be investigated.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Postpartum haemorrhage (PPH) - heaving bleeding within the first 24 hours after giving birth - is one of the main causes of death of women after childbirth. Antifibrinolytics, primarily tranexamic acid (TXA), have been shown to reduce bleeding in surgery and safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events.An earlier Cochrane review on treatments for primary PPH covered all the various available treatments - that review has now been split by types of treatment. This new review concentrates only on the use of antifibrinolytic drugs for treating primary PPH. OBJECTIVES: To determine the effectiveness and safety of antifibrinolytic drugs for treating primary PPH. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (28 May 2017) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), including cluster-randomised trials of antifibrinolytic drugs (aprotinin, TXA, epsilon-aminocaproic acid (EACA) and aminomethylbenzoic acid, administered by whatever route) for primary PPH in women.Participants in the trials were women after birth following a pregnancy of at least 24 weeks' gestation with a diagnosis of PPH, regardless of mode of birth (vaginal or caesarean section) or other aspects of third stage management.We have not included quasi-randomised trials, or cross-over studies. Studies reported as abstracts have not been included if there was insufficient information to allow assessment of risk of bias.In this review we only identified studies looking at TXA. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each study using an agreed form. We entered data into Review Manager software and checked for accuracy.For key review outcomes, we rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach. MAIN RESULTS: Three trials (20,412 women) met our inclusion criteria. Two trials (20,212 women) compared intravenous (IV) TXA with placebo or standard care and were conducted in acute hospital settings (labour ward, emergency department) (in high-, middle- and low-income countries).One other trial (involving 200 women) was conducted in Iran and compared IV TXA with rectal misoprostol, but did not report on any of this review's primary or GRADE outcomes. There were no trials that assessed EACA, aprotinin or aminomethylbenzoic acid.Standard care plus IV TXA for the treatment of primary PPH compared with placebo or standard care aloneTwo trials (20,212 women) assessed the effect of TXA for the treatment of primary PPH compared with placebo or standard care alone. The larger of these (The WOMAN trial) contributed over 99% of the data and was assessed as being at low risk of bias. The quality of the evidence varied for different outcomes, Overall, evidence was mainly graded as moderate to high quality.The data show that IV TXA reduces the risk of maternal death due to bleeding (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.65 to 1.00; two trials, 20,172 women; quality of evidence: moderate). The quality of evidence was rated as moderate due to imprecision of effect estimate. The effect was more evident in women given treatment between one and three hours after giving birth with no apparent reduction when given after three hours (< one hour = RR 0.80, 95% CI 0.55 to 1.16; one to three hours = RR 0.60, 95% CI 0.41 to 0.88; > three hours = RR 1.07, 95% 0.76 to 1.51; test for subgroup differences: Chi² = 4.90, df = 2 (P = 0.09), I² = 59.2%). There was no heterogeneity in the effect by mode of birth (test for subgroup differences: Chi² = 0.01, df = 1 (P = 0.91), I² = 0%). There were fewer deaths from all causes in women receiving TXA, although the 95% CI for the effect estimate crosses the line of no effect (RR 0.88, 95% CI 0.74 to 1.05; two trials, 20,172 women, quality of evidence: moderate). Results from one trial with 151 women suggest that blood loss of ≥ 500 mL after randomisation may be reduced (RR 0.50, 95% CI 0.27 to 0.93; one trial, 151 women; quality of evidence: low). TXA did not reduce the risk of serious maternal morbidity (RR 0.99, 95% CI 0.83 to 1.19; one trial, 20,015 women; quality of evidence: high), hysterectomy to control bleeding (RR 0.95, 95% CI 0.81 to 1.12; one trial, 20,017 women; quality of evidence: high) receipt of blood transfusion (any) (RR 1.00, 95% CI 0.97 to 1.03; two trials, 20,167 women; quality of evidence: moderate) or maternal vascular occlusive events (any), although results were imprecise for this latter outcome (RR 0.88, 95% CI 0.54 to 1.43; one trial, 20,018 women; quality of evidence: moderate). There was an increase in the use of brace sutures in the TXA group (RR 1.19, 95% CI 1.01, 1.41) and a reduction in the need for laparotomy for bleeding (RR 0.64, 95% CI 0.49, 0.85). AUTHORS' CONCLUSIONS: TXA when administered intravenously reduces mortality due to bleeding in women with primary PPH, irrespective of mode of birth, and without increasing the risk of thromboembolic events. Taken together with the reliable evidence of the effect of TXA in trauma patients, the evidence suggests that TXA is effective if given as early as possible.Facilities for IV administration may not be available in non-hospital settings therefore, alternative routes to IV administration need to be investigated. |
Roberts, Ian; Shakur-Still, Haleema; Bellomo, Rinaldo; Bion, Julian; Finfer, Simon; Hunt, Beverley; Myburgh, John; Perner, Anders; Reinhart, Konrad Hydroxyethyl starch solutions and patient harm. Journal Article Lancet, 391 (10122), pp. 736–, 2018. @article{lshtm4646757, title = {Hydroxyethyl starch solutions and patient harm.}, author = {Ian Roberts and Haleema Shakur-Still and Rinaldo Bellomo and Julian Bion and Simon Finfer and Beverley Hunt and John Myburgh and Anders Perner and Konrad Reinhart}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4646757/}, year = {2018}, date = {2018-02-01}, journal = {Lancet}, volume = {391}, number = {10122}, pages = {736--}, publisher = {Elsevier}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Dineen, Rob A; Pszczolkowski, Stefan; Flaherty, Katie; Law, Zhe K; Morgan, Paul S; Roberts, Ian; Werring, David J; Salman, Rustam Al-Shahi; England, Tim; Bath, Philip M; Sprigg, Nikola BMJ open, 8 (2), pp. e019930–, 2018. @article{lshtm4646668, title = {Does tranexamic acid lead to changes in MRI measures of brain tissue health in patients with spontaneous intracerebral haemorrhage? Protocol for a MRI substudy nested within the double-blind randomised controlled TICH-2 trial.}, author = {Rob A Dineen and Stefan Pszczolkowski and Katie Flaherty and Zhe K Law and Paul S Morgan and Ian Roberts and David J Werring and Rustam Al-Shahi Salman and Tim England and Philip M Bath and Nikola Sprigg}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4646668/}, year = {2018}, date = {2018-02-01}, journal = {BMJ open}, volume = {8}, number = {2}, pages = {e019930--}, publisher = {BMJ Publishing Group}, abstract = {OBJECTIVES: To test whether administration of the antifibrinolytic drug tranexamic acid (TXA) in patients with spontaneous intracerebral haemorrhage (SICH) leads to increased prevalence of diffusion-weighted MRI-defined hyperintense ischaemic lesions (primary hypothesis) or reduced perihaematomal oedema volume, perihaematomal diffusion restriction and residual MRI-defined SICH-related tissue damage (secondary hypotheses). DESIGN: MRI substudy nested within the double-blind randomised controlled Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 trial (ISRCTN93732214). SETTING: International multicentre hospital-based study. PARTICIPANTS: Eligible adults consented and randomised in the TICH-2 trial who were also able to undergo MRI scanning. To address the primary hypothesis, a sample size of n=280 will allow detection of a 10% relative increase in prevalence of diffusion-weighted imaging (DWI) hyperintense lesions in the TXA group with 5% significance, 80% power and 5% imaging data rejection. INTERVENTIONS: TICH-2 MRI substudy participants will undergo MRI scanning using a standardised protocol at day textttchar1265 and day textttchar12690 after randomisation. Clinical assessments, randomisation to TXA or placebo and participant follow-up will be performed as per the TICH-2 trial protocol. CONCLUSION: The TICH-2 MRI substudy will test whether TXA increases the incidence of new DWI-defined ischaemic lesions or reduces perihaematomal oedema or final ICH lesion volume in the context of SICH. ETHICS AND DISSEMINATION: The TICH-2 trial obtained ethical approval from East Midlands - Nottingham 2 Research Ethics Committee (12/EM/0369) and an amendment to allow the TICH-2 MRI sub study was approved in April 2015 (amendment number SA02/15). All findings will be published in peer-reviewed journals. The primary outcome results will also be presented at a relevant scientific meeting. TRIAL REGISTRATION NUMBER: ISRCTN93732214; Pre-results.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVES: To test whether administration of the antifibrinolytic drug tranexamic acid (TXA) in patients with spontaneous intracerebral haemorrhage (SICH) leads to increased prevalence of diffusion-weighted MRI-defined hyperintense ischaemic lesions (primary hypothesis) or reduced perihaematomal oedema volume, perihaematomal diffusion restriction and residual MRI-defined SICH-related tissue damage (secondary hypotheses). DESIGN: MRI substudy nested within the double-blind randomised controlled Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 trial (ISRCTN93732214). SETTING: International multicentre hospital-based study. PARTICIPANTS: Eligible adults consented and randomised in the TICH-2 trial who were also able to undergo MRI scanning. To address the primary hypothesis, a sample size of n=280 will allow detection of a 10% relative increase in prevalence of diffusion-weighted imaging (DWI) hyperintense lesions in the TXA group with 5% significance, 80% power and 5% imaging data rejection. INTERVENTIONS: TICH-2 MRI substudy participants will undergo MRI scanning using a standardised protocol at day textttchar1265 and day textttchar12690 after randomisation. Clinical assessments, randomisation to TXA or placebo and participant follow-up will be performed as per the TICH-2 trial protocol. CONCLUSION: The TICH-2 MRI substudy will test whether TXA increases the incidence of new DWI-defined ischaemic lesions or reduces perihaematomal oedema or final ICH lesion volume in the context of SICH. ETHICS AND DISSEMINATION: The TICH-2 trial obtained ethical approval from East Midlands - Nottingham 2 Research Ethics Committee (12/EM/0369) and an amendment to allow the TICH-2 MRI sub study was approved in April 2015 (amendment number SA02/15). All findings will be published in peer-reviewed journals. The primary outcome results will also be presented at a relevant scientific meeting. TRIAL REGISTRATION NUMBER: ISRCTN93732214; Pre-results. |
Hibbs, Stephen P; Roberts, Ian; Shakur-Still, Haleema; Hunt, Beverley J Post-partum haemorrhage and tranexamic acid: a global issue. Journal Article British journal of haematology, 180 (6), pp. 799–807, 2018. @article{lshtm4646117, title = {Post-partum haemorrhage and tranexamic acid: a global issue.}, author = {Stephen P Hibbs and Ian Roberts and Haleema Shakur-Still and Beverley J Hunt}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4646117/}, year = {2018}, date = {2018-01-01}, journal = {British journal of haematology}, volume = {180}, number = {6}, pages = {799--807}, publisher = {Wiley}, abstract = {Post-partum haemorrhage (PPH) remains the major cause of maternal death worldwide, with the overwhelming majority of bleeding deaths occurring in low income countries. These bleeding deaths occur due to a complex network of biological and socioeconomic factors, including changes to haemostasis and fibrinolysis during pregnancy. Tranexamic acid (TxA) has been shown to reduce death in bleeding trauma patients safely and is effective in reducing bleeding in surgical patients, however its role in PPH has been less well established. We discuss the impact of the recently published World Maternal Antifibrinolytic (WOMAN) trial, which demonstrated a significant reduction in bleeding deaths (Risk ratio 0?81) in women with PPH who received intravenous TxA compared to those receiving placebo. There were no increases in post-partum thrombotic rates in mothers or breast-fed babies. This trial has shown that intravenous TxA can be used safely and effectively to treat PPH, and should be implemented widely to reduce death due to PPH. However, for the full benefit of TxA to be fully realised in resource-constrained settings, the effectiveness of oral or topical administration and/or pre-emptive dosing need to be investigated.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Post-partum haemorrhage (PPH) remains the major cause of maternal death worldwide, with the overwhelming majority of bleeding deaths occurring in low income countries. These bleeding deaths occur due to a complex network of biological and socioeconomic factors, including changes to haemostasis and fibrinolysis during pregnancy. Tranexamic acid (TxA) has been shown to reduce death in bleeding trauma patients safely and is effective in reducing bleeding in surgical patients, however its role in PPH has been less well established. We discuss the impact of the recently published World Maternal Antifibrinolytic (WOMAN) trial, which demonstrated a significant reduction in bleeding deaths (Risk ratio 0?81) in women with PPH who received intravenous TxA compared to those receiving placebo. There were no increases in post-partum thrombotic rates in mothers or breast-fed babies. This trial has shown that intravenous TxA can be used safely and effectively to treat PPH, and should be implemented widely to reduce death due to PPH. However, for the full benefit of TxA to be fully realised in resource-constrained settings, the effectiveness of oral or topical administration and/or pre-emptive dosing need to be investigated. |
Shakur-Still, Haleema; Roberts, Ian Finding Better Ways to Prevent Postpartum Hemorrhage. Journal Article The New England journal of medicine, 379 (8), pp. 790–792, 2018. @article{lshtm4648997, title = {Finding Better Ways to Prevent Postpartum Hemorrhage.}, author = {Haleema Shakur-Still and Ian Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4648997/}, year = {2018}, date = {2018-01-01}, journal = {The New England journal of medicine}, volume = {379}, number = {8}, pages = {790--792}, publisher = {Massachusetts Medical Society}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
2017 |
Ker, Katharine; Prieto-Merino, David; Sprigg, Nikola; Mahmood, Abda; Bath, Philip; Law, Zhe Kang; Flaherty, Katie; Roberts, Ian Wellcome open research, 2 , pp. 120–, 2017. @article{lshtm4646583, title = {The effectiveness and safety of anti-fibrinolytics in patients with acute intracranial haemorrhage: statistical analysis plan for an individual patient data meta-analysis.}, author = {Katharine Ker and David Prieto-Merino and Nikola Sprigg and Abda Mahmood and Philip Bath and Zhe Kang Law and Katie Flaherty and Ian Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4646583/}, year = {2017}, date = {2017-12-01}, journal = {Wellcome open research}, volume = {2}, pages = {120--}, publisher = {F1000Research}, abstract = {INTRODUCTION: The Anti-fibrinolytics Trialists Collaboration aims to increase knowledge about the effectiveness and safety of anti-fibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of anti-fibrinolytics for acute intracranial haemorrhage. METHODS: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42019128260). We will conduct an individual patient data meta-analysis of randomised controlled trials with 500 patients or more assessing the effects of anti-fibrinolytics in acute intracranial haemorrhage. The primary outcomes will be 1) death from stroke or head injury within 30 days of randomisation, and 2) death from stroke or head injury, or dependency within 90 days of randomisation. The primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of anti-fibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of anti-fibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. CONCLUSIONS: This IPD meta-analysis will examine important clinical questions about the effects of anti-fibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice.}, keywords = {}, pubstate = {published}, tppubtype = {article} } INTRODUCTION: The Anti-fibrinolytics Trialists Collaboration aims to increase knowledge about the effectiveness and safety of anti-fibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of anti-fibrinolytics for acute intracranial haemorrhage. METHODS: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42019128260). We will conduct an individual patient data meta-analysis of randomised controlled trials with 500 patients or more assessing the effects of anti-fibrinolytics in acute intracranial haemorrhage. The primary outcomes will be 1) death from stroke or head injury within 30 days of randomisation, and 2) death from stroke or head injury, or dependency within 90 days of randomisation. The primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of anti-fibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of anti-fibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. CONCLUSIONS: This IPD meta-analysis will examine important clinical questions about the effects of anti-fibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice. |
Herrett, Emily; Williamson, Elizabeth; Beaumont, Danielle; Prowse, Danielle; Youssouf, Nabila; Brack, Kieran; Armitage, Jane; Goldacre, Ben; MacDonald, Thomas; van Staa, Tjeerd; Roberts, Ian; Shakur-Still, Haleema; Smeeth, Liam BMJ open, 7 (12), pp. e016604–, 2017. @article{lshtm4645552, title = {Study protocol for statin web-based investigation of side effects (StatinWISE): a series of randomised controlled N-of-1 trials comparing atorvastatin and placebo in UK primary care.}, author = {Emily Herrett and Elizabeth Williamson and Danielle Beaumont and Danielle Prowse and Nabila Youssouf and Kieran Brack and Jane Armitage and Ben Goldacre and Thomas MacDonald and Tjeerd van Staa and Ian Roberts and Haleema Shakur-Still and Liam Smeeth}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4645552/}, year = {2017}, date = {2017-12-01}, journal = {BMJ open}, volume = {7}, number = {12}, pages = {e016604--}, publisher = {BMJ Publishing Group}, abstract = {INTRODUCTION: Statins are effective at preventing cardiovascular disease, widely prescribed and their use is growing. Uncertainty persists about whether they cause symptomatic muscle adverse effects, such as pain and weakness, in the absence of statin myopathy. Discrepancies between data from observational studies, which suggest statins are associated with excess muscle symptoms, and from randomised trials, which suggest no such excess, have caused confusion. N-of-1 trials offer the opportunity to establish whether muscle symptoms during statin use are caused by statins in particular individuals. METHODS AND ANALYSIS: This series of 200 randomised, double-blinded N-of-1 trials in primary care will determine (1) the effect of statins on all muscle symptoms and (2) the effect of statins on muscle pain that is perceived to be statin related. Patients who are considering discontinuing statin use due to muscle symptoms and those who have discontinued in the last 3 years due to such symptoms will be recruited. Participants will be randomised to a sequence of six 2-month treatment periods during which they will receive atorvastatin 20 mg per day or matched placebo. On each of the last 7 days of each treatment period, participants will rate their muscle symptoms on a Visual Analogue Scale (VAS).At the end of their trial, participants will be shown numerical and graphical summaries of their own symptom data during statin and placebo periods. The primary analysis on the aggregate data from all participants will be a linear mixed model for VAS muscle symptom score, comparing scores during treatment with statin and placebo. ETHICS AND DISSEMINATION: This trial received a favourable opinion from South Central-Hampshire A Research Ethics Committee. Results will be published in a peer-reviewed medical journal. Dissemination of results to patients will take place via the media, website (statinwise.lshtm.ac.uk) and patient organisations. TRIAL REGISTRATION NUMBER: ISRCTN30952488.}, keywords = {}, pubstate = {published}, tppubtype = {article} } INTRODUCTION: Statins are effective at preventing cardiovascular disease, widely prescribed and their use is growing. Uncertainty persists about whether they cause symptomatic muscle adverse effects, such as pain and weakness, in the absence of statin myopathy. Discrepancies between data from observational studies, which suggest statins are associated with excess muscle symptoms, and from randomised trials, which suggest no such excess, have caused confusion. N-of-1 trials offer the opportunity to establish whether muscle symptoms during statin use are caused by statins in particular individuals. METHODS AND ANALYSIS: This series of 200 randomised, double-blinded N-of-1 trials in primary care will determine (1) the effect of statins on all muscle symptoms and (2) the effect of statins on muscle pain that is perceived to be statin related. Patients who are considering discontinuing statin use due to muscle symptoms and those who have discontinued in the last 3 years due to such symptoms will be recruited. Participants will be randomised to a sequence of six 2-month treatment periods during which they will receive atorvastatin 20 mg per day or matched placebo. On each of the last 7 days of each treatment period, participants will rate their muscle symptoms on a Visual Analogue Scale (VAS).At the end of their trial, participants will be shown numerical and graphical summaries of their own symptom data during statin and placebo periods. The primary analysis on the aggregate data from all participants will be a linear mixed model for VAS muscle symptom score, comparing scores during treatment with statin and placebo. ETHICS AND DISSEMINATION: This trial received a favourable opinion from South Central-Hampshire A Research Ethics Committee. Results will be published in a peer-reviewed medical journal. Dissemination of results to patients will take place via the media, website (statinwise.lshtm.ac.uk) and patient organisations. TRIAL REGISTRATION NUMBER: ISRCTN30952488. |
Li, Bernadette; Miners, Alec; Shakur-Still, Haleema; Roberts, Ian; Collaborators, WOMAN Trial The Lancet Global health, 6 (2), pp. e222–e228, 2017. @article{lshtm4646360, title = {Tranexamic acid for treatment of women with post-partum haemorrhage in Nigeria and Pakistan: a cost-effectiveness analysis of data from the WOMAN trial.}, author = {Bernadette Li and Alec Miners and Haleema Shakur-Still and Ian Roberts and WOMAN Trial Collaborators}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4646360/}, year = {2017}, date = {2017-11-01}, journal = {The Lancet Global health}, volume = {6}, number = {2}, pages = {e222--e228}, publisher = {Elsevier}, abstract = {BACKGROUND: Sub-Saharan Africa and southern Asia account for almost 85% of global maternal deaths from post-partum haemorrhage. Early administration of tranexamic acid, within 3 h of giving birth, was shown to reduce the risk of death due to bleeding in women with post-partum haemorrhage in the World Maternal Antifibrinolytic (WOMAN) trial. We aimed to assess the cost-effectiveness of early administration of tranexamic acid for treatment of post-partum haemorrhage. METHODS: For this economic evaluation we developed a decision model to assess the cost-effectiveness of the addition of tranexamic acid to usual care for treatment of women with post-partum haemorrhage in Nigeria and Pakistan. We used data from the WOMAN trial to inform model parameters, supplemented by estimates from the literature. We estimated costs (calculated in 2016 US$), life-years, and quality-adjusted life-years (QALYs) with and without tranexamic acid, calculated incremental cost-effectiveness ratios (ICERs), and compared these to threshold values in each country. Costs were assessed from the health-care provider perspective and discounted at 3% per year in the base case analysis. We did a series of one-way sensitivity analyses and probabilistic sensitivity analysis to assess the robustness of the results to parameter uncertainty. FINDINGS: Early treatment of post-partum haemorrhage with tranexamic acid generated an average gain of 0·18 QALYs at an additional cost of $37·12 per patient in Nigeria and an average gain of 0·08 QALYs at an additional cost of $6·55 per patient in Pakistan. The base case ICER results were $208 per QALY in Nigeria and $83 per QALY in Pakistan. These ICERs were below the lower bound of the cost-effectiveness threshold range in both countries. The ICERs were most sensitive to uncertainty in parameter inputs for the relative risk of death due to bleeding with tranexamic acid, the discount rate, the cost of the drug, and the baseline probability of death due to bleeding. INTERPRETATION: Early treatment of post-partum haemorrhage with tranexamic acid is highly cost-effective in Nigeria and Pakistan, and is likely to be cost-effective in countries in sub-Saharan Africa and southern Asia with a similar baseline risk of death due to bleeding. FUNDING: London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Sub-Saharan Africa and southern Asia account for almost 85% of global maternal deaths from post-partum haemorrhage. Early administration of tranexamic acid, within 3 h of giving birth, was shown to reduce the risk of death due to bleeding in women with post-partum haemorrhage in the World Maternal Antifibrinolytic (WOMAN) trial. We aimed to assess the cost-effectiveness of early administration of tranexamic acid for treatment of post-partum haemorrhage. METHODS: For this economic evaluation we developed a decision model to assess the cost-effectiveness of the addition of tranexamic acid to usual care for treatment of women with post-partum haemorrhage in Nigeria and Pakistan. We used data from the WOMAN trial to inform model parameters, supplemented by estimates from the literature. We estimated costs (calculated in 2016 US$), life-years, and quality-adjusted life-years (QALYs) with and without tranexamic acid, calculated incremental cost-effectiveness ratios (ICERs), and compared these to threshold values in each country. Costs were assessed from the health-care provider perspective and discounted at 3% per year in the base case analysis. We did a series of one-way sensitivity analyses and probabilistic sensitivity analysis to assess the robustness of the results to parameter uncertainty. FINDINGS: Early treatment of post-partum haemorrhage with tranexamic acid generated an average gain of 0·18 QALYs at an additional cost of $37·12 per patient in Nigeria and an average gain of 0·08 QALYs at an additional cost of $6·55 per patient in Pakistan. The base case ICER results were $208 per QALY in Nigeria and $83 per QALY in Pakistan. These ICERs were below the lower bound of the cost-effectiveness threshold range in both countries. The ICERs were most sensitive to uncertainty in parameter inputs for the relative risk of death due to bleeding with tranexamic acid, the discount rate, the cost of the drug, and the baseline probability of death due to bleeding. INTERPRETATION: Early treatment of post-partum haemorrhage with tranexamic acid is highly cost-effective in Nigeria and Pakistan, and is likely to be cost-effective in countries in sub-Saharan Africa and southern Asia with a similar baseline risk of death due to bleeding. FUNDING: London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation. |
Gayet-Ageron, Angèle; Prieto-Merino, David; Ker, Katharine; Shakur-Still, Haleema; Ageron, François-Xavier; Roberts, Ian; Collaboration, Antifibrinolytic Trials Lancet, 391 (10116), pp. 125–132, 2017. @article{lshtm4645705, title = {Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients.}, author = {Angèle Gayet-Ageron and David Prieto-Merino and Katharine Ker and Haleema Shakur-Still and François-Xavier Ageron and Ian Roberts and Antifibrinolytic Trials Collaboration}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4645705/}, year = {2017}, date = {2017-11-01}, journal = {Lancet}, volume = {391}, number = {10116}, pages = {125--132}, publisher = {Elsevier}, abstract = {BACKGROUND: Antifibrinolytics reduce death from bleeding in trauma and post-partum haemorrhage. We examined the effect of treatment delay on the effectiveness of antifibrinolytics. METHODS: We did an individual patient-level data meta-analysis of randomised trials done with more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials done between Jan 1, 1946, and April 7, 2017, from MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, PubMed, Popline, and the WHO International Clinical Trials Registry Platform. The primary measure of treatment benefit was absence of death from bleeding. We examined the effect of treatment delay on treatment effectiveness using logistic regression models. We investigated the effect of measurement error (misclassification) in sensitivity analyses. This study is registered with PROSPERO, number 42016052155. FINDINGS: We obtained data for 40 138 patients from two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Overall, there were 3558 deaths, of which 1408 (40%) were from bleeding. Most (884 [63%] of 1408) bleeding deaths occurred within 12 h of onset. Deaths from post-partum haemorrhage peaked 2-3 h after childbirth. Tranexamic acid significantly increased overall survival from bleeding (odds ratio [OR] 1?20, 95% CI 1?08-1?33; p=0?001), with no heterogeneity by site of bleeding (interaction p=0?7243). Treatment delay reduced the treatment benefit (pensuremath<0?0001). Immediate treatment improved survival by more than 70% (OR 1?72, 95% CI 1?42-2?10; pensuremath<0?0001). Thereafter, the survival benefit decreased by 10% for every 15 min of treatment delay until 3 h, after which there was no benefit. There was no increase in vascular occlusive events with tranexamic acid, with no heterogeneity by site of bleeding (p=0?5956). Treatment delay did not modify the effect of tranexamic acid on vascular occlusive events. INTERPRETATION: Death from bleeding occurs soon after onset and even a short delay in treatment reduces the benefit of tranexamic acid administration. Patients must be treated immediately. Further research is needed to deepen our understanding of the mechanism of action of tranexamic acid. FUNDING: UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation (CRASH-2 trial). London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation (WOMAN trial).}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Antifibrinolytics reduce death from bleeding in trauma and post-partum haemorrhage. We examined the effect of treatment delay on the effectiveness of antifibrinolytics. METHODS: We did an individual patient-level data meta-analysis of randomised trials done with more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials done between Jan 1, 1946, and April 7, 2017, from MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, PubMed, Popline, and the WHO International Clinical Trials Registry Platform. The primary measure of treatment benefit was absence of death from bleeding. We examined the effect of treatment delay on treatment effectiveness using logistic regression models. We investigated the effect of measurement error (misclassification) in sensitivity analyses. This study is registered with PROSPERO, number 42016052155. FINDINGS: We obtained data for 40 138 patients from two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Overall, there were 3558 deaths, of which 1408 (40%) were from bleeding. Most (884 [63%] of 1408) bleeding deaths occurred within 12 h of onset. Deaths from post-partum haemorrhage peaked 2-3 h after childbirth. Tranexamic acid significantly increased overall survival from bleeding (odds ratio [OR] 1?20, 95% CI 1?08-1?33; p=0?001), with no heterogeneity by site of bleeding (interaction p=0?7243). Treatment delay reduced the treatment benefit (pensuremath<0?0001). Immediate treatment improved survival by more than 70% (OR 1?72, 95% CI 1?42-2?10; pensuremath<0?0001). Thereafter, the survival benefit decreased by 10% for every 15 min of treatment delay until 3 h, after which there was no benefit. There was no increase in vascular occlusive events with tranexamic acid, with no heterogeneity by site of bleeding (p=0?5956). Treatment delay did not modify the effect of tranexamic acid on vascular occlusive events. INTERPRETATION: Death from bleeding occurs soon after onset and even a short delay in treatment reduces the benefit of tranexamic acid administration. Patients must be treated immediately. Further research is needed to deepen our understanding of the mechanism of action of tranexamic acid. FUNDING: UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation (CRASH-2 trial). London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation (WOMAN trial). |
Roberts, Ian; Shakur-Still, Haleema Tranexamic acid for post-partum haemorrhage in the WOMAN trial - Authors' reply. Journal Article Lancet, 390 (10102), pp. 1584–, 2017. @article{lshtm4573075, title = {Tranexamic acid for post-partum haemorrhage in the WOMAN trial - Authors' reply.}, author = {Ian Roberts and Haleema Shakur-Still}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4573075/}, year = {2017}, date = {2017-09-01}, journal = {Lancet}, volume = {390}, number = {10102}, pages = {1584--}, publisher = {Elsevier}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Mahmood, Abda; Roberts, Ian; Shakur-Still, Haleema Trials, 18 (1), pp. 330–, 2017. @article{lshtm4121139, title = {A nested mechanistic sub-study into the effect of tranexamic acid versus placebo on intracranial haemorrhage and cerebral ischaemia in isolated traumatic brain injury: study protocol for a randomised controlled trial (CRASH-3 Trial Intracranial Bleeding Mechanistic Sub-Study [CRASH-3 IBMS]).}, author = {Abda Mahmood and Ian Roberts and Haleema Shakur-Still}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4121139/}, year = {2017}, date = {2017-07-01}, journal = {Trials}, volume = {18}, number = {1}, pages = {330--}, publisher = {BMC}, abstract = {BACKGROUND: Tranexamic acid prevents blood clots from breaking down and reduces bleeding. However, it is uncertain whether tranexamic acid is effective in traumatic brain injury. The CRASH-3 trial is a randomised controlled trial that will examine the effect of tranexamic acid (versus placebo) on death and disability in 13,000 patients with traumatic brain injury. The CRASH-3 trial hypothesizes that tranexamic acid will reduce intracranial haemorrhage, which will reduce the risk of death. Although it is possible that tranexamic acid will reduce intracranial bleeding, there is also a potential for harm. In particular, tranexamic acid may increase the risk of cerebral thrombosis and ischaemia. The protocol detailed here is for a mechanistic sub-study nested within the CRASH-3 trial. This mechanistic sub-study aims to examine the effect of tranexamic acid (versus placebo) on intracranial bleeding and cerebral ischaemia. METHODS: The CRASH-3 Intracranial Bleeding Mechanistic Sub-Study (CRASH-3 IBMS) is nested within a prospective, double-blind, multi-centre, parallel-arm randomised trial called the CRASH-3 trial. The CRASH-3 IBMS will be conducted in a cohort of approximately 1000 isolated traumatic brain injury patients enrolled in the CRASH-3 trial. In the CRASH-3 IBMS, brain scans acquired before and after randomisation are examined, using validated methods, for evidence of intracranial bleeding and cerebral ischaemia. The primary outcome is the total volume of intracranial bleeding measured on computed tomography after randomisation, adjusting for baseline bleeding volume. Secondary outcomes include progression of intracranial haemorrhage (from pre- to post-randomisation scans), new intracranial haemorrhage (seen on post- but not pre-randomisation scans), intracranial haemorrhage following neurosurgery, and new focal ischaemic lesions (seen on post-but not pre-randomisation scans). A linear regression model will examine whether receipt of the trial treatment can predict haemorrhage volume. Bleeding volumes and new ischaemic lesions will be compared across treatment groups using relative risks and 95% confidence intervals. DISCUSSION: The CRASH-3 IBMS will provide an insight into the mechanism of action of tranexamic acid in traumatic brain injury, as well as information about the risks and benefits. Evidence from this trial could inform the management of patients with traumatic brain injury. TRIAL REGISTRATION: The CRASH-3 trial was prospectively registered and the CRASH-3 IBMS is an addition to the original protocol registered at the International Standard Randomised Controlled Trials registry ( ISRCTN15088122 ) 19 July 2011, and ClinicalTrials.gov on 25 July 2011 (NCT01402882).}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: Tranexamic acid prevents blood clots from breaking down and reduces bleeding. However, it is uncertain whether tranexamic acid is effective in traumatic brain injury. The CRASH-3 trial is a randomised controlled trial that will examine the effect of tranexamic acid (versus placebo) on death and disability in 13,000 patients with traumatic brain injury. The CRASH-3 trial hypothesizes that tranexamic acid will reduce intracranial haemorrhage, which will reduce the risk of death. Although it is possible that tranexamic acid will reduce intracranial bleeding, there is also a potential for harm. In particular, tranexamic acid may increase the risk of cerebral thrombosis and ischaemia. The protocol detailed here is for a mechanistic sub-study nested within the CRASH-3 trial. This mechanistic sub-study aims to examine the effect of tranexamic acid (versus placebo) on intracranial bleeding and cerebral ischaemia. METHODS: The CRASH-3 Intracranial Bleeding Mechanistic Sub-Study (CRASH-3 IBMS) is nested within a prospective, double-blind, multi-centre, parallel-arm randomised trial called the CRASH-3 trial. The CRASH-3 IBMS will be conducted in a cohort of approximately 1000 isolated traumatic brain injury patients enrolled in the CRASH-3 trial. In the CRASH-3 IBMS, brain scans acquired before and after randomisation are examined, using validated methods, for evidence of intracranial bleeding and cerebral ischaemia. The primary outcome is the total volume of intracranial bleeding measured on computed tomography after randomisation, adjusting for baseline bleeding volume. Secondary outcomes include progression of intracranial haemorrhage (from pre- to post-randomisation scans), new intracranial haemorrhage (seen on post- but not pre-randomisation scans), intracranial haemorrhage following neurosurgery, and new focal ischaemic lesions (seen on post-but not pre-randomisation scans). A linear regression model will examine whether receipt of the trial treatment can predict haemorrhage volume. Bleeding volumes and new ischaemic lesions will be compared across treatment groups using relative risks and 95% confidence intervals. DISCUSSION: The CRASH-3 IBMS will provide an insight into the mechanism of action of tranexamic acid in traumatic brain injury, as well as information about the risks and benefits. Evidence from this trial could inform the management of patients with traumatic brain injury. TRIAL REGISTRATION: The CRASH-3 trial was prospectively registered and the CRASH-3 IBMS is an addition to the original protocol registered at the International Standard Randomised Controlled Trials registry ( ISRCTN15088122 ) 19 July 2011, and ClinicalTrials.gov on 25 July 2011 (NCT01402882). |
Reith, Florence CM; Lingsma, Hester F; Gabbe, Belinda J; Lecky, Fiona E; Roberts, Ian; Maas, Andrew IR Differential effects of the Glasgow Coma Scale Score and its Components: An analysis of 54,069 patients with traumatic brain injury. Journal Article Injury, 48 (9), pp. 1932–1943, 2017. @article{lshtm3962416, title = {Differential effects of the Glasgow Coma Scale Score and its Components: An analysis of 54,069 patients with traumatic brain injury.}, author = {Florence CM Reith and Hester F Lingsma and Belinda J Gabbe and Fiona E Lecky and Ian Roberts and Andrew IR Maas}, url = {http://researchonline.lshtm.ac.uk/id/eprint/3962416/}, year = {2017}, date = {2017-06-01}, journal = {Injury}, volume = {48}, number = {9}, pages = {1932--1943}, publisher = {Elsevier}, abstract = {INTRODUCTION: The Glasgow Coma Scale (GCS) is widely used in the assessment of clinical severity and prediction of outcome after traumatic brain injury (TBI). The sum score is frequently applied, but the differential influence of the components infrequently addressed. We aimed to investigate the contribution of the GCS components to the sum score, floor and ceiling effects of the components, and their prognostic effects. METHODS: Data on adult TBI patients were gathered from three data repositories: TARN (n=50,064), VSTR (n=14,062), and CRASH (n=9,941). Data on initial hospital GCS-assessment and discharge mortality were extracted. A descriptive analysis was performed to identify floor and ceiling effects. The relation between GCS and outcome was studied by comparing case fatality rates (CFR) between different component-profiles adding up to identical sum scores using Chi2-tests, and by quantifying the prognostic value of each component and sum score with Nagelkerke's R2 derived from logistic regression analyses across TBI severities. RESULTS: In the range 3-7, the sum score is primarily determined by the motor component, as the verbal and eye components show floor-effects at sum scores 7 and 8, respectively. In the range 8-12, the effect of the motor component attenuates and the verbal and eye components become more relevant. The motor, eye and verbal scores reach their ceiling-effects at sum 13, 14 and 15, respectively. Significant variations were exposed in CFR between different component-profiles despite identical sum scores, except in sum scores 6 and 7. Regression analysis showed that the motor score had highest R2 values in severe TBI patients, whereas the other components were more relevant at higher sum scores. The prognostic value of the three components combined was consistently higher than that of the sum score alone. CONCLUSION: The GCS-components contribute differentially across the spectrum of consciousness to the sum score, each having floor and ceiling effects. The specific component-profile is related to outcome and the three components combined contain higher prognostic value than the sum score across different TBI severities. We, therefore, recommend a multidimensional use of the three-component GCS both in clinical practice, and in prognostic studies.}, keywords = {}, pubstate = {published}, tppubtype = {article} } INTRODUCTION: The Glasgow Coma Scale (GCS) is widely used in the assessment of clinical severity and prediction of outcome after traumatic brain injury (TBI). The sum score is frequently applied, but the differential influence of the components infrequently addressed. We aimed to investigate the contribution of the GCS components to the sum score, floor and ceiling effects of the components, and their prognostic effects. METHODS: Data on adult TBI patients were gathered from three data repositories: TARN (n=50,064), VSTR (n=14,062), and CRASH (n=9,941). Data on initial hospital GCS-assessment and discharge mortality were extracted. A descriptive analysis was performed to identify floor and ceiling effects. The relation between GCS and outcome was studied by comparing case fatality rates (CFR) between different component-profiles adding up to identical sum scores using Chi2-tests, and by quantifying the prognostic value of each component and sum score with Nagelkerke's R2 derived from logistic regression analyses across TBI severities. RESULTS: In the range 3-7, the sum score is primarily determined by the motor component, as the verbal and eye components show floor-effects at sum scores 7 and 8, respectively. In the range 8-12, the effect of the motor component attenuates and the verbal and eye components become more relevant. The motor, eye and verbal scores reach their ceiling-effects at sum 13, 14 and 15, respectively. Significant variations were exposed in CFR between different component-profiles despite identical sum scores, except in sum scores 6 and 7. Regression analysis showed that the motor score had highest R2 values in severe TBI patients, whereas the other components were more relevant at higher sum scores. The prognostic value of the three components combined was consistently higher than that of the sum score alone. CONCLUSION: The GCS-components contribute differentially across the spectrum of consciousness to the sum score, each having floor and ceiling effects. The specific component-profile is related to outcome and the three components combined contain higher prognostic value than the sum score across different TBI severities. We, therefore, recommend a multidimensional use of the three-component GCS both in clinical practice, and in prognostic studies. |
Roberts, Ian; Edwards, Phil; Prieto, David; Joshi, Miland; Mahmood, Abda; Ker, Katharine; Shakur-Still, Haleema Tranexamic acid in bleeding trauma patients: an exploration of benefits and harms. Journal Article Trials, 18 (1), pp. 48–, 2017. @article{lshtm3449335, title = {Tranexamic acid in bleeding trauma patients: an exploration of benefits and harms.}, author = {Ian Roberts and Phil Edwards and David Prieto and Miland Joshi and Abda Mahmood and Katharine Ker and Haleema Shakur-Still}, url = {http://researchonline.lshtm.ac.uk/id/eprint/3449335/}, year = {2017}, date = {2017-01-01}, journal = {Trials}, volume = {18}, number = {1}, pages = {48--}, publisher = {BMC}, abstract = {BACKGROUND: The CRASH-2 trial showed that tranexamic acid (TXA) administration reduces mortality in bleeding trauma patients. However, the effect appeared to depend on how soon after injury TXA treatment was started. Treatment within 3 h reduced bleeding deaths whereas treatment after 3 h increased the risk. We examine how patient characteristics vary by time to treatment and explore whether any such variations explain the time-dependent treatment effect. METHODS: Exploratory analysis were carried out, including per-protocol analyses, of data from the CRASH-2 trial, a randomised placebo-controlled trial of the effect of TXA on mortality in 20,211 trauma patients with, or at risk of, significant bleeding. We examine how patient characteristics (age, type of injury, presence or absence of head injury, Glasgow coma scale (GCS), systolic blood pressure and capillary refill time) vary with time to treatment and use univariable (restriction) and multivariable methods to examine whether any such variations explain the time-dependent effect of TXA. If not explained by differences in patient characteristics, we planned to conduct separate prespecified subgroup analyses for the early benefit and late harm. RESULTS: There was no substantial variation in age or capillary refill by time to treatment. However, the proportion of patients with blunt trauma, the proportion with head injury and mean systolic blood pressure increased as time to treatment increased. Mean GCS decreased as time to treatment increased. Analyses restricted to patients with blunt trauma, those without head injury and those with a systolic blood pressure ensuremath<100 mmHg showed that these characteristics did not explain the time-dependent treatment effect. In a multivariable analysis the interaction with time to treatment remained highly significant (p ensuremath< 0.0001). Separate subgroup analyses that examine how the benefits of early TXA treatment and the harms of late TXA treatment vary by systolic blood pressure ($łeq$75, 76-89, ensuremath>89 mmHg); GCS (severe 3-8, moderate 9-12, mild 13-15); and type of injury (penetrating versus blunt) showed no significant heterogeneity. CONCLUSIONS: The time-dependent effect of TXA in bleeding trauma patients is not explained by the type of injury, the presence or absence of head injury or systolic blood pressure. When given within 3 h of injury, TXA reduces death due to bleeding regardless of type of injury, GCS or blood pressure. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00375258 . Registered on 11 September 2006.}, keywords = {}, pubstate = {published}, tppubtype = {article} } BACKGROUND: The CRASH-2 trial showed that tranexamic acid (TXA) administration reduces mortality in bleeding trauma patients. However, the effect appeared to depend on how soon after injury TXA treatment was started. Treatment within 3 h reduced bleeding deaths whereas treatment after 3 h increased the risk. We examine how patient characteristics vary by time to treatment and explore whether any such variations explain the time-dependent treatment effect. METHODS: Exploratory analysis were carried out, including per-protocol analyses, of data from the CRASH-2 trial, a randomised placebo-controlled trial of the effect of TXA on mortality in 20,211 trauma patients with, or at risk of, significant bleeding. We examine how patient characteristics (age, type of injury, presence or absence of head injury, Glasgow coma scale (GCS), systolic blood pressure and capillary refill time) vary with time to treatment and use univariable (restriction) and multivariable methods to examine whether any such variations explain the time-dependent effect of TXA. If not explained by differences in patient characteristics, we planned to conduct separate prespecified subgroup analyses for the early benefit and late harm. RESULTS: There was no substantial variation in age or capillary refill by time to treatment. However, the proportion of patients with blunt trauma, the proportion with head injury and mean systolic blood pressure increased as time to treatment increased. Mean GCS decreased as time to treatment increased. Analyses restricted to patients with blunt trauma, those without head injury and those with a systolic blood pressure ensuremath<100 mmHg showed that these characteristics did not explain the time-dependent treatment effect. In a multivariable analysis the interaction with time to treatment remained highly significant (p ensuremath< 0.0001). Separate subgroup analyses that examine how the benefits of early TXA treatment and the harms of late TXA treatment vary by systolic blood pressure ($łeq$75, 76-89, ensuremath>89 mmHg); GCS (severe 3-8, moderate 9-12, mild 13-15); and type of injury (penetrating versus blunt) showed no significant heterogeneity. CONCLUSIONS: The time-dependent effect of TXA in bleeding trauma patients is not explained by the type of injury, the presence or absence of head injury or systolic blood pressure. When given within 3 h of injury, TXA reduces death due to bleeding regardless of type of injury, GCS or blood pressure. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00375258 . Registered on 11 September 2006. |
2016 |
McCarthy, Ona L; French, Rebecca S; Baraitser, Paula; Roberts, Ian; Rathod, Sujit D; Devries, Karen; Bailey, Julia V; Edwards, Phil; Wellings, Kaye; Michie, Susan; Free, Caroline Safetxt: a pilot randomised controlled trial of an intervention delivered by mobile phone to increase safer sex behaviours in young people. Journal Article BMJ open, 6 (12), pp. e013045–, 2016. @article{lshtm3298893, title = {Safetxt: a pilot randomised controlled trial of an intervention delivered by mobile phone to increase safer sex behaviours in young people.}, author = {Ona L McCarthy and Rebecca S French and Paula Baraitser and Ian Roberts and Sujit D Rathod and Karen Devries and Julia V Bailey and Phil Edwards and Kaye Wellings and Susan Michie and Caroline Free}, url = {http://researchonline.lshtm.ac.uk/id/eprint/3298893/}, year = {2016}, date = {2016-12-01}, journal = {BMJ open}, volume = {6}, number = {12}, pages = {e013045--}, publisher = {BMJ Publishing Group}, abstract = {OBJECTIVE: To test the procedures proposed for a main trial of a safer sex intervention for young people delivered by mobile phone text message ('safetxt'). DESIGN AND SETTING: Pilot randomised controlled trial. Participants were recruited through sexual health services in the UK. An independent online randomisation system allocated participants to receive the safetxt intervention or to receive the control text messages (monthly messages about participation in the study). Texting software delivered the messages in accordance with a predetermined schedule. PARTICIPANTS: Residents of England aged 16-24 who had received either a positive chlamydia test result or reported unsafe sex in the last year (defined as more than 1 partner and at least 1 occasion of sex without a condom). INTERVENTION: The safetxt intervention is designed to reduce sexually transmitted infection in young people by supporting them in using condoms, telling a partner about an infection and testing before unprotected sex with a new partner. Safetxt was developed drawing on: behavioural science; face-to-face interventions; the factors known to influence safer sex behaviours and the views of young people. OUTCOMES: The coprimary outcomes of the pilot trial were the recruitment rate and completeness of follow-up. RESULTS: We recruited 200 participants within our target of 3 months and we achieved 81% (162/200) follow-up response for the proposed primary outcome of the main trial, cumulative incidence of chlamydia at 12 months. CONCLUSIONS: Recruitment, randomisation, intervention delivery and follow-up were successful and a randomised controlled trial of the safetxt intervention is feasible. TRIAL REGISTRATION NUMBER: ISRCTN02304709; Results.}, keywords = {}, pubstate = {published}, tppubtype = {article} } OBJECTIVE: To test the procedures proposed for a main trial of a safer sex intervention for young people delivered by mobile phone text message ('safetxt'). DESIGN AND SETTING: Pilot randomised controlled trial. Participants were recruited through sexual health services in the UK. An independent online randomisation system allocated participants to receive the safetxt intervention or to receive the control text messages (monthly messages about participation in the study). Texting software delivered the messages in accordance with a predetermined schedule. PARTICIPANTS: Residents of England aged 16-24 who had received either a positive chlamydia test result or reported unsafe sex in the last year (defined as more than 1 partner and at least 1 occasion of sex without a condom). INTERVENTION: The safetxt intervention is designed to reduce sexually transmitted infection in young people by supporting them in using condoms, telling a partner about an infection and testing before unprotected sex with a new partner. Safetxt was developed drawing on: behavioural science; face-to-face interventions; the factors known to influence safer sex behaviours and the views of young people. OUTCOMES: The coprimary outcomes of the pilot trial were the recruitment rate and completeness of follow-up. RESULTS: We recruited 200 participants within our target of 3 months and we achieved 81% (162/200) follow-up response for the proposed primary outcome of the main trial, cumulative incidence of chlamydia at 12 months. CONCLUSIONS: Recruitment, randomisation, intervention delivery and follow-up were successful and a randomised controlled trial of the safetxt intervention is feasible. TRIAL REGISTRATION NUMBER: ISRCTN02304709; Results. |
Shakur-Still, Haleema; Fawole, Bukola; Kuti, Modupe; Olayemi, Oladapo; Bello, Adenike; Ogunbode, Olayinka; Kotila, Taiwo; Aimakhu, Chris O; Huque, Sumaya; Gregg, Meghann; Roberts, Ian Wellcome open research, 1 , pp. 31–, 2016. @article{lshtm3682726, title = {Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): protocol and statistical analysis plan for a randomized controlled trial.}, author = {Haleema Shakur-Still and Bukola Fawole and Modupe Kuti and Oladapo Olayemi and Adenike Bello and Olayinka Ogunbode and Taiwo Kotila and Chris O Aimakhu and Sumaya Huque and Meghann Gregg and Ian Roberts}, url = {http://researchonline.lshtm.ac.uk/id/eprint/3682726/}, year = {2016}, date = {2016-12-01}, journal = {Wellcome open research}, volume = {1}, pages = {31--}, publisher = {F1000Research}, abstract = {Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid has the potential to reduce bleeding and a large randomized controlled trial of its effect on maternal health outcomes in women with PPH (The WOMAN trial) is ongoing. We will examine the effect of tranexamic acid on fibrinolysis and coagulation in a subset of WOMAN trial participants. Methods. Adult women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion in the WOMAN trial. In a sub-group of trial participants, blood samples will be collected at baseline and 30 minutes after the first dose of tranexamic acid or matching placebo. Our primary objective is to evaluate the effect of tranexamic acid on fibrinolysis. Fibrinolysis will be assessed by measuring D-dimers and by rotational thromboelastometry (ROTEM). Secondary outcomes are international normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, haemoglobin and platelets. We aim to include about 180 women from the University College Hospital, Ibadan in Nigeria. Discussion: This sub-study of WOMAN trial participants should provide information on the mechanism of action of tranexamic acid in women with postpartum haemorrhage. We present the trial protocol and statistical analysis plan. The trial protocol was registered prior to the start of patient recruitment. The statistical analysis plan was completed before un-blinding. Trial registration: The trial was registered: ClinicalTrials.gov, Identifier NCT00872469 https://clinicaltrials.gov/ct2/show/NCT00872469; ISRCTN registry, Identifier ISRCTN76912190 http://www.isrctn.com/ISRCTN76912190 (Registration date: 22/03/2012).}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid has the potential to reduce bleeding and a large randomized controlled trial of its effect on maternal health outcomes in women with PPH (The WOMAN trial) is ongoing. We will examine the effect of tranexamic acid on fibrinolysis and coagulation in a subset of WOMAN trial participants. Methods. Adult women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion in the WOMAN trial. In a sub-group of trial participants, blood samples will be collected at baseline and 30 minutes after the first dose of tranexamic acid or matching placebo. Our primary objective is to evaluate the effect of tranexamic acid on fibrinolysis. Fibrinolysis will be assessed by measuring D-dimers and by rotational thromboelastometry (ROTEM). Secondary outcomes are international normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, haemoglobin and platelets. We aim to include about 180 women from the University College Hospital, Ibadan in Nigeria. Discussion: This sub-study of WOMAN trial participants should provide information on the mechanism of action of tranexamic acid in women with postpartum haemorrhage. We present the trial protocol and statistical analysis plan. The trial protocol was registered prior to the start of patient recruitment. The statistical analysis plan was completed before un-blinding. Trial registration: The trial was registered: ClinicalTrials.gov, Identifier NCT00872469 https://clinicaltrials.gov/ct2/show/NCT00872469; ISRCTN registry, Identifier ISRCTN76912190 http://www.isrctn.com/ISRCTN76912190 (Registration date: 22/03/2012). |
Dallaku, Kastriot; Shakur-Still, Haleema; Edwards, Phil; Beaumont, Danielle; Roberts, Ian; Huque, Sumaya; Delius, Maria; Mansmann, Ulrich Statistical analysis plan for the WOMAN-ETAPlaT study: Effect of tranexamic acid on platelet function and thrombin generation. Journal Article Wellcome open research, 1 , pp. 30–, 2016. @article{lshtm4259156, title = {Statistical analysis plan for the WOMAN-ETAPlaT study: Effect of tranexamic acid on platelet function and thrombin generation.}, author = {Kastriot Dallaku and Haleema Shakur-Still and Phil Edwards and Danielle Beaumont and Ian Roberts and Sumaya Huque and Maria Delius and Ulrich Mansmann}, url = {http://researchonline.lshtm.ac.uk/id/eprint/4259156/}, year = {2016}, date = {2016-12-01}, journal = {Wellcome open research}, volume = {1}, pages = {30--}, publisher = {F1000Research}, abstract = {Background. Postpartum haemorrhage (PPH) is a potentially life-threatening complication for women, and the leading cause of maternal mortality. Tranexamic acid (TXA) is an antifibrinolytic used worldwide to treat uterine haemorrhage and to reduce blood loss in general surgery. TXA may have effects on thrombin generation, platelet function and coagulation factors as a result of its inhibition on the plasmin. Methods. WOMAN ETAPlaT is a sub-study of the World Maternal Antifibrinolitic trial (WOMAN trial). All adult women clinically diagnosed with PPH after a vaginal delivery or caesarean section, are eligible for inclusion in the study. Blood samples will be collected at the baseline and 30 minutes after the first dose of study treatment is given. Platelet function will be evaluated in whole blood immediately after sampling with Multiplate? tests (ADPtest and TRAPtest). Thrombin generation, fibrinogen, D-dimer, and coagulation factors vW, V and VIII will be analysed using platelet poor plasma. Results. Recruitment to WOMAN ETAPlaT started on 04 November 2013 and closed on 13 January 2015, during this time 188 patients were recruited. The final participant follow-up was completed on 04 March 2015. This article introduces the statistical analysis plan for the study, without reference to unblinded data. Conclusion. The data from this study will provide evidence for the effect of TXA on thrombin generation, platelet function and coagulation factors in women with PPH. Trial registration: ClinicalTrials.gov Identifier: NCT00872469; ISRCTN76912190.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background. Postpartum haemorrhage (PPH) is a potentially life-threatening complication for women, and the leading cause of maternal mortality. Tranexamic acid (TXA) is an antifibrinolytic used worldwide to treat uterine haemorrhage and to reduce blood loss in general surgery. TXA may have effects on thrombin generation, platelet function and coagulation factors as a result of its inhibition on the plasmin. Methods. WOMAN ETAPlaT is a sub-study of the World Maternal Antifibrinolitic trial (WOMAN trial). All adult women clinically diagnosed with PPH after a vaginal delivery or caesarean section, are eligible for inclusion in the study. Blood samples will be collected at the baseline and 30 minutes after the first dose of study treatment is given. Platelet function will be evaluated in whole blood immediately after sampling with Multiplate? tests (ADPtest and TRAPtest). Thrombin generation, fibrinogen, D-dimer, and coagulation factors vW, V and VIII will be analysed using platelet poor plasma. Results. Recruitment to WOMAN ETAPlaT started on 04 November 2013 and closed on 13 January 2015, during this time 188 patients were recruited. The final participant follow-up was completed on 04 March 2015. This article introduces the statistical analysis plan for the study, without reference to unblinded data. Conclusion. The data from this study will provide evidence for the effect of TXA on thrombin generation, platelet function and coagulation factors in women with PPH. Trial registration: ClinicalTrials.gov Identifier: NCT00872469; ISRCTN76912190. |
Dallaku, Kastriot; Shakur-Still, Haleema; Roberts, Ian; Edwards, Phil; Beaumont, Danielle; Delius, Maria; Siegmund, Braun; Gliozheni, Orion; Tasha, Ilir; Cenameri, Saimir; Mansmann, Ulrich Effects of tranexamic acid on platelet function and thrombin generation (ETAPlaT): WOMAN trial sub-study. Journal Article Scientific reports, 1 , pp. 29–, 2016. @article{lshtm3364155, title = {Effects of tranexamic acid on platelet function and thrombin generation (ETAPlaT): WOMAN trial sub-study.}, author = {Kastriot Dallaku and Haleema Shakur-Still and Ian Roberts and Phil Edwards and Danielle Beaumont and Maria Delius and Braun Siegmund and Orion Gliozheni and Ilir Tasha and Saimir Cenameri and Ulrich Mansmann}, url = {http://researchonline.lshtm.ac.uk/id/eprint/3364155/}, year = {2016}, date = {2016-12-01}, journal = {Scientific reports}, volume = {1}, pages = {29--}, publisher = {Nature Research (part of Springer Nature)}, abstract = {Background. Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid (TXA) has the potential to reduce bleeding and a large randomized placebo controlled trial of its effect in women with PPH (The WOMAN trial) is underway. TXA might also affect coagulation factors and platelets. Objectives. To examine the effect of TXA on thrombin generation, platelet function, fibrinogen, D-dimer and coagulation factors in women with PPH. Methods. We will conduct a sub-study within the WOMAN trial. Women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion. Blood samples will be collected at baseline and 30 minutes after the first dose of study treatment. Using platelet poor plasma we will measure thrombin generation, fibrinogen, D-dimer, factor V and VIII, and Von Willebrand factor. Platelet function will be evaluated in whole blood using Multiplate? tests. Outcomes. The primary outcome is the effect of TXA on thrombin generation. Secondary outcomes include the effect of TXA on platelet function, fibrinogen, D-dimer and coagulation factors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background. Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid (TXA) has the potential to reduce bleeding and a large randomized placebo controlled trial of its effect in women with PPH (The WOMAN trial) is underway. TXA might also affect coagulation factors and platelets. Objectives. To examine the effect of TXA on thrombin generation, platelet function, fibrinogen, D-dimer and coagulation factors in women with PPH. Methods. We will conduct a sub-study within the WOMAN trial. Women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion. Blood samples will be collected at baseline and 30 minutes after the first dose of study treatment. Using platelet poor plasma we will measure thrombin generation, fibrinogen, D-dimer, factor V and VIII, and Von Willebrand factor. Platelet function will be evaluated in whole blood using Multiplate? tests. Outcomes. The primary outcome is the effect of TXA on thrombin generation. Secondary outcomes include the effect of TXA on platelet function, fibrinogen, D-dimer and coagulation factors. |
