Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

The Effects of Moxifloxacin and Gemifloxacin on the ECG Morphology in Healthy Volunteers: A Phase 1 Randomized Clinical Trial

Moxifloxacin and gemifloxacin are the two newer broad-spectrum 8-methoxy-quinolone derivatives that are used to treat various bacterial infections in cardiac patients. In this research study, we assessed the impact of moxifloxacin and gemifloxacin on the QT intervals of electrocardiograms in normal adult doses and draw a comparison, in a controlled environment, on healthy volunteers. Additionally, the effect of both test drugs on the QRS complex was checked. Sixty healthy volunteers were randomly assigned to two groups via R-software, and each respectively received moxifloxacin and gemifloxacin for five days. The research ethics committee approved the research, and it was registered for clinical trial under NCT 04692623. The participants’ electrocardiograms were obtained before the start of the dose (baseline) and on the fifth day. Significant prolongation of QT interval was noted in moxifloxacin (p p < 0.0001) QT interval prolongation (QTIP) as compared to gemifloxacin. In contrast to the previously reported literature, the prominent effect of moxifloxacin on the widening of the QRS-complex was noted with no such effect on QRS-widening in the gemifloxacin-treated group. It is concluded that both drugs have the potential for considerable QT interval prolongation (QTIP) effects, which is one of the risk factors for developing torsade de pointes (TdPs) in cardiac patients. Thus, clinicians should exercise caution when prescribing moxifloxacin and gemifloxacin to cardiac patients and should consider alternate treatment options

Insulinotropic Potential of Moxifloxacin and Gemifloxacin: An In Vivo Rabbits Model Study Followed by Randomized Phase I Clinical Trial

Fluoroquinolones (FQs) have been reported to cause dysglycemia in both diabetic and non-diabetic patients. However, diabetic patients are usually on polypharmacy, so we cannot attribute the dysglycemia specifically to FQs. To answer the question as to whether Moxifloxacin and Gemifloxacin influence blood glucose levels and serum insulin levels or otherwise, rabbits were used as experimental animals in an in vivo model followed by a phase I randomized clinical trial in euglycemic healthy volunteers. The effects on the serum insulin and blood glucose levels in the Moxifloxacin and Gemifloxacin treated groups were, respectively, determined on the fifth day in both the in-vivo rabbits model and in the test subjects of the phase I clinical trial. The effects of these drugs were also checked on the histomorphology of the pancreas in the rabbits. The findings of our study suggest that Moxifloxacin and Gemifloxacin significantly (p &lt; 0.05) reduced the blood glucose levels via a subsequent significant shift in the serum insulin levels both in the in vivo animal model and in the test subjects of the phase I clinical trial. No prominent effects on the beta cells histomorphology were noted in this study. Moxifloxacin showed a more significant effect than Gemifloxacin. The insulinotropic effect was comparable to the effect of Glibenclamide. It is concluded that Moxifloxacin and Gemifloxacin have a significant blood glucose lowering effect mediated through insulinotropic action. (Clinical Trials.gov identifier: NCT04692623)