Bleeding

Concomitant Use of Selective Serotonin Reuptake Inhibitors and Oral Anticoagulants and Risk of Major Bleeding: A Systematic Review and Meta-analysis.

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BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs), the most prescribed antidepressants, are associated with a modestly increased risk of major bleeding. However, in patients treated with both SSRIs and oral anticoagulants (OACs), the risk of major bleeding may be substantial.

OBJECTIVE: To assess the risk of major bleeding associated with concomitant use of SSRIs and OACs, compared with OAC use alone.

METHODS: We searched MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials (from inception to December 1, 2021) for clinical trials and observational studies assessing the association between concomitant use of SSRIs and OACs and the risk of major bleeding. Given sufficient homogeneity of studies, we conducted a random-effects meta-analysis to estimate a pooled hazard ratio (HR) of major bleeding associated with concomitant use of SSRIs and OACs, compared with OAC use alone.

RESULTS: The review comprised 14 studies, including 7 cohort and 7 nested case-control studies. Following assessment of clinical and methodological heterogeneity, eight studies with a total of 98,070 patients were eligible for the meta-analysis. The pooled HR of major bleeding associated with concomitant use of SSRIs and OACs was 1.35 (95% confidence interval [CI]: 1.14-1.58). In secondary analyses, the pooled HR for concomitant use of SSRIs and direct OACs was 1.47 (95% CI: 1.03-2.10).

CONCLUSIONS: Concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding. Overall, our findings suggest that physicians may need to tailor treatment according to individual patient risk factors for bleeding when prescribing SSRIs to patients using OACs.

GALILEO: Rivaroxaban raises death, thrombotic, bleeding risk vs. antiplatelet therapy after TAVR

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Among patients who underwent successful transcatheter aortic valve replacement and were not on chronic oral anticoagulation, rivaroxaban was linked to higher risk for death/thromboembolic complications and bleeding compared with antiplatelet therapy, according to results from the GALILEO trial.

In the GALILEO 4D substudy, rivaroxaban (Xarelto, Janssen/Bayer) was linked to a lower rate of abnormalities related to subclinical leaflet thrombosis compared with antiplatelet therapy.

Both studies were presented at the American Heart Association Scientific Sessions and published in The New England Journal of Medicine.

GALILEO

In the intention-to-treat analysis of GALILEO, at a median follow-up of 17 months, the rivaroxaban group had a higher rate of the primary efficacy outcome of death or first thromboembolic event compared with the antiplatelet group (9.8 per 100 person-years vs. 7.2 per 100 person-years; HR = 1.35; 95% CI, 1.01-1.81), George D. Dangas, MD, PhD, professor of medicine (cardiology) and surgery at Icahn School of Medicine at Mount Sinai, said during a presentation, noting the treatment effect was consistent across subgroups.

He also said, in the intention-to-treat analysis of the primary safety outcome of major, disabling or life-threatening bleeding, the rivaroxaban group had a numerically higher rate compared with the antiplatelet group (4.3 per 100 person-years vs. 2.8 per 100 person-years; HR = 1.5; 95% CI, 0.95-2.37).

In addition, the rate of death was higher in the rivaroxaban group (5.8 per 100 person-years vs. 3.4 per 100 person-years; HR = 1.69; 95% CI, 1.13-2.53), driven by non-CV mortality (2.6 per 100 person-years vs. 1 per 100 person-years; HR = 2.67; 95% CI, 1.33-5.35), according to the researchers.

“The mechanism underlying the higher mortality in the rivaroxaban arm observed in the intention-to-treat analysis in this trial is unclear,” Dangas said during the presentation. “The mortality rate differences were attenuated in the on-treatment analysis and many occurred late after discontinuation of the study drug.”

There were no differences between the groups in death from CV causes or any thromboembolic event, symptomatic valve thrombosis, stroke or MI.

In the on-treatment analysis, the primary efficacy outcome occurred at a rate of 8.1 per 100 person-years in the rivaroxaban group and 6.8 per 100 person-years in the antiplatelet group (HR = 1.21; 95% CI, 0.86-1.7), and the primary safety outcome occurred at a rate of 4.6 per 100 person-years in the rivaroxaban group and 2.7 per 100 person-years in the antiplatelet group (HR = 1.53; 95% CI, 0.94-2.49), and there was no difference between the groups in all-cause mortality (HR = 1.23; 95% CI, 0.71-2.15), according to the researchers.

The rivaroxaban group (n = 826; mean age, 80 years; 52% men) received rivaroxaban 10 mg daily for the duration of the study and aspirin 75 mg to 100 mg daily for the first 3 months. The antiplatelet group (n = 818; mean age, 81 years; 50% men) received aspirin 75 mg to 100 mg daily for the duration of the study and clopidogrel 75 mg daily for the first 3 months. The protocol called for those in the antiplatelet group who had never taken clopidogrel to take a loading dose of at least 300 mg. Operators could use any TAVR valve approved in their country. All patients were not previously taking an anticoagulant for any condition.

Janssen issued a statement to Healio by email after the results were released. It read: “Xarelto (rivaroxaban) has a proven, well-established safety and efficacy profile. Health care professionals performing TAVR worldwide were informed of the GALILEO results more than 1 year ago, and reminded that, like all [direct oral anticoagulants], Xarelto use is not recommended for people with prosthetic heart valves. As the GALILEO population was distinctly different from those participating in other Xarelto trials, the safety and efficacy profile of Xarelto across its eight FDA-approved indications remains positive.”

GALILEO 4D

For the GALILEO-4D substudy, 231 patients who had successful TAVR (mean age, 80 years; 64% men) underwent four-dimensional CT approximately 90 days after randomization. The primary endpoint was percentage of patients with at least one valve leaflet with a reduced motion grade of at least 3, defined as involving more than at least 50% of the leaflet. The researchers also analyzed leaflet thickening.

The primary endpoint occurred in 2.1% of the rivaroxaban group compared with 10.9% of the antiplatelet group (difference, –8.8 percentage points; 95% CI, –16.5 to –1.9), Ole De Backer, MD, PhD, MBA, cardiologist at the Heart Center, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, said during a presentation.

Thickening of at least one leaflet occurred in 12.4% of the rivaroxaban group and in 32.4% of the antiplatelet group (difference, –20 percentage points; 95% CI, –30.9 to –8.5), he said.

The per-protocol analyses showed similar results, he said.

“The overall proportion of patients with reduced leaflet motion grade 3 or more and leaflet thickening was significantly less frequent with the rivaroxaban-based strategy as compared to the antiplatelet strategy,” De Backer said during the presentation. “Echocardiography was not useful in identifying patients with these valve abnormalities.” – by Erik Swain

References:

Dangas GD, et al.

De Backer O, et al. Late Breaking Science III: Controversies in Contemporary Management of AS. Both presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Dangas GD, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1911425.

De Backer O, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1911426.

Disclosures: The study was funded by Bayer and Janssen Pharmaceuticals. Dangas reports he received grants from Bayer, personal fees from Bayer, Daiichi Sankyo, Janssen and Sanofi Aventis and other fees from Medtronic. De Backer reports he received grants and personal fees from Abbott and personal fees from Boston Scientific. Please see the studies for the other authors’ relevant financial disclosures.

PERSPECTIVE

BACK TO TOP B. Hadley Wilson, MD, FACC)

B. Hadley Wilson, MD, FACC

We do not know the optimal anticoagulant or antiplatelet regimen for patients who have had TAVR. Aspirin and clopidogrel have been the most common agents prescribed post-TAVR for at least 3 months. However, there have been concerns that a post-TAVR anticoagulation regimen might be more effective.

The hypothesis in GALILEO was that there would be fewer deaths and thromboembolic events in the rivaroxaban group. But actually, there were more deaths and thromboembolic complications in the rivaroxaban group compared with the standard aspirin and clopidogrel regimen. This study shows the regimen of rivaroxaban plus aspirin after TAVR is not beneficial and is actually quite harmful for patients. Questions must be asked about whether this was the right dose and the right anticoagulant. Further studies could help determine if a lower dose of rivaroxaban may be safer and provide equal or better outcomes than standard care for patients who had TAVR. Right now, the results endorse aspirin plus clopidogrel for at least 3 months post-TAVR.

GALILEO-4D pushes on the theory of using direct oral anticoagulants in post-TAVR patients. We have observed other recent studies showing there is leaflet thrombus accumulation and leaflet thickening post-TAVR, particularly early on, despite the standard treatment of aspirin plus clopidogrel. Indeed, the study showed there was better leaflet motion and reduced thickening, especially early on, with an oral anticoagulant, but the clinical results from the larger GALILEO study did not support that made a clinical difference in avoidance of more serious complications. And in GALILEO-4D, the leaflet motion and thickening results evened out over time.

These two studies point in different directions. GALILEO-4D suggests oral anticoagulation will be beneficial to patients post-TAVR, but the larger GALILEO study showed the opposite. It does not necessarily mean we should discard all anticoagulants and all anticoagulant regimens for this population. But right now, we should stick with the standard of care with aspirin and clopidogrel.

B. Hadley Wilson, MD, FACC

Interventional Cardiologist

Executive Vice Chair, Atrium Health’s Sanger Heart & Vascular Institute

Clinical Professor of Medicine

UNC School of Medicine

Member, Board of Trustees, American College of Cardiology

How to Stop a Cut From Bleeding So You Can Get Back to Your Life

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It’s time to brush up on first aid.

When you get a cut, you might say a few expletives because it hurts, freak out because, ugh, blood, or both. Then, of course, comes figuring out how to stop the bleeding ASAP. First aid to the rescue.

Not only will a few first aid techniques help stop a cut from bleeding, they’ll ensure your wound is clean and ready to heal as well as possible (this is key in preventing infection). Here’s what you need to know.

When you get a cut, your body immediately kicks into overdrive to try to stop the bleeding (but it may need a little help).

It does this via coagulation, aka the process of forming a blood clot, Joshua Russell, M.D., an emergency medicine physician at Legacy-GoHealth Urgent Care, tells SELF. (This is a normal mechanism, not like a blood clot that can form in the veins of your legs and, if it travels to your lungs, can put your life at risk.) In this complex process known as a coagulation cascade, an enzyme in your blood called thrombin allows a protein called fibrinogen to form a net-like structure that hardens and contracts. Coupled with platelets, which are components of your blood that plug up broken blood vessels, this helps to form a blood clot.

That’s usually how it works, anyway—there are some exceptions. Medications like aspirin can thin the blood, and health conditions like hemophilia or idiopathic thrombocytopenic purpura (ITP) can mess with the clotting mechanism in your body. This can all make it harder than usual to stop a cut’s bleeding on your own.

Your first step after you get a cut depends on how big the gash is.

If you nicked your finger while slicing up some tomatoes or cut yourself while shaving, you’ll want to first wash your hands to avoid infecting the wound, says the Mayo Clinic. Then, grab a paper towel, gauze, or tissue, and use it to apply pressure to the area to try to get the bleeding to stop, Matthew Kippenhan, M.D., an emergency medicine physician at Northwestern Memorial Hospital, tells SELF. Pressure on the wound helps to slow blood flow, which allows your body to more easily form a clot. The bleeding should stop or slow down significantly within a few minutes.

After that, you can gently run water over the wound and wash the area—not the wound itself—with soap. Apply an antibiotic cream to further avoid infection. Next up, you should cover the cut with a Band-Aid or gauze and tape (you should change this once a day, per the Mayo Clinic). This helps to protect it from outside germs or re-opening.

If you have a larger cut, the method is slightly different. “For larger cuts, stopping the bleeding immediately becomes a priority because it is possible to lose a significant amount of blood relatively quickly,” Dr. Russell says. That’s why he recommends applying direct, focused pressure on the site of the bleeding for at least 10 minutes to try to get it to stop. It can take several minutes before a stable clot begins to form, and using direct pressure on a wound will prevent significant blood loss in the meantime, he explains.

Once the bleeding has stopped, run tap water over the wound, wash around the area with soap (and clean hands!), then apply an antibiotic cream and a bandage, Dr. Kippenhan says.

In either scenario, you should get a tetanus shot if you haven’t had one in five years and the wound is dirty or deep.

Some parts of your body are going to bleed more than others, so don’t automatically get nervous if you see a lot of blood.

If you got what seems like a pretty minor cut on your shin, but it seems like it’s taking forever for the bleeding to stop, don’t panic.

“The amount of bleeding is determined by the blood flow to the area and the pressure in those blood vessels,” says Dr. Russell. Bleeding from your lower extremities, like your shins and ankles, can be pretty severe because gravity causes blood to pool in veins of the legs, he explains. And a cut on your head is likely to bleed a fair amount, just because it has a lot of blood vessels, Dr. Kippenhan says.

While cuts are often not a huge deal, there are some distinct signs you should head to the emergency room or otherwise get medical attention ASAP.

Those include seeing bone, muscle, or any similar structure, and having a cut that’s big enough to worry you, Brett Etchebarne, M.D., Ph.D., an assistant professor of emergency medicine at Michigan State University, tells SELF. Also, seek medical attention immediately if your blood is spurting instead of flowing normally, or if you haven’t stopped bleeding profusely even though you’ve gone through the above steps. These are all signs that you may need stitches to help close the wound or even surgery to repair internal damage.

It’s also a good idea to have a doctor look at any large cut over a joint (like your knee) since moving that joint could reopen the wound and cause issues with healing, Dr. Kippenhan says. Again, you might need stitches to make sure it can heal properly.

Another red flag is if you notice that you’re having any numbness or tingling after your injury. That could be a sign you cut an important nerve and didn’t realize it, Dr. Etchebarne says, so you know the drill: It’s time to see a doctor. Same goes for if you’ve noticed any signs of infection, like warmth, redness, or increasing pain.

Ultimately, if you have a cut and you’re not sure if you should get it checked out, call your doctor. Every cut is different, and they can help guide you on next steps.

Edoxaban may prevent recurrent VTE, bleeding in patients with cancer

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Professor Gary Raskob

The noninferiority of edoxaban compared with dalteparin in preventing recurrent venous thromboembolism (VTE) and major bleeding in patients with cancer highlights edoxaban as a potential alternative to low molecular weight heparin (LMWH) in this group of patients, suggests results of the Hokusai VTE-Cancer Study presented at ASH 2017.

According to study lead author Professor Gary E. Raskob from the University of Oklahoma College of Public Health, Oklahoma City, Oklahoma, US, major guidelines (eg, ASCO*, ESMO**) currently recommend the use of subcutaneous LMWH to treat VTE. However, subcutaneous injections may be burdensome and lead to treatment discontinuation, making direct oral anticoagulants a more attractive choice in these patients.

“For the vast majority of patients with cancer-associated VTE, treatment with oral edoxaban can replace the injectable dalteparin,” said Raskob.

In this multicentre (114 sites in North America, Europe, Australia, and New Zealand), open-label, blinded outcome trial, 1,050 patients with cancer and VTE were randomized 1:1 to the LMWH dalteparin (200 IU/kg reduced to 150 IU/kg on day 30; n=524) or 5 days of LMWH followed by oral edoxaban (60 mg QD; n=522) for at least 6 months and up to 12 months.

Incidence of the primary composite outcome (first recurrent VTE or major bleeding event) was comparable between patients on edoxaban and dalteparin in the primary analysis (12.8 percent vs 13.5 percent; hazard ratio [HR], 0.97, 95 percent confidence interval [CI], 0.70–1.36; p=0.006). The incidence of the primary outcome was also similar between groups at 6 months in a sensitivity analysis (10.5 percent vs 10.7 percent; HR, 1.01, 95 percent CI, 0.69–1.46; p=0.018). [ASH 2017, abstract LBA-6]

There was a lower rate of recurrent VTE among patients on edoxaban vs dalteparin (6.5 percent vs 10.3 percent; -3.8 percent absolute risk difference), and a higher rate of major bleeding events (6.3 percent vs 3.2 percent; 3.1 percent absolute risk difference).

The elevated rate of major bleeding was driven primarily by the higher number of upper gastrointestinal bleeds in patients on edoxaban compared with dalteparin (n=17 vs 3) and mostly affected patients who had gastrointestinal cancers at study entry, said Raskob.

The incidence of category 3 and 4 bleeding (life-threatening emergency and fatal bleeding, respectively) was comparable between patients on edoxaban and dalteparin (2.3 percent in each group), as was event-free survival at 12 months (55.0 percent vs 56.5 percent).

“Treatment of cancer-associated VTE is challenging because the risk of recurrence and bleeding complications with treatment are both higher in cancer patients than in noncancer patients. Both of these complications … contribute to morbidity and mortality but importantly, for oncologists, they may interfere with … definitive anticancer therapy to the patients,” said Raskob.

“Preventing VTE recurrence and major bleeding can allow the oncologist to really focus on the patient’s cancer treatment,” he said, suggesting that the lower rate of recurrent VTE as observed among patients on edoxaban can be offset by a similar increase in major bleeding risk.

“A huge question is whether or not to use direct oral anticoagulants in patients with cancer … but the studies just hadn’t been done. This is practice-changing,” said Professor Robert Brodsky from the Johns Hopkins School of Medicine in Baltimore, Maryland, US who moderated the ASH 2017 late-breaking abstract session.

*ASCO: American Society of Clinical Oncology

**ESMO: European Society for Medical Oncology

Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes

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This Cochrane Review examines the effects of different policies for clamping the umbilical cord after birth for babies born at term. It compares early cord clamping, which usually takes place within 60 seconds of birth, versus later clamping that usually involves clamping the cord more than one minute after birth or when cord pulsation has ceased.

In the past, the umbilical cord has usually been clamped shortly following the birth of the baby, as part of the active management of the third stage of labour. This strategy might also involve the infant being placed on the mother’s abdomen, put to the breast or more closely examined on a warmed cot if resuscitation was required. However, more recent guidelines for management of the third stage of labour no longer recommend immediate cord clamping, and later clamping of the umbilical cord might take place when cord pulsation has ceased or beyond the first minute following the birth of the baby. However, there is ongoing uncertainty about the relative benefits, or harms, of the two approaches. There have been concerns that late cord clamping might increase the mother’s risk of a postpartum haemorrhage, that could outweigh potential benefits to the baby of delaying clamping which might arise from the extra time for a transfer of the fetal blood in the placenta to the infant at the time of birth. This placental transfusion can provide the infant with an additional 30% more blood volume and up to 60% more red blood cells.

The authors of this updated Cochrane Review searched the Cochrane Pregnancy and Childbirth Group’s Trials Register in February 2013. This Register is maintained through electronic searching of the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE; along with dedicated searching of dozens of journals and the proceedings of major conferences. After checking 74 reports representing 58 studies, they excluded 37 studies and included 15 in the review. A further 4 studies are awaiting assessment and 2 ongoing studies were also identified. The 15 included randomized trials recruited a total of 3911 mother and baby pairs.

The primary outcome measures for the review included maternal death and severe maternal morbidity as a composite outcome, but none of the included studies reported data on these. However, in the five trials (2066 women) that reported another of the primary outcome measures, severe postpartum haemorrhage (PPH) (blood loss of ≥1000 ml blood), there were no significant differences between early versus late cord clamping (risk ratio (RR): 1.04, 95% confidence interval (CI): 0.65 to 1.65). There were also no significant differences for PPH of ≥500 ml (RR: 1.17, 95% CI: 0.94 to 1.44, 5 trials, 2260 women), mean blood loss (mean difference (MD): 5.11 ml, 95% CI: -23.18 to 33.39, 2 trials, 1345 women), or maternal haemoglobin values at 24 to 72 hours after the birth (MD: -0.12 g/dl, 95% CI: -0.30 to 0.06, 3 trials, 1128 women).

The primary outcome measure for the babies was neonatal mortality but data were only available from two trials, in which four of the 381 babies died. There was no significant difference between the early and late cord clamping groups (RR: 0.37, 95% CI: 0.04 to 3.41). Other infant outcomes with no significant differences between early and late cord clamping were Apgar scores below 7 at 5 minutes (RR: 1.23, 95% CI: 0.73 to 2.07, 2 trials, 1342 neonates), and admission to a special care baby nursery or neonatal intensive care unit (RR: 0.79, 95% CI: 0.48 to 1.31, 4 trials, 1675 infants). Fewer infants in the early cord clamping group required phototherapy for jaundice than in the late cord clamping group (RR: 0.62, 95% CI: 0.41 to 0.96, 7 trials, 2324 infants), haemoglobin concentration was significantly lower in the early cord clamping group at 24 to 48 hours (MD: -1.49 g/dl, 95% CI: -1.78 to -1.21, 4 trials, 884 infants) and infants in the early cord clamping were more than twice as likely to be iron deficient at three to six months (RR: 2.65, 95% CI: 1.04 to 6.73, 5 trials, 1152 infants. On the negative side for late cord clamping, babies in the early clamping group were less likely to require phototherapy for jaundice (RR: 0.62, 95% CI: 0.41 to 0.96, 7 trials, 2324 infants). Unlike many of the outcomes of interest to the reviewers, birthweight was reported across a large proportion of the studies. The mean weight of babies was found to be significantly higher in the late cord clamping group (MD: 101 g increase, 95% CI 45 to 157, 12 trials, 3139 infants) but with high statistical heterogeneity (I2: 62%).

The authors write that a more liberal approach to delaying clamping of the umbilical cord in healthy term infants appears to be warranted, particularly in light of the growing evidence that delayed cord clamping increases early haemoglobin concentrations and iron stores in infants. They conclude that delayed cord clamping is likely to be beneficial, as long as access to treatment for jaundice requiring phototherapy is available.

Soure: Cochrane Library

Effect on Postpartum Hemorrhage of Prophylactic Oxytocin (10 IU) by Injection by Community Health Officers in Ghana: A Community-Based, Cluster-Randomized Trial.

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Background

Oxytocin (10 IU) is the drug of choice for prevention of postpartum hemorrhage (PPH). Its use has generally been restricted to medically trained staff in health facilities. We assessed the effectiveness, safety, and feasibility of PPH prevention using oxytocin injected by peripheral health care providers without midwifery skills at home births.

Methods and Findings

This community-based, cluster-randomized trial was conducted in four rural districts in Ghana. We randomly allocated 54 community health officers (stratified on district and catchment area distance to a health facility: ≥10 km versus <10 km) to intervention (one injection of oxytocin [10 IU] one minute after birth) and control (no provision of prophylactic oxytocin) arms. Births attended by a community health officer constituted a cluster. Our primary outcome was PPH, using multiple definitions; (PPH-1) blood loss ≥500 mL; (PPH-2) PPH-1 plus women who received early treatment for PPH; and (PPH-3) PPH-2 plus any other women referred to hospital for postpartum bleeding. Unsafe practice is defined as oxytocin use before delivery of the baby. We enrolled 689 and 897 women, respectively, into oxytocin and control arms of the trial from April 2011 to November 2012. In oxytocin and control arms, respectively, PPH-1 rates were 2.6% versus 5.5% (RR: 0.49; 95% CI: 0.27–0.88); PPH-2 rates were 3.8% versus 10.8% (RR: 0.35; 95% CI: 0.18–0.63), and PPH-3 rates were similar to those of PPH-2. Compared to women in control clusters, those in the intervention clusters lost 45.1 mL (17.7–72.6) less blood. There were no cases of oxytocin use before delivery of the baby and no major adverse events requiring notification of the institutional review boards. Limitations include an unblinded trial and imbalanced numbers of participants, favoring controls.

Conclusion

Maternal health care planners can consider adapting this model to extend the use of oxytocin into peripheral settings including, in some contexts, home births.

Discussion

This community-based, cluster-randomized trial of prophylactic oxytocin (10 IU) administered via Uniject by peripheral health care providers without midwifery skills showed statistically significant reductions of 51% in the risk of PPH for blood loss ≥500 mL and 66% for blood loss ≥500 mL or with gushing and large blood clots. Results for severe PPH (≥1,000 mL) were not statistically significant. All secondary outcomes suggested the intervention was safe.

The magnitude of protective effect for blood loss ≥500 mL in this trial is similar to results shown for community-based prophylactic misoprostol (600 mcg) versus placebo in rural India (47% reduction in PPH) [10] and to a meta-analysis of health facility–based prophylactic use of intramuscular and intravenous oxytocin versus no uterotonics in high-income countries (50% reduction in PPH defined as ≥500 mL blood loss; 95% CI: 0·43–0·59) [9]. PPH reduction in this study was greater than trial results shown for prophylactic misoprostol (600 mcg) versus placebo in rural Pakistan (24% reduction in PPH) and in Guinea Bissau (11% non-significant reduction in PPH) . Mean blood loss among both oxytocin and control women in this trial was lower than that reported in these community-based misoprostol trials. Our results show mean blood loss of 185.5 mL and 229.2 mL among oxytocin and control deliveries, respectively, as compared to results from India (214.3 mL versus 262.3 mL), Pakistan (337 mL versus 366 mL), and Guinea Bissau (443 mL versus 496 mL) . Lower blood loss in this trial is expected, as early treatment of PPH with an additional injection of oxytocin (10 IU) in both our trial arms likely reduced ultimate blood loss among all PPH cases.

Several limitations of this study warrant discussion. The ratios of numbers of women in oxytocin and control arms of the trial range from 0.68 at the identification of eligible pregnancies to 0.77 at enrollment. Prior to randomization, CHO catchment areas were stratified by distance to emergency obstetric care, but not by population size, as these data were only available for Kintampo North and South. In these two districts, the ratio of population in the oxytocin versus control catchment areas is 0.88, explaining some, but not all, of the imbalance. As shown inTable 2, fertility between study arms is similar. There was no evidence that field workers in the oxytocin arm systematically missed identifying more pregnant women than in the control arm. However, if they did, it is unlikely that these women would have substantially different characteristics than the homogenous group that provided initial consent for the study (and which represented 99% of all identified pregnancies in both groups).

Two CHO behaviors differed by arm of the trial. First, control CHOs initiated blood-loss measurement (i.e., unfolded the drape) on average one minute later than oxytocin CHOs following delivery, possibly leading to an underestimate of blood loss in the control group. However, if delayed unfolding of the drape by control CHOs reduced blood loss measures, it would underestimate impact of oxytocin on outcomes. Second, CHOs in the oxytocin group referred women prior to delivery more frequently (17.3%) than control CHOs (12.5%), possibly indicating that the analyzable sample in the oxytocin group excluded a larger pool of women having a difficult delivery and thus potentially at higher risk of PPH. Data extracted from hospital records for referred women did not, however, indicate a higher risk (6 PPH cases among 198 referred women in the oxytocin group = 3.0%).

In an un-blinded study, differential measurement errors across arms of the trial are possible and thus, lack of blinding constitutes a study limitation. However, in this study the intervention was provided by CHOs who were not birth attendants. They were not responsible for managing the births nor were they responsible for the birth outcome, two issues which we believe would decrease the chances that they influenced the study outcome. The CHO’s job was to respond to the call, to give (or not give) the injection and measure blood. They had no previous experience with birth, or visual blood loss estimation and possible associations with bad maternal outcomes.

This trial provides evidence that administration of intramuscular prophylactic oxytocin in Uniject by peripheral health care providers without midwifery skills can effectively decrease the risk of PPH at home births under research conditions. Furthermore, none of the secondary outcomes reflecting safety suggested that this intervention was unsafe. Across trial arms, service was successfully provided to three-quarters of all calls requesting CHO assistance. However, CHO compliance varied widely, and was likely due to CHOs working alone in their catchment area per trial protocol; that is, they were on call 24 hours per day for 19 months. In a scaled-up program, additional staffing or the ability to refer calls to a neighboring CHO would be required to increase and sustain CHO compliance. There is no evidence that the intervention decreased health facility–based births. However, 17% of pregnant women (n = 5919) chose to deliver at home without a CHO and research is needed to understand the barriers to reaching these women. Another concern was the frequent lack of compliance with free referral to hospital for PPH cases. Refusal of referrals was unexpected and underscores the importance of providing community-based early treatment to women reluctant to seek care outside the home.

Cost is an important component of intervention feasibility. Oxytocin in Uniject is currently commercially available only in a few Latin American countries and thus its eventual market-driven cost is unknown. The United Nations Commission on Life-Saving Commodities for Women and Children includes oxytocin among 13 medicines unavailable to women due to issues such as cost or supply because they are not subsidized by global bulk purchase agreements or advance market commitments. The Commission has developed specific recommendations to address these issues as well as to promote oxytocin in a Uniject-type device [24]. It is anticipated that oxytocin in Uniject will cost US$1.00 or less, and potentially substantially less once sustained demand is established. The oxytocin in Unijects used in this study, were purchased on a non-commercial basis at a cost of $1.40 per dose. A commercial price for the product, should sustainable demand emerge, could be lower as economies of scale play a significant role in the cost of producing pharmaceutical products.

These results also raise additional questions. For example, if oxytocin in Uniject is not an option, could providers entrusted to vaccinate children and provide other injections use a traditional syringe and ampoule for oxytocin administration? The skills required are the same as are issues regarding needle disposal. As a cost-saving measure, could a time/temperature indicator be placed on a flat of oxytocin ampoules (versus individual ampoules), since ampoules within a flat are generally exposed to the same environmental conditions? This issue is mentioned in the UN Commission on Life-Saving Commodities for Women and Children and will likely be determined by the willingness of pharmaceutical companies to allow it. Regarding the duration that oxytocin can remain out of the cold chain in hot climates, additional analyses from this trial are currently underway to assess the number of days that oxytocin can remain out of the cold chain under field conditions in central Ghana prior to indication by the time/temperature indicator that the device should be discarded. Such information will serve health care planners in determining the required resupply schedule and the feasibility of this schedule locally. Could a lay provider safely and effectively use oxytocin in Uniject? (A randomized trial assessing use of oxytocin in Uniject by traditional birth attendants to prevent PPH is underway in Senegal now; clinicaltrials.gov: NCT01713153.) Is the BRASSS-V calibrated plastic drape used here necessary or could a simplified drape that indicates only when treatment and referral are needed (versus a quantitative blood loss measure), or other PPH detection pads suffice? This choice will be determined by the objectives of local health planners and the ability to easily obtain or import supplies. In Ghana, local manufacture of the blood loss measurement drape is considered a priority for scaled-up use.

While the move towards use of skilled birth attendants is gathering global momentum, poverty and inequity—particularly in selected areas in countries—will remain issues for the foreseeable future. Prophylactic use of uterotonics to prevent PPH, the biggest killer of women during childbirth, is a key intervention and use of oxytocin as the drug of choice should be considered where its use is feasible. It is unhelpful to pose this issue as oxytocin versus misoprostol. The more appropriate question is: Where and under what circumstances can each of these proven effective drugs be used? Ultimately, decisions regarding the balance of advantages and disadvantages of using oxytocin or misoprostol for PPH prevention at home births will depend on local conditions, human resources, infrastructure, and national policies.

Source:PLOS

Reducing trauma deaths in the UK.

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Traumatic haemorrhage is a leading cause of death in young adults in the UK.1 The CRASH-2 trial showed that the early administration of tranexamic acid safely reduces mortality in bleeding trauma patients.2 Further study demonstrated that the treatment is widely practicable and cost effective.3

RoadPeace—the UK national charity for road crash victims—represented trauma victims on the CRASH-2 trial steering committee, and we are now committed to ensuring that victims benefit from this life-saving treatment. To assess whether bleeding trauma patients in the UK are treated with tranexamic acid, we sent freedom of information requests to 291 UK hospitals in September, 2012, which asked the following questions: does your hospital’s trauma protocol include administration of tranexamic acid to bleeding trauma patients; and in 2011, how many acute trauma patients received a blood transfusion and, of those, how many were treated with tranexamic acid?

209 (72%) of the 291 hospitals responded. Of these 209 hospitals, 11 stated that they did not treat trauma patients and 19 failed to answer the question about trauma protocols. Of the 179 remaining hospitals, 159 (89%) include tranexamic acid in their trauma protocols. The second question aimed to assess whether bleeding trauma patients received tranexamic acid. Most hospitals did not answer this question (citing the pertinent Freedom of Information Act 2000 clause) on the basis that it would be too costly to obtain the data. 34 hospitals reported the number of trauma patients that received a blood transfusion and the number given tranexamic acid. Of 451 trauma patients transfused at these 34 hospitals, 34 (8%) received tranexamic acid. Four of these 34 hospitals were major trauma centres. Of 285 trauma patients transfused at these four major trauma centres, 13 (5%) received tranexamic acid.

Although tranexamic acid is included in most hospital trauma protocols, our data show that few bleeding trauma patients were given this treatment in 2011. Patients with trauma severe enough to require blood transfusion would be expected to benefit from tranexamic acid, and we are concerned that patients were denied this life-saving treatment. One explanation for the low use is that tranexamic acid might not have been incorporated into trauma protocols for the full duration of 2011. Since most hospitals now include tranexamic acid in their trauma protocols, more recent figures might be higher.

We will repeat this survey in 2013 to assess progress. We are optimistic that use will improve because of recent and rapid policy responses—notably, the aforementioned trauma protocol coverage, the Trauma Promise, and the NHS move to include tranexamic acid administration in its 2013—14 best practice tariff for major trauma centres.4, 5 To support these efforts, we recommend that tranexamic acid be included in trauma audit at all UK accident and emergency hospitals and that hospitals regularly publish data on the proportion of trauma patients that are appropriately given the treatment. We urge all UK hospitals to reaffirm their commitment to providing effective trauma care by making the Trauma Promise.

Source: Lancet

 

Oral Apixaban for the Treatment of Acute Venous Thromboembolism.

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BACKGROUND

Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism.

METHODS

In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding.

RESULTS

The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], −0.4 percentage points; 95% CI, −1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups.

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CONCLUSIONS

A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding

Source: NEJM

 

 

 

 

Clopidogrel Is Safe Before Hip Fracture Surgery.

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In an observational study, clopidogrel did not confer risk for serious perioperative bleeding.

In general, surgery should be done promptly after hip fracture. However, when the patient has been taking clopidogrel (Plavix), the surgeon might be concerned about excessive perioperative bleeding. In fact, the following statement appears in the official prescribing information for clopidogrel: “If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue Plavix five days prior to surgery.”

In this retrospective cohort study from Mayo Clinic, investigators identified 40 hip-fracture patients who were taking clopidogrel at admission and who underwent surgery within 36 hours. Cases were compared with 80 controls (matched for age, sex, and several other clinical variables) who also underwent prompt surgery for hip fractures and who had not been taking clopidogrel. Two major bleeding events occurred in the clopidogrel group, and three occurred among controls (a nonsignificant difference). The incidence of a broader combined bleeding outcome (encompassing major bleeding events, need for transfusions, and fall in hemoglobin level) also was similar in the two groups.

Comment: This study suggests that clopidogrel is not associated with substantial excess risk for serious bleeding in patients who undergo hip fracture surgery. Whether surgeons had more technical difficulty in controlling intraoperative bleeding in clopidogrel recipients than in controls was not addressed in this report.

 

Source: Journal Watch General Medicine

 

 

Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism.

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Dabigatran, which is administered in a fixed dose and does not require laboratory monitoring, may be suitable for extended treatment of venous thromboembolism. Methods In two double-blind, randomized trials, we compared dabigatran at a dose of 150 mg twice daily with warfarin (active-control study) or with placebo (placebo-control study) in patients with venous thromboembolism who had completed at least 3 initial months of therapy. Results In the active-control study, recurrent venous thromboembolism occurred in 26 of 1430 patients in the dabigatran group (1.8%) and 18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44; 95% confidence interval [CI], 0.78 to 2.64; P=0.01 for noninferiority). Major bleeding occurred in 13 patients in the dabigatran group (0.9%) and 25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54; 95% CI, 0.41 to 0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P=0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; 95% CI, 0.02 to 0.25; P<0.001). Major bleeding occurred in 2 patients in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (hazard ratio, 2.92; 95% CI, 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups. Conclusions Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo.

Source:NEJM