2 Minute Medicine Rewind February 26, 2018

Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty

Many studies have suggested that aspirin may be effective in the prevention of venous thromboembolism (VTE) after total hip or total knee arthroplasty. However, few randomized controlled trials comparing aspirin with direct oral anticoagulants are available. In this multicenter, double-blind, randomized, controlled trial, 3424 patients received once-daily oral rivaroxaban (10 mg) until postoperative day 5 and were then randomly assigned to continue rivaroxaban or switch to aspirin (81 mg daily) for an additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty. Patients were followed up for 90 days for symptomatic VTE as the primary outcome, and bleeding complications as the primary safety outcome. Researchers found no significant between group difference in VTE incidence, with 11 of 1707 patients (0.64%) in the aspirin group and 12 of 1717 patients (0.70%) in the rivaroxaban group affected (difference 0.06%, 95% Cl -0.55% to 0.66%, p<0.001 for non-inferiority, p=0.84 for superiority). There was also no significant between group difference in terms of major bleeding complications (difference 0.18%, 95% Cl -0.65% to 0.29%, p=0.42). Researchers therefore concluded that in patients who received 5 days of rivaroxaban prophylaxis after total hip or total knee arthroplasty, extended prophylaxis with aspirin was not significantly different from rivaroxaban in the prevention of symptomatic VTE.

Human Neonatal Rotavirus Vaccine (RV3-BB) to Target Rotavirus from Birth

There is widespread evidence that rotavirus vaccines are very effective in the prevention of related gastroenteritis. However, more than 90 million infants around the world still lack access to the rotavirus vaccine. Barriers to global implementation include cost, suboptimal efficacy in low-income countries, and lingering safety concerns. An oral rotavirus vaccine administered early, at birth, has the potential to address some of these challenges. In this randomized, double-blind, placebo-controlled trial, 1513 healthy newborns in Indonesia were randomized to receive 3 doses of an oral human neonatal rotavirus vaccine (RV3-BB) administered according to a neonatal schedule (0 to 5 days, 8 weeks, and 14 weeks of age), infant schedule (8 weeks, 14 weeks, and 18 weeks of age) or placebo, to study the efficacy of RV3-BB against severe rotavirus gastroenteritis up to 18 months of age. Researchers found that severe rotavirus gastroenteritis occurred in 5.6% of the participants in the placebo group, in 1.4% of participants in the neonatal-schedule vaccine group, and in 2.7% of participants in the infant-schedule vaccine group. Based on an intention-to-treat analysis, this resulted in a vaccine efficacy of 68% (95% Cl 35% to 86%, p=0.001) in the neonatal-schedule group, 52% (95% CI 11% to 76%, p=0.02in the infant-schedule group, and 60% (95% CI 31% to 76%, p<0.001) in the neonatal-schedule and infant-schedule groups combined. Vaccine response, as evidenced by serum immune response or shedding of RV3-BB in the stool, occurred in 94% of participants in the neonatal-schedule group and in 99% of participants in the infant-schedule group. The incidence of adverse events was similar across the groups. No episodes of intussusception occurred within the 21-day risk period after administration of any dose of vaccine or placebo, and one episode of intussusception occurred 114 days after the third dose of vaccine in the infant-schedule group. Researchers therefore concluded that RV3-BB was efficacious in preventing severe rotavirus gastroenteritis when administered according to a neonatal or an infant schedule in Indonesia.

Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium: The REDUCE Randomized Clinical Trial 

Results of studies on the use of prophylactic haloperidol in critically-ill adults are inconclusive, especially in patients at high risk of delirium. In this randomized, double-blind, placebo-controlled study, 1789 critically-ill adults were randomized to receive either 1 mg haloperidol (n = 350), 2 mg haloperidol (n = 732) or placebo (n = 707) to determine whether prophylactic haloperidol improves survival among critically-ill adults at high risk of delirium. Patients were identified at high risk if they had an anticipated intensive care unit (ICU) stay of at least 2 days. The 1 mg haloperidol group was prematurely stopped because of futility. In addition, there was no difference in the median days patients survived in the 28 days of follow-up in the 2 mg haloperidol group versus the placebo group (HR 1.003, 95% CI 0.78 to 1.30, p=0.82). The number of reported adverse effects also did not differ between groups. This study therefore shows that among critically-ill adults at high risk of delirium, the use of prophylactic haloperidol does not improve survival at 28 days when compared to placebo. These findings do not support the use of prophylactic haloperidol for reducing mortality in critically-ill adults.

Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association With Genotype Pattern or Insulin Secretion: The DIETFITS Randomized Clinical Trial

While it has been well established that dietary modification is key in successful weight loss, no one dietary strategy has emerged as being consistently superior to others for the general population. Previous research suggests that genotype or insulin-glucose dynamics may modify the effects of diets. In this randomized controlled trial, 609 individuals age 18 to 50 years with a body mass index between 28 and 40 were randomized to a 12-month healthy low-fat (HLF) diet or a healthy low-carbohydrate (HLC) diet to study the effect of these diets on weight change, and whether genotype pattern or insulin secretion are related to dietary effects on weight loss. Researchers found that the mean weight change between groups at 12 months was not statistically different at 0.7 kg (95% Cl -0.2 kg to 1.6 kg).  In addition, there was no significant diet-genotype pattern interaction (p = 0.20) or diet-insulin secretion (INS-30) interaction (p = 0.47) with 12-month weight loss. This study therefore shows that there was no significant difference in weight change between a healthy low-fat diet versus a healthy low-carbohydrate diet, and neither genotype pattern nor baseline insulin secretion was associated with the dietary effects.

Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Systemic adjuvant treatment may mitigate the high risk of disease recurrence in patients with resected stage IIC–III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma. In this phase 3, international, double-blind, randomized, placebo-controlled study, 498 adults with histologically-confirmed stage IIC–IIIA–IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected, were randomized to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks. The primary endpoint was disease-free survival, evaluated separately in each cohort. In cohort 2, the median disease-free survival was 23.1 months (95% CI 18.6 months to 26.5 months, p=0.05) in the vemurafenib group versus 15.4 months (95% Cl 11.1 months to 35.9 months, p=0.05) in the placebo group (HR 0.80, 95% CI 0.54 to 1.18, p=0.026). In cohort 1, median disease-free survival in the vemurafenib group was improved compared to the placebo group (HR 0.54, 95% CI 0.37 to 0.78, p=0.0010), although this result was not significant due to the prespecified hierarchical prerequisite for the primary disease-free survival of cohort 2 to show a significant disease-free survival benefit. This study therefore shows that while the primary disease-free survival endpoint in patients with stage IIIC disease was not met, patients with resected vemurafenib therapy may improve disease-free survival in patients with stage IIC–IIIA–IIIB BRAFV600 mutation-positive melanoma.

Image: PD

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