Trial Files: Top 5 RCTs for 2024
Check out this week’s episode of The Rounds Table Podcast for a deeper dive into this year’s top 5 RCTs.
Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes (FLOW)
Perkovic V et al. NEJM (May 2024)
Bottom Line: This randomized controlled trial, with a median follow-up of 3.4 years, evaluated the efficacy and safety of subcutaneous semaglutide at a dose of 1.0 mg weekly in patients with type 2 diabetes and chronic kidney disease. The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. The results showed a 24% lower risk in the semaglutide group compared to the placebo group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; P=0.0003). Secondary outcomes, including the mean annual eGFR slope, risk of major cardiovascular events, and risk of death from any cause, also favoured semaglutide. Serious adverse events were reported in a lower percentage of participants in the semaglutide group. In conclusion, semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in this patient population.
Antibiotic Treatment for 7 versus 14 Days in Patients with Bloodstream Infections (BALANCE)
The BALANCE Investigators. NEJM (November 2024)
Bottom Line: This multicenter, noninferiority trial included 3608 hospitalized patients with bloodstream infection who were randomly assigned to receive either 7 or 14 days of antibiotic treatment. Antibiotic selection, dosing, and route were at the discretion of the treating team. The primary outcome was death from any cause by 90 days after diagnosis, with a noninferiority margin of 4 percentage points. The results showed that 14.5% of patients receiving 7-day treatment died by 90 days, compared to 16.1% of patients receiving 14-day treatment (difference, −1.6 percentage points [95.7% confidence interval {CI}, −4.0 to 0.8]), demonstrating noninferiority of the shorter treatment duration. The study also found that patients were treated for longer than the assigned duration in 23.1% of the 7-day group and 10.7% of the 14-day group. These findings were consistent across secondary clinical outcomes and subgroups defined according to patient, pathogen, and syndrome characteristics. The conclusion is that 7-day antibiotic treatment is noninferior to 14-day treatment for hospitalized patients with bloodstream infection.
Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (FINEARTS-HF)
Solomon S et al. NEJM (September 2024)
Bottom Line: This international, double-blind trial evaluated the efficacy and safety of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in patients with heart failure and mildly reduced or preserved ejection fraction of 40% or greater. A total of 6001 patients were randomly assigned to receive either finerenone (at a maximum dose of 20 mg or 40 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes over a median follow-up of 32 months. There were 1083 primary outcome events in 624 patients in the finerenone group, compared to 1283 events in 719 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P=0.007). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia. In conclusion, compared to placebo, finerenone showed a significant reduction in total worsening heart failure events and death from cardiovascular causes in patients with heart failure and mildly reduced or preserved ejection fraction.
Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis with Liver Fibrosis (SYNERGY-NASH)
Loomba R et al. NEJM (June 2024)
Bottom line: This phase 2, double-blind, randomized, placebo-controlled trial evaluated the efficacy and safety of tirzepatide in 190 patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and moderate or severe fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary outcome was resolution of MASH without worsening of fibrosis at 52 weeks. Criteria for resolution of MASH was met in 10% of the placebo group, 44% in the 5 mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10 mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15 mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The most common adverse events were mild or moderate gastrointestinal events. Overall, tirzepatide showed significant improvement in resolution of MASH without worsening of fibrosis compared to placebo, though larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH.
Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity (SURMOUNT-OSA)
Malhotra A et al. NEJM (June 2024)
Bottom line: This pair of phase 3, double-blind, randomized, controlled trials evaluated the efficacy and safety of tirzepatide in adults with moderate-to-severe obstructive sleep apnea and obesity. Patients who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, while those receiving PAP therapy at baseline were enrolled in trial 2. Participants were assigned to receive either tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary outcome was the change in the apnea-hypopnea index (AHI, which is the number of apneas and hypopneas during an hour of sleep) from baseline. In both trials, significant improvements were observed in the tirzepatide group compared to placebo. There was an estimated treatment difference of −20.0 events per hour with tirzepatide in trial 1 (95% CI, −25.8 to −14.2) (P<0.001) and −23.8 events per hour with trial 2 (95% CI, −29.6 to −17.9) (P<0.001). Tirzepatide also showed significant improvements in body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure. The most common adverse events were gastrointestinal in nature and mostly mild to moderate in severity.
Trial Files Issue #2024-25
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