The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher.

BACKGROUND Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications. METHODS This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. FINDINGS Between March 12, 2013, and May 10, 2016, we ; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043). INTERPRETATION Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding. FUNDING Bayer AG. Methods This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, i...

No abstract

No abstract

Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Background The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear. Methods We randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed. Results A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P=0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group. Conclusions Among patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114 .)

No abstract

No abstract