Cardiology Trials

Epizode

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  Summary and discussion of EAST-AFNET 4 28.07.2026 1h

  For full review of the trial, please visit https://cardiologytrials.substack.com/ Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe
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  Summary and discussion of ANDROMEDA, ATHENA and PALLAS 16.07.2026 31min

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• 
  Summary and discussion of SAFE-T and RACE II 23.06.2026 41min

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• 
  Summary and discussion of AFFIRM and RACE 03.06.2026 44min

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• 
  Special episode (ACC 2026: CHAMPION-AF, HI-PEITHO) 06.04.2026 52min

  This is the article John referenced that discusses Watchman https://www.heartrhythmjournal.com/article/S1547-5271(17)31200-6/abstract Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe
• 
  Summary and discussion of VICTORIA and VICTOR 16.03.2026 34min

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• 
  Summary and discussion of DAPA-HF and EMPEROR-Reduced 10.02.2026 38min

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• 
  Special episode (AHA 2025: OCEAN, ADAPT AF-DES) 29.12.2025 47min

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• 
  Special episode (AHA 2025: VESALIUS-CV, DECAF) 08.12.2025 40min

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• 
  Summary and discussion of PARADIGM-HF and PIONEER-HF 20.11.2025 35min

  For full review of the trials, please visit https://cardiologytrials.substack.com/ Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe
• 
  Special episode (ESC 2025: AQUATIC, VICTOR) 25.09.2025 50min

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• 
  Special episode (ESC 2025: REBOOT-CNIC, BETAMI-DANBLOCK, DIGIT-HF) 09.09.2025 41min

  Discussion of landmark trials presented at the European Society of Cardiology (ESC) congress 2025 Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe
• 
  Summary and discussion of BEST and SENIORS 15.08.2025 31min

  For full review of the trials, please visit https://cardiologytrials.substack.com/ Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe
• 
  Review of the A-HeFT trial 01.07.2025 9min

  N Engl J Med 2004;351:2049-2057Background: Endothelial dysfunction, reduced nitric oxide availability, and increased oxidative stress occur in patients with heart failure and contribute to cardiac remodeling. In the V-HeFT I trial, combining isosorbide dinitrate (a nitric oxide donor) with hydralazine (an antioxidant) improved outcomes in patients with systolic heart failure. However, its long-term effectiveness in patients already receiving neurohormonal blockade was unclear.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Racial differences exist in heart failure prevalence, mechanisms, and outcomes. Patients who identify as Black may have a less active renin–angiotensin system and lower nitric oxide availability. Prior analyses suggested that Black patients respond well to isosorbide dinitrate + hydralazine and respond less to Angiotensin Converting Enzyme Inhibitors (ACEi). For example, in a subgroup analysis of the V-HeFT I trial, isosorbide dinitrate + hydralazine reduced mortality in Black but not White patients.The African-American Heart Failure Trial (A-HeFT) sought to assess the efficacy of isosorbide dinitrate + hydralazine in Black patients with systolic heart failure.Patients: Patients were eligible if they self-identified as Black (defined as African decent), and had NYHA class III or IV heart failure for at least 3 months. The left ventricular ejection fraction had to be 35% or less or less than 45% if the ventricle was dilated. In addition, patients had to be on guideline medical therapy for at least 3 months.Patients were excluded if they had acute coronary syndrome or stroke within 3 months, cardiac surgery or percutaneous coronary intervention within 3 months, significant valvular disease, hypertrophic or restrictive cardiomyopathy plus many others.Baseline characteristics: Patients were recruited from 161 centers in the United States. The trial randomized 1,050 patients – 518 randomized to receive isosorbide dinitrate + hydralazine and 532 to receive placebo.The average age of patients was 57 years and 60% were men. The average left ventricular ejection fraction was 24% and the average left ventricular internal diastolic diameter was 6.5 cm. The cause of cardiomyopathy was ischemic in 23% of the patients, hypertensive in 39%, idiopathic in 26%, and other causes constituted the rest. The NYHA class was III in 96% of the patients. The average systolic blood pressure was 126 mm Hg.Approximately 40% had diabetes, 17% had chronic kidney disease and 17% had atrial fibrillation.At the time of enrollment, 90% were taking a diuretic, 69% were taking an ACEi, 17% were taking an angiotensin receptor blocker, 74% were taking a beta-blocker, 39% were taking spironolactone and 60% were taking digoxin.Procedures: The trial was double-blinded. Patients were randomized in a 1:1 ratio to receive fixed-dose combination of isosorbide dinitrate + hydralazine or to receive placebo. The initial dose was one tablet taken three times daily, containing either placebo or a combination of 37.5 mg of hydralazine and 20 mg of isosorbide dinitrate. If no side effects, the dose was increased to two tablets three times a day.Patients had follow up by phone every month and clinic visits every 3 months.Endpoints: The primary endpoint was a composite of weighted values of all-cause mortality, first hospitalization for heart failure within 18 months, and change in quality of life at 6 months. Quality of life was assessed using the Minnesota Living with Heart Failure Questionnaire, a 21-question self-administered questionnaire in which scores range from 0 to 5, with higher scores reflecting worse quality of life.The table below summarizes how the weighted score for the primary outcome was calculated.Analysis was performed based on the intention to treat principle. The main manuscript did not mention the estimated number of events for sample size calculation but did mention that 1,100 patients would provide sufficient power with a p
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  Review of the CHARM-Alternative trial 24.06.2025 10min

  THE LANCET 2003;362:772-776Background: Angiotensin converting enzyme inhibitors (ACEi) reduce mortality and morbidity in patients with systolic heart failure (see CONSENSUS and SOLVD trials). However, registry data showed that up to 20% of patients with systolic heart failure were not taking ACEi. One of the frequent causes for intolerance to ACEi is cough. Angiotensin converting enzyme inhibitors work by blocking the conversion of angiotensin I to angiotensin II, a key step in the renin–angiotensin–aldosterone system (RAAS). Angiotensin II receptor blockers were tolerated in patients with systolic heart failure who were intolerant to ACEi. However, data on long term effectives as an alternative to ACEi were lacking.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Alternative trial sough to assess if the angiotensin-receptor blocker (ARB) candesartan, could improve outcomes in patients with systolic heart failure who are intolerant to ACEi.Patients: Eligible patients had left ventricular ejection fraction of 40% or less and NYHA class II, III or IV symptoms of at least 4 weeks duration. Patients had also to be intolerant to ACEi.Exclusion criteria were not provided in the main manuscript.Baseline characteristics: Patients were recruited from 618 centers in 26 countries. The trial randomized 2,028 patients – 1,013 randomized to receive candesartan and 1,015 to receive placebo.The average age of patients was 67 years and 68% were men. The average left ventricular ejection fraction was 30%. Cardiomyopathy was ischemic in 68% of the patients. The NYHA class was II in 48% of the patients, III in 49% and IV in 4%.Approximately 50% had hypertension, 27% had diabetes, 61% had prior myocardial infarction, 9% had stroke, 25% had atrial fibrillation and 14% were current smokers.At the time of enrollment, 85% were taking a diuretic, 46% were taking digoxin, 55% were taking beta-blockers and 24% were taking spironolactone.The most common reasons for ACEi intolerance were cough in 72% of the patients, hypotension in 13%, renal dysfunction in 12% and angioedema or anaphylaxis in 4%.Procedures: The trial was double-blinded. Patients were assigned in a 1:1 ratio to receive candesartan starting at 4 or 8mg once daily or placebo. The treatment was doubled every two weeks to a target dose of 32mg once daily.After randomization, follow up occurred at 2, 4, and 6 weeks, 6 months and every 4 months thereafter.Endpoints: The primary outcome was a composite of cardiovascular death or heart failure hospitalizations. All deaths were classified as cardiovascular unless there was a clear non-cardiac cause.Analysis was performed based on the intention-to-treat principle. The estimated sample size to have 80% power at 5% alpha was 2,000 patients. The sample size calculation assumed 18% relative risk reduction in the primary outcome with candesartan assuming a 15% annual event rate in the placebo arm.Results: The median follow up time was 34 months. The mean candesartan daily dose was 23mg at 6 months.Candesartan reduced the primary endpoint of cardiovascular death or heart failure hospitalizations (33.0% vs 40.0%, adjusted HR: 0.70, 95% CI: 0.60 – 0.81; p< 0.001). Candesartan reduced the individual components of the primary outcome - (21.6% vs 24.8%; p= 0.02) for cardiovascular death and (20.4% vs 28.2%; p< 0.001) for heart failure hospitalizations. All-cause death was also lower with candesartan (26.2% vs 29.2%, adjusted HR: 0.83, 95% CI: 0.70–0.99; p= 0.033). The number of patients who had any hospitalization as well as the total number of hospitalizations were numerically but not statistically significantly lower with candesartan (60.2% with candesartan vs 63.3%; p= 0.16) and (1,718 vs 1,835; p= 0.06).Candesartan was associated with more hypotension (3.7% vs 0.9%), more increase in creatinine (6.1% vs 2.7%) and more hyperkalemia (1.9% vs 0.3%). Angioedema occurred in three patients in the candesartan group and none in the placebo group. Cough occurred in two patients taking candesartan and four taking placebo.Authors reported no significant subgroup interactions, however, a corresponding graph was not provided.Conclusion: In patients with systolic heart failure who are intolerant to ACEi, candesartan reduced the primary composite outcome of cardiovascular death or heart failure hospitalizations with a number needed to treat of approximately of 14 patients over 34 months of follow up. Candesartan also reduced all-cause death with a number needed to treat of approximately 33 patients. Adverse events including hypotension, increase in creatinine and hyperkalemia were more common with candesartan.The reduction in the primary endpoint with candesartan was significant and offers an alternative for patients who are unable to tolerate ACEi. Of note, 72% of the patients enrolled in the trial were intolerant to ACEi due to cough. This trial did not include a head-to-head comparison between ARBs and ACEi, and therefore does not address which agent should be preferred as first-line therapy. Only 24% of participants were receiving spironolactone. The combination of ARBs with spironolactone, may increase the risk of adverse events, particularly hyperkalemia and kidney injury.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe
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  Summary and discussion of Carvedilol Prospective Randomized Cumulative Survival Study, Val-HeFT, CHARM-Added and CIBIS-II 19.06.2025 57min

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• 
  Review of the CIBIS-II Trial 17.06.2025 5min

  The Lancet Volume 353, Issue 9146 p9-13 January 02, 1999Background: Accumulating data at the time suggested functional benefits of antagonism of beta-adrenoreceptors in patients with heart failure. Multiple specific beta-blockers were being tested in trials. The CIBIS 1 trial found a trend towards 20% lower mortality in the bisoprolol (a highly cardio-selective beta-blocker) group and 30% fewer admissions to hospital for worsening heart failure. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) trial was designed to test this evidence further.Patients Eligible patients had New York Heart Association Class III-IV symptoms with LVEF ≤ 35% and were stable on diuretics and ACE-inhibitors. Exclusion criteria included recent MI or coronary intervention, AV block or resting heart rate less 60 bpm and systolic BP < 100 mmHg. Patients already on beta-blockers or with planned therapy with beta-blockers were also not enrolled.Cardiology Trial’s remains independent, free of industry ads, due to reader generosity. Please consider becoming a free or paid subscriber.Baseline Characteristics The mean age of patients was 61 years, 81% male, and 83% Class III. The mean LVEF was 28%. About half the patients had ischemic heart disease, 12% primary dilated cardiomyopathy and nearly 40% had a mixture of valvular heart disease, hypertensive heart disease or unproven ischemic disease.The mean SBP on enrollment was 130 mmHg and resting HR was 80 bpm. The mean duration of heart failure before enrollment was 3.5 years. About 20% had AF at baseline. Nearly all patients were on ACE-I and half were on digoxin.Trial Procedures There was no run-in period. CIBIS II was double blinded. Slightly more than 2,600 patients were randomized 1:1 to bisoprolol or placebo in 274 hospitals across 18 countries.Patients in the bisoprolol group were started at 1.25 mg daily and titrated up weekly to as high as 10 mg daily. The goal was to attempt the highest tolerated dose. Patients were seen every 3 months.Endpoints The primary endpoint was all-cause mortality. Secondary endpoints included all-cause hospital admissions, cardiovascular mortality, combined CV death and CV hospital admissions, and premature treatment withdrawals.The authors estimated a 11.2% mortality in the placebo group and powered the trial to find a 25% reduction in death in the bisoprolol arm over 2 years.Results The trial was sopped early (mean follow-up 1.3 years) after the planned second interim analysis for benefit. The primary outcome of all-cause death occurred in 11.8% in the bisoprolol group vs 17.3% in the placebo arm (HR 0.66 (95% CI 0.54-0.81, p < 0.0001)).Bisoprolol reduced sudden death (3.6% vs 6.3%), all-cause hospitalization (33% vs 39%), CV death (9% vs 12%). Permanent treatment withdrawal occurred in 15% of both arms.The subgroup analysis showed no substantial treatment heterogeneity. The most common dose was 10 mg daily reached in 43% of patients.Conclusion The 34% reduction in death was clinically meaningful and statistically robust. Our confidence in such a large effect size stems from a) previous data on beta-blockers, which found similar effects, b) the 42% reduction in sudden death in the bisoprolol arm and c) the large reductions in all-cause hospitalization. In addition, the trial conduct appeared strong with almost no lost-to-follow up. The lack of run-in period strengthens the external validity of CIBIS II.The same caveats seen in the US carvedilol trial also apply to CIBIS II, namely that patients were ambulatory, outpatients, mostly with Class III symptoms. Patients enrolled in the trial had a mean SBP of 130 mmHg and a resting heart rate of 80. Nearly all patients were tolerating ACE-I and half were taking digoxin. In addition, patients were started on low-dose and gradually titrated higher. The majority of patients were on higher than 5 mg daily.The authors warned against applying these results to non-ambulatory patients with Class IV symptoms, especially if there was recent instability. Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe
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  Review of the CHARM-Added trial 11.06.2025 10min

  THE LANCET 2003;362:767-771Background: Angiotensin II which plays a role in ventricular remodeling and progression of heart failure can be produced by pathways independent of angiotensin convening enzyme. Preliminary studies showed that the combination of angiotensin II blockers with angiotensin-converting enzyme inhibitors (ACEi) improves hemodynamics and reduces ventricular remodeling.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial sough to assess if adding the angiotensin-receptor blocker (ARB), candesartan, to ACEi could improve outcomes in patients with systolic heart failure.Patients: Eligible patients had left ventricular ejection fraction of 40% or less within the previous 6 months, and NYHA class II, III or IV symptoms. Patients with NYHA class II symptoms had to have cardiac-related hospitalization within 6 months. Patients also had to have treatment with ACEi at a constant dose for at least 30 days.Exclusion criteria were not provided in the main manuscript.Baseline characteristics: Patients were recruited from 618 centers in 26 countries. The trial randomized 2,548 patients – 1,276 randomized to receive candesartan and 1,272 to receive placebo.The average age of patients was 64 years and 79% were men. The average left ventricular ejection fraction was 28%. Cardiomyopathy was ischemic in 62% of the patients. The NYHA class was II in 24% of the patients, III in 73% and IV in 3%.Approximately 48% had hypertension, 30% had diabetes, 56% had prior myocardial infarction, 9% had stroke, 27% had atrial fibrillation and 17% were current smokers.At the time of enrollment, 90% were taking a diuretic, 58% were taking digoxin, 55% were taking beta-blockers, 17% were taking spironolactone and all but two patients were taking ACEi.Procedures: The trial was double-blinded. Patients were assigned in a 1:1 ratio to receive candesartan starting at 4 or 8mg once daily or placebo. The treatment was doubled every two weeks to a target dose of 32mg once daily.After randomization, follow up occurred at 2, 4, and 6 weeks, 6 months and every 4 months thereafter.Endpoints: The primary outcome was a composite of cardiovascular death or heart failure hospitalizations. All deaths were classified as cardiovascular unless there was a clear non-cardiac cause.Analysis was performed based on the intention-to-treat principle. The estimated sample size to have 80% power at 5% alpha was 2,300 patients. The sample size calculation assumed 16% relative risk reduction in the primary outcome with candesartan assuming an 18% annual event rate in the placebo arm.Results: The median follow up time was 41 months. The mean candesartan daily dose was 24mg at 6 months.Candesartan reduced the primary endpoint of cardiovascular death or heart failure hospitalizations (37.9% vs 42.3%, adjusted HR: 0.85, 95% CI: 0.75 – 0.96; p= 0.01). Candesartan reduced the individual components of the primary outcome - (23.7% vs 27.3%; p= 0.021) for cardiovascular death and (24.2% vs 28.0%; p= 0.018) for heart failure hospitalizations. There was no significant reduction in all-cause death (29.5% with candesartan vs 32.4%; p= 0.105). The number of patients who had any hospitalization was similar in both groups (66.8% with candesartan vs 67.5%; p= 0.7), however, the total number of hospitalizations was lower with candesartan (2,462 vs 2,798; p= 0.023).Serum creatinine at least doubled in 7% of the patients in the candesartan group vs 6% in the placebo group. In the subset of patients taking spironolactone, serum creatinine at least double in 11% of the patients taking candesartan compared to 4% of the patients taking placebo.Hyperkalemia, defined as serum potassium of 6 mmol/L or higher, occurred in 3% of the patients in the candesartan group vs 1% in the placebo group. In the subset of patients taking spironolactone, hyperkalemia occurred in 4% of the patients taking candesartan compared to 1% of the patients taking placebo.There were two cases of angioedema in the candesartan group and three in the placebo group. All patients were taking an ACEi.There were no significant subgroup interactions, including in patients taking both beta-blockers and ACEi at baseline.Conclusion: In patients with systolic heart failure, adding candesartan to an ACEi reduced the primary composite outcome of cardiovascular death or heart failure hospitalizations with a number needed to treat of approximately of 23 patients over 41 months of follow up. The total number of all-cause hospitalizations was reduced by 336 with candesartan. All-cause death was not significantly reduced with candesartan.While the results of the trial appear impressive, the high number of adverse outcomes with candesartan in patients taking spironolactone is concerning. Spironolactone led to significant reduction in all-cause mortality in patients with systolic heart failure, as seen in the RALES trial, and should be prioritized over adding candesartan. Notably, fewer than 20% of patients in the trial were on spironolactone at baseline; if more had been, the incremental benefit of candesartan would likely have been reduced due to an increased risk of adverse effects from triple neurohormonal blockade (ACEi, ARBs, and mineralocorticoid receptor antagonists). Furthermore, spironolactone acts by blocking the aldosterone receptor, which is downstream in the renin–angiotensin–aldosterone system. Since candesartan blocks angiotensin II upstream in the same pathway, simultaneous inhibition at multiple points may lead to diminishing benefit.Finally, the differences observed in the subgroup of patients on beta-blockers between this trial and Val-HeFT remain unclear and may simply reflect the play of chance. As we previously discussed, patients receiving both an ACEi and beta-blockers had worse outcomes with valsartan in the Val-HeFT trial.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe
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  Review of the Val-HeFT trial 06.06.2025 11min

  N Engl J Med 2001;345:1667-1675Background: Angiotensin II is a peptide hormone that is part of the renin–angiotensin–aldosterone system (RAAS). Angiotensin II is a potent vasoconstrictor and growth-stimulating hormone. Data suggested that it plays a role in ventricular remodeling and progression of heart failure. Although treatment with angiotensin-converting enzyme inhibitors (ACEi) reduce angiotensin II levels, physiologically active levels of angiotensin II may persist despite long-term therapy.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.The Valsartan Heart Failure Trial (Val-HeFT) sough to assess whether the angiotensin-receptor blocker valsartan, could reduce mortality and morbidity when added to optimal medical therapy in patients with systolic heart failure.Patients: Eligible patients had left ventricular ejection fraction less than 40% and left ventricular dilation, in addition to having clinical heart failure for at least 3 months with NYHA class II, III or IV symptoms. Patient also had to have been receiving a fixed-dose drug regimen for at least two weeks, that could include ACEi, diuretics, digoxin, and beta-blockers.There were many exclusion criteria. We mention some here: Postpartum cardiomyopathy, acute myocardial infarction within 3 months, coronary artery disease likely to require intervention, serum creatinine >2.5 mg/dL and life expectancy less than 5 years.Baseline characteristics: Patients were recruited from 302 centers in 16 countries. The trial randomized 5,010 patients – 2,511 randomized to receive valsartan and 2,499 to receive placebo.The average age of patients was 63 years and 80% were men. The average left ventricular ejection fraction was 27%. Cardiomyopathy was ischemic in 57% of the patients. The NYHA class was II in 62% of the patients, III in 36% of the patients and IV in 2%.Approximately 26% had diabetes and 12% had atrial fibrillation.At the time of enrollment, 86% were taking a diuretic, 67% were taking digoxin, 35% were taking beta-blockers, and 93% were taking ACEi.Procedures: The trial was double-blinded. The trial had an initial run-in period for 2 - 4 weeks where patients received placebo twice daily. This was performed to confirm patients’ eligibility, clinical stability and compliance.Patients were assigned in a 1:1 ratio to receive valsartan or placebo. Randomization was stratified according to whether or not they were receiving a beta-blocker.Valsartan was started at a dose of 40 mg twice a day, and the dose was doubled every two weeks to the target dose of 160 mg twice a day. Placebo doses were adjusted in a similar way.Follow up occurred at 2, 4, and 6 months and every 3 months thereafter.Endpoints: The trial had two primary end points. The first was all-cause mortality. The second was the combined end point of mortality and morbidity, which was defined as cardiac arrest with resuscitation, hospitalization for heart failure, or administration of intravenous inotropic or vasodilator drugs for four hours or more without hospitalization.The estimated sample size was 5,000 patients. The sample size calculation assumed 20% relative risk reduction in mortality with valsartan assuming 906 patients would die during the trial. This sample size would provide the trial 90% power at 0.02 alpha. Alpha was 0.02 instead of the traditional 0.05 since the trial had two primary endpoints and to adjust for the interim analyses.Results: The target valsartan dose of 160 mg twice a day was achieved in 84% of the patients. The reduction in systolic blood pressure was greater with valsartan vs placebo – mean of 5.2 ± 15.8 mm with valsartan compared to 1.2 ± 14.8 mm Hg with placebo, at 4 months.All-cause mortality was not different between both groups (19.7% with valsartan vs 19.4% with placebo, RR: 1.02, 95% CI: 0.88 – 1.18; p= 0.80). The second co-primary endpoint was reduced with valsartan (28.8% vs 32.1%, RR: 0.87, 95% CI: 0.77 – 0.97; p= 0.009). This was driven by reduction in hospitalizations for heart failure (13.8% vs 18.2%). Cardiac arrest with resuscitation was 0.6% with valsartan and 1.0% with placebo. All-cause hospitalization was numerically lower with valsartan, however, this was not statistically significance (2,856 vs 3,106; p= 0.14). The mean change in ejection fraction was higher with valsartan (4.0% vs 3.2%; p= 0.001). More patients had improvement in NYHA classification with valsartan (23.1% vs 20.7%; p
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  Review of the Carvedilol Prospective Randomized Cumulative Survival Study 04.06.2025 14min

  N Engl J Med 2001;344:1651-1658Background: The MERIT-HF trial demonstrated the efficacy of the selective beta blocker metoprolol CR/XL for well selected patients with chronic systolic heart failure who were on optimal therapy with an ACEi and diuretic. The trial randomized nearly 4,000 patients and was stopped early due to the benefit of the drug on all-cause mortality but it also reduced major morbidity as indicated by significant reductions in hospitalization. It represented the first large scale trial to show a morbidity and mortality benefit for beta blockers in patients with chronic systolic heart failure. Prior to MERIT-HF, the nonselective beta blocker carvedilol reduced morbidity and mortality in a smaller trial of patients with chronic stable heart failure. Limitations of the trial included its size and the fact that it was not originally designed to test mortality. Furthermore, it was stopped early without clearly prespecified stopping rules and 8% of total patients selected for participation in the trial were excluded prior to randomization after a 2 week, open-label run-in phase with the study drug. During the run-in period, 24 patients (2%) experienced worsening heart failure or death and were excluded from participation in the trial - the difference in total deaths between groups was 9 when the trial was stopped. In our opinion, the results of this trial were far from definitive and there are theoretical reasons why selective and nonselective beta blockers could have different effects on cardiac outcomes.The primary difference between selective and nonselective beta blockers lies in their specificity of action; while both types block adrenaline from binding to beta receptors on nerves, selective beta blockers primarily affect those found in the heart whereas nonselective ones also impact those located in the lungs and blood vessels. In the lungs, adrenaline causes bronchodilation and in the blood vessels, vasoconstriction. Thus, nonselective beta blockers also reduce afterload, which can improve cardiac hemodynamics in the failing heart.The Carvedilol Prospective Randomized Cumulative Survival Study was a large-scale trial that sought to test the hypothesis that the nonselective beta blocker carvedilol reduces mortality in patients with chronic stable heart failure who are on optimal treatment.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients: Patients with “severe chronic heart failure” were recruited from 334 sites in 21 countries. Severe chronic heart failure was defined by the presence of dyspnea or fatigue at rest or on minimal exertion for at least 2 months and a LVEF of /= 65 years; based on sex; LVEF < vs >/= 20%; ischemic vs nonischemic cardiomyopathy; location of study center (North or South America vs Other); and history or lack of history of hospitalization for heart failure within 1 year before enrollment in the study. Additional post-hoc subgroups analyses were performed.Results: The trial was stopped early based on the finding of a significant benefit of carvedilol on survival that exceeded the prespecified interim monitoring boundaries. At the time of stopping, 2289 patients had been randomized with 1133 to the placebo group and 1156 to the carvedilol group. The mean duration of follow-up was 10.4 months. After 4 months, 78% of surviving patients in the placebo group and 65% of those in the carvedilol group were receiving the target doses. The mean dose of placebo was 41 mg daily and carvedilol was 37 mg daily.Compared to placebo, carvedilol significantly reduced the risk of death by 35% (11.2% vs 16.8%; P=0.0014). The survival curves began to separate at 3 months and steadily diverge thereafter. Carvedilol also significantly reduced the risk of death or being hospitalized by 24% (36.8% vs 44.7%; P