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Discussion of landmark trials presented at the European Society of Cardiology (ESC) congress 2025

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N Engl J Med 2004;351:2049-2057

Background: 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.

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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 <0.02.

Results: The trial was stopped early after 1,050 patients were randomized (instead of the planned 1,100) and the mean follow up time at the time of trial termination was 10 months (planned follow up time was 18 months). The target dose was achieved in 68.0% of the patients in the isosorbide dinitrate + hydralazine group.

The primary composite score was lower in the isosorbide dinitrate + hydralazine group (-0.1±1.9 vs -0.5±2.0; p= 0.01). Isosorbide dinitrate + hydralazine reduced the outcome of all-cause death (6.2% vs 10.2%; p= 0.02) and first hospitalization with heart failure (16.4% vs 24.4%; p= 0.001). Quality of life was also better with isosorbide dinitrate + hydralazine (-5.6± 20.6 vs -2.7±21.2; p= 0.02).

Isosorbide dinitrate + hydralazine was associated with more headaches (47.5% vs 19.2%; p <0.001) and more dizziness (29.3% vs 12.3%; p<0.001).

No subgroup analysis was provided.

Conclusion: In Black patients with systolic heart failure, isosorbide dinitrate + hydralazine reduced the composite of weighted scores of all-cause mortality, first hospitalization for heart failure within 18 months, and change in quality of life at 6 months.

In our opinion, the trial has several limitations that affect the adoption of its findings. First, the primary endpoint was a composite of weighted scores that included hard outcomes such as all-cause mortality and heart failure hospitalization, alongside a softer measure - quality of life. The use of weighted scoring for outcomes is not traditional in trials of cardiovascular medicine. It introduces complexity and may obscure the true magnitude of treatment benefit, particularly given that the scoring system used in this trial was arbitrary. Second, the manuscript lacks details regarding power calculations. Third, the trial was stopped early, raising the possibility that a longer follow-up could have resulted in a smaller observed effect size. Fourth, the authors did not report all-cause hospitalizations, an important outcome, especially considering the high rate of adverse events associated with isosorbide dinitrate + hydralazine. While a reduction in all-cause mortality was observed, the study was not powered for this as a primary outcome. Finally, the three-times-daily dosing regimen may pose adherence challenges, particularly in real-world settings where polypharmacy is common.

It is also important to note that the trial generated some controversy due to its enrollment of only self-identified Black patients. This design has raised concerns about the ethics and implications of race-based medicine. Critics argue that race is a social construct rather than a biological determinant, and relying on it for treatment decisions may oversimplify the complex interplay of genetic, socioeconomic, and environmental factors.

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THE LANCET 2003;362:772-776

Background: 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.

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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.

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The Lancet Volume 353, Issue 9146 p9-13 January 02, 1999

Background: 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.

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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.