THE LANCET 2003;362:767-771

Background: 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.

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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.

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N Engl J Med 2001;345:1667-1675

Background: 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.

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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<0.001).

Valsartan was associated with more dizziness (1.6% vs 0.4%), more hypotension (1.3% vs 0.8%), and more renal impairment (1.1% vs 0.2%).

There were significant subgroup interactions based on background medications used. Patients were divided into 4 groups based on their use of ACEi and beta-blockers (ACEi yes/no and beta-blockers yes/no). The interaction p value was 0.009 for all-cause mortality and 0.001 for the second primary endpoint. For patients who were receiving both ACEi and beta-blockers at baseline (32% of the patients), valsartan increased all-cause mortality (p= 0.009) and had a trend toward worsening the second primary endpoint (p= 0.10). Among patients who were not receiving ACEi at baseline (7% of the patients), valsartan reduced all-cause mortality (RR: 0.67) as well as the second primary endpoint (RR: 0.56).

Conclusion: In patients with systolic heart failure, adding valsartan to standard background therapy did not reduce mortality but was associated with a reduction in heart failure hospitalizations. Although all-cause hospitalizations were numerically lower with valsartan, the difference was not statistically significant.

It’s important to note that this trial evaluated valsartan vs placebo when added to an ACEi.

Based on this trial, valsartan is not an attractive option as an add-on therapy for patients with systolic heart failure, as the observed benefit was modest and outcomes were worse in patients who were also receiving both an ACEi and a beta-blocker - both reduce mortality in patients with systolic heart failure.

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N Engl J Med 2001;344:1651-1658

Background: 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.

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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 <25%, despite optimal treatment with diuretics at a dose to achieve euvolemia and an ACEi or ARB. Treatment with other common agents was allowed but not required. Hospitalized patients could be enrolled if they did not have any continuing requirements for inpatient care. Recent adjustments in medicines were allowed, but intravenous inotropes or intravenous vasodilators were not permitted within 4 days of screening.

Patients were excluded if: they had heart failure caused by uncorrected primary valvular disease or a reversible form of cardiomyopathy; had severe primary pulmonary, renal, or hepatic disease; or had a contraindication to beta blocker therapy; if SBP <85 mmHg; heart rate <68 bpm; serum Cr >2.8 mg/dl; serum K <3.5 mmol/l or >5.2 mmol/l; or an increase of more than 0.5 mg/dl in serum Cr or a change in body weight of >1.5 kg during the screening period (3 to 14 days).

Baseline characteristics: The mean age of patients was 63 years and approximately 80% were male. The average EF was 20%. The average SBP was 123 mmHg and heart rate was 83 bpm. Ischemic cardiomyopathy accounted for 67% of cases and nonischemic causes accounted for 33%. Most patients were on an ACE inhibitor or ARB (97%) and diuretic (99%). Digoxin was used in 66%.

Trial procedures: All patients who met the entry criteria were randomly assigned in a 1:1 ratio and in a double-blind fashion to receive either carvedilol or matching placebo at an initial dose of 3.125 mg twice daily. This was increased at 2-week intervals (if tolerated), to 6.25 mg, then to 12.5 mg, and finally to a target dose of 25 mg twice daily. Thus, the standard patient would go from the starting dose of 3.125 mg twice daily to the target dose of 25 mg twice daily over a 6 week period. During this period of up-titration, patients were followed closely and the study drug could be decreased, if such an adjustment was clinically warranted. After this period, patients were evaluated every 2 months until the end of the study. If the patient’s condition deteriorated during the study, investigators could use any interventions that were clinically indicated; however, investigators were instructed not to institute open-label treatment with a beta-blocker.

Endpoints: The primary outcome was all-cause mortality. It was estimated that 900 deaths would need to occur to detect a 20% reduction with carvedilol based on an anticipated 1-year mortality rate of 28% in the placebo group. This would provide 90% power with a two-sided alpha of 0.05.

The study was monitored by an independent safety committee who periodically reviewed unblinded results and was empowered to recommend early termination if the treatment effect on survival exceeded prespecified boundaries.

Subgroup analysis was performed on patients < vs >/= 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<0.001). No significant subgroup interactions were identified, including in patient groups who were at the highest absolute risk of dying or being hospitalized.

Less patients in the carvedilol group required permanent discontinuation of treatment because of adverse effects or for reasons other than death (P=0.02)

Conclusions: In this trial of patients with severe chronic systolic heart failure, who were optimized on an ACEi or ARB and diuretic, the nonselective beta blocker carvedilol significantly reduced all-cause mortality as well as the combined endpoint of death or hospitalization. Approximately 18 patients would need to be treated with carvedilol compared to placebo for 10.4 months to prevent 1 death.

This trial represents another significant win for beta blockade in patients with chronic systolic heart failure. The NNT in this trial is lower than in any trial of patients with chronic systolic heart failure that we have reviewed, with the exception of the CONSENSUS trial that compared enalapril to placebo in patients with NYHA class IV heart failure. While the 1-year death totals were high in this trial at 18.5% in the placebo group, they were significantly lower than in CONSENSUS, where the 1-year rate was 52%. This suggests that patients in the current trial, defined as having “severe chronic heart failure” were not as sick as those with classically defined NYHA class IV heart failure. This is also supported by data from MERIT-HF where the 1-year death rate for NYHA class IV patients in the placebo group was 25% (it was 18.5% in the current trial).

Strengths of this trial are that it did not employ a run-in phase, like the earlier trial we reviewed on carvedilol, and it had more statistical power. While it was still stopped early, prespecified rules for stopping are described in the methods but not prespecified rules for when to look at the data. It is curious that the anticipated 1-year death rate in the placebo group was so much higher than it turned out to be and yet, the effect size was so significant. It is certainly possible that with longer follow up the effect size would not have been so large.

The external validity in this trial is limited by patient selection; however, not nearly to the extent that it is in many other trials we have reviewed thus far. Results cannot be applied to patients with severe kidney disease, primary pulmonary disease or hypotension. Finally, a large percentage of patients were taking digoxin.

In conclusion, this is a strong trial in patients with severe chronic heart failure that supports the efficacy of the nonselective beta blocker carvedilol for reducing death and hospitalization.

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Circulation 1999;100:2312-2318

Background: The CONSENSUS and SOLVD trials established the effectiveness of angiotensin converting enzyme inhibitors (ACEi) in reducing mortality and morbidity in patients with systolic heart failure. Both trials used enalapril with a target dose of 20mg twice a day (max dose) in the CONSENSUS trial and 10mg twice a day (medium dose) in the SOLVD trials. In real-world settings, ACEi are sometimes prescribed at lower doses, likely reflecting concerns about adverse effects or patients’ tolerance. It was unclear whether the benefit from low doses of ACEi is comparable to high doses.

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The Assessment of Treatment with Lisinopril and Survival (ATLAS) trial sought to assess the efficacy and safety of low vs high doses of ACE inhibition in patients with systolic heart failure.

Patients: Eligible patients had left ventricular ejection fraction of 30% or less and had NYHA class II, III or IV despite treatment with diuretics for two or more months.

Patients were excluded if they had any of the following: Acute coronary syndrome or revascularization procedure within 2 months, history of sustained or symptomatic ventricular tachycardia, known intolerance to ACEi, serum creatinine >2.5 mg/dL, or any noncardiac condition that could limit survival.

Baseline characteristics: The trial randomized 3,164 patients – 1,596 randomized to the low-dose arm and 1,568 to the high dose arm.

The average age of patients was 64 years and 80% were men. The average left ventricular ejection fraction was 23%. Cardiomyopathy was ischemic in 65% of the patients. The NYHA class was II in 16% of the patients, III in 77% and IV in 7%.

Data on baseline comorbid conditions were not provided in the main manuscript.

Procedures: The study was double blinded. At the beginning of the study, all patients received open-label lisinopril for four weeks to assess who is able to tolerate the drug. Patients who were able to tolerate lisinopril 12.5 mg to15 mg daily for two or more weeks were randomized in a 1:1 ratio to receive low-dose or high-dose ACEi. The target dose of lisinopril in the lose dose group was 2.5 to 5.0mg daily and was 32.5 to 35mg daily in the high dose group.

All patients received open-label lisinopril 2.5 to 5mg daily. This dose was selected by the investigator. In addition, patients received up to three 10mg tablets of lisinopril or matching placebo.

Endpoints: The primary endpoint was all-cause mortality. Secondary end points included cardiovascular mortality, all-cause hospitalization and cardiovascular hospitalizations.

Analysis was performed based on the intention-to-treat principle. The estimated sample size was 3,000 patients. This sample size had 90% power at 5% alpha to detect 15% relative risk difference in the mortality between both treatment groups assuming 19% 1-year mortality in the high dose group.

Results: Of the 3,793 patients who entered the initial open-label tolerability phase, 83.4% were randomized. A total of 176/3,793 (4.6%) were withdrawn for possible side effects. The median follow-up time was 46 months.

Target doses were achieved in 92.7% of the patients in the low-dose group and 91.3% in the high-dose group. Study medication was discontinued by 30.6% of patients in the low-dose group and 27.2% in the high-dose group.

All-cause mortality was not significantly different between both treatment groups (44.9% with low dose vs 42.5% with high dose, HR: 0.92, 95% CI: 0.82 – 1.03; p= 0.128). Cardiovascular mortality was numerically lower in the high dose group but this was not statistically significant (37.2% vs 40.2%, HR: 0.90, 95% CI: 0.81 – 1.01; p= 0.073). All-cause hospitalization was lower in the high dose group (3,819 hospitalizations vs 4,397; p= 0.021). Hospitalizations for cardiac causes and hospitalizations for heart failure were also lower in the high dose group (2,456 vs 2,923; p= 0.05) and (1,199 vs 1,576; p= 0.002), respectively.

Patients in the high-dose group experienced more dizziness (19% vs 12%), more hypotension (11% vs 7%), more worsening renal function (10% vs 7%), and more hyperkalemia (6% vs 4%), but reported less cough (11% vs 13%) and had less hypokalemia (1% vs 3%).

There were no significant subgroup interactions for the primary outcome.

Conclusion: In patients with systolic heart failure, high dose ACE inhibition did not significantly reduce mortality compared to low-dose but it led to significantly less hospitalizations. In this trial of 3,164 patients and with a median follow up of 46 months, there were 578 less hospitalizations in the high dose group.

Based on these results, we recommend up-titrating ACEi and use higher doses if tolerated. Although, side effects were more common in the high dose group, these can generally be managed with reducing the dose in the outpatient settings.

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Lancet 1999;353:2001-07

Background: Beta-blockers directly reduce cardiac contractility and myocardial oxygen demand. For decades, they were avoided in patients with acute and chronic heart failure over concerns they would facilitate decompensation of the condition. The therapeutic cornerstones of treatment, prior to the modern era of clinical trials, focused on managing symptoms and quality of life with diuretics and inotropic agents like digoxin; however, new paradigms were arising that focused on addressing neurohormonal mechanisms of chronic disease that were over-activated in the failing heart.

The first major success came with inhibition of the renin angiotensin aldosterone system with angiotensin converting enzyme inhibitors whose effect on mortality for patients with mild and severe forms of chronic heart failure were demonstrated in the V-HEFT II, CONSENSUS, and SOLVD trials. Additional benefits were demonstrated with the mineralocorticoid receptor antagonist spironolactone in the RALES trial. These drug classes primarily work by reducing afterload and volume retention. Appreciating why they work for improving cardiac performance and managing symptoms in heart failure patients is straightforward when we consider the major factors that effect cardiac stroke volume - preload, afterload and contractility; however, it is also noteworthy the effects these agents have on sudden death.

How beta-blockade benefits the failing heart is less obvious (outside prevention of sudden death). Mechanistic studies in patients with chronic heart failure have consistently shown that when beta blockers are used for more than 1 month, left ventricular function improves. Beta blocker therapy appears to restore the density of beta-adrenergic receptors after they have been downregulated by the chronic overactivity of the sympathetic nervous system.

The first major placebo-controlled RCT to demonstrate a mortality benefit used the non-selective beta blocker carvedilol. The trial was small and not originally designed to test mortality and was stopped early without clearly predefined stopping rules. Furthermore, 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, which saw 2% of all patients experience worsening heart failure or death representing 24 patients (the difference in total deaths between groups was 9 when the trial was stopped). The Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) was the first large scale trial designed to test the hypothesis that beta-blockade with metoprolol controlled/extended release (CR/XL) added to optimum medical therapy reduces mortality in patients with chronic systolic heart failure.

Patients: Patients were recruited from 313 sites in 13 European countries and the United States. Eligible patients were men and women between the age of 40 to 80 years with symptomatic heart failure (NYHA class II-IV) for >/= 3 months before randomization. They had to be on a diuretic and ACE inhibitor for at least 2 weeks. Other drugs, including digoxin, could also be used. Patients also had to have an EF of /=68 beats per minute.

Patients were excluded if: they had an MI or unstable angina within 28 days; had an indication or contraindication for treatment with beta-blocker; beta blockade within 6 weeks; heart failure due to systemic disease (i.e., amyloidosis) or alcohol abuse; scheduled or performed cardiac transplant; an ICD; procedures such as CABG or PCI planned or performed in the past 4 months; 2nd or 3rd degree AV block unless a pacemaker was present; unstable or decompensated heart failure defined by pulmonary edema or hypoperfusion or supine systolic BP <100 mmHg; any other serious disease that might complicate management and follow-up; use of calcium antagonists; use of amiodarone within 6 months before enrollment; poor compliance, defined as >25% deviation of the number of observed versus expected consumed placebo tablets during the run-in period.

Baseline characteristics: The mean age of patients was 64 years and approximately 78% were male. Slightly more than 30% of patients were above the age of 70. The average EF was 28%. The average SBP was 130 mmHg and heart rate was 82 bpm. Most patients had mild to moderate heart failure, with 41% in NYHA Class II, 56% in Class III, and only 3% in Class IV. Ischemic cardiomyopathy accounted for 65% of cases and nonischemic causes accounted for 35%. Most patients were on an ACE inhibitor or ARB (95%) and diuretic (90%). Digoxin was used in 63%.

Trial procedures: Prior to randomization, the study was preceded by a single-blind, 2-week placebo run-in period. Patients meeting eligibility were then randomized to placebo or metoprolol CR/XL. The starting dose of placebo or metoprolol CR/XL was 12.5 mg daily for patients in NYHA class III or IV and 25 mg daily for patients in NYHA class II. The dose was doubled every 2 weeks until the target dose of 200 mg daily was reached. Patients were followed every 3 months.

Endpoints: The primary outcome was all-cause mortality. It was estimated that 3,200 patients would need to be followed for 2.4 years to detect a 30% relative reduction in mortality based on annual mortality rate of 9.4% in the placebo group. This would achieve at least 80% power with a 2-sided alpha of 0.04. Patients were recruited faster then planned and so the final sample size of 3,991 patients increased the power of the study.

The study was monitored by an independent safety committee and predefined stopping rules for efficacy were based on all-cause mortality, done when 25%, 50%, and 75% of expected deaths had occurred.

Results: The trial was stopped early after the 2nd preplanned interim analysis when 50% of expected deaths had occurred. The mean duration of follow-up at the time of stopping was 1 year. The mean daily dose of metoprolol CR/XL was 159 mg once daily, with 87% receiving 100 mg or more and 64% receiving the target dose of 200 mg daily. In the placebo group, the corresponding values were 179 mg daily, 91% and 82%. The study drug was discontinued permanently in 14% of patients in the metoprolol group and 15% in the placebo group. Six months after randomization, heart rate decreased by 14 bpm in the metoprolol group compared to only 3 bpm in the placebo group. Systolic blood pressure decreased less in the metoprolol group (-2.1 vs 3.5 mmHg).

Compared to placebo, metoprolol significantly reduced all-cause mortality (7.3% vs 10.8%; RR 0.66; 95% CI 0.53—0.81). Cardiovascular mortality accounted for 91% of all deaths; with sudden death accounting for 58% and death from worsening heart failure accounting for 24% of all deaths. All 3 of these causes of death were significantly reduced by metoprolol. The relative and absolute effects on death were greatest for patients with NYHA class III heart failure.

Conclusions: In this trial of stable patients with mild to moderate chronic systolic heart failure, who were optimized on an ACEi or ARB and diuretic, metoprolol CR/XL significantly reduced all-cause mortality. Approximately 30 patients would need to be treated with metoprolol compared to placebo for 1 year to prevent 1 death.

This trial represents a significant win for beta blockade in patients with chronic systolic heart failure. While the NNT in this trial is slightly higher than in SOLVD, it is important to appreciate that follow-up time in SOLVD was more than 3x longer.

Limitations to external validity in this trial include the run-in period and stringent inclusion and exclusion criteria. Our enthusiasm is also tempered by early stopping, which has been found to be associated with false positive or exaggerated results but this concern is mitigated to some extent in this trial because the rules for early stopping were clearly defined in the protocol.

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N Engl J Med 1999;341:709-717

Background: The renin–angiotensin–aldosterone system (RAAS) is activated in patients with systolic heart failure. While this activation initially helps increase blood volume and maintains blood pressure, chronic activation promotes cardiac fibrosis and remodeling. In patients with systolic heart failure, inhibition of the RAAS with angiotensin-converting enzyme inhibitors (ACEi) significantly reduced mortality and morbidity, as seen in the CONSENSUS and SOLVD trials.

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Preliminary data suggested that adding the aldosterone-receptor blocker spironolactone to ACEi, reduced the levels of atrial natriuretic peptide and did not lead to serious hyperkalemia.

The Randomized Aldactone Evaluation Study (RALES) sought to test the hypothesis that spironolactone would significantly reduce the risk of all-cause death in patients with severe systolic heart failure.

Patients: Eligible patients had left ventricular ejection fraction of 35% or less, had NYHA class IV heart failure within the 6 months before enrollment and NYHA class III or IV at the time of enrollment, and were treated with ACEi (if tolerated) and a loop diuretic.

Patients were excluded if they had primary operable valvular disease (other than mitral or tricuspid regurgitation), congenital heart disease, unstable angina, primary liver failure, active cancer or any life-threatening condition, other than heart failure, prior heart transplant or awaiting heart transplant, serum creatinine >2.5 mg/dL, or serum potassium > 5.0 mmol/L.

Baseline characteristics: Patients were recruited from 195 centers in 15 countries. The trial randomized 1,663 patients – 822 randomized to receive spironolactone and 841 to receive placebo.

The average age of patients was 65 years and 73% were men. The average left ventricular ejection fraction was 25%. Cardiomyopathy was ischemic in 55% of the patients and non-ischemic in the rest. The NYHA class was III in 71% of the patients and IV in 29%.

Data on baseline comorbid conditions were not provided.

At the time of enrollment, 100% were taking loop diuretics, 94% were taking ACEi, 73% were taking digitalis, and 10% were taking beta-blockers. The mean daily dose of ACEi were as following: 63mg for captopril, 15mg for enalapril, and 14mg for lisinopril.

Note: Max daily dose is 450mg for captopril, 40mg for enalapril, and 40mg for lisinopril.

Procedures: The trial was double-blinded. Patients were assigned in a 1:1 ratio to receive spironolactone 25mg PO daily or placebo.

The dose could be increased to 50mg daily after 8 weeks of treatment, If the patient had worsening heart failure and had no evidence of hyperkalemia. In the event of hyperkalemia, the dose could be lowered to 25 mg every other day. Laboratory testing including potassium were performed every 4 weeks for the first 12 weeks, then every 3 months for up to 1 year and every 6 months thereafter until the end of the study.

Endpoints: The primary outcome was all-cause death. Secondary end points included death from cardiac causes, hospitalization for cardiac causes and change in the NYHA class.

Analysis was performed based on the intention-to-treat principle. The planned sample size was not mentioned in the methods. However, the results mention that recruitment was complete. The sample size calculation assumed 38% mortality rate in the placebo group and that spironolactone would reduce mortality by 17% (relative risk reduction). The power of the study was set at 90% with a two-sided alpha of 5%.

Results: Recruitment was complete in Dec, 1996 with follow up planned through Dec, 1999. However, the study was stopped early on Aug, 1998 after interim analysis showed significant reduction in mortality with spironolactone. The mean follow up time was 24 months. After 24 months of follow up, the mean daily dose of spironolactone was 26 mg.

Spironolactone reduced all-cause death (35% vs 46%, RR: 0.70, 95% CI: 0.60 - 0.82; p< 0.001). Death from cardiac causes was also reduced with spironolactone (27% vs 37%, RR: 0.69, 95% CI: 0.58 - 0.82; p<0.001). Patients who were assigned to spironolactone had less hospitalizations for cardiac causes 260 patients vs 336 patients, RR: 0.70, 95% CI: 0.59 - 0.82; p<0.001).

In the placebo group, NYHA class improved in 33% of the patients, worsened in 48% and did not change in 18%. In the spironolactone group, NYHA class improved in 41% of the patients, worsened in 38% and did not change in 21%. The difference between placebo and spironolactone was significant (p<0.001 by the Wilcoxon test).

The median potassium levels increased by 0.3 mmol/L in the spironolactone group and did not change in the placebo group. Serious hyperkalemia occurred in 2% of patients in the spironolactone group and 1% in the placebo group. Gynecomastia occurred in 9% of the men in the spironolactone group and 1% of the men in the placebo group.

There were no significant subgroup interactions for the primary outcome.

Conclusion: In patients with severe systolic heart failure, spironolactone reduced all-cause death with a number need to treat of approximately 9 patients over 2 years of follow up. This benefit was consistent among all subgroups. This is a large treatment benefit that is infrequently seen in trials of cardiovascular medicine. It further supports the role of RAAS inhibition in patients with systolic heart failure. A key strength of the trial is that low-dose spironolactone was sufficient to demonstrate benefit, without requiring high doses.

The risk of hyperkalemia in the trial was low. However, one should appreciate that the dose of ACEi used was low and that concomitant use of high-dose ACEi and spironolactone will likely increase this risk, therefore, frequent monitoring of such patients is required.

The trial did not report the number of patients screened to enrolled, which limits its external validity. Nonetheless, based on the the large treatment benefit observed, we recommend spironolactone for patients with systolic heart failure who do not meet the exclusion criteria particularly regarding creatinine (>2.5 mg/dL) and potassium (>5.0 mmol/L) levels.

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N Engl J Med 1997;336:525-33

Background: Digoxin is a natural drug that comes from the Foxglove plant (Digitalis purpurea). It has been used for the treatment of congestive heart failure for over 200 years. At the time this trial was undertaken, it was given to the overwhelming majority of patients with severe congestive heart failure. The percentage of patients on digoxin was over 90% in all of the seminal heart failure trials we have reviewed thus far. However, despite its frequent use, it was unknown whether the drug improved major morbidity or mortality, and new drug classes were emerging with positive effects on hard outcomes. The primary aim of the Digitalis Investigation Group was to design a large, pragmatic trial to test the long-term effect of digoxin versus placebo on all-cause mortality as well as hospitalization for heart failure.

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Patients: The study enrolled 6,800 patients with congestive heart failure and an EF of 45% in an ancillary trial. The patient population in the trial was intended to be diverse with no upper age limit. If patients were already on an ACE inhibitor, and had been stable for at least 2 weeks, they could be randomized immediately. For patients not on an ACE inhibitor, they were prescribed the drug and reevaluated in 2 weeks, at which time they could be randomized, if stable. Patients could be randomized into the trial whether they were taking digoxin or not and there was no washout phase.

Important exclusion criteria included an MI, cardiac surgery or percutaneous coronary intervention within 4 weeks; unstable or refractory angina for less than 1 month; 2nd or 3rd degree AV block or sick sinus syndrome without a pacemaker; atrial fibrillation or atrial flutter; cor pulmonale; acute myocarditis; amyloid cardiomyopathy; hypertrophic cardiomyopathy; complex congenital heart disease; current treatment with IV inotropes; potassium <3.2 or >5.5 mmol/L; need for cardiac surgery or percutaneous coronary intervention in near future; patients on heart transplant list; severe kidney (Cr >3.0 mg/dL) or liver disease; any non-cardiac disease that shortens life-expectancy to <3 years (i.e., most cancers).

Baseline Characteristics: The mean age of patients was 63.5 years and approximately 78% were male. Nearly 30% of patients were above the age of 70. The average EF was 29% and the median duration of CHF was 17 months. Most patients had mild to moderate heart failure, with 13% in NYHA Class I, 53% in Class II, 31% in Class III, and only 2% in Class IV. Ischemic cardiomyopathy was the main cause of heart failure (71%); idiopathic causes and hypertensive heart disease accounted for 15% and 9%, respectively. Most patients were on an ACE inhibitor (95%) and diuretic (82%). Nitrates or other vasodilators were used in 44%. Prior to enrollment, 44% of patients used digoxin.

Trial Procedures: This was designed to be a pragmatic trial. Entry conditions required only a 2 week period of clinical stability, which was not rigorously defined. A recent hospitalization for heart failure was not an exclusion; however, patients could not be on IV inotropic agents. Patients could be on digoxin at the time of screening and if so, were randomized without a washout period. For patients not already on an ACE inhibitor, an ACE inhibitor was to be prescribed with reassessment in 2 weeks and randomization if stable.

Randomization was stratified by study center and EF (45%). The recommended initial dose of the study drug (digoxin or placebo) was determined with an algorithm based on the patient’s age, sex, weight and renal function. Local investigators were permitted to modify the dose on the basis of other factors. All patients returned for follow-up visits 4 weeks and 16 weeks after randomization and every 4 months thereafter.

Monitoring of serum digoxin levels for dose titration and toxicity via use of local laboratories was not encouraged in the trial. High serum digoxin levels without clinical signs of toxicity do not prove toxicity and conversely, a portion of patients with true toxicity have serum digoxin levels in the normal range. If a serum digoxin level was felt to be essential for clinical management, local investigators sent blood samples to a central laboratory and the results were reported as either: subtherapeutic, therapeutic or possibly toxic, or probably toxic within 48 hours. A subset of patients in the trial had serum digoxin levels drawn at 4 weeks and 12 months. This data was not used for the individual management of patients in the trial but rather to assess the safety and efficacy of the dosing algorithm used.

If during the trial, patients had worsening symptoms of heart failure, it was recommended that other therapy for heart failure be used in an optimal fashion. If patients remained symptomatic despite efforts to optimize other forms of treatment, open-label treatment with digoxin was allowed and the study drug was discontinued.

Endpoints: The primary outcome was all-cause mortality. The secondary outcomes included mortality from cardiovascular causes, death from worsening heart failure, hospitalization for worsening heart failure, and hospitalization for other causes, including suspected digoxin toxicity. In the ancillary trial, the primary endpoint was a composite of death or hospitalization due to worsening heart failure.

It was estimated that 6,700 patients would be needed to detect a 15% relative reduction in mortality based on an estimated 3-year mortality rate of 27% in the placebo group. It was anticipated that 3 years would be required to recruit the anticipated number of participants and follow-up would be for a minimum of 2 years and maximum of 5 years. In a methods paper, which proceeded publication of the main results, a range of sample size estimates are provided.

Results: The mean duration of follow-up was 37 months or 3.1 years. At randomization, the median daily dose of the assigned study drug was 0.250 mg in both groups. Among the 1485 patients in the digoxin group for whom blood samples were obtained, the mean steady-state serum digoxin level was 0.86 ng/ml at the 1-month visit and 0.80 ng/ml at the 12-month visit. At 1-month, 88% of patients in the digoxin group had serum digoxin levels within the therapeutic range of 0.5 to 2.0 ng/ml. At 1-year, 86% of patients in the digoxin group were taking the study drug and 83% of patients in the placebo group were taking placebo.

At the final study visit, 71% of surviving patients in the digoxin group were taking the study drug, and an additional 10% were taking open-label digoxin. In the placebo group, 68% of the surviving patients were taking placebo and 16% were taking open-label digoxin. Open-label digoxin was used at some point in the trial by 14% of patients in the digoxin group versus 22% of patients in the placebo group (P<0.001). The primary reason for discontinuing the study drug were the use of open-label digoxin to treat worsening heart failure.

There was no significant difference in overall mortality, which was 34.8% in the digoxin group and 35.1% in the placebo group. There was also no significant difference in cardiac mortality; however, there was a trend toward a lower risk of mortality due to worsening heart failure in the digoxin group (11.6% vs 13.2%; RR 0.88; 95% CI 0.77 to 1.01).

Significantly fewer patients were hospitalized for worsening heart failure symptoms in the digoxin group (26.8% vs 34.7%; RR 0.72; 95% CI 0.66 to 0.79). Overall, there were 626 fewer hospitalizations for worsening heart failure in the digoxin group.

The risk of death from any cause or hospitalization for worsening heart failure was significantly reduced in the digoxin group (RR 0.85; 95% CI 0.79 to 0.91) as was the endpoint of death from worsening heart failure or hospitalization due to worsening heart failure (RR 0.75; 95% CI 0.69 to 0.82). These benefits were seen soon after randomization, and they persisted throughout the trial.

Significantly fewer patients were hospitalized for any cause in the digoxin group (64.3% vs 67.1%; RR 0.92; 95% CI 0.87 to 0.98) and there were 6% fewer hospitalizations for any cause in the digoxin group (6356 vs 6777) and 10% fewer hospitalizations for cardiovascular causes (4106 vs 4570). There were fewer hospitalizations per patient for any cause in the digoxin group (P=0.01) as well as fewer hospitalizations per patient for cardiovascular causes (P<0.001).

Significantly more patients were hospitalized with suspected digoxin toxicity in the digoxin group compared to placebo (2.0% vs 0.9%; RR 2.17; 95% CI 1.42 to 3.32). The proportion of patients hospitalized for non-cardiovascular reasons was similar in both groups.

Based on planned pre-specified subgroup analysis there was no significant treatment effect heterogeneity noted on a relative scale. However, with respect to the combined endpoint of mortality from worsening heart failure or hospitalization from worsening heart failure, the absolute benefit of digoxin was greater among patients at the highest risk. The absolute risk differences for patients with an EF <25%, a cardiothoracic ratio >0.55, and a NYHA class III or IV was approximately -11%, which translates to a NNT of less than 10 patients to prevent 1 from experiencing the combined endpoint.

In the ancillary trial involving patients with an EF >45%, digoxin did not significantly reduce the primary endpoint of all-cause death or hospitalization for worsening heart failure, but this was likely due to low power as the treatment effect was consistent with the result in the main trial (RR 0.82; 95% CI 0.63 to 1.07).

Conclusions: In this large, pragmatic clinical trial, digoxin did not reduce all-cause mortality compared to placebo, but it did significantly reduce other important endpoints including all-cause hospitalizations and hospitalizations for worsening heart failure as well as combined endpoints including mortality and heart failure hospitalizations. Moreover, the benefits of digoxin were more evident on an absolute scale for patients at the highest levels of risk.

This trial has important strengths including its large size and pragmatic design. It did not have a run-in period, serum digoxin levels were not used for monitoring purposes, and the entry criteria were relatively lax, which increases its external validity.

A unique feature of the trial that compromised its internal validity and may have made it more difficult to show a benefit for digoxin was the allowance for open-label digoxin use in patients with symptomatic heart failure who could not be treated effectively with other measures. The potential benefit of digoxin on mortality may have been masked by such crossover. This is supported by the fact that approximately 8% more patients in the placebo group used open-label digoxin during the trial and the primary purpose for its use was to treat worsening heart failure. This is not generally considered standard practice for trials of new drugs. In fact, in the trial of carvedilol in severe heart failure that we will review in the coming weeks, investigators were explicitly instructed not to institute open-label treatment with a beta-blocker.

In conclusion, digoxin did not reduce mortality but did significantly reduce other important measures of morbidity in a diverse population of heart failure patients and some of the benefits may have been masked by allowance of crossover to open-label digoxin in patients with worsening heart failure. In our opinion, this trial supports a strong effect of digoxin on heart failure morbidity with high external validity, and it does not exclude the possibility that digoxin could reduce death in a trial employing more traditional design methods for establishing proof of efficacy.

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N Engl J Med 1996;334:1349-1355

Background Before 1990, the prevailing idea held that the negative inotropy of beta-blockers would harm patients with impaired systolic function. Yet part of the progression of systolic heart failure involved over stimulation of the sympathetic nervous system. Norepinephrine can exert adverse effects on the circulation, both directly and indirectly. Smaller trials of beta-blockers in systolic heart failure found trends for benefit with beta-blockers, however, a mortality benefit had not yet been proven. The U.S. Carvedilol Heart Failure Study aimed to study mortality in patients with heart failure with a reduced ejection fraction.

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Patients The study enrolled 1094 patients with chronic heart failure symptoms for at least 3 months, LVEF ≤ 0.35%, at least 2 months of treatment with diuretics and an angiotensin-converting enzyme (ACE) inhibitor (if tolerated). Treatment with digoxin, hydralazine, or nitrates was permitted but not required.

Exclusion criteria were extensive and important to understand. These included any recent major cardiac events or surgery within the previous 3 months, uncorrected valvular disease, active myocarditis, sustained VT or higher degrees of AV block not controlled by pacing, systolic blood pressure of more than 160 or less than 85 mm Hg or diastolic blood pressure of more than 100 mm Hg, clinically significant kidney or liver disease or use of calcium-channel blockers, adrenergic agonists/antagonists, or class IC/III antiarrhythmic agents. Patients receiving β-adrenergic agonists or antagonists (presumably for another indication) were not enrolled.

Baseline Characteristics The results of this and other beta-blocker trials in heart failure will be clear. One of the most important points for translating this evidence to patients will be the baseline characteristics. It is vital to understand who these patients were.

The mean age was 58 years and approximately 76% were male. Most patients had mild to moderate heart failure, with 53% in NYHA Class II, 44% in Class III, and only 3% in Class IV. The etiology of heart failure was nearly evenly split between coronary artery disease (47%) and nonischemic cardiomyopathy (53%).

Patients had significantly impaired cardiac function with a mean LVEF of 0.23. The mean six-minute walk distance ranged from 386 to 390 meters. Hemodynamic parameters were relatively stable, with mean systolic blood pressure of 116 mmHg, and mean heart rate of 83-84 beats per minute. Most patients were receiving standard heart failure therapy at baseline, including digitalis (90-91%), loop diuretics (95%), and ACE inhibitors (95%), while approximately one-third (32%) were on direct-acting vasodilators.

Trial Procedures Patients were assessed for eligibility during a 3-week screening period during which exercise capacity was assessed with a 6-minute walk test. Notable was that these were outpatients able to complete a 6-minute walk test.

Enrollment was stratified to one of four treatment protocols on the basis of the patients' performance on the exercise test: patients able to walk between 426 and 550 m when tested were assigned to the mild-heart-failure protocol; those able to walk between 150 and 425 m were assigned either to the moderate-heart-failure protocol or to a dose-ranging protocol, depending on the location of the study center; and those able to walk only less than 150 m were assigned to the severe-heart-failure protocol.

After this base-line testing, all patients received 6.25mg of carvedilol twice daily for two weeks in an open-label run-in period. Those who tolerated this initial dose were then randomized to receive either placebo (n=398) or carvedilol (n=696) on a double-blind basis, in addition to their usual medications.

The allocation ratio (carvedilol:placebo) was 2:1 in the mild and severe heart failure protocols and 1:1 in the moderate heart failure protocol. The dose was gradually increased to target levels of 25-50mg twice daily over 2-10 weeks, followed by maintenance therapy for an additional 6 months (12 months for mild heart failure).

Endpoints At the time of trial planning, the original intent was safety. That is, to show that carvedilol did not increase mortality. The original intent was to enroll 1100 patients. As smaller trials on beta-blockers were published, the statistical plan included the possibility of beta-blocker benefit. The trialists therefore planned two sided statistical analysis.

Cumulative survival curves were constructed as time-to-first-event plots by Kaplan–Meier survivorship methods and differences between the curves were tested for significance by the log-rank statistic with use of a Cox proportional-hazards regression model (which included the protocol as a covariate).

Results Median follow-up was only 6.5 months due to early termination for benefit. The patients mean total daily dose of carvedilol was 45±27 mg.

Overall mortality was 7.8% in the placebo group vs. 3.2% in carvedilol group. The relative risk reduction from carvedilol vs placebo was 65% (95% CI, 39-80%; p<0.001).

The authors also noted similar reduction in mortality across all subgroups regardless of age, sex, cause of heart failure, ejection fraction, exercise tolerance, blood pressure, or heart rate. Progressive heart failure deaths (3.3% vs. 0.7%) and sudden deaths (3.8% vs. 1.7%) were also reduced by carvedilol.

Carvedilol also improved morbidity. There was a 27% reduction in risk of hospitalization for cardiovascular causes (19.6% vs. 14.1%, p=0.036) and a 38% reduction in combined risk of hospitalization or death (24.6% vs. 15.8%, p<0.001).

Safety signals were reassuring. While heart rate decreased significantly in the carvedilol vs placebo group (12.6±12.8 vs. 1.4±12.2 beats/min, p<0.001). there were no significant changes in systolic or diastolic blood pressure. Discontinuation rates were similar: 7.8% in placebo vs. 5.7% in carvedilol group.

Conclusion This was the first trial to demonstrate that a beta-blocker could reduce mortality (and morbidity) in patients with symptomatic heart failure and reduced systolic function. Not only did it establish carvedilol as a foundational therapy in systolic heart failure, but it also strongly supported the notion that sympathetic activation was a detrimental process in progressive heart failure.

We at Cardiology Trials cannot emphasize enough the trial procedures and baseline characteristics of these patients. These were young, mostly male, ambulatory outpatients who were shown to be tolerant of carvedilol. Patients on beta-blocker for another indication were not randomized. Patients with a recent major adverse cardiac event were not randomized. What’s more, the mean daily dose of carvedilol was nearly 50mg daily.

We believe that patients in the US Carvedilol trial resemble those who would be in a chronic heart failure clinic. We caution against translating these results to older patients with multiple comorbid conditions and less robust hemodynamics.

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