Cardiology Trials

• Review of the CHARM-Added trial

  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. 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  10:32
• Review of the Val-HeFT trial

  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%; pValsartan 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.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 Carvedilol Prospective Randomized Cumulative Survival Study

  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 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 2.8 mg/dl; serum K 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 /= 65 years; based on sex; LVEF /= 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). 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.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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  14:23
• Summary and discussion of U.S. Carvedilol Heart Failure, DIG, RALES, MERIT-HF, and ATLAS

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  1:09:37
• Review of the ATLAS trial

  Circulation 1999;100:2312-2318Background: 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.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 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.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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  9:22

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