Cardiology Trials

This is the article John referenced that discusses Watchman https://www.heartrhythmjournal.com/article/S1547-5271(17)31200-6/abstract Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe

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Discussion of landmark trials presented at the European Society of Cardiology (ESC) congress 2025 Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe

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

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

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The Lancet Volume 353, Issue 9146 p9-13 January 02, 1999Background: Accumulating data at the time suggested functional benefits of antagonism of beta-adrenoreceptors in patients with heart failure. Multiple specific beta-blockers were being tested in trials. The CIBIS 1 trial found a trend towards 20% lower mortality in the bisoprolol (a highly cardio-selective beta-blocker) group and 30% fewer admissions to hospital for worsening heart failure. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) trial was designed to test this evidence further.Patients Eligible patients had New York Heart Association Class III-IV symptoms with LVEF ≤ 35% and were stable on diuretics and ACE-inhibitors. Exclusion criteria included recent MI or coronary intervention, AV block or resting heart rate less 60 bpm and systolic BP Cardiology Trial’s remains independent, free of industry ads, due to reader generosity. Please consider becoming a free or paid subscriber.Baseline Characteristics The mean age of patients was 61 years, 81% male, and 83% Class III. The mean LVEF was 28%. About half the patients had ischemic heart disease, 12% primary dilated cardiomyopathy and nearly 40% had a mixture of valvular heart disease, hypertensive heart disease or unproven ischemic disease.The mean SBP on enrollment was 130 mmHg and resting HR was 80 bpm. The mean duration of heart failure before enrollment was 3.5 years. About 20% had AF at baseline. Nearly all patients were on ACE-I and half were on digoxin.Trial Procedures There was no run-in period. CIBIS II was double blinded. Slightly more than 2,600 patients were randomized 1:1 to bisoprolol or placebo in 274 hospitals across 18 countries.Patients in the bisoprolol group were started at 1.25 mg daily and titrated up weekly to as high as 10 mg daily. The goal was to attempt the highest tolerated dose. Patients were seen every 3 months.Endpoints The primary endpoint was all-cause mortality. Secondary endpoints included all-cause hospital admissions, cardiovascular mortality, combined CV death and CV hospital admissions, and premature treatment withdrawals.The authors estimated a 11.2% mortality in the placebo group and powered the trial to find a 25% reduction in death in the bisoprolol arm over 2 years.Results The trial was sopped early (mean follow-up 1.3 years) after the planned second interim analysis for benefit. The primary outcome of all-cause death occurred in 11.8% in the bisoprolol group vs 17.3% in the placebo arm (HR 0.66 (95% CI 0.54-0.81, p Bisoprolol reduced sudden death (3.6% vs 6.3%), all-cause hospitalization (33% vs 39%), CV death (9% vs 12%). Permanent treatment withdrawal occurred in 15% of both arms.The subgroup analysis showed no substantial treatment heterogeneity. The most common dose was 10 mg daily reached in 43% of patients.Conclusion The 34% reduction in death was clinically meaningful and statistically robust. Our confidence in such a large effect size stems from a) previous data on beta-blockers, which found similar effects, b) the 42% reduction in sudden death in the bisoprolol arm and c) the large reductions in all-cause hospitalization. In addition, the trial conduct appeared strong with almost no lost-to-follow up. The lack of run-in period strengthens the external validity of CIBIS II.The same caveats seen in the US carvedilol trial also apply to CIBIS II, namely that patients were ambulatory, outpatients, mostly with Class III symptoms. Patients enrolled in the trial had a mean SBP of 130 mmHg and a resting heart rate of 80. Nearly all patients were tolerating ACE-I and half were taking digoxin. In addition, patients were started on low-dose and gradually titrated higher. The majority of patients were on higher than 5 mg daily.The authors warned against applying these results to non-ambulatory patients with Class IV symptoms, especially if there was recent instability. Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe

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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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

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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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

Lancet 1999;353:2001-07Background: 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 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.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

N Engl J Med 1999;341:709-717Background: 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.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.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; pIn 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 (pThe 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.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

N Engl J Med 1997;336:525-33Background: 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.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: 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 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 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 (PThere 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 (PSignificantly 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 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.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. 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N Engl J Med 1996;334:1349-1355Background 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.Cardiology Trial’s Substack remains free of industry ads because of your support. Thank you. Please consider becoming a free or paid subscriber.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%; pThe 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%, pSafety 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, pConclusion 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. Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe

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N Engl J Med 1991;325:293-302N Engl J Med 1992;327:685-691Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Background: Systolic heart failure affects millions worldwide and is associated with high mortality and morbidity. If left untreated, the one-year mortality ranges from 15-50%, depending on the severity of the disease.The CONSENSUS trial found mortality benefit with the use of the angiotensin converting enzyme inhibitor (ACEi) enalapril in patients with New York Heart Association (NYHA) class IV heart failure. Data on less severe heart failure were lacking.The Studies of Left Ventricular Dysfunction (SOLVD) sought to assess whether an ACEi, enalapril, would reduce mortality in patients with low left ventricular ejection fractions defined as 35% of less.Patients: Eligible patients had left ventricular ejection fraction of 35% or less. The ejection fraction was measured using radionuclide techniques in 68% of the patients, contrast angiography in 11%, and two-dimensional echocardiography in 21%.Patients were excluded if they were over 80 years of age, or if they had significant valvular disease requiring surgery, unstable angina pectoris, angina requiring revascularization procedures, myocardial infarction during the previous month, severe pulmonary disease, serum creatinine >2 mg/ dl, or any other disease that might significantly impact survival.At the end of the run-in period for placebo, patients who had overt congestive heart failure were enrolled in the Treatment trial, and patients who were not having overt congestive heart failure were enrolled in the Prevention trial.Baseline characteristics: Patients were recruited from 83 hospitals linked to 23 centers in the United States, Canada, and Belgium.The Treatment trial randomized 2,569 patients – 1,285 patients randomized to receive enalapril and 1,284 randomized to receive placebo. The average age of patients was 61 years and 80% were men. The average left ventricular ejection fraction was 25%. Approximately 42% had hypertension, 26% had diabetes, 71% had ischemic heart disease and 22% were current smokers. The NYHA class was I in 11% of the patients, II in 57% of the patients, III in 30% and IV 2%. At the time of enrollment, 8% were taking beta-blockers, 67% were taking digitalis, 85% were taking diuretics, 9% were taking potassium-sparing diuretics and 51% were taking vasodilators (other than ACEi).The Prevention trial randomized 4,228 patients – 2,111 patients randomized to receive enalapril and 2,117 randomized to receive placebo. The average age of patients was 59 years and 89% were men. The average left ventricular ejection fraction was 28%. Approximately 37% had hypertension, 15% had diabetes, 83% had ischemic heart disease and 23% were current smokers. The NYHA class was I in 67% of the patients and II in 33%. At the time of enrollment, 24% were taking beta-blockers, 12% were taking digitalis, 17% were taking diuretics, 4% were taking potassium-sparing diuretics and 46% were taking vasodilators (other than ACEi).Procedures: A total of 7,402 patients were deemed eligible across both the Treatment and Prevention trials.Eligible patients for either trial entered a run-in and stabilization phase. Patients were given enalapril 2.5 mg twice daily in a single-blind fashion for 2 - 7 days to identify patients who could not tolerate even a small dose of the drug or those who were unable to comply with the regimen. A total of 310/7402 patients (4.2%) were excluded from the study during this phase. Following the active dosing phase, patients were placed on a regimen of matching placebo in a single-blind manner for 14 - 17 days. This allowed identification of individuals whose clinical condition deteriorated after drug withdrawal or who demonstrated poor compliance. During this phase, 295/ 7,092 patients (4.2%) were excluded from the study.At the end of the run-in period for placebo, patients who had overt congestive heart failure were enrolled in the Treatment trial, and patients who were not having overt congestive heart failure were enrolled in the Prevention trial.After that patients were randomized in a 1:1 ratio to receive enalapril or placebo.Treatment with enalapril or placebo was initiated at 2.5 mg or 5 mg twice daily, based on the patient's clinical status and physician judgment. The dose was titrated up to 10 mg twice daily if tolerated without symptomatic hypotension or worsening renal function. After randomization, follow-up visits occurred at two weeks, six weeks, four months, and every four months thereafter until study completion.Endpoints: The primary outcome for both trials was all-cause mortality. Heart failure hospitalization was assessed as a secondary outcome.The estimated sample size was 2,500 patients for the treatment trial and 4,600 for the prevention trial. These sample sizes would provide 90% power at 5% two-sided alpha to detect 25% relative risk reduction in mortality, with the use of enalapril. The estimated 3-year mortality in the control group was 32% in the Treatment trial and 17% in the Prevention trial.Authors reported risk reduction which was calculate as (1 – relative risk)*100.Results: A total of 39,924 patients with a left ventricular ejection fraction of 35% or less were identified. Of these, 6.4% were enrolled in the Treatment trial and 7.4% in the Prevention trial. Among the excluded patients, the main reasons were prior use of an ACEi (28%), cardiovascular problems (12%), contraindications to using ACEi (11%), lack of patient consent (11%), administrative reasons (21%), cancer or other life-threatening illnesses (12%), and other miscellaneous reasons (5%).The average follow up time was 41.4 months in the Treatment trial and 37.4 months in the Prevention trial.In the Treatment trial, enalapril reduced all-cause mortality (35.2% vs 39.7%, risk reduction: 16%, 95% CI: 5% – 26%; pIn the Prevention trial, enalapril did not have a significant effect on mortality (14.8% with enalapril vs 15.8% with placebo, risk reduction: 8%, 95% CI: -8% – 21%; p= 0.30). Enalapril significantly reduced the development of heart failure (20.7% vs 30.2%; pIn both trials, the benefit of enalapril was seen early after treatment initiation.Conclusion: In patients with left ventricular ejection fraction of 35% or less and overt congestive heart failure, enalapril reduced all-cause mortality with a number needed to treat of approximately 22 patients. In patients with a left ventricular ejection fraction of 35% or less and without overt congestive heart failure, enalapril had no significant effect on mortality but it reduced the development of heart failure with an number needed to treat of approximately 11 patients.The SOLVD trials provide strong evidence supporting the use of ACEi in patients with systolic heart failure. The role of ACEi in systolic heart failure has been examined across diverse patient groups, and the totality of evidence consistently supports their use. However, when examining the SOLVD trials in isolation, it is important to recognize the selective nature of enrollment, which limits the trials’ external validity. Additionally, the use of a run-in period introduces bias in favor of enalapril, although this concern is less significant when the primary outcome is all-cause mortality.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

N Engl J Med 1991; 325:303-10Background Enalapril was found to be superior to placebo for patients with severe, class IV heart failure in the CONSENSUS trial and the regimen of Hydralazine-Isosorbide dinitrate was found to be superior to Prazosin as well as placebo for stable patients with mild heart failure in the original V-HEFT I trial. No sufficiently powered trials in this space had been performed to assess whether Enalapril improved long-term morbidity or mortality for heart failure patients with milder symptoms and the CONSENSUS trial had important limitations. The V-HEFT II trial was undertaken to compare 2 vasodilator regimens (Enalapril and Hydralazine-Isosorbide dinitrate) in patients with chronic congestive heart failure. Besides comparing efficacy of these agents on mortality, investigators sought to understand how these agents affected physiologic endpoints. The trial was sponsored by the Veterans Administration and enrolled men and the patient population and methods were identical to the original V-HEFT trial.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients Men between the ages of 18 and 75 were recruited from 13 participating Veterans Administration hospitals and had to have chronic congestive heart failure based on either evidence of cardiac dilatation or left ventricular dysfunction (EF Baseline characteristics Only 29% of screened patients were ultimately enrolled. The average age of patients in the trial was 61 years. Over 50% of patients had coronary artery disease and/or previous MI and about 20% had previous bypass surgery. Excess alcohol use as well as hypertension were also present in about 40% of patients and diabetes was present in about 20%. Prior to randomization, about 60% of patients were taking vasodilators, 25% antiarrhythmics, 20% sublingual nitroglycerin and 20% anticoagulants. The average BP was about 126/78 mmHg, HR 78 bpm, and EF 30%.Procedures After screening, a baseline period of at least 4 weeks was required to establish optimal therapy with digoxin and a diuretic agent and to allow any non-study drugs to be discontinued. Clinical evaluations and exercise-tolerance tests on 2 consecutive visits, two weeks apart, had to reveal clinical and exercise stability before randomization could occur.Randomized patients received three bottles of medication, the first containing 5 mg of enalapril or matching placebo, the second containing 37.5 mg of hydralazine or matching placebo, and the third containing 40 mg of isosorbide dinitrate or matching placebo. Each patient received either a bottle of enalapril and 2 bottles of placebo or a bottle of hydralazine, a bottle of isosorbide dinitrate, and a bottle of placebo.They began treatment by taking 1 tablet 2 times daily from the first bottle, 1 tablet 4 times daily from the second bottle, and one-half tablet from the third bottle 4 times daily. After 2 weeks, if the patient tolerated these doses of each medication, the doses were doubled, so that the full daily treatment consisted other either 20 mg (10 mg bid) of enalapril or 300 mg (75 mg qid) of hydralazine plus 160 mg (80 mg bid) of isosorbide dinitrate.Follow up visits were scheduled at 3 months intervals after the titration of the initial dose at 2 weeks. In addition to clinical and laboratory evaluation, they also had exercise testing with gas exchange after 13 weeks and at 6 month intervals, yearly chest radiography, radionuclide EF measurements and assays of plasma norepinephrine levels and quality of life questionnaires every 6 months.Endpoints The primary endpoint was mortality, which was assessed on an intention-to-treat basis. All deaths were reviewed blindly by the investigator at the local site and classified as: 1) sudden (observed or unobserved), 2) sudden but with some premonitory worsening of cardiac status, 3) progressive pump failure, 4) another cardiovascular event, and 5) non-cardiovascular.Secondary endpoints included changes over time in clinical measurements, which were analyzed at each follow up visit by comparing the mean changes from base line in the two treatment arms with use of a t-test. It is unclear from the methods whether secondary endpoints were assessed on an ITT basis.Results 804 patients were enrolled (403 in the enalapril group and 401 in the hydralazine-isosorbide dinitrate group). Twenty-two percent of patient discontinued enalapril prior to their final visit and an additional 8% reduced the dose. Twenty-nine percent of patients discontinued hydralazine and 10% reduced the dose whereas 31% discontinued isosorbide and 10% had reduced the dose. Adherence with the prescribed regimen, based on pill counts, averaged 86%. The average daily dose of enalapril was 15 mg, hydralazine was 199 mg and isosorbide was 100 mg.The mean follow-up was 2.5 years (range 6 months to 5.7 years). Six patients in the enalapril arm and 2 in the hydralazine-isosorbide arm received a heart transplant and their data were censored from the analysis at that time. There were 132 deaths in the enalapril group (33%; 13 per 100 patient years) and 153 in the hydralazine-dinitrate group (39%; 15 per 100 patient years). A statistically significant reduction in mortality was observed at 2 years (p = 0.016) but not over the duration of the trial (p = 0.08). The reduction in mortality was highest after 1 year and began to diminish thereafter.There were 245 patients who were also included in the original V-HEFT I trial. There was no interaction on survival between subgroups of those who did versus did not participate.The reduction in death in the enalapril group was driven by sudden death; there was no difference between groups in death due to pump failure.Prespecified subgroup analysis in CAD vs no CAD stratification showed no significant treatment effect heterogeneity for hydralazine-nitrate among those with CAD although the absolute difference in mortality between groups was numerically higher for patients with CAD.BP was reduced more in the enalapril group whereas ejection fraction increased in both groups but was greater in the hydralazine-isosorbide group. Exercise tolerance was also better in the hydralazine-isosorbide group.Hospitalization for heart failure was unchanged in both groups at approximately 18%.Headaches were more common in the hydralazine-isosorbide group whereas symptomatic hypotension and cough were higher in the enalapril group.Conclusions This study compared enalapril to hydralazine-isosorbide in patients with chronic congestive heart failure who were optimized on digoxin and diuretic therapy. In this young (60 years) and highly selected population of clinically stable male veterans with dilated cardiomyopathies and NYHA class II and III symptoms, enalapril reduced death by 2 per 100 patient years compared to hydralazine-isosorbide but this was not statistically significant over the duration of the trial. This difference was driven by sudden death and not pump failure. The external validity is limited by intensive monitoring following enrollment and the fact that this is a population of male veterans whose etiologic distribution of cardiomyopathy and heart failure is likely different from a general heart failure population. Furthermore, like V-HEFT I, the population is likely highly selected and it’s unclear how many patients from the general heart failure population would meet study criteria. It’s probable that the majority would not. Similar to V-HEFT I, results from this study provide no guidance on the management of heart failure patients in the inpatient setting. Finally, differences in mortality were not correlated with differences in the physiologic endpoints of EF and exercise tolerance.Thanks for reading Cardiology Trial’s Substack! This post is public so feel free to share it. Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe

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N Engl J Med 1987; 314:1429-35Background Prior to the publication of this study, digoxin and diuretics were the mainstay of chronic heart failure management. No therapy had yet been shown to reduce mortality or improve heart failure outcomes in patients with severe disease. The results of the V-HEFT trial had been published in the prior year, which demonstrated that the vasodilator combination of hydralazine and isosorbide reduced death in patients with chronic, stable heart failure. CONSENSUS was the first study to test whether vasodilator therapy in general, and angiotensin converting enzyme inhibitors in particular could modify heart failure disease trajectory for those with severe disease when used as part of chronic disease management. The CONSENSUS trial was designed to test the hypothesis that Enalapril compared to placebo reduced mortality in patients with severe (NYHA IV) congestive heart failure.Patients Men and women with severe (NYHA IV) congestive heart failure and cardiomegaly based on heart size >600 ml/m2 in men or >550 ml/m2 in women were recruited from 35 centers in Finland, Norway and Sweden. Measurement of LV function was not required. Patients were excluded if they had 1) acute pulmonary edema, 2) hemodynamically important aortic or mitral valve stenosis, 3) MI within the previous 2 months, 4) unstable angina, 5) planned cardiac surgery, 6) right heart failure due to pulmonary disease, or 7) serum creatinine >3.4 mg/dL.It is not specified whether patients could be recruited from the inpatient or outpatient setting or both but prior to randomization, a 14-day period was allowed to stabilize patients on digoxin and diuretics. If during this period, their condition improved to NYHA class III or less they were not randomized.Baseline characteristics The majority of participants were male (70%) and their average age was 70. The average heart rate and blood pressure were 80 bpm and 120/75 mmHg and the average serum creatinine was about 1.5 mg/dL. Coronary artery disease was present in over 70% of participants and nearly 50% had suffered a previous heart attack. Hypertension and diabetes were present in over 20% and atrial fibrillation in 50%. The use of medications at baseline was evenly distributed between groups with nearly all patients being on digoxin and furosemide. About 50% of participants were also taking spironolactone as well as other vasodilator drugs. About 50% of patients had heart failure for more than 4 years.Procedures Treatment with enalapril or an identical placebo was initially started in the hospital with a dose of 5 mg twice a day. After 1 week it was increased to 10 mg twice a day if the patient did not have symptoms of hypotension or other side effects. According to the clinical response, a further increase in dosage could occur up to a maximum dose of 20 mg twice a day.Patients were evaluated after 1, 2, 3, 6, and 16 weeks, 6, 9, and 12 months and at the end of the study. In patients with worsening symptoms, additional vasodilator therapy with isosorbide dinitrate, hydralazine, or prazosin, in that sequence was recommended.Early in the trial the occurrence of symptomatic hypotension led to revision of the protocol after 67 patients had been randomized. No patient’s treatment was unblinded but in patients with 1) serum sodium Endpoints The primary endpoints were stated as 6-month mortality and cause of death. The cause of death was determined by 2 blinded investigators independently. Secondary endpoints were 12-month and overall mortality during the entire trial period, according to the intention-to-treat principle.A sample size of 400 patients was calculated on the assumption that the 6-month mortality would be 40% in the control group and 24% in the enalapril group (alpha = 0.05, power = 90%, two-tailed test). All randomized patients were included in the mortality analyses. No formal rule was adopted governing the interruption of the trial for the purpose of interim analyses by the Ethical Review Committee.Results The trial was terminated early by the Ethical Review Committee after only 63% of the target population number had been enrolled for a total of 253 patients – 126 in the placebo group and 127 in the enalapril group. It is reported that at this time the difference in outcomes was sufficient enough to recommend termination. Only 194/253 (77%) patients achieved a 6 month follow up, and 102/253 (40%) achieved a 12 month follow up and this is not broken down by treatment group. Despite these limits, 6-month, 12-month and total mortality data is provided for all 253 patients. Information is not provided on how the trial was conducted after it was terminated and information is not provided on whether the protocol was maintained or not. No details of this are provided in the manuscript and in the discussion, readers are informed that a detailed report from the Ethical Review Committee is available upon request.Based on what is reported, the mean overall follow up time was 160 days (0.44 years) in the placebo group and 215 days (0.59 years) in the enalapril group. Again, based on the reported results, which include a high percentage of follow up time occurring after study termination, the 6-month death totals were 55 (44%) in the placebo group and 33 (26%) in the enalapril group for a p value of 0.002. The 12-month totals were 66 (52%) in the placebo group and 46 (36%) in the enalapril group for a p value of 0.001. Total mortality was 68 (54%) in the placebo group versus 50 (39%) in the enalapril group for a p value of 0.003. Based on the total mortality, the estimated death rate per 100 patient years in the placebo group was 124 and in the enalapril group was 67 for a difference of 57 deaths per 100 patient years.Total cardiac death occurred in 64 (51%) of the placebo group and 50 (39%) of the enalapril group for a p value of 0.001. The estimated cardiac death rate per 100 patient years in the placebo group was 116 and 59 in the enalapril group for a difference of 57 cardiac deaths per 100 patient years.For patients who were alive after results were reported (58 in placebo group and 77 in enalapril group), this was the breakdown of NYHA class for placebo and enalapril groups: for class 4 (34% vs 27%), class 3 (43% vs 49%), class 2 (3% vs 17%), and class 1 (0% vs 4%).There was no significant difference in overall withdrawals between groups with 18 (14%) in the placebo group and 22 (17%) in the enalapril group; however, hypotension led to the withdrawal of 7 patients in the enalapril group and 0 in the placebo group. In the initial phase of the study, when a starting dose of 5 mg twice a day was used, 4 of the first 34 patients in the enalapril group withdrew due to hypotension (12%); however, after the protocol change, where high-risk patients were started on 2.5 mg daily, only 3 of the remaining 93 patients in the enalapril group withdrew due to hypotension (3%). The number of withdrawals due to deterioration in creatinine were 4 (3%) in the placebo group and 6 (5%) in the enalapril group, respectively.The average time to withdrawal was 67 days in the placebo group and 75 in the enalapril group and the average survival time following withdrawal was 27 days in the placebo group and 80 in the enalapril group.After the 1st dose, the fall in SBP was greater in the enalapril group compared to placebo (118 to 98 [20] mmHg vs 121 to 111 [10] mmHg), respectively and mean heart rate was unchanged.The final mean dose of enalapril was 18.4 mg (Conclusions The CONSENSUS trial compared enalapril with placebo in patients with NYHA 4 congestive heart failure. The fragility of this patient population is supported by the very high death rates in both groups (this makes the mortality rate per 100 patient years higher than 100); however, enalapril significantly reduced death and increased survival. Results from this trial would seem to apply to very sick outpatients or inpatients admitted with acute decompensations. It should be remembered that stabilization of patients’ conditions with digoxin and diuretics was a requirement. Enthusiasm for these results must be tempered by concerns for bias in the trial.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Thanks for reading Cardiology Trial’s Substack! This post is public so feel free to share it. Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe

N Engl J Med 1986; 314:1547-52Background Into the mid-1980’s, digoxin and diuretics were the mainstay of chronic disease management for congestive heart failure. Vasodilator agents were also commonly used based on limited data of their favorable hemodynamic effects. No sufficiently powered trials in this space had been performed to assess whether administration of vasodilators or any other agents improved long-term morbidity or mortality for heart failure patients. The V-HEFT trial was undertaken to test the hypotheses that 2 widely used vasodilator regimens (prazosin or a combination of hydralazine and isosorbide dinitrate) were superior for reducing death versus placebo. The trial was sponsored by the Veterans Administration and only enrolled men.Patients Men between the ages of 18 and 75 were recruited from 11 participating Veterans Administration hospitals and had to have chronic congestive heart failure based on either evidence of cardiac dilatation or left ventricular dysfunction (EF Baseline characteristics The average age of patients in the trial was 58 years. Over 40% of patients had coronary artery disease and/or previous MI and about 13% had previous bypass surgery. Excess alcohol use as well as hypertension were also present in about 40% of patients and diabetes was present in about 20%. There was a notable difference in the diabetes rates between groups that nearly reached statistical significance (placebo [24.5%], prazosin [18.7%], hydralazine-nitrate [17.2%]). Prior to randomization, about 40% of patients were taking vasodilators, 27% antiarrhythmics, 20% sublingual nitroglycerin and 20% anticoagulants.The average symptom score of participants was 5.6 on a scale of 4-12. Symptoms included dyspnea, fatigue, orthopnea and PND each scored from 1 (none) to 3 (severe). The average BP was about 119/76 mmHg, HR 81 bpm, and EF 30%.Procedures Prior to randomization, digoxin and diuretic therapy were adjusted to achieve a digoxin blood level >0.7 ng/mL and euvolemic volume status. Clinical evaluations and exercise-tolerance tests on 2 consecutive visits, two weeks apart, had to reveal clinical and exercise stability before randomization could occur. Following randomization, patients continued to receive the optimal dose of digoxin and diuretic along with 1 of 3 study regimens. The placebo group was given placebo tablets and placebo capsules and instructed to take them 4 times a day. The prazosin group took 2.5 mg prazosin capsules and placebo tablets 4 times a day. The hydralazine-isosorbide dinitrate group took 37.5 mg hydralazine capsules and 20 mg isosorbide dinitrate tablets 4 times a day.In all groups, therapy began with 1 capsule and 1 tablet to be taken 4 times a day. In the absence of side effects, this was increased to 2 capsules and 2 tablets 4 times a day for a total of 20 mg of prazosin or 300-160 mg of hydralazine-isosorbide dinitrate. If drug-related side effects occurred, the dose could be reduced to half a tablet 4 times per day or to one capsule 2 times per day. If the dose was reduced, an attempt was made later to reinstitute the full dose.In order to limit dropouts, rigorous criteria were established for “treatment failures.” Physicians were advised to hospitalize patients with worsening symptoms, and, if appropriate, to use temporary intravenous vasodilator or inotropic interventions for stabilization. Physicians were encouraged to resume study medications upon discharge. At least 2 such hospitalizations were required, along with objective evidence of deterioration, before the study medications were discontinued and replaced with known therapy.Endpoints The primary endpoint was all-cause mortality.Results 642 patients were enrolled (273 in placebo group, 183 in prazosin group and 186 in the hydralazine-isosorbide dinitrate group). Excluding discontinuations that took place within 1 month before death, 47 patients (17%) discontinued one or both types of placebos, 43 patients (23%) discontinued prazosin, and 60 patients (32%) discontinued either one or both drugs in the hydralazine-isosorbide group. Six months after randomization, the average prescribed doses were 18.6 mg per day of prazosin, 270 mg per day of hydralazine, and 136 mg per day of isosorbide dinitrate. More than 85% of the prescribed drugs were taken in each treatment group.The mean follow-up was 2.3 years (range 6 months to 5.7 years). Only 4 patients were lost to follow up (2 in placebo group, 1 in prazosin group, and 1 in hydralazine-dinitrate group). There were 120 deaths in placebo group (44%; 19 per 100 patient years), 91 in the prazosin group (50%; 22 per 100 patient years), 72 in the hydralazine-dinitrate group (39%; 17 per 100 patient years). A reduction in mortality over the entire follow-up period was observed in the hydralazine-nitrate group compared with placebo (p = 0.093 on the log-rank test and p = 0.046 on the generalized Wilcoxon test, which gives more weight to treatment differences occurring in the earlier part of the mortality curves and less weight to the latter part, where the numbers are smaller). The absolute difference in mortality between these groups increased during three years and then began to diminish. The absolute difference in mortality between the placebo group and hydralazine-isosorbide groups at years 1 through 4 was 7%, 9%, 11% and 4%, respectively.Prespecified subgroup analysis in CAD vs no CAD stratification showed no significant treatment effect heterogeneity for hydralazine-nitrate among those with CAD although the absolute difference in mortality between groups was numerically higher for patients with CAD.At 8 weeks and 1 year, SBP (-4.1 and -4.6 mmHg) and DBP (-3.2 and -2.7 mmHg) decreased the most in the prazosin group compared to placebo. Hydralazine-nitrate was not associated with a statistically significant nor clinically significant difference in BP with exception of DBP at 8 weeks. The EF rose significantly at 8 weeks and 1 year in the hydralazine-nitrate group (+2.9 and +4.2) compared to placebo but not in the prazosin group.Side effects were reported in 4.0% of placebo patients, 11% of prazosin patients and 19% of hydralazine-nitrate patients, respectively. The most common side effects were headache and dizziness. Headache was reported in 12% of hydralazine-nitrate patients.Conclusions This study compared the combination of hydralazine-isosorbide dinitrate or prazosin to placebo in patients with chronic congestive heart failure who were optimized on digoxin and diuretic therapy. In what appears to be a young (58 years) and highly selected population of clinically stable, male veterans with dilated cardiomyopathies and low symptom burdens, the combination of hydralazine-isosorbide reduced death by 2 per 100 patient years, increased EF by 4% at 1 year and did not significantly alter BP compared to placebo. Side effects were reported in approximately 1 out of 5 patients with the most common being headache and approximately 1 out of 3 discontinued 1 or both study drugs. Prasozin did not reduce death or increase EF but did reduce BP compared to placebo. The internal validity of the study is high with only a few minor imbalances in baseline characteristics, which do not appear clinically relevant nor to consistently favor any one group. Less than 1% of patients were lost to follow up with no significant imbalances between groups. The external validity is limited by the fact that this is a population of male veterans and the etiologic distribution of cardiomyopathy and heart failure is likely different from a general heart failure population; etiologic causes of death are also likely to be different. Furthermore, the population is highly selected and its unclear how many patients from the general heart failure population would meet study criteria.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

N Engl J Med 2017;377:2419-2432Background: A small fraction of patients with acute myocardial infarction (5-10%) have cardiogenic shock. These patients have a high baseline mortality. Early revascularization had been established as better than initial stabilization with medical therapy. Many patients with cardiogenic shock due to acute myocardial infarction (AMI) have multivessel disease. The question arises about whether to do culprit-only percutaneous coronary intervention (PCI) or more complete PCI at the time of the initial intervention.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 Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial was designed to test the hypothesis that PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, would result in better clinical outcomes than immediate multivessel PCI among patients who have multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock.Patients: The trial enrolled 706 patients with acute myocardial infarction (ST-segment elevation or non-ST-segment elevation) complicated by cardiogenic shock who had multivessel coronary artery disease. Cardiogenic shock was defined as SBP 2 mmol/L).Exclusion criteria were extensive and designed to exclude patients with extremely poor prognosis: prolonged resuscitation, no intrinsic heart action, fixed dilated pupils, an indication for urgent CABG, a mechanical cause of shock, age > 90 years, massive pulmonary embolism, or severe renal insufficiency at baseline.Baseline Characteristics: The median age was 70 years, and approximately 75% were male. About 63% of patients had three-vessel disease. More than half the patients had ST-segment elevation myocardial infarction (about 62%), and anterior ST-segment elevation MI accounted for approximately 54% of these cases. About 53% of patients required resuscitation before randomization. The median left ventricular ejection fraction was between 30-33%.Procedures: In the culprit-lesion-only PCI group, only the culprit lesion was treated during the initial procedure, with staged revascularization encouraged based on residual ischemic lesions. In the multivessel PCI group, PCI of all major coronary arteries with >70% stenosis was performed, including attempts to recanalize chronic total occlusions. Crossover from the culprit-lesion-only PCI group to the multivessel PCI group occurred in 12.5% of patients, while crossover in the opposite direction happened in 9.4% of patients. The overall dose of contrast material was significantly higher and the duration of fluoroscopy significantly longer in the multivessel PCI group. Other interventional therapeutic measures were allowed, independent of the assigned treatment strategy.Endpoints: The primary endpoint was a composite of death from any cause or severe renal failure leading to renal-replacement therapy within 30 days after randomization. Secondary endpoints included the individual components of the primary endpoint, recurrent myocardial infarction, rehospitalization for heart failure, repeat revascularization, time to hemodynamic stabilization, catecholamine therapy duration, ICU stay duration, and measurements of renal and myocardial injury. Safety end points included bleeding, which was defined as type 2, 3, or 5 on the Bleeding Academic Research Consortium (BARC) scale.Trialists estimated an event rate of the composite primary endpoint of 38% in the culprit-only group vs 50% in the complete group. Using a global type I error level of 0.05, the authors calculated that a sample of 684 patients would give the trial 80% power to rule out the null hypothesis of no difference between the two treatment groups in the event rate for the primary end point.Results: At 30 days, the composite primary endpoint occurred in 45.9% of patients in the culprit-lesion-only PCI group versus 55.4% in the multivessel PCI group (relative risk, 0.83; 95% CI, 0.71 to 0.96; P=0.01). Death occurred in 43.3% of the culprit-lesion-only PCI group versus 51.6% of the multivessel PCI group (relative risk, 0.84; 95% CI, 0.72 to 0.98; P=0.03). The rate of renal-replacement therapy was 11.6% in the culprit-lesion-only PCI group and 16.4% in the multivessel PCI group (relative risk, 0.71; 95% CI, 0.49 to 1.03; P=0.07).Rates of recurrent myocardial infarction, rehospitalization for heart failure, bleeding, and stroke did not differ significantly between groups. Subgroup analyses showed consistent results across all prespecified subgroups. The time to hemodynamic stabilization, the use of catecholamine therapy and the duration of such therapy, the duration of the ICU stay, and the use of mechanical ventilation and the duration of such therapy also did not differ significantly between the two groups.Conclusion: In patients with myocardial infarction and cardiogenic shock, culprit-only PCI was superior to multivessel PCI. Both components of the primary endpoint, death and severe renal failure were lower in the culprit-only arm. The authors and editorialists speculate why these findings contrast with trials in hemodynamically stable myocardial infarction patients, where early multivessel PCI showed benefit over culprit-only PCI.If you accept the thesis that multi-vessel PCI was superior to culprit-only PCI in stable AMI patients, the likely reason for the disparate results are that patients with cardiogenic shock differ substantially from stable patients. The sicker patients with cardiogenic shock benefit from a less-is-more approach where culprit-only PCI reduces treatment harm relative to multivessel PCI.We at CardiologyTrials, however, find the evidence for complete revascularization in stable AMI patients less than clear. The COMPLETE trial found benefit from multivessel PCI over culprit-only, but both composite endpoints were driven largely by non-fatal MI. CV death was not substantially different. The difference in MI could have been related to excluding procedure-related MI.What’s more, the FULL-REVASC trial, which also compared culprit-only and multivessel PCI, failed to replicate the COMPLETE trial results. In FULL-REVASC the rates of the composite primary outcome of death, MI or unplanned revascularization were not significantly different. Sadly, FULL-REVASC was stopped early when COMPLETE results were published, which led to a possible loss of power.It’s possible, likely even, that the null results of CULPRIT-SHOCK are not really that disparate from prior trials in patients with more stable AMI.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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N Engl J Med 2024;391:1673-1684Background: Non-ST elevation myocardial infarction (NSTEMI) is the most common acute coronary syndrome subtype in adults over 75 years old. However, these patients were underrepresented in landmark NSTEMI trials. Older adults with multiple comorbidities face an increased risk of mortality. While NSTEMI contributes to this risk, they also have competing risks such as advanced age, frailty, and chronic kidney disease. The presence of competing risks means that aggressively managing one condition may have a smaller impact on overall mortality compared to a younger, otherwise healthy adult with myocardial infarction, whose primary risk of death stems from the myocardial infarction itself. Additionally, comorbid conditions like advanced kidney disease and diffuse atherosclerosis can increase the risks associated with revascularization.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.A patient-level meta-analysis of smaller trials, including 1,479 patients, found that in elderly patients with NSTEMI, an invasive strategy reduced myocardial infarction and urgent revascularization but not mortality.The Older Patients with Non–ST-Segment Elevation Myocardial Infarction Randomized Interventional Treatment (SENRIOR-RITA) trial sought to assess invasive vs conservative management of elderly patients with NSTEMI, in a more pragmatic design.Patients: Eligible patients had to have type I NSTEMI and be 75 years or older.Patients were excluded if they had cardiogenic shock or life expectancy less than 1 year.Baseline characteristics: The trial randomized 1,518 patients from hospitals across England and Scotland – 753 randomized to invasive strategy and 765 to conservative strategy.The average age of patients was 82 years and 55% were men. Approximately 65% had hypertension, 31% had diabetes, 31% had hyperlipidemia, 31% had prior myocardial infarction, 15% had prior stroke or TIA, 21% had kidney disease, 15% had chronic obstructive pulmonary disease, and 5% were current smokers.The average Charlson comorbidity index was 5.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo invasive or conservative strategy.In the invasive strategy, patients underwent coronary angiogram, and revascularization was performed as appropriate. In the conservative arm, patients were treated (unless contraindicated) with aspirin, a P2Y12 receptor antagonist, statin, beta-blocker and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. Patients in the conservative arm were allowed to have a coronary angiogram if they had worsening clinical status.Endpoints: The primary end point was a composite of cardiovascular death or nonfatal myocardial infarction. Secondary outcomes included all-cause death, subsequent coronary revascularization, hospitalization for heart failure, stroke and bleeding.Analysis was performed based on the intention-to-treat principle. The trial aimed to detect a hazard ratio of 0.78, assuming a 20% risk of the primary outcome in the conservative arm. A sample size of 1,668 patients with at least 688 primary outcome events would provide 90% power at 5% alpha, while 520 events would provide 80% power.Results: Among the patient randomized to the invasive arm, 90% underwent coronary angiography and 50% underwent revascularization. The medium number of days from admission to coronary angiography was 5. Among patients randomized to the conservative arm, 5.6% underwent coronary angiography within 7 days. The median follow-up time was 4.1 years.The primary outcome was not significantly different between both groups (25.6% with invasive vs 26.3% with conservative, HR: 0.94, 95%: 0.77 - 1.14; p= 0.53).There was also no difference in all-cause death (36.1% vs 32.3%), cardiovascular death (15.8% vs 14.2%), stroke (4.2% vs 5.2%), hospitalization for heart failure (10.9% vs 10.7%), or major bleeding (8.2% vs 6.4%) “incidence for invasive mentioned first”. Future coronary revascularization was more frequent in the conservative arm (13.7% vs 3.9%). Non-fatal myocardial infarction was significantly lower with an invasive strategy (11.7% vs 15.0%).Procedural related complications occurred in less than 1% of the patients.There were no significant subgroup interactions for the primary outcome.Conclusion: In older patients with NSTEMI, an invasive strategy compared to conservative strategy, did not reduce the primary composite endpoint of cardiovascular death or nonfatal myocardial infarction, over a median of 4.1 years.The trial enrolled fewer patients than planned, and the lower-than-expected event rate reduced its statistical power. Additionally, the median 5-day delay before coronary angiography may have biased the results toward the conservative strategy.Despite its limitations, this trial demonstrates that a conservative approach is a reasonable option for selected older patients with NSTEMI. It also highlights that, although enrolling older patients with comorbidities in trials is challenging, it is feasible, and greater effort is needed to include more of this population in future trials.Finally, in this trial of patients with myocardial infarction, about one-third died over a median of 4.1 years, with less than half of these deaths attributed to cardiovascular disease. Even if an invasive strategy had reduced cardiovascular mortality, its impact on all-cause mortality would have been less significant. This concept extends beyond this trial; when interventions are applied to older patients with multiple competing risks, their overall benefit diminishes.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

JAMA Intern Med 2023;183:407-415Background: As we have previously discussed, trials comparing invasive versus conservative management in patients with non-ST elevation myocardial infarction (NSTEMI) have yielded mixed results. The average age of participants in these studies was in the 60s, and multiple comorbidities were relatively uncommon. However, many NSTEMI patients seen in clinical practice are older and have multiple comorbidities. These patients have worse prognosis and have competing risks for mortality. Whether an invasive strategy provides a benefit for this population remains uncertain.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 MOSCA-FRAIL trial sought to compare invasive vs conservative strategy in older adults with frailty and NSTEMI.Patients: Eligible patients had to have NSTEMI, be 70 years or older, and have frailty defined by 4 points or greater on the Clinical Frailty Scale.Patients were excluded if they were known to have nonrevascularizable coronary artery disease, significant concomitant non-ischemic heart disease, or life expectancy less than 12 months.Baseline characteristics: The trial randomized 167 patients from 13 hospitals in Spain – 84 randomized to invasive strategy and 83 to conservative strategy.The average age of patients was 86 years and 47% were men. Approximately 92% had hypertension, 56% had diabetes, 77% had hyperlipidemia, 31% had prior myocardial infarction, 27% had history of atrial fibrillation, 18% had prior stroke, 44% had chronic kidney disease, and 3% were current smokers.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo invasive or conservative strategy.In the invasive strategy, patients underwent coronary angiogram within 72 hours of admission, and revascularization was performed as appropriate. In the conservative arm, patients were treated with medical therapy alone. A coronary angiogram was permitted for recurrent ischemia during the index admission.Medical treatment was given according to the guidelines at the time. In both arms, dual antiplatelet was recommended for one year. In patients with high bleeding risk or taking an oral anticoagulant, one antiplatelet could be stopped after the first month.Endpoints: The primary end point was the number of days alive and out of the hospital between discharge from the index hospitalization to 1 year. The coprimary end point was the composite of cardiac death, reinfarction, or post-discharge revascularization.Analysis was performed based on the intention-to-treat principle. The estimated sample size to provide 80% power at 5% alpha was 176 patients. This assumed that the number of days for the primary outcome in the conservative arm was 273 days and that an invasive strategy would increase that by 20%, that is 55 days.Results: Due to the COVID pandemic, the trial was terminated early after randomizing 95% of the planned sample size. During the index admission, 98% of the patients in the invasive arm underwent coronary angiogram and 60% underwent revascularization. Among patients in the conservative arm, 9.6% underwent revascularization due to recurrent ischemia during the index admission.The primary outcome (number of days alive and out of the hospital between discharge from the index hospitalization to 1 year) was numerically lower with the invasive arm but this was not statistically significant (mean difference 28 days, 95% CI: -7 – 62; p= 0.12).There was no difference in the coprimary end point - cardiac death, reinfarction, or post-discharge revascularization – absolute values were not provided. The invasive strategy was associated with significantly more bleeding events requiring hospitalization (8 patients vs 1 patient, incidence rate ratio: 14.9, 95% CI: 1.7 – 129.0; p= 0.02) including 4 deaths related to bleeding.Conclusion: In older, frail patients with NSTEMI, an invasive strategy did not significantly reduce the number of days of being alive and out of the hospital at 1-year. It also did not reduce the coprimary end point which was the composite of cardiac death, reinfarction, or post-discharge revascularization. An invasive strategy was associated with more bleeding requiring hospitalization.The trial is small, and its results should be interpreted with caution. Nonetheless, it is an important study that paves the way for future, larger trials in this population. The primary endpoint is both meaningful and relevant to this population. The average age of participants in this trial is approximately 20 years older than those in TACTICS-TIMI 18, RITA 3, and ICTUS. It is important to recognize that older, frail patients with multiple comorbidities are significantly underrepresented in clinical trials and likely derive less benefit or even harm from interventions.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. 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N Engl J Med 2005;353:1095-1104Background: Prior trials on revascularization in patients with acute coronary syndromes without ST-segment elevation have yielded mixed results. While FRISC II and TACTICS-TIMI 18 demonstrated a significant reduction in myocardial infarction, this benefit was not observed in RITA 3. None of these trials showed a significant reduction in mortality. Further research is needed to guide treatment strategies in this population, particularly after the introduction of early use of clopidogrel and intensive lipid-lowering 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 Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) trial sough to test the hypothesis that an early invasive strategy is superior to selective invasive strategy for patients with non-ST elevation myocardial infarction (NSTEMI).Patients: Eligible patients had to have all of the following: Worsening symptoms of ischemia or symptoms at rest with the last episode being 24 hours before randomization, elevated cardiac troponin T level (≥0.03 μg per liter); and either ischemic EKG changes (defined as ST-segment depression or transient ST-segment elevation exceeding 0.05 mV, or T-wave inversion of ≥0.2 mV in two contiguous leads) or a documented history of coronary artery disease.Patients were excluded if they were older than 80 years, had an indication for primary percutaneous coronary intervention or fibrinolytic therapy, hemodynamic instability or overt congestive heart failure, oral anticoagulant drugs use in the past 7 days, fibrinolytic treatment within the past 96 hours, percutaneous coronary intervention within the past 14 days, elevated bleeding risk, plus others.Baseline characteristics: The trial randomized 1,200 patients from 42 Dutch hospitals – 604 randomized to early invasive strategy and 596 randomized to selective invasive strategy.The average age of patients was 62 years and 74% were men. Approximately 39% had hypertension, 14% had diabetes, 35% had hyperlipidemia, 23% had prior myocardial infarction and 41% were current smokers.Approximately 48% of the patients had ST deviation equal to or greater than 0.1 mV.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo early invasive vs selective invasive strategy.Patients received 300 mg of aspirin at the time of randomization, followed by at least 75 mg daily indefinitely, and enoxaparin (1 mg/kg for a maximum of 80 mg) subcutaneously twice daily for at least 48 hours. The early use of clopidogrel (300 mg immediately, followed by 75 mg daily) in addition to aspirin was recommended to the investigators after the drug was approved for acute coronary syndrome in 2002. Intensive lipid-lowering therapy, preferably atorvastatin 80 mg daily or the equivalent was recommended as soon as possible after randomization. All interventional procedures during the index admission were performed with the use of abciximab.Patients assigned to the early invasive strategy were scheduled to undergo angiography within 24 - 48 hours after randomization. Patients assigned to the selective invasive strategy underwent coronary angiography if they had refractory angina despite optimal medical therapy, hemodynamic or rhythm instability, or significant ischemia on pre-discharge exercise test.In both groups, percutaneous coronary intervention (PCI) was performed when appropriate, without providing more details in the manuscript.The level of creatine kinase MB was measured at 6-hour intervals during the first day, after each new clinical episode of ischemia, and after each percutaneous revascularization procedure.Endpoints: The primary endpoint was a composite of all-cause death, myocardial infarction, or rehospitalization for angina at 1-year.The estimated sample size to provide 80% power to detect 25% relative risk difference between the two treatment groups at 5% alpha was 1,200 patients. This assumed that 21% of the patients in the early invasive arm would experience the primary outcome.Results: During the index admission, 98% of the patients in the early invasive strategy arm underwent coronary angiogram compared to 53% in the selective invasive arm. At 1-year, 79% of the patients in the early invasive strategy arm underwent revascularization compared to 54% in the selective invasive arm.The primary outcome was not significantly different between both treatment groups (22.7% with early invasive vs 21.2% with selective invasive, RR: 1.07; 95% CI: 0.87 - 1.33; p= 0.33). All-cause death was the same in both groups (2.5%). Myocardial infarction was significantly higher with the early invasive strategy (15.0% vs. 10.0%, RR: 1.50, 95% CI: 1.10 – 2.04; p= 0.005), while rehospitalization for angina was lower with early invasive (7.4% vs. 10.9%, RR: 0.68, 95% CI: 0.47 – 0.98; p= 0.04). Most myocardial infarctions were revascularization related and these were significantly more frequent with early invasive (11.3% vs 5.4%). Spontaneous myocardial infarctions were 3.7% with early invasive and 4.6% with selective invasive and this was not statistically significant.Major bleeding, not related CABG, during the index admission was more frequent with the early invasive strategy (3.1% vs 1.7%).There were no significant subgroup interactions for the primary outcome, including based on ST deviation and troponin levels.Conclusion: In patients with NSTEMI, an early invasive strategy was not superior to selective invasive strategy in reducing the composite endpoint of all-cause death, myocardial infarction, or rehospitalization for angina at 1-year. An early invasive strategy was associated with more myocardial infarctions with a number needed to harm of 20 patients, which was secondary to revascularization related myocardial infarction. An early invasive strategy reduced rehospitalization for angina with a number needed to treat of approximately 29 patients.The ICTUS trial showed that revascularization can cause harm and highlighted how counting procedural myocardial infarctions can influence outcome estimates. While there is ongoing debate about the significance of periprocedural myocardial infarctions, evidence indicates an association with increased mortality. Whether periprocedural myocardial infarctions are 'less severe' than spontaneous myocardial infarctions remains controversial, as their impact varies based on infarct size and patient characteristics. This underscores the importance of including all-cause mortality or advanced systolic heart failure as endpoints in trials of revascularization.Patients in ICTUS received better background medical therapy compared to prior trials in this area. While this could be responsible for the divergent results compared to other prior trials. It also highlights the heterogeneity of NSTEMI patients and that an invasive strategy is not appropriate for all.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

The Lancet 2002;360:743-751Background: The TACTICS-TIMI 18 trial showed that an early invasive strategy in beneficial in selected patients with unstable angina or non-ST-elevation myocardial infarction (NSTEMI). These positive findings contrasted the findings from some earlier studies.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 British Heart Foundation RITA 3 randomized trial sought to compare invasive vs conservative strategy in patients with unstable angina or NSTEMI, similar to the trial question of TACTICS-TIMI 18.Patients: Eligible patients had suspected cardiac chest pain at rest with at least one of the following: Evidence of ischemia on electrocardiogram (ST depression, transient ST elevation, old left bundle branch block, or T wave inversion), pathologic Q waves suggesting previous myocardial infarction, or documented coronary artery disease on prior coronary angiogram.Patients were excluded if they had evolving myocardial infarction in which reperfusion therapy was indicated. Patients were also excluded if creatine kinase or creatine kinase MB concentrations were twice the upper limit of normal before randomization, if they had myocardial infarction within a month, had percutaneous coronary intervention (PCI) in the previous 12 months, or coronary artery bypass grafting (CABG) at any time.Baseline characteristics: The trial randomized 1,810 patients – 895 randomized to the invasive strategy and 915 randomized to conservative strategy. Patients were recruited from 45 hospitals in England and Scotland.The average age of patients was 63 years and 62% were men. Approximately 35% had hypertension on drugs, 13% had diabetes and 28% had prior myocardial infarction.The majority (92%) of the patients were enrolled because they met the criteria for evidence of ischemia on electrocardiogram.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo invasive vs conservative strategy.In the conservative arm, patients received aspirin and enoxaparin 1mg/kg subcutaneously twice a day for 2-8 days. Beta-blockers, other antiplatelets and glycoprotein IIb/IIIa inhibitors could also be used. Coronary angiography could be performed if patients had anginal symptoms at rest or with minimal exertion despite appropriate therapy or if they had ischemia on stress testing.Patients in the invasive strategy arm received similar medical therapy to the conservative arm. Coronary angiogram was to be performed as soon as possible after randomization and ideally within 72 hours. Revascularization was recommended for lesions of at least 70% stenosis or 50% or more if left main.Endpoints: The trial had two co-primary outcomes. The first was a composite of death from any cause, nonfatal myocardial infarction, or refractory angina at 4 months. The second was a composite of death from any cause or nonfatal myocardial infarction at 1 year.Analysis was performed based on the intention-to-treat principle. The estimated sample size to provide 80% power at 5% alpha, was 1,770 patients. This assumed that 12% of the patients in the conservative arm would experience the outcome of death or non-fatal myocardial infarction at 1-year, and that the invasive strategy would result in 33% relative risk reduction in this outcome.Results: In the invasive strategy, 97% of the patients underwent coronary angiogram at a median of 2 days after randomization, and 55.3% underwent PCI or CABG. In the conservative arm, 10.3% had revascularization during the index admission, and 17.3% had revascularization at 1-year. The median follow time was 2 years and 97% of the patients had at least 1-year of follow up.The first primary composite outcome of death from any cause, nonfatal myocardial infarction, or refractory angina at 4 months was lower with the invasive strategy (9.6% vs 14.5%, HR: 0.66, 95% CI: 0.51 – 0.85; p= 0.001). The second primary composite outcome of death from any cause or nonfatal myocardial infarction at 1 year was not significantly different between both groups (7.6% with invasive vs 8.3% with conservative, HR: 0.91, 95% CI: 0.67 – 1.25; p= 0.58). At 1-year, 4.6% patients died in the invasive arm compared to 3.9% in the conservative arm, and this was not statistically significant. Myocardial infarction at 1-year occurred in 3.8% of the patients in the invasive arm compared to 4.8% in the conservative arm, and this was not statistically significant as well.All bleeding occurred in 8.2% in the invasive arm and 3.5% in the conservative arm.Subgroup analysis showed that men benefited from an invasive strategy while women did not (p for interaction= 0.011). The endpoint of death or myocardial infarction at 1-year, in women, was 5.1% in the conservative arm and 8.6% in the invasive arm, while in men, the incidence of this endpoint was 10.1% in the conservative arm and 7.0% in the invasive arm.Conclusion: In patients with unstable angina or NSTEMI, an invasive strategy compared to conservative strategy, reduced refractory angina but not myocardial infarction or death at 1-year.The reduction in angina is a subjective endpoint, prone to bias and faith healing, as we have previously discussed in other trials of PCI. The reduction in this endpoint alone should not justify widespread adoption of invasive strategy for unstable angina or NSTEMI.A key distinction between this trial and TACTICS-TIMI 18—which demonstrated a reduction in myocardial infarction with an invasive approach—is that this study included patients with smaller myocardial infarctions. Only 41% of participants had ST depression or transient ST elevation, and patients were excluded if creatine kinase or creatine kinase MB levels were more than twice the upper limit of normal before randomization. This highlights the heterogeneity among patients with unstable angina and NSTEMI, where baseline risk and the extent of myocardial necrosis influence treatment effects. We encourage you to read again the subgroup interactions of TACTICS-TIMI 18.Additionally, in the current era, high-sensitivity troponin assays enable the detection of smaller myocardial infarctions, potentially limiting the applicability of older trial results to all present NSTEMI patients.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

N Engl J Med 2001;344:1879-1887Background: Acute coronary syndrome is broadly categorized into unstable angina, non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI). In unstable angina, there is no rise in cardiac biomarkers, although some challenge this clinical entity in the current era of high sensitivity troponins. In NSTEMI, there is elevation of cardiac biomarkers but no ST segment elevation on the electrocardiogram. In STEMI, there is an ST segment elevation on the electrocardiogram as well as a rise in cardiac biomarkers.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.In patients with STEMI, percutaneous coronary intervention (PCI) significantly improves outcomes. However, its role in acute coronary syndrome without ST-segment elevation is less clear for several reasons. Patients with NSTEMI tend to be older and have more comorbidities, increasing procedural risks. This also means that they have competing risks for mortality, potentially reducing the benefit of PCI. Another key challenge is that NSTEMI patients frequently have multivessel disease, making it more difficult to identify the culprit lesion; since there is usually only partial occlusion of the culprit coronary artery. In contrast, there is usually complete occlusion of a coronary artery in STEMI and ST-segment elevation on the electrocardiogram helps localize the infarcted area, making it relatively easy to identify the culprit artery.The findings from previous randomized trials of revascularization in unstable angina and NSTEMI, have been inconsistent. The TACTICS–Thrombolysis in Myocardial Infarction 18 trial sought to compare early invasive vs conservative strategy in patients with unstable angina or NSTEMI.Patients: Eligible patients had angina within 24 hours that was: >20 minutes in duration, accelerating angina, or recurrent episodes at rest or with minimal effort. Patients also had to have one of the following: ST-segment depression of at least 0.05 mV, transient (Patients were excluded if they have persistent ST elevation, PCI or CABG within 6 months, LBBB or paced rhythm, high bleeding risk, severe congestive heart failure or cardiogenic shock, serious systemic illness, or serum creatinine > 2.5 mg/dL.Baseline characteristics: The trial randomized 2,220 patients – 1,114 randomized to early invasive strategy and 1,106 randomized to conservative strategy.The average age of patients was 62 years and 66% were men. Approximately 28% had diabetes and 39% had prior myocardial infarction.Troponin T levels were elevated (>0.01 ng/ml) in 54% of the patients.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo early invasive vs conservative strategy.Patients received aspirin 325 mg daily, intravenous unfractionated heparin (5000U bolus, followed by an infusion at 1000U/ hour for 48 hours), and intravenous tirofiban (0.4 μg/kg/minute for 30 minutes followed by an infusion of 0.1 μg/kg/minute for 48 hours or until revascularization with tirofiban administered for at least 12 hours after PCI).Patients in the early invasive arm underwent coronary angiogram between 4 and 48 hours after randomization and underwent PCI as appropriate. Patients in the conservative arm were treated medically. If stable, they underwent an exercise-tolerance test before discharged (83% of these tests were with nuclear perfusion or echocardiography imaging). Patients in the conservative arm underwent coronary angiography with PCI if they had angina at rest associated with ischemic EKG changes or elevation in cardiac biomarkers, had clinical instability or had ischemia on their stress test.Endpoints: The primary outcome was a composite of death from any cause, nonfatal myocardial infarction, and rehospitalization for an acute coronary syndrome, at six months.The estimated sample size to provide 80% power was 1,720 patients. This assumed that 22% of the patients in the conservative arm would experience the primary outcome and that the early invasive strategy would result in 25% relative risk reduction in the primary outcome. The sample size was later increased to 2,220 patients.Results: In the early invasive strategy, 97% of the patients underwent coronary angiogram after a medium of 22 hours after randomization, and 60% underwent PCI or CABG. In the conservative arm, 51% underwent coronary angiogram and 36% underwent revascularization during the index hospitalization.The primary composite endpoint was lower with the early invasive strategy (15.9% vs 19.4%, odds ratio: 0.78, 95% CI: 0.62 - 0.97; p= 0.025). The Kaplan-Meier curves started to separate at approximately one week. This benefit was driven by lower myocardial infarction and lower rehospitalization for an acute coronary syndrome with the early invasive strategy; (4.8% vs 6.9%) and (11.0% vs 13.7%), respectively. There was no difference in all-cause death (3.3% vs 3.5%).There were 3 important subgroup interactions. First is based on ST changes where patients with ST changes at presentation had all the benefit with an early invasive strategy (16.4% vs 26.3% [for patients with ST changes] and 15.6% vs 15.3% [for patients without ST changes]). Second is based on Troponin T levels where patients with troponin T> 0.1 ng/mL had significantly more benefit with an early invasive strategy (16.4% vs 24.5% and 15.1% vs 16.6%). The third is based on TIMI score where patients with higher TIMI score had more benefit with an early invasive approach. For a high TIMI score of 5-7, the event rate was 19.5% with early invasive vs 30.6% with conservative approach. Patients with TIMI score of 0-2 had no benefit with an early invasive strategy (12.8% with early invasive vs 11.8% with conservative strategy).Note to readers: TIMI score is a risk stratification tool used to predict 14-day adverse outcomes in patients with unstable angina or NSTEMI. The score ranges from 0 to 7 with higher scores indicating worse prognosis.Conclusion: In patients with unstable angina or NSTEMI, an early invasive strategy reduced the composite endpoint of death from any cause, nonfatal myocardial infarction, and rehospitalization for an acute coronary syndrome at six months with a number needed to treat of approximately 29 patients.The subgroup analysis of this trial is particularly important and biologically plausible, as the presence of ST changes and level of cardiac biomarkers elevation indicate more significant myocardial ischemia or necrosis. Patients without ST changes comprised 62% of the study participants, while those with negative cardiac biomarkers made up 59%, and the study results should not be generalized to these subgroups.Another key consideration is the lack of detailed criteria for what was deemed ‘appropriate’ revascularization. Only 60% of patients in the early invasive strategy group underwent revascularization, underscoring that not all patients with unstable angina or NSTEMI benefit from coronary angiography and that further risk stratification is necessary.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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N Engl J Med 2024;390:1481-1492Background: In patients with ST-elevation myocardial infarction (STEMI), opening the culprit artery improves outcomes. Nearly half of STEMI patients have disease in other coronary arteries. Whether revascularizing these non-culprit arteries improves outcomes remained uncertain. The PRAMI trial showed improvement in outcomes with complete revascularization but was relatively small, included 465 patients, and did not require the use of fractional flow reserve (FFR).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 FFR-Guidance for Complete Nonculprit Revascularization (FULL REVASC) trial sought to assess if FFR-guided completed revascularization improves outcomes compared to culprit-only percutaneous coronary intervention (PCI).The COMPLETE trial was not published by the time the FULL REVASC trial started enrolling patients.Patients: Eligible patients had STEMI and were undergoing PCI or had high risk NSETMI undergoing urgent PCI. High risk NSTEMI included patients with dynamic ST–T-wave changes, ongoing chest pain, acute heart failure, hemodynamic instability independent of electrocardiographic changes, or life-threatening ventricular arrhythmias.Eligible patients had to have multivessel coronary artery disease, defined as one or more lesions in a nonculprit artery with a diameter of ≥ 2.5 mm and a visually graded stenosis of 50 - 99%.Patients were excluded if they had previous CABG, left main disease or cardiogenic shock.Baseline characteristics: The trial randomized 1,542 patients – 778 randomized to culprit-only PCI and 764 randomized to complete revascularization. Patients were recruited from 32 centers in 7 countries.Approximately 91% of the patients had STEMI and 9% had high risk NSTEMI.The average age of patients was 65 years and 76% were men. Approximately 51% had hypertension, 16% had diabetes, 23% were on treatment for hyperlipidemia, 8% had prior myocardial infarction, and 35% were current smokers.The number of residual coronary arteries with stenosis of 50-99% was 1 in 72% of the patients and 2 or more in the rest.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo culprit-only PCI or FFR-guide complete revascularization. The study was open label.Patients in the culprit-PCI only group did not receive further revascularization during the index hospitalization. Patients in the FFR-guided complete revascularization could receive further revascularization during the index procedure or during the index hospitalization. PCI of non-culprit lesion was recommended if FFR was 0.80 or less.Endpoints: The primary outcome was a composite of death from any cause, myocardial infarction, or unplanned revascularization. The main secondary outcomes were a composite of death from any cause or myocardial infarction and unplanned revascularizationAnalysis was performed based on the intention-to-treat principle. The estimated sample size to achieve 80% with a two-sided alpha of 0.05 was 4,052 patients. This sample size would detect 0.75 risk ratio for the composite outcome of death or myocardial infarction at 1-year assuming 9.9% event rate in the culprit-only PCI. After the publication of the COMPLETE trial, the trial was stopped early due to ethical and feasibility concerns. Consequently, the original key secondary outcome (death from any cause, myocardial infarction, or unplanned revascularization) became the new primary outcome, and events after 1 year of follow-up were included in the primary analysis.Results: The trial was stopped after randomizing 38.1% of the original sample size. Among the patients assigned to the FFR-guided complete-revascularization arm, the procedure was followed in 95.9% of the patients, and among these patients, 17.9% underwent FFR-guided complete revascularization of non-culprit lesions during the primary PCI and the rest during the index hospitalization. Among the patients assigned to culprit-only arm, the assigned strategy was followed in 99.6% of the patients. The median follow-up time was 4.8 years.FFR was 0.8 or less in 392 (47.3%) of non-culprit vessels assessed, and PCI was performed in 369 (94.1%) of these vessels. In total, PCI was performed in 18.8% of the total non-culprit vessels. The average number of stents during the index hospitalization was 1 in the culprit-only PCI group and 2 in the complete revascularization group.The primary composite outcome was not significantly different between both treatment groups (19.0% with complete-revascularization vs 20.4% with culprit-only PCI, HR: 0.93, 95% CI: 0.74 - 1.17; p= 0.53). There were also no significant differences in composite endpoint of death from any cause or myocardial infarction (16.5% with complete revascularization vs 15.3% with culprit-only PCI) or unplanned revascularization (9.2% with complete revascularization vs 11.7% with culprit-only PCI).Stent thrombosis and stent restenosis were significantly more frequent in the complete revascularization arm (2.5% vs 0.9%, HR: 2.80, 95% CI: 1.18 – 6.67) and (4.2% vs 2.3%, HR: 1.84, 95% CI: 1.03 – 3.28), respectively.Baseline risk or coronary anatomy did not significantly affect subgroup interactions for the primary outcome.Conclusion: In patients with STEMI or high risk NSTEMI, FFR-guided complete revascularization compared to culprit-only PCI, did not improve the outcomes of death from any cause, myocardial infarction, or unplanned revascularization, over a median follow up time of 4.8 years. Complete revascularization resulted in more stent thrombosis and stent restenosis.The study lost some statistical power by stopping early, resulting in a final power of 74%. We disagree with the authors' decision to halt the trial prematurely based on the findings of the COMPLETE trial. COMPLETE was the first large trial to demonstrate a benefit in hard outcomes when revascularizing stable plaques, and its results warrant further confirmation. Furthermore, COMPLETE used different strategy as FFR was not required.Note to readers: Power measures the study’s ability to avoid a Type II error (false negative) and it equals 1 - β with β being the probability of a Type II error. In other words, power represents the probability of correctly rejecting the null hypothesis (H₀) when the alternative hypothesis (H₁) is true. Most clinical trials aim for 80% or 90% power. For example, a study with 80% power has a 20% risk of failing to detect a real effect.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

N Engl J Med 2019;381:1411-1421Background Percutaneous coronary intervention (PCI) had been clearly established as the standard of care for ST elevation myocardial infarction. Yet many patients taken for PCI have multiple lesions in addition to the culprit. The benefit of routinely treating additional significant lesions has been unclear, with previous smaller trials showing reductions in composite outcomes primarily driven by reduced revascularization rates.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 COMPLETE (Complete vs Culprit-Only Revascularization Strategies to Treat Multivessel Disease after Early PCI for STEMI) trial investigated whether performing percutaneous coronary intervention (PCI) on non-culprit lesions reduces cardiovascular risk in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease.Patients The trial enrolled 4,041 patients from 140 centers in 31 countries between February 2013 and March 2017. Eligible patients had STEMI with successful culprit-lesion PCI and at least one non-culprit coronary artery lesion with ≥70% stenosis (or 50-69% stenosis with FFR ≤0.80) in a vessel ≥2.5mm in diameter. Patients were randomized within 72 hours after successful culprit-lesion PCI. Exclusion criteria included planned surgical revascularization and previous coronary bypass surgery.Baseline Characteristics The mean age was approximately 62 years, with about 80% being male. Approximately 19% had diabetes, 8% had previous MI, and 7% had previous PCI. Over 90% of patients underwent primary PCI (vs. pharmacoinvasive or rescue PCI), with 80% using radial access.The groups were well-balanced, with similar SYNTAX scores at baseline and similar culprit and non-culprit lesion characteristics. About 76% had one residual diseased vessel and 24% had two or more. Guideline directed medical therapy was robust and balanced, including more than 99% on dual antiplatelet therapy, 98% on statins, 88% on beta blocker, and 85% on ACEi or ARB.In patients in the complete revascularization group designated for non-culprit PCI during index hospitalization, the mean time to PCI was 1 day. In the group designated for non-culprit PCI after discharge, the mean time was 23 days.Trial procedures Patients were randomized to complete revascularization (n=2,016) or culprit-lesion-only PCI (n=2,025). In the complete revascularization group, investigators specified before randomization whether non-culprit PCI would occur during index hospitalization or after discharge (within 45 days).Everolimus-eluting stents were recommended for all procedures. Both groups received guideline-based medical therapy including dual antiplatelet therapy with aspirin and ticagrelor for at least one year.Endpoints The first coprimary outcome was cardiovascular death or new myocardial infarction. The second coprimary outcome was cardiovascular death, myocardial infarction, or ischemia-driven revascularization. Secondary outcomes included individual components of the composite outcomes, all-cause mortality, and safety outcomes like major bleeding, stroke, and stent thrombosis.Trialists estimated that a sample of 4000 patients would give 80% power to detect a 22% lower risk of the composite of cardiovascular death or myocardial infarction in the complete-revascularization group than in the culprit-lesion-only PCI group, assuming an event rate of 5% per year in the culprit-lesion-only PCI group. The first coprimary outcome was tested at a P value of 0.045 and the second at a P value of 0.0119.The co-primary endpoints were analyzed according to the time to first event approach. Confidence intervals for secondary and exploratory efficacy outcomes were not adjusted for multiple comparisons, and therefore inferences drawn from these intervals may not be reproducible.Results Over a median follow-up of 36.2 months, the first coprimary outcome occurred in 7.8% of the complete-revascularization group versus 10.5% of the culprit-lesion-only group (hazard ratio 0.74, 95% CI: 0.60-0.91; p= 0.004). Benefit was driven by reduced myocardial infarction rates (5.4% vs 7.9%) while cardiovascular death rates were similar (2.9% vs 3.2%).The second coprimary outcome was also reduced with complete revascularization (8.9% versus 16.7%, HR: 0.51, 95% CI: 0.43-0.61; pThe Kaplan-Meier curves show that the benefit of complete revascularization seemed to have emerged over time, with continued divergence of the Kaplan–Meier curves for several years.There was a trend toward higher contrast-induced kidney injury in the complete revascularization arm (Odds ratio: 1.59, 95% CI: 0.89 - 2.84; p= 0.11).Conclusion Among STEMI patients with multivessel coronary artery disease, a strategy of complete revascularization was superior to culprit-lesion-only PCI in reducing the composite outcome of cardiovascular death or myocardial infarction. This benefit was driven by reduction in myocardial infarctions without significant reduction in cardiovascular death.The benefit was consistent whether non-culprit PCI was performed during the index hospitalization or after discharge. The number needed to treat to prevent one cardiovascular death or myocardial infarction was 37 patients over 3 years.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

N Engl J Med 2013;369:1115-23Background: The COURAGE trial was published in 2007. It compared up-front PCI to medical therapy alone in patients with stable CAD. Preventive PCI did not reduce the chance of dying or having a heart attack over a median follow up time of 5 years. The results rocked the cardiology world because for years prior to the publication of COURAGE, the standard of care called for revascularization of obstructive coronary stenosis. Despite what we would consider minor criticisms of COURAGE, the results have held over time as a preventive PCI strategy has failed repeatedly to reduce death or MI compared to medicine alone in subsequent large trials (BARI 2D, FAME 2, ISCHEMIA and ISCHEMIA-CKD) involving patients with stable CAD. But what about patients with acute coronary syndromes who have, a clearly defined “culprit” lesion and stable coronary stenosis of a non-infarct vessel? On the surface, the answer might seem simple - treat the “culprit” lesion with PCI and leave the stable disease alone. Continue optimal medical treatment of stable CAD indefinitely with consideration of revascularization only if new symptoms arise. But what if a stable coronary stenosis behaves differently in a patient with an acute coronary syndrome than in patients without it? Are these patients predisposed or particularly susceptible to acute plaque rupture and thrombogenesis to such an extent that they would benefit from a preventive revascularization strategy? The Primary Angioplasty in Myocardial Infarction (PRAMI) trial sought to test the hypothesis that immediate preventive PCI of non-culprit vessels plus the culprit vessel compared to culprit vessel only PCI would improve outcomes in patients with a STEMI and coronary stenosis of a non-infarct related artery.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: From 2008 through 2013, patients were enrolled from 5 coronary care centers in the United Kingdom. Patients could be any age with acute STEMI and multivessel CAD detected at the time of emergency PCI. The trial was limited to patients with STEMI because ST-segment elevation, unlike ST-segment depression, localizes the area of ischemia in the myocardium and an “infarct-artery” is usually easy to distinguish. Clinically stable patients were considered for eligibility after undergoing PCI of the infarct artery while they were in the catheterization lab. They were eligible if successful PCI of infarct artery was performed and there was stenosis of 50% or more in one or more non-infarct arteries. Exclusion criteria included cardiogenic shock, previous CABG, had left main or significant disease in the ostia of both the LAD and circumflex vessels, or if the only non-infarct stenosis was a chronic total occlusion.Baseline characteristics: The trial screened 2,428 patients and randomized 465 patients (19%) with 234 to preventive PCI and 231 to no preventive-PCI. The majority of patients were excluded for single vessel disease (1122/1922 [58%]). The average age of patients was 62 years and more than 75% were men. Close to 50% were current smokers. The infarct artery was anterior in 35%, inferior in 60% and lateral in 5%. Approximately 65% of patients had 2 vessel disease and 35% had 3 vessel disease.Procedures: After completion of PCI in the infarct artery, eligible patients were randomized and those assigned to the preventive-PCI group underwent the procedure immediately in all non-infarct arteries with a coronary stenosis >50%. PCI was discouraged at a later date (sometimes this strategy is referred to as “staged PCI”) in the no preventive-PCI group unless it was symptom driven. Any patient in the trial with subsequent symptoms of angina that were not controlled with medicine was required to undergo objective assessment of ischemia to secure a diagnosis of refractory angina. Follow-up information was collected at 6 weeks and then yearly thereafter.Endpoints: The primary endpoint was a composite of death from cardiac causes, nonfatal MI, or refractory angina. Secondary outcomes included the individual components of the composite endpoint along with noncardiac death and repeat revascularization. Myocardial infarction was defined as symptoms of cardiac ischemia and a troponin level >99% URL. However, within 14 days after randomization, MI diagnosis also required ECG evidence of new STE or left bundle branch block and angiographic evidence of coronary artery occlusion (essentially this makes it so only in-stent thrombosis or spontaneous STEMI count and other causes of peri-procedural MI do not - this would bias the trial in favor of the preventive-PCI group).Refractory angina was defined as angina despite medical therapy and objective evidence of myocardial ischemia (i.e., ischemia on ECG during spontaneous episode of pain or abnormal results on functional testing).It was determined that 600 patients would be needed to achieve 80% power to detect a 30% relative reduction in the preventive-PCI group, at a 5% level of significance, assuming an annual rate of the primary outcome of 20% in the control group. Stopping criteria were prespecified if the results from the trial showed a primary outcome difference at the 0.001 level of significance. Results: The trial was stopped early based on a significant difference (PCompared to no preventive-PCI, preventive-PCI significantly reduced the primary outcome (9.0% vs 23%; HR 0.35; 95% CI 0.21-0.58) along with the individual components of nonfatal MI (3.0% vs 8.7%; HR 0.32; 95% CI 0.13-0.75) and refractory angina (5.1% vs 13.0%; HR 0.35; 95% CI 0.18-0.69). Cardiac death was also numerically reduced with preventive-PCI but did not reach statistical significance due to low power. Conclusions: In patients with STEMI and non-infarct artery coronary stenosis >50%, preventive PCI significantly reduced a primary composite outcome of cardiac death, nonfatal MI and refractory angina in the PRAMI trial with an estimated NNT of 7 patients over 2 years. Individual components of the primary endpoint that were significantly reduced included nonfatal MI and refractory angina by similarly large margins. These results may seem impressive at first glance but we urge extreme caution in their interpretation. First, this is a relatively small trial with a historically large effect size, especially when considering hard endpoints like cardiac death and nonfatal MI were included. Such results are often later found to be falsely positive when larger, confirmatory studies are conducted. Second, the trial was stopped early and early stopping is prone to yield false positive and/or exaggerated results. Third, inclusion of refractory angina in the primary endpoint, an endpoint susceptible to bias in an unblinded study (see earlier discussion of “faith healing” and “subtraction anxiety” in FAME 2; consideration also must be given to nocebo effects in patients who know they have “untreated blockages”), clouds the main findings by inflating the effect size and making the trial susceptible to large differences in underpowered endpoints before sufficient data can be accumulated on hard outcomes. For example, if the trial had sought to detect a conservative difference of 30% in a primary composite endpoint that only included cardiac death or nonfatal MI, based on an event rate of 12% in the control group (the actual event rate in the trial), over 2,200 patients would be needed for 80% power at a 5% level of significance. The estimated number of actual events would be around 230. However, only 47 events occurred in PRAMI making the results highly susceptible to noise.While results of PRAMI suggest a beneficial role for preventive-PCI in patients with STEMI, more evidence is needed to confirm the results.Thanks for reading Cardiology Trial’s Substack! This post is public so feel free to share it. Get full access to Cardiology Trial’s Substack at cardiologytrials.substack.com/subscribe

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N Engl J Med 2013;369:1587-1597N Engl J Med 2014;371:1111-1120Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Background: In the TAPAS trial, thrombus aspiration in patients with ST elevation myocardial infarction (STEMI) improved coronary reperfusion as evident by coronary blush grade and electrocardiogram. The improvement in these surrogate endpoints was large and generated enthusiasm within the cardiology community regarding the potential of thrombus aspiration. While the trial demonstrated a trend toward improvement in clinical outcomes, this was not statistically significant and the trial was not powered for these clinical outcomes.The Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial was designed to assess the impact of thrombus aspiration in patients with STEMI, and was powered to detect differences in clinical endpoints.Patients: Patients were included if they had chest pain suggestive of myocardial ischemia for at least 30 minutes but less than 24 hours before hospital admission, and if the EKG showed new ST-segment elevation or left bundle-branch block.Patients were excluded if they couldn’t provide informed consent or if they needed emergency coronary artery bypass grafting.The trial enrolled patients from all 29 PCI centers in Sweden, 1 in Iceland and 1 in Denmark.Baseline characteristics: The trial randomized 7,244 patients – 3,621 randomized to thrombus aspiration and 3,623 randomized to conventional PCI.The average age of patients was 66 years and 75% were men. Approximately 42% had hypertension, 12% had diabetes, 21% had hyperlipidemia, 12% had prior myocardial infarction, and 31% were current smokers.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo thrombus aspiration follow by PCI or conventional PCI. The study was open label.The use of anticoagulants during PCI was left to the discretion of the treating physician. Stenting was encouraged with the type of stent left to the discretion of the physician. The administration of P2Y12 inhibitors was also left to the discretion of the physician. Lifelong treatment with aspirin was recommended in all patients.Endpoints: The primary end point was all-cause death at 30 days. Data on mortality were obtained from the national population registry. The secondary end points, which were obtained from the SWEDEHEART registry and the national discharge registry, included 30-day rates of hospitalization for recurrent myocardial infarction, stent thrombosis, target-vessel revascularization, target-lesion revascularization, and the composite of all-cause mortality or recurrent myocardial infarction.Analysis was performed based on the intention-to-treat principle. To achieve 80% power with a two-sided alpha of 0.05, a total of 4,886 patients would be needed to detect a hazard ratio for death of at least 1.30 with PCI alone as compared with PCI plus thrombus aspiration. This calculation assumed the 30-day mortality with PCI alone to be 6.3%. Due to lower than expected mortality rate, the sample size was increased to 7,138 patients. The new sample size would detect an odds ratio for death with PCI alone as compared with PCI with thrombus aspiration of at least 1.5, assuming the 30-day mortality in the conventional PCI group to be 3.5%.Results: Out of the 11,709 patients with STEMI in Sweden or Iceland, 4,697 (40.1%) were not enrolled in the trial. Of these patients not enrolled, 1,162 (24.7%) underwent thrombus aspiration. The median time from onset of symptoms to PCI was approximately 3 hours. No patients were lost to follow up with respect to the primary outcome. Among patients assigned to thrombus aspiration, 93.9% of the patients underwent the procedure. Among patients assigned to conventional PCI, 4.9% underwent thrombus aspiration.The primary outcome of all-cause death at 30-days was similar between both treatment groups (2.8% with thrombus aspiration vs 3.0% with conventional PCI, HR: 0.94, 95% CI: 0.72 - 1.22; p= 0.63).There were no statistically significant differences in any of the secondary outcomes at 30-days (incidence for thrombus aspiration mentioned first): Hospitalization for recurrent myocardial infarction (0.5% vs 0.9%), stent thrombosis (0.2% vs 0.5%), target-vessel revascularization (1.8% vs 2.2%), target-lesion revascularization (1.2% vs 1.6%), and the composite of all-cause death or recurrent myocardial infarction (3.3% vs 3.9%).There was no difference in the incidence of stroke or neurological complications (0.5% in both groups), and no difference in the incidence of perforation or tamponade (0.4% in both groups).Authors published a 1-year follow up study. At 1-year, there was no significant difference in all-cause death (5.3% with thrombus-aspiration group vs. 5.6% with conventional PCI, HR: 0.94, 95% CI: 0.78 - 1.15; p= 0.57). Similarly, no significant differences were observed for any of the secondary endpoints (incidence for thrombus aspiration mentioned first): Hospitalization for recurrent myocardial infarction (2.7% in both groups), stent thrombosis (0.7% vs 0.9%), target-vessel revascularization (4.4% vs 4.9%), target-lesion revascularization (3.2% vs 3.5%), and the composite of all-cause death or recurrent myocardial infarction (7.7% vs 8.1%).There were no significant subgroup interactions for the primary outcome.Conclusion: In patients with ST elevation myocardial infarction, thrombus aspiration during PCI as compared to conventional PCI, did not improve the primary outcome of all-cause at 30-days. It also did not significantly reduce the secondary outcomes at 30-days which included hospitalization for recurrent myocardial infarction, stent thrombosis, target-vessel revascularization, target-lesion revascularization, and the composite of all-cause death or recurrent myocardial infarction. Results remained unchanged at 1-year.The TAPAS and TASTE trials highlight a critical lesson in research: Reliance on surrogate endpoints to guide medical practice can be misleading, even when surrogate outcomes suggest a substantial benefit, as seen in the TAPAS trial. Therefore, positive findings based on surrogate endpoints should always be validated by larger trials powered to assess clinical outcomes, before adopting them into clinical practice.The TAPAS trial did impact clinical practice, with approximately 1 in 4 patients with STEMI in Sweden during the TASTE study period, who were not enrolled in the TASTE trial, underwent thrombus aspiration.Another key takeaway is that results from smaller trials are not always replicated in larger studies. In TAPAS, thrombus aspiration was associated with a reduction in 30-day mortality, with a number needed to treat of approximately 53 patients. However, this finding was not statistically significant, raising questions about whether a larger sample size could have demonstrated a significant benefit. This assumption was refuted by the TASTE trial, highlighting the potential pitfalls of prematurely adopting interventions without robust evidence from sufficiently large trials.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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N Engl J Med 2008;358:557-567Background: ST-segment elevation myocardial infarction (STEMI) is caused by disruption of an atherosclerotic plaque, leading to intraluminal thrombosis that partially or completely blocks the coronary artery. Opening the blocked artery using percutaneous coronary intervention (PCI) restores blood flow and is the standard of therapy for these patients. In many patients, spontaneous embolization or embolization caused by thrombus fragmentation during PCI can lead to small thrombi migrating distally and obstructing the coronary microcirculation. This is associated with increased infarct size, reduction in left ventricular recovery and increased risk of mortality.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Several devices designed to retrieve intracoronary thrombus have been developed and have demonstrated improved coronary reperfusion in small studies. The Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study (TAPAS) sought to compare the efficacy of thrombus aspiration versus conventional PCI in patients with STEMI.Patients: Eligible patients were recruited from a single center in Netherlands. Patients had STEMI with symptoms lasting more than 30 minutes but less than 12 hours. The EKG criteria were ST-segment elevation of >1mm in at least two leads.Patients were excluded if they had rescue PCI after thrombolysis or if life expectancy was less than 6 months.Baseline characteristics: The trial randomized 1,071 patients – 535 randomized to thrombus aspiration and 536 randomized to conventional PCI.The average age of patients was 63 years and 70% were men. Approximately 35% had hypertension, 12% had diabetes, 25% had hyperlipidemia, 10% had prior myocardial infarction, and 47% were current smokers.Infarct-related vessel was the left anterior descending artery in 43% of the patients, the left circumflex artery in 17% and the right coronary artery in 38%.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo thrombus aspiration during PCI or conventional PCI. All placed stents were bare-metal stents.Before PCI, patients received 500 mg of aspirin, 600mg of clopidogrel and 5000 IU of heparin. Patients also received the glycoprotein IIb/IIIa inhibitor abciximab, if not contraindicated, and additional heparin during the procedure.Endpoints: The primary end point was the postprocedural frequency of a myocardial blush grade of 0 or 1. Secondary end points included complete resolution of ST-segment elevation and the absence of persistent ST-segment deviation. Clinical endpoints were also assessed as part of the secondary endpoints and included target-vessel revascularization, reinfarction or death, at 30 days.A 12-lead EKG was obtained at presentation and again at 30 to 60 minutes after PCI, and the ST-segments on the postprocedural EKG were compared with those at presentation.Not to readers: Myocardial blush is a qualitative angiographic method used to assess microvascular perfusion during coronary angiography. It evaluates how well contrast dye penetrates the myocardium. The grading of myocardial blush was: 0: no myocardial blush, 1: minimal myocardial blush or contrast density, 2: moderate myocardial blush or contrast density but less than that obtained during angiography of a contralateral or ipsilateral non–infarct-related coronary artery, and 3: normal myocardial blush or contrast density, similar to that obtained during angiography of a contralateral or ipsilateral non–infarct-related coronary artery. Persistent myocardial blush suggests leakage of contrast medium into the extravascular space and was given a grade of 0.Analysis was performed based on the intention-to-treat principle. To achieve 80% power with a two-sided alpha of 0.05, a total of 1,080 patients would be needed to detect a 25% reduction in the primary endpoint with thrombus aspiration compared to conventional PCI. This calculation assumed a 30% rate of myocardial blush grade 0 or 1 in the conventional PCI group.Results: Among the 1,161 patients screened for inclusion, 1,071 (92.2%) were randomized. Approximately, 94% of the patients in both groups underwent PCI. Among patients who underwent PCI in the thrombus aspiration group, 89% underwent thrombectomy. Among the patients who underwent thrombus aspiration, histopathological examination showed atherothrombotic material in 331 (72.9%) patients.The primary outcome of myocardial blush grade 0 or 1 was significantly lower in the thrombus aspiration group (17.1% vs 26.3%, RR: 0.65, 95% CI: 0.51 - 0.83; pi.e. thrombus aspiration led to improved blood flow to the coronary microcirculation].Complete ST-segment resolution was more frequent in the thrombus aspiration group (56.6% vs 44.2%; pAt 30 days, death was numerically lower in the thrombus aspiration group (2.1% vs 4.0%; p= 0.07), as well as reinfarction (0.8% vs 1.9%; p=0.11) and target-vessel revascularization (4.5% vs 5.8%; p= 0.34). The rates of death and major adverse cardiac events were significantly associated with myocardial blush grade, resolution of ST-segment elevation, and ST-segment deviation (P for association was 0.003 between death and myocardial blush grade and There were no significant subgroup interactions for the primary outcome.Intraprocedural complications were not significantly different between groups, approximately 1% in both groups.Conclusion: In patients with ST elevation myocardial infarction, thrombus aspiration during PCI as compared to conventional PCI, improved reperfusion as evident by myocardial blush. It also resulted in more resolution of ischemic EKG changes. The absolute treatment benefit for these endpoints was large – 9.2% for myocardial blush, 12.4% for ST-segment resolution and 12.6% for no persistent ST-segment deviation. There was a trend toward improvement in clinical outcomes, however, this was not statistically significant and the trial was not powered for these outcomes. These clinical outcomes were strongly associated with myocardial blush grade and EKG changes.In the original publications, the authors overstated the clinical endpoints by saying that thrombus aspiration [results in better reperfusion and clinical outcomes than conventional PCI, irrespective of clinical and angiographic characteristics at baseline].The trial enrolled most of the screened patients, enhancing its external validity. The primary outcome of this trial was a surrogate endpoint, which helps validate the pathophysiological mechanism of the treatment and informs the design of future larger trials powered to detect differences in hard clinical outcomes. While surrogate endpoints can provide valuable early insights, they do not always translate into actual clinical benefits. Therefore, relying solely on trials of surrogate outcomes to change clinical practice can be misleading and we do not recommend it.Next, we will review a trial of thrombus aspiration in STEMI patients powered for hard endpoints. Will it be positive?Note to Readers: Surrogate endpoints are sometimes used in clinical trials as substitutes for clinical outcomes, such as survival. Surrogate endpoints may include biomarkers, imaging findings, EKG changes, etc. These endpoints are selected based on their known correlation with clinical events. Utilizing surrogate endpoints enables trials to require smaller sample sizes and yield results more quickly.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

N Engl J Med 2013;368:1379-1387Background In 2013, it had been established that primary PCI for STEMI was the preferred strategy. Yet many patients did not have prompt access to primary-PCI capable hospitals and transfer delays could impact outcomes. The vast majority of patients with STEMI who present to non-PCI facilities do not subsequently get primary PCI within recommended times.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Delays led to the development of prehospital care, such as ECGs in the ambulance, and pre-hospital delivery of fibrinolysis. The Strategic Reperfusion Early after Myocardial Infarction (STREAM) study evaluated whether a fibrinolytic-therapy approach consisting of prehospital or early fibrinolysis with contemporary antiplatelet and anticoagulant therapy, coupled with timely coronary angiography, provides a clinical outcome similar to that with primary PCI in patients with STEMI who present early after symptom onset.Patients Eligible patients had a) STEMI within three hours, b) could not have primary PCI within one hour of first medical contact. No formal exclusion criteria were listed in the main manuscript.Baseline Characteristics A total of 1892 patients underwent randomization in 1:1 fashion. The mean age of patients was 59 years. Less than 15% of both groups were older than 75 years. Females were 20%. More than 90% of patients were Killip class 1. Less than 10% of enrolled patients had had prior CHF, MI, or PCI.Procedures Patients were randomized in a 1:1 ratio to fibrinolysis followed by timely coronary angiography or primary PCI. All patients were transferred to a PCI-capable hospital; for all non-PCI community hospitals participating in the study, a well-developed hub-and-spoke relationship with a PCI-capable site was required.The fibrinolytic strategy included early use of concomitant antiplatelet and anticoagulant medications, as well as additional discretionary glycoprotein IIb/IIIa antagonists. Tenecteplase was administered in a weight-based dose and was combined with low-molecular-weight enoxaparin, weight and age adjusted.Antiplatelet therapy consisted of clopidogrel in a 300-mg loading dose (omitted for patients ≥75 years of age) followed by 75 mg daily and aspirin (150 to 325 mg) immediately followed by 75 to 325 mg daily. Urgent coronary angiography in the fibrinolysis group was permitted at any time in the presence of hemodynamic or electrical instability, worsening ischemia, or progressive or sustained ST-segment elevation requiring immediate coronary intervention, according to the investigator's judgment.Endpoints The primary end point of the trial was a 30-day composite of death from any cause, shock, congestive heart failure, or reinfarction. Single efficacy end points as well as safety end points consisting of ischemic stroke, intracranial hemorrhage, nonintracranial bleeding, and other serious clinical events were recorded.The statistical analysis plan was complicated. A sample size of 1000 patients per study group was planned, and the rate of the primary end point in the primary PCI group was projected to be 15.0%. After one-fifth of patients had been enrolled, trialists amended the protocol to reduce the dose of tenecteplase by 50% in patients older than 75 years because of excess ICH. ECG criteria for inferior MI was also changed to require at least 3 mm (up from 2) of ST elevation in two contiguous leads.This trial was designed as a proof-of-concept study. All statistical tests were of an exploratory nature.Results The median time delay from the onset of symptoms to first medical contact and randomization was similar in the two groups ( 61-62 minutes). The median times between symptom onset and start of reperfusion therapy (bolus tenecteplase or arterial sheath insertion) were 100 minutes and 178 minutes, respectively (PAs expected, the median time from randomization to angiography was longer in the fibrinolysis group than in the primary PCI group, with a delay of 2.2 hours for the 36% of patients who required rescue or urgent intervention and 17 hours for the remaining 64% of patients.The primary end point (death from any cause, shock, congestive heart failure, or reinfarction up to 30 days) occurred in 116 of 939 patients (12.4%) in the fibrinolysis group and 135 of 943 patients (14.3%) in the primary PCI group (relative risk in the fibrinolysis group, 0.86; 95% confidence interval [CI], 0.68 to 1.09; P=0.21). None of the components of primary endpoint differed statistically.The incidence of the primary end point in the prespecified subgroups was generally similar to the overall result. No significant treatment interactions were found.Rates of stroke were low in the two study groups, but both intracranial hemorrhagic (1.0 vs 0.2) and primary ischemic strokes (0.6 vs 0.3) were more frequent in the fibrinolysis group than in the primary PCI group. After the dose reduction of tenecteplase in patients 75 years of age or older, there were no cases of intracranial hemorrhage (0 of 97 patients), as compared with 3 of 37 patients (8.1%) in this age group before the amendment. There was no statistically significant difference in major non-intracranial bleeding (6.5% vs 4.8%).Conclusions Patients with STEMI who presented early after symptom onset with an ST-segment elevation of at least 2 mm in two contiguous leads had similar rates of the primary composite end point of death, shock, congestive heart failure, or reinfarction at 30 days, regardless of whether they underwent prehospital fibrinolysis or primary PCI.Important caveats include the fact that patients who could have had early PCI (within one hour of first medical contact) were excluded and these results should not be applied to these patients. Similarly, these results should not be applied to patients who present with STEMI of longer than 3 hours after symptom onset.In addition, the sample size was moderate and there was no formal hypothesis testing. The 95% confidence intervals allow for a 32% lower rate of the primary endpoint as well as 9% worse outcome relative to primary PCI. The authors explain that the upper bound of a 9% relative risk increase would likely have fell below typical non-inferiority margins—though this was not prespecified as a noninferiority trial.Finally, the lack of clear superiority of fibrinolysis using this approach, in addition to the increase risk of bleeding associated with its use, limited the adoption of this study results.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support my 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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N Engl J Med 2006;355:2395-407Am Heart J 2011;161:611-21Background: Registry data suggests that 10-20% of patients with a STEMI present more than 12 hours after the onset of symptoms. The optimal treatment for such patients is unknown. In some cases, the inciting event may have occurred weeks prior and been mistaken for indigestion or another non-life threatening condition. Such patients may present to the hospital with a new diagnosis of congestive heart failure or atrial fibrillation. Echocardiography often reveals a a large wall motion abnormality, perfusion testing demonstrates an infarct with peri-infarct ischemia and an occluded vessel is seen on angiography. Should we try to open it? On the one hand, the damage has been done. Attempting to open an occluded vessel is associated with higher procedural risks and the patient’s themselves are more often than not sub-optimal candidates for intervention; often having some combination of heart failure, LV dysfunction, older age, multimorbidity and hemodynamic instability. But on the other hand, revascularization restores blood flow and that has to count for something, right?The Occluded Artery Trial (OAT) tested the hypothesis that a strategy of routine PCI for total occlusion of the infarct-related artery 3 to 28 days after AMI would improve cardiac outcomes compared to medical therapy alone.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 were eligible if coronary angiography, performed 3 to 28 days after MI, showed a total occlusion of the infarct-related artery with poor antegrade flow and either an EF less than 50% or the occlusion was in the proximal portion of a major coronary vessel with a large risk region, or both. The qualifying period of 3 to 28 days was based on calendar days with day 1 being the onset of symptoms and thus, the minimal time from the AMI to angiography was just over 24 hours. [This is important, readers should not take the inclusion criteria of 3 to 28 days to mean that patients were not eligible if angiography was performed Patients were excluded with NYHA III or IV heart failure, shock, serum creatinine >2.5 mg/dl, left main or 3 vessel disease, angina at rest, and severe ischemia on stress testing (stress testing was required if the infarct zone was not akinetic or dyskinetic).Baseline characteristics: The trial included 2,166 patients - 1,082 randomized to PCI and 1,084 to medical therapy. The average age of patients was 59 years and 78% were men. Over 80% were white. The median time between AMI and randomization was 8 days. Patients had normal kidney function with an average GFR of 81 ml/min. The mean EF was 48% with 20% of patients having an EF [This is pertinent to contemporary practice where the finding of peri-infarct ischemia on perfusion testing is often used to support the decision to pursue revascularization]Procedures: Patients were randomized to PCI or medical therapy in a 1:1 ratio. All patients received optimal medical therapy with aspirin, anticoagulation if indicated, ACEi, beta blocker and lipid lowering therapy unless contraindicated. Thienopyridines were recommended in both study groups for 1 year after MI. Patients assigned to PCI were to undergo the procedure within 24 hours after randomization. Stenting was recommended for the occluded vessel as well as for other high-grade stenoses in major coronary segments, whenever technically feasible in the PCI group. PCI of other non-infarct related stenosis was also permitted in the medical therapy; however, such non-infarct related stenting was not commonly performed (7% in PCI group and 6% in medical therapy group).A subgroup of 124 patients underwent baseline viability scanning to assess myocardial viability before the patient received the assigned treatment. Another subgroup of 381 patients underwent repeat cardiac catheterization at 1 year.Endpoints: The primary endpoint was a composite of death from any cause, reinfarction, or hospitalization for NYHA class IV heart failure. Certain stipulations were imposed to minimize post-PCI MI’s including exclusion of troponin level for diagnostic use within 10 days of index AMI. An MI in this case would have required required presence of symptoms for 30 minutes or more and electrocardiographic changes consistent with ischemia. It was originally estimated that 3,200 patients would be required for the study to have 90% power to detect a 25% reduction in the primary endpoint in the PCI group, assuming a 3-year event rate of 25% in the medical therapy group. The sample size was subsequently reduced to 2,400 because of recruitment challenges and a less than expected cross-over rate. The final enrollment of 2,166 patients afforded 94% power to detect a 25% reduction in the primary endpoint.Results: A total of 1,082 patients were randomized to PCI and 1,084 to medical therapy. PCI of the qualifying occlusion was successful in 87% of patients assigned to PCI. PCI of the non-infarct related artery was performed in 7% of patients in the PCI group and 6% in the medical therapy group. Crossover to PCI was 9% in the medical therapy group (3% within 30 days after randomization) and 4 patients (0.4%) in each of the 2 groups underwent CABG within 30 days. Patients were followed for an average of 2.9 years.In the main paper, event rates are reported as the estimated 4-year cumulative event rate and not the raw percentage of events per group. For this reason, there may appear to be discrepancies between the event rates and HR. Compared to patients assigned to medical therapy, PCI did not reduce the primary endpoint (17.2% vs 15.1%; HR 1.16; 95% CI 0.92-1.45) or any of the individual secondary endpoints. In an as-treated analysis comparing 937 patients in the PCI group who had successful PCI with 1057 patients in the medical therapy group who did not cross over to PCI within 30 days, the HR was 1.15.In the subgroup of patients who underwent repeated angiography, the infarct-related artery was patent at 1 year in 83% of patients in the PCI group and 25% in the medical therapy group. No major subgroup interactions were identified.The results of viability subgroup study were reported in a separate publication. At baseline, mean infarct size was 26% of the LV, mean infarct zone viability was 43% of peak uptake, and most patients (70%) had at least moderately retained infarct zone viability. In multivariable models, increasing baseline viability independently predicted improvement in EF but there was no interaction between infarct zone viability and treatment assignment for any measure of LV remodeling. The authors concluded that, “in the contemporary era of MED, PCI of the infarct-related artery compared with MED alone does not impact LV remodeling irrespective of viability.”Conclusions: In patients with a STEMI and an occluded infarct-related artery who are more than 24 hours out from the onset of symptoms, PCI does not improve outcomes compared to medical therapy alone. This is true whether there is evidence of viability or not. In the OAT trial, there were more events in the PCI group but the difference was not statistically significant; however, in the real world, it is very reasonable to assume that PCI would cause harm to patients meeting the general eligibility requirements for OAT. This is because patients in OAT were young (average age Based on data from the OAT trial, we strongly advise against PCI in STEMI patients with occluded infarct arteries who are more than 24 hours from the index event. But furthermore, we think this trial is pertinent for all patients with occluded vessels in whom PCI is being considered. If a benefit could not be found in this trial for opening the occluded artery, under what circumstance could it possibly be beneficial?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

N Engl J Med 2003;349:733-742Background: In patients with ST elevation myocardial infarction, treatment with balloon angioplasty improved outcomes compared to fibrinolysis, as seen in the Primary Angioplasty in Myocardial Infarction Study Group trial. Other trials showed similar findings. However, these trials were relatively small in size and mainly conducted at hospitals with high experience in angioplasty.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.At the time this trial was conducted, limited number of hospitals offered angioplasty. Transporting patients with ST-elevation myocardial infarction to these centers posed a significant challenge, and sometimes resulting in delays in treatment.The DANAMI-2 investigators sought to conduct a community-wide trial comparing on-site fibrinolysis vs transferring the patients for primary angioplasty.Patients: Eligible patients had ST-segment elevation myocardial infarction with symptoms lasting for at least 30 minutes but less than 12 hours. The EKG criteria were cumulative ST-segment elevation of at least 4 mm in at least two contiguous leads.Exclusion criteria were many and included contraindication to fibrinolysis, left bundle branch block, acute myocardial infarction and fibrinolytic treatment within the previous 30 days, pulseless femoral arteries, renal failure defined as creatinine > 2.83 mg/dL, life expectancy less than 12 months due to non-cardiac disease, and more. Patients were also excluded if they were high risk for transportation because of cardiogenic shock, persistent life-threatening arrhythmias, or a need for mechanical ventilation.Baseline characteristics: The trial randomized 1,572 patients – 790 randomized to angioplasty and 782 to fibrinolysis. A total of 1129 patients were randomized at referral hospitals, and 443 patients were randomized at invasive-treatment centers.The average age of patients was 63 years and 73% were men. Approximately 20% had hypertension, 7% had diabetes, 11% had prior myocardial infarction, and 58% were current smokers.Among patients who underwent angiography and data were available, 53% had single vessel disease, 25% had two vessel disease and 14% had three vessel disease. Approximately 3% had left main involvement.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo fibrinolysis or angioplasty. Patients were recruited from 24 referral hospitals without angioplasty facilities and 5 invasive-treatment hospitals with angioplasty facilities. For patients recruited from referral hospitals, transfer to angioplasty center had to be completed within 3 hours. A physician accompanied the patient. The participating hospitals served 62% of the Danish populationPatients assigned to fibrinolysis received 300 mg of aspirin orally, beta-blocker intravenously, tissue plasminogen activator (alteplase, given as a 15-mg bolus and an infusion of 0.75 mg/kg over 30 minutes, followed by an infusion of 0.5 mg/kg for 60 minutes), and an intravenous bolus of unfractionated heparin (5000 U), followed by a 48-hour infusion of unfractionated heparin.Patients assigned to angioplasty received 300 mg of aspirin intravenously, beta-blocker intravenously, and 10,000 U of unfractionated heparin bolus, with additional heparin during the angioplasty procedure to achieve an activated clotting time of 350 to 450 seconds.Angioplasty was only performed for target-vessel related infarct.Endpoints: The primary end point was a composite of death from any cause, clinical reinfarction or disabling stroke, at 30 days. Procedure-related reinfarction was not counted in the primary end point.The trial was designed with two parallel sub-studies: One involving patients randomized at referral hospitals and the other involving patients randomized at invasive-treatment centers.Analysis was performed based on the intention-to-treat principle. Sample size calculations assumed that the combined primary endpoint would occur within 30 days in 16% of patients assigned to fibrinolysis, 10% of those assigned to angioplasty at referral hospitals, and 9% of those assigned to angioplasty at invasive-treatment centers. Based on these assumptions, 1100 patients were needed to be enrolled at referral hospitals and 800 patients at invasive-treatment centers.Results: Among the 4,278 patients screened for inclusion, 1,572 (36.7%) were randomized. The study was stopped early after the third interim analysis demonstrated superiority of angioplasty in the referral-hospital sub-study. The median time from the onset of symptoms to randomization was 135 minutes. The median distance patients were transported from a referral hospital to an invasive-treatment center was 50 km. The time from randomization at the referral hospital to arrival in the catheterization laboratory was under 2 hours in 96% of the patients. There were no deaths during transportation.Among the patients randomized to fibrinolysis, 99% received the assigned treatment. Among the patients randomized to angioplasty, 98% underwent angiography. Angioplasty was attempted in 89.4% of the patients, and among them, stents were implanted in 90.4%.Angioplasty reduced the primary composite endpoint among all patients (8.0% vs 13.7%; p The reduction in the primary endpoint with angioplasty was seen in patients randomized in referral hospitals (8.5% vs 14.2%; p= 0.002) as well as patients randomized in invasive-treatment centers (6.7% vs 12.3%; p= 0.05).Procedure-related reinfarctions occurred in 10 patients assigned to fibrinolysis and 5 patients assigned to angioplasty. The inclusion of these events in the primary outcome did not significantly change the results.Repeated fibrinolysis within 12 hours after randomization was performed in 26 patients in the fibrinolysis group. A total of 15 patients in the fibrinolysis group underwent rescue angioplasty.No data provided on bleeding complications.There were no significant subgroup interactions.Conclusion: In patients with ST elevation myocardial infarction, angioplasty as compared to fibrinolysis reduced the composite endpoint of death from any cause, clinical reinfarction or disabling stroke, at 30 days with a number needed to treat of approximately 18 patients. This benefit was driven by reduction in reinfarction without a significant effect on death or stroke. The benefit was observed regardless whether patients were randomized at centers capable of performing angioplasty or at non-angioplasty centers, provided they were transferred to an angioplasty center within 2 hours.This study established that transferring a patient with ST elevation myocardial infarction to centers equipped for angioplasty leads to better outcomes compared to on-site thrombolysis, provided the patient can be at the catheterization lab within two hours. These findings have been incorporated into clinical guidelines and medical practice. 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

N Engl J Med 1993;328:673-679Background: Previous trials established that thrombolysis improves mortality in patients with acute myocardial infarction, as seen in the GISSI-1 and ISIS-2 trials. However, thrombolysis has limitations, including an increased risk of bleeding and the inability to achieve arterial patency in approximately 20% of the cases. As a result, there was a growing interest in the use of percutaneous transluminal coronary angioplasty (PTCA).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 Primary Angioplasty in Myocardial Infarction Study Group sought to test the hypothesis that PTCA compared to thrombolysis, improves outcomes and reduces bleeding in patients with acute myocardial infarction.Patients: Eligible patients presented within 12 hours of ischemic chest pain and had ST elevation of at least 1 mm in two or more contiguous electrocardiographic leads. Patients were excluded if they had dementia, LBBB, cardiogenic shock or elevated bleeding risk.Baseline characteristics: The study enrolled 395 patients – 195 assigned to the PTCA arm and 200 assigned to the thrombolysis arm. The average age of patients was 60 years with 73% being men. Approximately 14% had prior myocardial infarction, 43% had hypertension, 12% had diabetes and 2% had congestive heart failure. The average ejection fraction 52%.The infarct was anterior in 34% of the patients, inferior in 59% and lateral in 8%.Procedures: All patients were given 325 mg of aspirin plus 10,000-unit bolus of intravenous heparin. After that, patients were randomly assigned to thrombolytic therapy or PTCA. The thrombolytic agent used was tissue plasminogen activator (t-PA) at a dose of 100 mg (or 1.25 mg/kg of body weight for patients weighing less than 65 kg) over three hours. Patients randomly assigned to PTCA underwent immediate diagnostic catheterization.Angiographic criteria for exclusion from PTCA included left main stenosis of more than 70%, infarct-related vessel was patent, three-vessel disease, morphologic features of the lesion known to indicate high risk, small infarct-related vessels or stenosis Bypass surgery was recommended for high-risk patients.In both treatment groups, intravenous heparin was administered for 3 - 5 days, targeting PTT level 1.5 - 2 times the control value or activated clotting time 160 - 200 seconds.Endpoints: The primary end point was all-cause death or recurrent ischemia. Recurrent ischemia was defined as ischemic chest pain of more than 20 minutes despite nitrate therapy plus new ST- T-wave changes, new pulmonary edema, a holosystolic murmur, or hypotension. Secondary endpoints were reinfarction, and left ventricular function at 6 weeks using radionuclide ventriculography. Reinfarction was defined as recurrent chest pain longer than 30 minutes with new ST-segment elevation and either coronary angiography confirming an occluded vessel or recurrent elevation of cardiac enzymes.Statistical analysis was performed based on the intention-to-treat principle. The estimated sample size to provide 80% power was 370 patients, assuming an event rate of the primary outcome of 25% in the t-PA arm and 12% in the PTCA arm. The intended follow up time for the primary endpoint was not clearly defined but was provided for in-hospital and again at 6 months.Results: The average time from the onset of chest pain to treatment was approximately 4 hours in both groups. All of the patients assigned to the PTCA arm underwent coronary angiography but 10% did not undergo angioplasty based on the exclusion criteria mentioned previously. PTCA was successful in 97% of the patients who underwent the procedure.Of note, the sample size was based on the expected number of death and recurrent ischemia but authors focused on reporting death and reinfarction (rather than recurrent ischemia).The endpoint of in-hospital death or reinfarction was lower in the PTCA group (5.1% vs 12.0%; p= 0.02). In-hospital death and reinfarction were numerically lower with PTCA “number of events was the same for both endpoints” (2.6% vs 6.5%; p= 0.06). All 5 deaths in the PTCA group were due to cardiac causes. Among the 13 deaths in the t-PA group, 4 were due to intracranial bleeding and 9 were due to cardiac causes.Unscheduled coronary angiogram was significantly less common in the PTCA group (13.3% vs 63.0%; pDeath or infarction at 6-months was lower in the PTCA group (8.5% vs 16.8%; p= 0.02). Death at 6-months was numerically lower with PTCA (3.7% vs 7.9%; p= 0.08).In-hospital hemorrhagic strokes were more frequent in t-PA arm (2.0% vs 0.0%; p = 0.05). Non-CABG related bleeding requiring transfusion was not significantly different between both groups (6.2% with PTCA vs 5.0% with t-PA; p= 0.62).At 6 weeks, radionuclide ventriculography was performed in 65% of the survivors. The average left ventricular ejection fraction at rest was similar in both groups at 53 ± 13%.Subgroup analysis for mortality was performed based on “low-risk” vs “not low risk”. Not low risk was defined as anterior infarction, age >70 years or admission heart rate > 100 bpm. PTCA reduced in-hospital mortality in the “not low risk” group (2.0% vs 10.4%; p= 0.01) but not in the low risk group (3.1% vs 2.2%; p= 0.69).Conclusion: In patients with ST-elevation myocardial infarction, PTCA compared to t-PA reduced death and reinfarction at the hospital and at 6 months with a number needed to treat of approximately 14 and 12, respectively.This was one of the trials that established the foundation for the use of PTCA in patients with acute myocardial infarction. While the treatment effect was large, there are important considerations to keep in mind. First, the sample size was small. In comparison, GISSI-1 had almost 12,000 patients and ISIS-2 had over 17,000. The results of small trials are not always replicated in larger pragmatic trials. Second, the use of aspirin + heparin + t-PA likely increased bleeding in the t-PA arm as heparin plus thrombolysis compared to thrombolysis without heparin increased bleeding without improving outcomes, as seen in the GISSI-2 and ISIS-3 trials. Third, two thirds of the patients had inferior or lateral infarcts and these subgroups did not benefit from thrombolysis in the GISSI-1 trial. Finally, standalone angioplasty is infrequently performed nowadays and patients often receive a stent which has improved vessel patency.In the current era, patients with ST-elevation myocardial infarction receive early revascularization with stent placement, which improved outcomes in these patients. We discussed the limitations above to help readers and learners appraise clinical trials, as these limitations were important at the time of this trial's publication.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