Cardiology Trials

THE LANCET 2003;362:772-776Background: Angiotensin converting enzyme inhibitors (ACEi) reduce mortality and morbidity in patients with systolic heart failure (see CONSENSUS and SOLVD trials). However, registry data showed that up to 20% of patients with systolic heart failure were not taking ACEi. One of the frequent causes for intolerance to ACEi is cough. Angiotensin converting enzyme inhibitors work by blocking the conversion of angiotensin I to angiotensin II, a key step in the renin–angiotensin–aldosterone system (RAAS). Angiotensin II receptor blockers were tolerated in patients with systolic heart failure who were intolerant to ACEi. However, data on long term effectives as an alternative to ACEi were lacking.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Alternative trial sough to assess if the angiotensin-receptor blocker (ARB) candesartan, could improve outcomes in patients with systolic heart failure who are intolerant to ACEi.Patients: Eligible patients had left ventricular ejection fraction of 40% or less and NYHA class II, III or IV symptoms of at least 4 weeks duration. Patients had also to be intolerant to ACEi.Exclusion criteria were not provided in the main manuscript.Baseline characteristics: Patients were recruited from 618 centers in 26 countries. The trial randomized 2,028 patients – 1,013 randomized to receive candesartan and 1,015 to receive placebo.The average age of patients was 67 years and 68% were men. The average left ventricular ejection fraction was 30%. Cardiomyopathy was ischemic in 68% of the patients. The NYHA class was II in 48% of the patients, III in 49% and IV in 4%.Approximately 50% had hypertension, 27% had diabetes, 61% had prior myocardial infarction, 9% had stroke, 25% had atrial fibrillation and 14% were current smokers.At the time of enrollment, 85% were taking a diuretic, 46% were taking digoxin, 55% were taking beta-blockers and 24% were taking spironolactone.The most common reasons for ACEi intolerance were cough in 72% of the patients, hypotension in 13%, renal dysfunction in 12% and angioedema or anaphylaxis in 4%.Procedures: The trial was double-blinded. Patients were assigned in a 1:1 ratio to receive candesartan starting at 4 or 8mg once daily or placebo. The treatment was doubled every two weeks to a target dose of 32mg once daily.After randomization, follow up occurred at 2, 4, and 6 weeks, 6 months and every 4 months thereafter.Endpoints: The primary outcome was a composite of cardiovascular death or heart failure hospitalizations. All deaths were classified as cardiovascular unless there was a clear non-cardiac cause.Analysis was performed based on the intention-to-treat principle. The estimated sample size to have 80% power at 5% alpha was 2,000 patients. The sample size calculation assumed 18% relative risk reduction in the primary outcome with candesartan assuming a 15% annual event rate in the placebo arm.Results: The median follow up time was 34 months. The mean candesartan daily dose was 23mg at 6 months.Candesartan reduced the primary endpoint of cardiovascular death or heart failure hospitalizations (33.0% vs 40.0%, adjusted HR: 0.70, 95% CI: 0.60 – 0.81; p< 0.001). Candesartan reduced the individual components of the primary outcome - (21.6% vs 24.8%; p= 0.02) for cardiovascular death and (20.4% vs 28.2%; p< 0.001) for heart failure hospitalizations. All-cause death was also lower with candesartan (26.2% vs 29.2%, adjusted HR: 0.83, 95% CI: 0.70–0.99; p= 0.033). The number of patients who had any hospitalization as well as the total number of hospitalizations were numerically but not statistically significantly lower with candesartan (60.2% with candesartan vs 63.3%; p= 0.16) and (1,718 vs 1,835; p= 0.06).Candesartan was associated with more hypotension (3.7% vs 0.9%), more increase in creatinine (6.1% vs 2.7%) and more hyperkalemia (1.9% vs 0.3%). Angioedema occurred in three patients in the candesartan group and none in the placebo group. Cough occurred in two patients taking candesartan and four taking placebo.Authors reported no significant subgroup interactions, however, a corresponding graph was not provided.Conclusion: In patients with systolic heart failure who are intolerant to ACEi, candesartan reduced the primary composite outcome of cardiovascular death or heart failure hospitalizations with a number needed to treat of approximately of 14 patients over 34 months of follow up. Candesartan also reduced all-cause death with a number needed to treat of approximately 33 patients. Adverse events including hypotension, increase in creatinine and hyperkalemia were more common with candesartan.The reduction in the primary endpoint with candesartan was significant and offers an alternative for patients who are unable to tolerate ACEi. Of note, 72% of the patients enrolled in the trial were intolerant to ACEi due to cough. This trial did not include a head-to-head comparison between ARBs and ACEi, and therefore does not address which agent should be preferred as first-line therapy. Only 24% of participants were receiving spironolactone. The combination of ARBs with spironolactone, may increase the risk of adverse events, particularly hyperkalemia and kidney injury.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. 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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 < 100 mmHg. Patients already on beta-blockers or with planned therapy with beta-blockers were also not enrolled.Cardiology Trial's remains independent, free of industry ads, due to reader generosity. Please consider becoming a free or paid subscriber.Baseline Characteristics The mean age of patients was 61 years, 81% male, and 83% Class III. The mean LVEF was 28%. About half the patients had ischemic heart disease, 12% primary dilated cardiomyopathy and nearly 40% had a mixture of valvular heart disease, hypertensive heart disease or unproven ischemic disease.The mean SBP on enrollment was 130 mmHg and resting HR was 80 bpm. The mean duration of heart failure before enrollment was 3.5 years. About 20% had AF at baseline. Nearly all patients were on ACE-I and half were on digoxin.Trial Procedures There was no run-in period. CIBIS II was double blinded. Slightly more than 2,600 patients were randomized 1:1 to bisoprolol or placebo in 274 hospitals across 18 countries.Patients in the bisoprolol group were started at 1.25 mg daily and titrated up weekly to as high as 10 mg daily. The goal was to attempt the highest tolerated dose. Patients were seen every 3 months.Endpoints The primary endpoint was all-cause mortality. Secondary endpoints included all-cause hospital admissions, cardiovascular mortality, combined CV death and CV hospital admissions, and premature treatment withdrawals.The authors estimated a 11.2% mortality in the placebo group and powered the trial to find a 25% reduction in death in the bisoprolol arm over 2 years.Results The trial was sopped early (mean follow-up 1.3 years) after the planned second interim analysis for benefit. The primary outcome of all-cause death occurred in 11.8% in the bisoprolol group vs 17.3% in the placebo arm (HR 0.66 (95% CI 0.54-0.81, p < 0.0001)).Bisoprolol reduced sudden death (3.6% vs 6.3%), all-cause hospitalization (33% vs 39%), CV death (9% vs 12%). Permanent treatment withdrawal occurred in 15% of both arms.The subgroup analysis showed no substantial treatment heterogeneity. The most common dose was 10 mg daily reached in 43% of patients.Conclusion The 34% reduction in death was clinically meaningful and statistically robust. Our confidence in such a large effect size stems from a) previous data on beta-blockers, which found similar effects, b) the 42% reduction in sudden death in the bisoprolol arm and c) the large reductions in all-cause hospitalization. In addition, the trial conduct appeared strong with almost no lost-to-follow up. The lack of run-in period strengthens the external validity of CIBIS II.The same caveats seen in the US carvedilol trial also apply to CIBIS II, namely that patients were ambulatory, outpatients, mostly with Class III symptoms. Patients enrolled in the trial had a mean SBP of 130 mmHg and a resting heart rate of 80. Nearly all patients were tolerating ACE-I and half were taking digoxin. In addition, patients were started on low-dose and gradually titrated higher. The majority of patients were on higher than 5 mg daily.The authors warned against applying these results to non-ambulatory patients with Class IV symptoms, especially if there was recent instability. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

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%; p

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

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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; p< 0.001). Death from cardiac causes was also reduced with spironolactone (27% vs 37%, RR: 0.69, 95% CI: 0.58 - 0.82; p

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

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%; p

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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%; p< 0.0036). The majority of deaths (89%) were cardiovascular and the majority of these (79%) were heart failure or arrhythmia related. Enalapril also reduced all-cause hospitalization (69.5% vs 74.0%; p= 0.006). The total number of hospitalizations for heart failure was also reduced with enalapril – 683 vs 971. Subgroup analysis showed a numerical increase in death, with enalapril, in patients with an ejection fraction of 30-35% - this was not statistically significant.In 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%; p< 0.001). Total number of hospitalizations for heart failure was also significantly reduced with enalapril – 306 vs 454. The reduction in the development of heart failure was seen across all ejection fractions below 35%, although the benefit was larger with lower ejection fractions.In 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. 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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

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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

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 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 < 90 mmHg for more than 30 minutes or requiring pressors, clinical signs of pulmonary congestion, and signs of organ hypoperfusion (altered mental status, cold/clammy skin, oliguria, or lactate > 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 ( 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; p

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 (P50%, 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; p

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 (P

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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 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

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

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 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

THE LANCET 2011;377:1409-1420Background: When patients undergo coronary angiography, a hollow tube called a sheath is inserted into an artery. The primary function for the sheath is to provide a stable entry point into the artery, allowing for the safe navigation of instruments to the coronary arteries. Traditionally these sheaths were inserted into the femoral artery. One of the common complications associated with this approach is bleeding which is associated with worse outcomes. An alternative approach is inserting the sheath into the radial artery which is more superficial and more readily compressible compared to the femoral 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.Small randomized trials suggested that a radial artery access is associated with less bleeding with possible reduction in death and myocardial infarctions but also a signal of increased percutaneous coronary intervention (PCI) failure.The RIVAL trial sought to assess if radial artery access is superior to femoral artery access in patients with acute coronary syndrome (ACS) undergoing coronary angiography.Patients: Patients had acute coronary syndrome and an invasive strategy was planned. Dual circulation of the hand, as assessed by an Allen's test, had to be intact.Patients were excluded if they had cardiogenic shock, severe peripheral vascular disease precluding a femoral approach, active bleeding or high bleeding risk, or prior coronary artery bypass grafting (CABG) with the use of more than one internal mammary artery graft.Baseline characteristics: The trial randomized 7,021 patients in 32 countries – 3,507 randomized to radial access and 3,514 to femoral access.The average age of patients was 62 years and 73% were men. Approximately 60% had hypertension, 21% had diabetes, 18% had prior myocardial infarction, 2% had prior CABG, 2% had peripheral vascular disease, and 31% were current smokers.The diagnosis at admission was unstable angina in 45% of the patients, NSTEMI in 27% and STEMI in 28%.The use of antiplatelet and anti-thrombotic drugs was not significantly different between both groups.Procedures: The RIVAL trial initially enrolled patients within the CURRENT-OASIS 7 trial which was a trial of antiplatelets therapy in ACS. After the conclusion of the CURRENT-OASIS 7 trial, RIVAL enrolled additional patients.Patients were assigned in a 1:1 ratio to undergo femoral or radial artery access. The use of anti-thrombotic regimen at the time of PCI as well as femoral artery closure devices was at the discretion of the treating physician.Endpoints: The primary outcome was a composite of all-cause death, myocardial infarction, stroke, or non-CABG related major bleeding, within 30 days. Secondary outcomes included the components of the primary outcome as well as major vascular access site complications and PCI procedural success.The components of the primary outcome were adjudicated by a central committee blinded to the treatment assignment. Major vascular access site complications and PCI procedural success were reported by the investigators.Analysis was performed based on the intention-to-treat principle. Due to low event rate, the sample size was increased from 4,000 to 7,000. This new sample size would provide 80% power to detect 25% relative risk reduction in the primary endpoint assuming 6% event rate in the femoral access arm.The study had six prespecified subgroup analysis: Age (< 75 vs older), sex, body mass index, STEMI vs no STEMI, operator's annual radial PCI volume and center's median operator's radial PCI volume.Results: Among the 7,021 randomized patients, 99.8% underwent coronary angiography. The rate of crossover was 7.6% in the radial group and 2.0% in the femoral group. Most of the crossover in the radial group was due to failure of the coronary angiogram using the radial approach. There was no significant difference in the number of PCI catheters used between both groups. Fluoroscopy time was higher in the radial group (7.8 minutes vs 6.5 minutes; p< 0.001).The primary composite outcome at 30-days was not significantly different between both groups (3.7% with radial vs 4.0% with femoral, HR: 0.92, 95% CI: 0.72 – 1.71; p= 0.50). All of the components of the primary outcome were not significantly different between both groups: 1.3% vs 1.5% for death, 1.7% vs 1.9% for myocardial infarction, 0.6% vs 0.4% for stroke, and 0.7% vs 0.9% for non-CABG related major bleeding.PCI procedural success was 95% in both groups. Major vascular complications were lower using the radial approach (1.4% vs 3.7%; p< 0.001). Major vascular complications were defined as pseudoaneurysms needing closure, large hematoma, arteriovenous fistula, or an ischemic limb needing surgery.There were no significant subgroup interactions based on age, sex, body mass index or operator's radial PCI volume. There was significant interaction based on STEMI vs no STEMI (p for interaction= 0.025) and center's radial PCI volume (p for interaction 0.021), such as patients with STEMI and patients in centers with the highest tertile for PCI volume had reduction in the primary outcome with radial access.Significantly more patients in the radial group said to prefer radial approach if they need a future coronary angiography (90.2% vs 50.7%; p< 0.001).Conclusion: In patients with acute coronary syndrome undergoing coronary angiography, a radial approach compared to femoral approach, did not improve the primary composite outcome of all-cause death, myocardial infarction, stroke, or non-CABG related major bleeding, at 30 days. A radial approach reduced major vascular complications with a number needed to treat of approximately 43 patients. A radial artery approach was more commonly preferred by patients for future coronary angiography.One of the limitations of this trial is that the outcome of major vascular complications is subject to bias as it was reported by the investigators rather than centrally adjudicated.Given that this trial compares two approaches with similar costs, the observed reduction in vascular complications justifies an increased adoption of the radial approach. The safety of the radial approach has likely improved over the years as centers and operators have gained more experience. Moreover, patients have shown a clear preference for the radial approach, which is an important win as well.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 2009;360:213-24Lancet 2015;386:1853-60Background: Fractional flow reserve (FFR) is a measure of the physiologic significance of a coronary stenosis that is defined as the ratio of maximal blood flow in a stenotic artery to normal maximal flow. It is measured during coronary angiography by calculating the ratio of distal coronary pressure measured with a coronary pressure guidewire to aortic pressure measured simultaneously with the guiding catheter. FFR in a normal coronary artery equals 1.0 whereas a value 90% and is similar to information obtained with stress imaging studies.For patients with multivessel coronary disease, it can be a challenge in the cath lab to differentiate between blockages causing ischemia and those that are not and this may be especially challenging when patients have not undergone stress imaging prior (e.g., patients presenting with acute coronary syndromes without ST segment elevation). The FAME trial sought to test the hypothesis that revascularization guided by FFR would be superior to revascularization guided by angiography alone in a broad cohort of patients with multivessel disease in whom revascularization with PCI was indicated.Patients: Patients with multivessel CAD of at least 50% of the vessel diameter in at least 2 of the 3 major epicardial coronary arteries in whom PCI was indicated. Patients with a STEMI could be included if the infarction occurred at least 5 days before PCI. Patients with a NSTEMI could be included earlier than 5 days. Patients who had undergone previous PCI could be included.Patients were excluded if they had left main coronary disease, previous CABG, cardiogenic shock, extremely tortuous or calcified coronary arteries, a life expectancy less than 2 years, a contraindication to the placement of drug-eluting stents, or if patients were pregnant.Baseline characteristics: Information is not provided on patients screened to enrolled. The average age of patients was 64.5 years and approximately three quarters were men. It is not clear from the main manuscript how many patients presented with acute MI's. It appears that approximately one third of patients presented with unstable angina and about half of these patients had dynamic ECG changes. More than half of patients in the trial had class 2 angina or below. Approximately 25% of patients had diabetes and over 60% had hypertension. The average EF was 57%.The mean number of lesions per patient was 2.8. About 40% of blockages were estimated to be in the 50-70% range, another 40% were in the 71-90% range, 15% were 91-99% narrowed and 3% were chronic total occlusions. The minimal luminal diameter was 1.0 mm, mean reference vessel diameter was 2.5 mm, mean lesion length was 12.5 mm and the SYNTAX score was 14.5.Procedures: Patients were randomized after they were found to have multivessel disease, meeting the study criteria, and were thought to require PCI. Patients assigned to angiography-guided PCI underwent stenting of all indicated lesions with drug-eluting stents. Those assigned to FFR-guided PCI underwent FFR in each diseased coronary artery and drug-eluting stents were placed in lesions with FFR that was /=50% in 2 of 3 major epicardial coronary arteries) and an indication for PCI, that FFR-guidance may reduce stent use and improve outcomes over short-term follow-up. However, more data is needed to confirm this result and to distinguish patient populations most likely to benefit based on clinical indication for PCI and complexity of coronary anatomy.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 2016;375:1242-1252Background: The first drug-eluting stent (DES) was approved by the FDA in 2003 following the publication of the RAVEL trial. Since then, newer generations of DES were developed and were tested in clinical trials. The majority of trials comparing DES to bare-metal stents (BMS) showed reduction in repeat revascularization with DES but no significant reduction in death or myocardial infarction. Following these publications, the use of DES grew rapidly and was used in more than two thirds of percutaneous coronary interventions (PCI) by 2010.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.These trials, however, were very selective, had short follow up time (TAXUS-IV followed patients for 9 months and SPRIT IV followed patients for 12 months), and had limited power to assess hard outcomes.The NORSTENT trial investigators sought to compare DES to BMS in a more pragmatic design and follow patients for longer time.Patients: All patients who were undergoing PCI in Norway were assessed for enrollment. Patients had stable angina or acute coronary syndrome. Lesions were in native coronary arteries or bypass grafts.Patients were excluded if they had prior coronary stents, bifurcating lesions requiring a two-stent technique or life expectancy less than 5 years due to a medical condition other than coronary artery disease. Patients were also excluded if they had contraindications to dual antiplatelets or were taking warfarin.Baseline characteristics: The trial randomized 9,013 patients – 4,504 randomized to receive a DES and 4,509 to receive a BMS.The average age of patients was 63 years and 75% were men. Approximately 42% had hypertension, 54% had hyperlipidemia, 10% had prior myocardial infarction, 7% had prior CABG, 12% had diabetes, and 35% were current smokers.The indication for PCI was stable angina in 29% of the patients, unstable angina in 12% and STEMI or NSTEMI in 58%.Procedures: The study was open-label but outcomes assessment was blinded. Patients were randomly assigned in a 1:1 ratio to receive DES or BMS. Patients could receive several stents as clinically indicated but can only receive the assigned stent type during the index procedure.In all patients, aspirin 75 mg daily was given indefinitely while clopidogrel 75 mg daily was given for 9 months.Follow up visits were done as clinically appropriate without specification from the study protocol. Similarly, no routine follow up coronary angiography was performed.Endpoints: The primary outcome was a composite of all-cause death or spontaneous myocardial infarction. Secondary outcomes included repeat revascularization, stent thrombosis, major bleeding and health status based on the Seattle Angina Questionnaire.Clinical outcomes were collected by linking each patient unique national identification number to the Norwegian national patient registry.Analysis was performed based on the intention-to-treat principle. The study planned to enroll 8,000 patients to be followed for a median of 5 years. Assuming the 5-year event rate of the primary outcome to be 17%, the study would provide 93% power to detect 3% absolute risk difference between the study groups (rate ratio: 1.18). Due to lower than expected mortality, the sample size was increased to 9,000 patientsResults: Among the 20,663 patients who were assessed for eligibility, 12,425 met inclusion criteria. Among patients who met inclusion criteria, 9,013 were randomized. Figure 1 in the manuscript provides details for excluding patients and for not randomizing patients who met eligibility criteria. The most common reason for exclusion was prior PCI.The number of stents implanted per patient was 1.7 and more than 98% received the assigned stent type. The median follow up time was 5 years.The primary composite outcome of all-cause death or nonfatal spontaneous myocardial infarction was not significantly different between both treatment arms (16.6% with DES vs 17.1% with BMS, HR: 0.98; 95% CI: 0.88 - 1.09; p= 0.66).For the secondary outcomes – Hospitalization for unstable angina was similar between treatment groups (5.2% vs. 5.7%; p= 0.21). Stent thrombosis was lower with DES (0.8% vs 1.2%; p= 0.05). Target-lesion revascularization was also lower with DES (5.3% vs 10.3%; p< 0.001). Bleeding Academic Research Consortium (BARC) 3, 4 or 5 was similar between groups (5.5% vs 5.6%; p= 0.88).There was no significant difference in health status based on the Seattle Angina Questionnaire.There were no significant subgroup interactions.Conclusion: In patients undergoing PCI, the use of DES did not reduce the composite endpoint of death or spontaneous myocardial infarction compared to BMS. Target-lesion revascularization was reduced with DES with a number needed to treat of 20 patients.The findings of this study align with the results of other trials comparing DES to BMS. We have reviewed several key trials and included links to additional studies in this field below. Overall, DES significantly reduce target-lesion revascularization without significant effect on all-cause mortality or myocardial infarction.An important consideration in this and other related trials is that both stent types were studied using similar durations of dual antiplatelet therapy (DAPT) following PCI. For patients with stable angina, BMS typically require only one month of DAPT, while DES often necessitate three to twelve months. Since shorter durations of DAPT are generally safer for patients, a trial comparing DES with three to twelve months of DAPT compared to BMS with one month of DAPT would be insightful.A final teaching point is that less than 50% of screened patients were ultimately enrolled in this pragmatic trial, which had minimal exclusion criteria. It's not uncommon for trials to enroll less than 5% of screened patients which limits their external validity.* Other trials of DES vs BMShttps://pubmed.ncbi.nlm.nih.gov/21080780/https://pubmed.ncbi.nlm.nih.gov/22951305/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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Our initial review of the PLATO trial, published in April 2024, was based on the data available to us at that time. We have since became aware of new information that reduces our confidence in the PLATO results. This new information has major implications for clinical 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.Despite representing only 6.9% of the total P2Y12 inhibitor prescriptions among Medicare beneficiaries in 2020, Ticagrelor accounted for nearly two-thirds of total Medicare spending on these drugs in the same year. We summarize important points below but you can refer to this investigation at BMJ for more details.1. Unexplained Regional Variation: In our original review, we highlighted the treatment effect interaction based on region of enrollment, where ticagrelor was less effective compared to clopidogrel for patients enrolled in North America. It appeared to be a strong signal and was associated with a p-value for the interaction of 0.05. However, we were cautious in our interpretation since overall, patients enrolled in North America represented a relatively small fraction of total patients and we could not think of a reasonable explanation.Information in the BMJ investigation now sheds new light on these findings. In our review, we only presented data contained in the supplement accompanying the PLATO trial manuscript, which categorized patients based on region of enrollment but did not provide country specific information. The BMJ report notes that in a separate subgroup analysis, based on country of randomization, the primary outcome was numerically higher with ticagrelor in the United States (12.6% vs 10.1%, HR: 1.27, 95% CI: 0.92 – 1.75). This subgroup represented 7.6% of the total trial participants. Overall, 9.7% of trial participants were enrolled from North America. This means the US data drove the findings from the North American subgroup.The explanation provided by AstraZeneca (the manufacturer of ticagrelor) to explain the observed treatment effect heterogeneity was that aspirin dosing in the United States was higher than in other countries. It even led the FDA to issue a black box warning to avoid an aspirin maintenance dose of >100 mg in patients taking ticagrelor. An extensive statistical analysis of the regional variation in PLATO yielded four interesting points. First what was the prior likelihood of observing a ticagrelor vs clopidogrel HR of > 1.25 in the US, when the overall HR was actually equal to 0.84? That probability is ≤ 0.01. This alone suggests more than chance. Second point: a strong US/nonUS interaction was noted for each of the 3 components of the primary endpoint—CV death, MI, stroke. Third: they found a very strong interaction between treatment and median aspirin dose, and, importantly, the aspirin interaction effect was similar in US and nonUS settings. Fourth, an analysis of contract research organization (CRO) vs sponsor monitoring of the site accounted for 61% of the treatment-by- region interaction. The authors downplayed this finding because of the four countries monitored by a CRO (Israel, US, Georgia and Russia), the US made up the majority and thus is confounded by the aspirin interaction. Noteworthy was a lack of direct analysis of CRO vs sponsor test for interaction. One problem though: the BMJ investigation found that the lead author, Kevin Carroll was the head statistician at AstraZeneca and had worked at the company for 20 years. Carroll presented the PLATO results at the FDA advisory meeting. The paper lists Carroll as having no conflicts. Carroll told the BMJ that he had disposed of all conflicts of interest before submitting that analysis. But, in our opinion, the aspirin explanation does not pass muster because of biologic implausibility. See next section: How would a higher dose of aspirin reduce the efficacy of ticagrelor?The primary composite endpoint was vascular death, MI or stroke. If the higher aspirin dose impacted this, we would hypothesize that it caused more major bleeding in the ticagrelor group with some events resulting in vascular death, type 2 MI and hemorrhagic stroke, driving the treatment effect in favor of clopidogrel. But there is no evidence of this.The figure below is from the original subgroup plots provided in the PLATO supplement. The difference in the treatment effect for the primary endpoint for North American patients is striking but there is no difference for major bleeding.In our opinion and the opinion of others, the role of supervision of the centers could be important. Most centers were monitored by the sponsor. Four countries (Israel, US, Georgia and Russia) were monitored by a contract research organization. All four of these countries had numerically higher rates of the primary outcome in the ticagrelor group. This has major implications and we do not take them lightly. Essentially, it suggests malfeasance on the part of the sponsor. So is there anything else to support such a claim? Well, yes. 2. Concerns about event adjudication. Based on a report from Victor Serebruany, an adjunct faculty member at Johns Hopkins University, and the BMJ investigation, FDA records indicated that site reports documented 504 myocardial infarctions in patients who received ticagrelor compared to 548 in patients who received clopidogrel. However, after adjudication, the count increased only for the clopidogrel group, reaching 593. There was also some imbalance among groups in adjudicating death. These imbalances raise concerns about potential unblinding and result tampering. We read many of the authors' replies and we did not find a clear explanation of why all readjudicated extra MIs were in the clopidogrel group (45 clopidogrel; ticagrelor 0). 3. There were also concerns about the accuracy of death records as sites death records did not always match the FDA records.We cite from the BMJ: The BMJ's analysis also found omissions in PLATO's landmark publication. The paper, published in NEJM and reported as an intent-to-treat analysis, reports 905 total deaths from any cause among all randomized patients. An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths “discovered after withdrawal of consent.” The BMJ obtained some records for patients whose deaths were not reported in NEJM (see table 1) and asked the journal for a response.NEJM editor in chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice,” concluding that “it does not appear that correcting this 15-year-old article is going to have any impact.”It is noteworthy that the United States Department of Justice launched a formal investigation into the PLATO trial in 2013; however, the probe was closed in 2014. The BMJ column cited a spokesperson for the US attorney's office who said…”we determined that the allegations lacked sufficient merit such that it was not in the best interests of the US to intervene in the suit.” 4. Mortality reduction in PLATO defies explanation: Shortly after PLATO was published, Drs. Victor Serebruany and Dan Atar wrote an editorial in the European Heart Journal titled: The PLATO trial: do you believe in magic? They noted that the overall HR for all-cause death ticagrelor vs clopidogrel was 0.78 (95% CI: 0.69 - 0.89; p< 0.001). There were 107 more lives saved with ticagrelor vs clopidogrel. To explain the surprise of this massive effect size, they compared it to the COMMIT trial of clopidogrel vs placebo in patients with acute MI. In COMMIT, 119 lives were saved with clopidogrel (vs placebo), but COMMIT had three-fold more patients than PLATO—and the gain was vs placebo. They tempt the reader to ask: how could ticagrelor fare that well against a drug that crushed placebo? We note two other reasons to be concerned about the outsized mortality reduction in PLATO. One is plausibility. The all-cause mortality benefit exceeded the reduction in MI, CV death or stroke. Given the numerically higher rate of bleeding, how else does ticagrelor reduce death vs clopidogrel? The second reason is the lack of such a signal in Phase 2 studies, such as this one. 5. PLATO results are on outlier: Multiple observational studies have failed to replicate the benefits of ticagrelor observed in the PLATO trial. While observational studies are inherently limited by confounding factors and are inferior to randomized trials, their findings warrant a re-evaluation of ticagrelor's benefits. Furthermore, two randomized trials—one conducted predominantly in Japanese patients and another in South Korea—did not demonstrate the superiority of ticagrelor, instead showing higher bleeding rates and a numerical increase in ischemic events.Ticagrelor also significantly underperformed against another new antiplatelet drug, prasugrel. In the non-industry-funded ISAR-REACT 5 trial, which enrolled patients with acute coronary syndrome, the primary event of death, MI, or stroke was 36% higher in the ticagrelor arm (9.3% vs 6.9%, HR 1.36, 95% CI: 1.09 - 1.70). Major bleeding was also numerically higher in the ticagrelor arm. 6. PLATO authors have responded to these arguments.We provide links to four of the authors responses. * Thrombosis and Hemostasis https://www.wellesu.com/10.1160/TH11-03-0162* Stroke https://www.ahajournals.org/doi/10.1161/strokeaha.111.000514* Inter J of Cardiol https://doi.org/10.1016/j.ijcard.2014.06.029* Circulation https://doi.org/10.1161/CIRCULATIONAHA.111.047498Conclusion These are vitally important revelations regarding PLATO and ticagrelor. The FDA advisory committee recommended that FDA require a confirmatory trial. This was not done. As such, ticagrelor gained serious market share in the non-clopidogrel antiplatelet market for more than a decade. Yet no other compelling evidence for its benefit over clopidogrel has come to light. It clearly underperformed vs prasugrel. These old and new revelations have changed our positive view of ticagrelor. We no longer have confidence in this drug. We strongly agree with the recommendation for another properly controlled trial. We also believe this highlights the benefits of having either two regulatory trials or a single regulatory trial combined with a mandated post-approval trial. These revelations also emphasize the benefits of robust critical appraisal and skeptical but not cynical approaches to surprising evidence. 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 2010;362:1663-74.Background: The RAVEL and TAXUS-IV trials compared the sirolimus- and paclitaxel-eluting 2nd generation stents to 1st generation bare metal stents. Both trials reported improvements in surrogate endpoints - “in-stent luminal loss” was the primary endpoint of RAVEL and “ischemia-driven target-vessel revascularization” was the primary endpoint of TAXUS-IV. Neither trial showed differences in hard endpoints like death or MI but were not powered for such events.The observation that restenosis still occurred with 2nd generation stents drove interest in developing newer stent technology with improved bioavailability and drug delivery. The 3rd generation everolimus-eluting stent was felt to represent such a development but like its predecessors had only been tested in experiments using surrogate endpoints that were not driven by clinical symptoms. Thus, the SPIRIT IV trial sought to test the hypothesis that 3rd generation everolimus-eluting stents would reduce patient-driven clinical outcomes compared 2nd generation paclitaxel-eluting stents. Furthermore, it was designed to be large enough to provide data on important subgroups, especially patients with diabetes.Patients: Limited details are provided about inclusion and exclusion criteria in the main manuscript and readers are directed to a previous publication and supplemental appendix. Lesion characteristics had to be less than 28 mm in length with a reference-vessel diameter between 2.5 to 3.75 mm. Patients were excluded if they had features making them complex from either a clinical or angiographic standpoint. *Note to learners: Be especially skeptical of trials that do not include at least an abridged version of important inclusion and exclusion criteria in the main publication manuscript. This often indicates that the criteria are complex and that patients are highly selected, which limits the generalizability of the findings to routine practice. Baseline characteristics: The average age of patients was 63 years and 68% were men. Approximately 32% of patients had diabetes with about one quarter being insulin-dependent. Over 20%of patients smoked and a similar percentage had a previous heart attack.Three quarters of patients had 1 target lesion, 22% had 2 target lesions and 3% had 3 and 11% of patients had 1 or more complex lesions. The average lesion length was 15 mm, reference-vessel diameter was 2.75 mm, minimal luminal diameter was 0.75 mm, and average % stenosis was 72%.Procedures: Patients were randomized in a 2:1 ratio to receive an everolimus- or paclitaxel-eluting stent. They were stratified based on having diabetes or not, whether they had a single or complex lesion, and study site. Operators were not blind to the stent being used. At least 300 mg of aspirin was administered before catheterization and at least 300 mg of clopidogrel was recommended before the procedure and was required within 1 hour after stent implantation. Patients took at least 80 mg of aspirin daily for an indefinite period and 75 mg of clopidogrel for at least 12 months. Clinical follow-up visits were scheduled at 30, 180, 270, and 365 days and yearly through 5 years.Endpoints: The primary end point was ischemia-driven target lesion failure at 1 year defined by the composite of cardiac death, target-vessel myocardial infarction, or ischemia-driven target-lesion revascularization. As was the case in the TAXUS-IV trial, “ischemia-driven” did not necessarily mean “symptom-driven”. Two major secondary endpoints were also prespecified which included ischemia-driven target-lesion revascularization and the composite of death or target-vessel MI.The trial was powered for sequential testing of noninferiority and superiority for both the primary and 2 major secondary endpoints. The criteria for noninferiority would be met if the upper limit of the 97.5% confidence interval was not more than 3.1%. This was based on an assumed 1 year target-lesion failure rate of 8.2% for both groups. The trial had 90% power to show non-inferiority. Superiority testing was prespecified if the criterion for noninferiority was met. It was estimated that 3690 patients would have 90% power to detect a 2.9% absolute reduction in the primary end point, at a two-sided alpha of 0.05. The trial also had 90% power to test noninferiority for ischemia-driven target-lesion revascularization and the composite of cardiac death or target-vessel MI at a 2.1% margin. It had 90% and 91% power to test for superiority of these endpoints if noninferiority was met.*Note to learners: The statistical analysis plan for this trial demonstrates 2 important concepts in hypothesis testing. First, trials can be powered in a prespecified manner for non-inferiority and superiority testing. Second, trials can be powered for prespecified hypothesis testing of more than just a single endpoint.Results: Patients were enrolled over a 2 year period from 66 U.S. sites. There were a total of 3,687 patients included in the final analysis with 2,458 in the everolimus-eluting stent group and 1,229 in the paclitaxel-eluting stent group. There were some significant differences for patients receiving everolimus-eluting stents that included the number of stents per lesion, total stent length per lesion, the ratio of stent length to lesion length and the maximum pressure used.At 1 year, everolimus-eluting stents met non-inferiority for the primary and major secondary endpoints and met superiority for 2 of 3. Everolimus-eluting stents reduced the primary endpoint of target-lesion failure (4.2% vs 6.8%; RR 0.62; 95% CI 0.46 to 0.82) and the major secondary endpoint of ischemia-driven target lesion revascularization (2.5 vs 4.6%; RR 0.55; 95% CI 0.38 to 0.78) but not the other major secondary endpoint of cardiac death or target-vessel MI (2.2% vs 3.2%; RR 0.69; 95% CI 0.46 to 1.04). Differences in target-lesion failure were driven by statistically significant reductions in target-lesion revascularization (2.5% vs 4.6%) as well as MI (1.9% vs 3.1%) but not all-cause (1.0% vs 1.3%) or cardiac death (0.4% vs 0.4%). Stent thrombosis was also significantly reduced but rates were very low in both groups and the trial was not powered for this endpoint.Interestingly, subgroup analysis of the primary endpoint revealed a statistically significant interaction for treatment efficacy in patients with diabetes such that diabetics did not appear to benefit from everolimus-eluting stents (6.4% vs 6.9%) compared to non-diabetics (3.3% vs 6.7%; p for interaction = 0.02).Conclusions: In patients with stable CAD who underwent generally non-complex PCI procedures, 3rd generation everolimus-eluting stents compared to 2nd generation paclitaxel-eluting stents reduced a composite endpoint of ischemia-driven target-lesion failure by 38% with a number needed to treat of approximately 40 patients. This was associated with statistically significant reductions in nonfatal MI with a NNT of approximately 100 patients and ischemia-driven target lesion revascularization with a NNT of approximately 50 patients. Everolimus-eluting stents did not reduce death.There was an interaction noted for diabetic patients who did not appear to significantly benefit from everolimus-eluting stents. Notably, diabetics exhibited more severe angiographic disease with a higher prevalence of multivessel disease, diffuse plaque burden, and a greater likelihood of left main coronary artery involvement. This subgroup finding along with the highly selected nature of the study cohort reduces our confidence that the 3rd generation everolimus-eluting stent confers significant advantages over 2nd generation stents for many patients who receive them in clinical practice.One final consideration is that the trial was single blinded and operators were aware of stent type which could have biased their performance and the study results.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 2004;350:221-31Background: For the past year we have been posting reviews of seminal trials in cardiovascular medicine. It is our anticipation that these will ultimately be published in a textbook format that will be indexed by major subject headings and the reviews will be presented in chronological order. However, in curating postings for Substack we have had to jump around in order to maintain some consistency in the topics being presented. We started this year by reviewing medical therapies for patients with acute coronary syndrome. After that we moved to the management of patients with mostly stable coronary artery disease and have completed reviews on trials involving CABG and percutaneous coronary interventions compared to medical therapy and to each other, in the case of patients with left main and multivessel disease. In completing that stream of trials, we intentionally skipped trials that have been instrumental in developing those techniques, especially coronary stenting. While perhaps not that important to general readers, medical trainees, especially in the field of cardiovascular medicine need to be familiar with these trials. They are not intended to address questions involving stenting versus medical care but instead, to address the question of “If you're going to stent, is it better to use product A or B?”In that vein, we recently reviewed the RAVEL trial that compared sirolimus-eluting stents to bare metal stents. This is an issue of interest because a common problem following PCI is restenosis of the treated area due to the process of neointimal proliferation that involves the migration and proliferation of smooth muscle cells from the injured arterial wall. The idea behind drug coated stents was that the drug coatings would reduce this process locally (at the level of stented arterial wall) by blocking the process of neointimal proliferation and hyperplasia, which is not the same as atherosclerosis.RAVEL was a small trial showing that a sirolimus-eluting stent improved the surrogate endpoint of in-stent luminal loss at 6 months compared to a bare metal stent. The TAXUS-IV trial was undertaken for similar purposes but on a larger scale and sought to test a more clinically relevant endpoint. It sought to test the hypothesis that a paclitaxel-eluting stent would reduce ischemia-driven target-vessel revascularization compared to a bare metal stent.*Note to learners: A common parlance for describing stents in the clinical setting is to refer to them based on generation (e.g., first, second, or third generation). First generation stents are bare metal stents. Second and third generation stents are drug eluting stents with newer generations often featuring improved biocompatibility and drug delivery mechanisms. Sirolimus- and paclitaxel-eluting stents are considered second generation stents.Patients: Patients had to be 18 years of age or older, have stable or unstable angina or provokable ischemia, and were undergoing PCI for a single, previously untreated lesion in a native coronary artery. Angiographic inclusion required a single target lesion with a reference-vessel diameter on visual examination of 2.5 to 3.75 mm and a lesion length of 10 to 28 mm that could be covered by a single study stent. There were many exclusion criteria that can be summarized as follows: acute MI, complex coronary disease (including left main, ostial target lesion or bifurcating target lesion), complex patient and predisposition to bleeding.Baseline characteristics: The average age of patients was 62 years and 72% were men. Approximately 30% of patients had diabetes with nearly a quarter requiring insulin. Over 20% were smokers and 30% had a previous MI. The average LV EF was 55%. The target lesion was located in the LAD in 40%, the circumflex in close to 30% and the right coronary artery in 30%. The reference-vessel diameter was >/=3.0 mm in over 75% of patients. The average lesion length was 13 mm, average reference-vessel diameter was 2.75 mm, average minimal luminal diameter was 0.92 mm, and average % stenosis was 66%.Procedures: Patients were assigned in equal proportions in a double-blind fashion to treatment with either the paclitaxel-eluting stent or a visually indistinguishable bare-metal stent. Unfractionated heparin was administered according to standard practice, and the use of glycoprotein IIb/IIIa inhibitors was at the operator's discretion. After mandatory balloon dilation, patients received an appropriately-sized stent. A postprocedural electrocardiogram was obtained, and cardiac enzymes were measured every 8 hours for 24 hours. Patients took 325 mg of aspirin daily indefinitely and 75 mg of clopidogrel daily for 6 months. Clinical follow-up was scheduled at 1, 4 and 9 months and yearly thereafter for 5 years.Endpoints: The primary end point was the 9 month incidence of ischemia-driven target-vessel revascularization. It was considered to be “ischemia driven” if the stenosis of the target vessel was at least 50% of the luminal diameter on the basis of quantitative analysis with either: 1) ECG changes while the patient was at rest or 2) a functional study indicating ischemia in the distribution of the target vessel. It was also considered “ischemia driven” if there was a 70% stenosis in conjunction with recurrent symptoms alone.*It should be noted that in this case “ischemia driven” does not necessarily mean symptom driven.Major adverse cardiac events were defined as death from cardiac causes, MI, or ischemia-driven target-vessel revascularization. Target-vessel failure was defined as death, MI or ischemia-driven target vessel revascularization related to the target vessel. Analysis was based on the intention-to-treat principle. A total of 1172 patients were needed to detect a 40% relative reduction (6% absolute reduction) in the primary endpoint based on an anticipated event rate of 15% in the bare-metal stent group. This sample size would have 85% power with an alpha level of 0.05 to detect the difference described above while allowing for a drop out rate of 10%.Results: A total of 1,326 patients were enrolled over a 3 month period from 73 US centers and 1,314 were included in the final analysis with 662 in the paclitaxel-eluting stent group and 652 in the bare-metal stent group. The initial angiographic results were similar in the 2 groups.At 9 months, paclitaxel-eluting stents reduced the primary endpoint of ischemia-driven target vessel revascularization by 61% (4.7% vs 12.0%; RR 0.39; 95% CI 0.26-0.59). There were no differences in death from cardiac causes (1.4% vs 1.1%), MI (3.5% vs 3.7%), or stent thrombosis (0.6% vs 0.8%). In a prespecified subset of patients who underwent coronary angiography at 9 months, paclitaxel-eluting stents were associated with better angiographic features compared to bare-metal stents.Conclusions: In patients with stable and unstable angina (not acute MI), paclitaxel-eluting stents significantly reduced ischemia-driven target vessel revascularization at 9 months of follow-up with a number needed to treat of approximately 14 patients. There were no differences in any hard endpoints. While some would hail this as a remarkably positive trial we have reservations. Firstly, the primary endpoint is not symptom-driven and it should be regarded as a surrogate endpoint. At the time this trial was undertaken it was routine practice for patients to undergo surveillance testing with ECG's and functional tests following coronary revascularization and this is likely how the majority of patients came to undergo revascularization (not via a symptom-driven route). Had these elective revascularizations not occurred, it is unknown whether it would have resulted in any deleterious consequences.Second, patients enrolled in the trial were highly selected and no information is provided in the main manuscript on how many underwent screening. Commonly-occurring angiographic features of coronary lesions, for which patients undergo PCI, were excluded (i.e., ostial and bifurcating lesions, lesions in vessels with reference vessel diameters

N Engl J Med 2002;346:1773-1780Background: Percutaneous revascularization of the coronary arteries is frequently performed for patients with stable and unstable angina. By the late 1990s and early 2000s, most percutaneous coronary interventions (PCI) were performed with intracoronary stent placement rather than balloon angioplasty alone given lower rates of angiographic detected restenosis with stent placement. However, stent restenosis was a common cause of repeat revascularization. Unlike the process of atherosclerotic plaque development, stent restenosis is caused by a distinct process of neointimal proliferation. When a blood vessel is injured during a procedure like coronary stenting, the body's natural healing response triggers the migration and proliferation of smooth muscle cells from the vessel wall into the inner lining (intima), creating a new tissue layer called neointima. If the neointima grows excessively, it can narrow the blood vessel lumen, leading to restenosis, which can cause symptoms like angina.Early coronary stenting was performed using bare-metal stents that were prone to neointimal proliferation. Animal studies and a small clinical study at the time suggested that the systemic or local administration of the drug sirolimus could reduce neointimal proliferation. Sirolimus is a macrocyclic lactone that inhibits cytokine-mediated and growth-factor–mediated proliferation of lymphocytes and smooth-muscle cells.The RAVEL trial sought to assess the performance of stents coated with sirolimus (drug-eluting stents ”DES”) compared to uncoated stents (bare-metal stents “BMS”).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: Eligible patients had stable angina, unstable angina, or silent ischemia. Only patients with single target lesions in a native coronary artery were included. The stenosis had to be 51-99% and could be covered by an 18 mm stent. The coronary artery had to be 2.5 – 3.5 mm in diameter.Patients were excluded if they had evolving myocardial infarction, left main disease unprotected by a graft, ostial lesions, calcified lesions that couldn't be completely dilated, angiographically visible coronary thrombus, ejection fraction

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