Cardiology Trials

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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. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

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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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The Lancet Volume 403, Issue 10438 p1753-1765May 04, 2024Background Cardiologist have long been taught that acute plaque rupture leading to myocardial infarction is more likely to come from non-flow-limiting lipid-rich atherosclerotic plaques. The concept of the vulnerable plaque is surely one of the reasons that revascularization of high-grade stable coronary artery disease does not reduce myocardial infraction or death over optimal medical therapy.The search for and treatment of the vulnerable plaque remains one of the important research areas in modern cardiology. South Korean investigators set out to test whether PCI of non-flow-limiting, high-risk vulnerable plaques identified by intracoronary imaging would reduce major adverse cardiac outcomes over medical therapy in the Preventive percutaneous coronary intervention versus optimal medical therapy alone for the treatment of vulnerable atherosclerotic coronary plaques (PREVENT).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 recruited in the cardiac catheterization lab. Both ACS and stable CAD patients were included. FFR was done to exclude significant flow limitations. Clinically relevant lesions with an FFR ≤ 0.80 underwent PCI with a drug-eluting stent before randomization.All untreated, non-culprit lesions (ie, those that were clearly not responsible for the presenting clinical syndrome) with an angiographic diameter stenosis of 50% or more by site visual estimation were functionally assessed by fractional flow reserve.Then, intermediate non-flow-limiting lesions (FFR >0.80) were assessed by intra-coronary imaging—with one of four techniques (at the discretion of the operator). These included grey-scale intravascular ultrasonography (IVUS), radiofrequency intravascular ultrasonography, a combination of grey-scale intravascular ultrasonography and near-infrared spectroscopy, or optical coherence tomography (OCT).Vulnerable plaques were defined as lesions possessing at least two of the following four characteristics: a minimal lumen area of less than 4·0 mm2 by IVUS or OCT; a plaque burden of more than 70% by IVUS; a lipid-rich plaque by near-infrared spectroscopy (defined as maximum lipid core burden index within any 4 mm pullback length [maxLCBI4mm] >315); or a thin-cap fibroatheroma detected by radiofrequency intravascular ultrasonography or optical coherence tomography (defined as a ≥10% confluent necrotic core with >30° abutting the lumen in three consecutive frames on radiofrequency intravascular ultrasonography or as a lipid plaque with arc >90° and fibrous cap thickness

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N Engl J Med 2009;360:2503-2515Background: Type 2 diabetes increases the risk of cardiovascular events and death. Previous trials comparing revascularization versus medical therapy included patients with diabetes, however, a large-scale trial specifically focusing on patients with type 2 diabetes was lacking.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial sought to assess the optimal treatment strategy for patients with type 2 diabetes and stable coronary artery disease.Patients: Eligible patients had type 2 diabetes and stable coronary artery disease. Coronary artery disease was defined as a stenosis in a major coronary artery of 50% or more and a positive stress test or 70% or more and classic angina. Patients had to be candidates for percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) without further specification.Patients were excluded if they had left main disease, prior PCI or CABG within 12 months, class III or IV heart failure, hepatic dysfunction, creatinine> 2 mg/dL or glycated hemoglobin> 13%.Baseline characteristics: The trial randomized 2,368 patients – 1,176 randomized to the revascularization arm and 1,192 to the medical therapy arm. Among the 1,176 patients in the revascularization arm, 32% were planned to undergo CABG and 68% planned to undergo PCI.The average age of patients was 62 years and 70% were men. The mean glycated hemoglobin was 7.7% and the mean duration of diabetes was 10.4 years. Approximately 32% had prior myocardial infarction, 7% had congestive heart failure and 24% had peripheral artery disease. Approximately 18% had no angina or angina equivalent. Angina class within 6 weeks was 1-2 in 43% of the patients and 3-4 in 9%.The mean left ventricular ejection fraction was 57%. Approximately 31% had three-vessel disease and 13% had proximal left anterior descending artery disease.Baseline characteristics were well balanced between the revascularization arm and the medical therapy alone arm. However, patients who were in the CABG stratum had more three-vessel disease (52% vs 20%) and more proximal left anterior descending artery disease (19% vs 10%).Procedures: The trial was a 2 x 2 factorial design and patients were randomly assigned to two treatment strategies. The first was randomization to revascularization or medical therapy. The second was randomization to insulin-sensitization therapy or insulin-provision therapy. Randomization was stratified based on the method of revascularization (PCI vs CABG) which was determined by the treating physician.In this review, we will focus on the first strategy of revascularization vs medical therapy.For patients randomized to the revascularization arm, the procedure was to be performed within 4 weeks after randomization. Patients in the medical arm could receive revascularization on follow up for any of the following: Progression of angina, acute coronary syndrome or severe ischemia.Patients were seen monthly for the first 6 months and every 3 months thereafter.Endpoints: The primary endpoint was death from any cause. Secondary end point was a composite of death, myocardial infarction, or stroke.Analysis was performed based on the intention-to-treat principle. The original sample size of 2,800 patients was not met, and therefore, the average follow up time was increased by 1.5 years to become 5.3 years. Using the new follow up duration, the study had 88% power to detect a 33% relative risk reduction of death (from 14.0% to 9.8%), and a 95% power to detect a 25% relative risk reduction in the secondary composite endpoint (from 24.0% to 18.0%).Results: Among the patients randomized to the revascularization arm, 95.4% underwent revascularization at 6 months compared to 13.0% of the patients randomized to the medical arm. At 5-years, 42.1% of the patients randomized to the medical arm had undergone revascularization. Among patients who underwent PCI in the revascularization arm, procedures were attempted on average of 1.5 lesions and 56.0% received a bare metal stent. Among patients who underwent CABG in the revascularization arm, 94.2% received an internal mammary artery graft and the mean number of distal anastomoses was 3.0.The average follow up time was 5.3 years.There was no significant difference in the primary outcome of all-cause death. Survival was 88.3% in the revascularization arm and 87.8% in the medical arm (difference: 0.5%; 95% CI: −2.0 - 3.1; p=0.97). There was also no significant difference for the secondary composite endpoint. Freedom from events for the secondary endpoint was 77.2% in the revascularization arm and 75.9% in the medical arm (difference: 1.3%; 95% CI, −2.2 - 4.9; p=0.70).Survival was not significantly different between both treatment strategies in the CABG stratum (86.4% with revascularization vs 83.6% with medical therapy; p= 0.33). However, patients in the CABG stratum had more freedom from the secondary composite endpoint (77.6% vs 69.5%; p= 0.01).In the PCI stratum, revascularization did not improve survival (89.2% with revascularization vs. 89.8% with medical therapy; p= 0.48) or freedom from the secondary composite endpoint (77.0% with revascularization vs 78.9% with medical therapy; p= 0.15).Conclusion: In patients with type 2 diabetes and stable coronary artery disease, revascularization compared to medical therapy did not improve the primary outcome of all-cause death, or the composite secondary outcome of death, myocardial infarction or stroke over an average follow up time of 5.3 years.The observed benefit of revascularization within the CABG stratum should be viewed as hypothesis-generating rather than conclusive evidence that CABG is superior to PCI in this patient population.One potential limitation of this trial is that the authors included patients who were candidates for either PCI or CABG without providing enough details on what makes someone not a candidate. This lack of clarity limits physicians' ability to fully understand which patients would have been suitable for inclusion.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

N Engl J Med 2022;386:128-137Background: Patients with three-vessel coronary artery disease have better outcomes when revascularization is performed using coronary artery bypass grafting (CABG) compared to percutaneous coronary intervention (PCI), as seen in the SYNTAX and FREEDOM trials. Fractional flow reserve (FFR) was not required and was not routinely performed in these trials.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) 3 trial sought to compare the outcomes of FFR-guided PCI vs CABG in patients with three-vessel coronary artery disease.Patients: Eligible patients had three-vessel coronary artery disease defined as 50% or more stenosis, by visual estimation, in any of the three major coronary arteries or major branches. Lesions had to be amenable to revascularization by PCI and CABG as determined by the heart team.Major exclusion criteria were left main disease, cardiogenic shock, STEMI within 5 days, active NSTEMI with cardiac troponin still rising, left ventricular ejection fraction

N Engl J Med 2016;375:2223-2235Background: Smaller randomized trials have shown that outcomes are not significantly different when patients with left main disease are treated with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). In the subgroup of patients with left main disease in the SYNTAX trial, outcomes were similar between PCI and CABG in patients with low or intermediate SYNTAX score but PCI was associated with worse outcomes in patients with high SYNTAX score.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial sought to assess if PCI was noninferior to CABG in patients with left main coronary artery disease.Patients: Eligible patients had left main stenosis of 70% or more. Patients with stenosis of 50% to 69% were enrolled if the stenosis was hemodynamically significant as determined by non-invasive or invasive testing. Patients were also required to have low or intermediate SYNTAX score defined as a score of 32 or less.Patients were excluded if they had prior PCI to the left main coronary artery, PCI to any other coronary artery within 1 year, prior CABG, a need for a concomitant cardiac surgery, elevated CK-MB, or life expectancy less than 3 years due to non-cardiac conditions.Baseline characteristics: The trial randomized 1,905 patients – 948 randomized to PCI and 957 to CABG.The average age of patients was 66 years and 77% were men. Approximately 74% had hypertension, 70% had hyperlipidemia, 29% had diabetes, 17% had prior myocardial infarction and 22% were current smokers. The average left ventricular ejection fraction was 57%.The clinical presentation was myocardial infarction within 7 days in 14% of the patients, unstable angina in 24%, stable angina in 53%, and silent ischemia or other in 8%.Distal left main bifurcation or trifurcation disease was present in 81% of the patients, and 2- or 3-vessel coronary artery disease was present in 51%. SYNTAX score based on a core laboratory evaluation was low (22 or less) in 36% of the patients, intermediate (23-32) in 40% and high (33 or more) in 24%. However, based on site assessment, SYNTAX score was low in 61% of the patients and intermediate in 39%.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo CABG or PCI using fluoropolymer-based cobalt–chromium everolimus-eluting stents (XIENCE, Abbott Vascular). Randomization was stratified based on the presence of diabetes, SYNTAX score (low vs intermediate) and study center.Dual antiplatelets were given for at least 12 months following PCI.CABG was performed with or without cardiopulmonary bypass based on the operator discretion. The use of arterial grafts was recommended.Endpoints: The primary endpoint was a composite of death from any cause, myocardial infarction and stroke at 3 years. Secondary endpoints included the components of the primary endpoint as well as repeat revascularization.Analysis was performed based on the intention-to-treat principle. Sample size was calculated based on non-inferiority. The sample size to provided 80% power with one-sided alpha of 0.025 was 1,900 patients. This calculation was based on an assumed 11% event rate in each study group and 4.2% absolute difference non-inferiority margin.The original sample size was 2,600 patients which would have provided 90% power. However, both were adjusted due to slow enrollment.Results: Among the 948 patients assigned to the PCI arm, 99% underwent the procedure. The mean number of stents implanted per patient was 2.4. Among the 957 patients assigned to the CABG arm, 96% underwent the surgery. The mean number of grafts per patient was 2.6. An internal mammary artery graft was used in 99% of the patients. The median follow up time was 3 years.The primary composite endpoint was not significantly different between CABG and PCI (14.7% with CABG vs 15.4% with PCI, absolute difference: 0.7%, upper bound of the 97.5% CI: 4.0%; p= 0.02 for non-inferiority). There was no significant difference in death from any cause (5.9% with CABG vs 8.2% with PCI; p= 0.11), myocardial infarction (8.3% with CABG vs 8.0% with PCI, p= 0.64) or stroke (2.9% with CABG vs 2.3% with PCI; p= 0.37). Ischemia-driven revascularization was higher with PCI (12.6% vs 7.5%; p

Lancet 2016;388:2743-52Background: PCI was commonly used for the management of patients with left main coronary artery disease and favorable pathology (i.e., absence of complex lesions). This was recommended by the guidelines at the time and based mainly on the prespecified subgroup of 705 patients with left main disease in the SYNTAX trial. The NOBLE trial sought to more rigorously test the hypothesis that PCI with drug eluting stents was non-inferior to CABG in patients with unprotected left main coronary artery stenosis.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: Inclusion criteria for study enrollment were stable angina pectoris, unstable angina, or acute coronary syndrome with a left main lesion with visually assessed stenosis diameter >/= 50% or fractional flow reserve I. The number of target lesions was 2 in both groups. The average SYNTAX score was 22.5 (for reference, it was 28.7 in the SYNTAX trial). The percentage of patients with stable angina was 82% and acute coronary syndrome was 18%. Patients were enrolled from 36 different centers but 5 centers contributed 42% of them. A screening log from these 5 centers was presented in the main paper. For these centers, the enrolled/screened ratio was 52%. The most common reasons for exclusion were unsuitable coronary anatomy for PCI.Procedures: Patients were assigned 1:1 to undergo PCI with drug eluting stents or CABG. After treatment of 73 patients with PCI, the Biolimus-eluting stent became the recommended study stent. Randomization was stratified by sex, the presence of a distal left main bifurcation lesion, and diabetes.The intent was to achieve complete revascularization of all vessels with significant lesions. The techniques for CABG and PCI as well as post-treatment medicines were chosen based on local practice but included 75-150 mg of aspirin lifelong. In both groups, patients with acute coronary syndrome received 75 mg of clopidogrel daily for 12 months. All patients in the PCI group also received 75 mg clopidogrel daily for 12 months and prasugrel or ticagrelor could be substituted at the discretion of the PCI operator.Endpoints: The primary endpoint was a composite of death from any cause, non-procedural myocardial infarction, repeat revascularization, or stroke.Analysis was performed based on the intention-to-treat principle. The primary analysis was a non-inferiority analysis. The main hypothesis tested was non-inferiority of PCI to CABG, assessed as the upper limit of the 95% CI of the hazard ratio (HR) of PCI to CABG, not exceeding 1.35 at median 3 years of follow-up. It should be noted that the sample size calculation for NOBLE was based on 1 year event estimates from the SYNTAX trial that were extrapolated to 2 years. The sample size of 1,200 patients came from the original hypothesis test of non-inferiority corresponding to a total of 275 events at median 2 years of follow-up. However, due to slow accrual of events, assessment of the primary endpoint could not be reached within the limit of the study and so the primary endpoint assessment was pushed back to 3 years of follow-up. Despite this, the prespecified event total (275 events) was not reached.Results: 1,201 patients were enrolled, which included 598 in the PCI group and 603 in the CABG group; however, only 592 patients in each group were entered into the final intention-to-treat analysis. Compared to CABG, PCI increased the primary composite endpoint (28% vs 18%; HR 1.51; 95% CI 1.13-2.00). Since the upper bound of the 95% CI was >1.35, PCI did not pass the test for non-inferiority. The primary outcome was driven mainly by differences in non-procedural MI (6% vs 2%; HR 2.87; 1.40-5.89) and repeat revascularization (15% vs 10%; HR 1.50; 1.04-2.17), which favored the CABG group. There was no difference in all-cause mortality (11% vs 9%; HR 1.08; 0.67-1.74) or its sub-component of cardiovascular mortality (3% vs 3%; HR 0.92; 0.44-1.90). The outcome of stroke was numerically higher with PCI but the difference was not statistically significant (5% vs 2%; HR 2.20; 0.91-5.36). When examining the Kaplan-Meier curves for the primary outcome, the curves start to diverge at 1 year.PCI was associated with significantly lower 30 day morbidity compared to CABG exemplified by 3 outcomes: duration of index treatment admission (2 vs 9 days; p

N Engl J Med 2012;367:2375-2384Background: The first large trial to compare PCI vs CABG was SYNTAX. In the subgroup of patients with diabetes, which made up approximately 25% of the trial population, PCI was associated with a higher rate of adverse events compared to CABG, primarily driven by higher rates of repeat revascularization in the PCI group.The Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial sought to assess the optimal revascularization strategy for patients with diabetes and multivessel coronary artery disease.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 diabetes and multivessel coronary artery disease defined as a stenosis of 70% or more in two or more major coronary arteries supplying at least two separate territories.Patients with left main stenosis of 50% or more were excluded as well as patients with severe congestive heart failure, prior CABG or valve surgery, stroke within 6 months, significant bleeding within 6 months, 2 or more chronic total occlusions in major coronary territories that are targets for revascularization, and patients with STEMI within 72 hours.Baseline characteristics: The trial randomized 1,900 patients – 953 randomized to PCI and 947 to CABG.The average age of patients was 63 years and 71% were men. The average HbA1c was 7.8 and 32% were using insulin. Approximately 26% had prior myocardial infarction and 16% were current smokers. The average left ventricular ejection fraction was 66%.Approximately 83% had three vessel disease and 6% of the lesions were classified as chronic total occlusions. The SYNTAX score was low (22 or less) in 35% of the patients, intermediate (23 - 32) in 45% and high (33 or more) in 20%.Procedures: Patients were randomized in a 1:1 ratio to undergo CABG or PCI using drug-eluting stents. The use of arterial conduits was encouraged for patients undergoing CABG.Dual antiplatelet therapy with aspirin and clopidogrel was recommended for at least 12 months following PCI.Endpoints: The primary endpoint was a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke. Secondary analysis was performed based on the SYNTAX score and study center location; north America vs not.Analysis was performed based on the intention-to-treat principle. The estimated sample size was 1,900 patients to be followed up for at least 2 years. This sample size would provide 80% power to detect a 27% relative risk reduction in one treatment group based on an estimated event rate of 21.5% in the arm with higher event rate.It's important to note that the initial sample size was 2,400 patients but this was amended twice due to slow recruitment.Authors performed 3 interim analyses and therefore, the p value to indicate statistical significance for the primary outcome was adjusted to be 0.044.Results: Among 32,966 patients who were screened for inclusion, 3,309 (10%) were found eligible. Among eligible patients, 1,900 consented to the trial and were randomized. The breakdown for excluding patients was not provided. The median follow up time was 3.8 years (interquartile range: 2.5 - 4.9). In the PCI arm, the average number of lesions stented per patient was 3.5 and 34% underwent a staged procedure. In the CABG arm, the average number of vessels grafted was 2.9 and 94% had a left internal mammary artery graft.At 5-years, the primary outcome was lower in the CABG arm (18.7% vs 26.6%, absolute difference 7.9%, 95% CI: 3.3 – 12.5; p= 0.005). All-cause death was lower with CABG (10.9% vs 16.3%; p= 0.049) as well as myocardial infarction (6.0% vs 13.9%; p< 0.001). When examining the Kaplan-Meier curves for the primary endpoint as well as death (figure 1 of the manuscript), the curves start to diverge, in favor of surgery, at approximately 2-years of follow up.Stroke was higher with CABG (5.2% vs 2.4%; p= 0.03). Excess stroke in the CABG arm was largely within 30-days after the procedure (1.8% vs 0.3%).Major bleeding within 30-days after revascularization was not significantly different between both treatment groups (3.6% with CABG vs 2.4% with PCI; p= 0.13). Acute renal failure requiring dialysis within 30-days after revascularization was higher with CABG (0.8% vs 0.1%; p= 0.02).There were no significant subgroup interactions that included the SYNTAX score, sex, 2- or 3-vessel disease and study center location; north America vs not.Conclusion: In patients with diabetes and multi-vessel stable coronary artery disease, CABG was superior to PCI in reducing the primary endpoint that consisted of death from any cause, nonfatal myocardial infarction, and nonfatal stroke with a number need to treat (NNT) of approximately 13 patients over an average follow-up period of 3.8 years. All-cause death and myocardial infraction were significantly lower with CABG with a NNT of approximately 19 and 13, respectively. Stroke was higher with CABG with a number needed to harm (NNH) of 36 patients. CABG also increased the risk of acute renal failure requiring dialysis within 30-days after revascularization with a NNH of approximately 143.A key difference between this trial and the early CABG trials is the frequent use of internal mammary grafts in FREEDOM (94% vs 10%). Internal mammary grafts are resistant to atherosclerosis and have high patency rates. One possible explanation for the divergent results between this trial and SYNTAX, which also used arterial grafts frequently, is the follow up time. In SYNTAX, patients were followed for 1 year while FREEDOM followed patients up to 5 years and the curves for the primary outcome and death favoring CABG started to diverge at approximately 2 years.When deciding between CABG and PCI for patients meeting the trial's eligibility criteria, it's important to consider the early risks associated with surgery, with the benefits of CABG becoming more apparent after 2 years. Cardiology Trial's Substack is a reader-supported publication. 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N Engl J Med 2009;360:961-972Background: After its introduction in 1968, the use of coronary artery bypass grafting (CABG) in patients with coronary artery disease grew rapidly. Although early trial results were mixed (see the Veterans Administration Cooperative study, the European Coronary Surgery Study and the CASS study), advancements in surgical techniques and the use of arterial conduits improved survival and reduced graft occlusion rates. In 1977, percutaneous coronary intervention (PCI) was introduced, and subsequent improvements in PCI techniques and stents have led to fewer complications and better stent patency. Large trials comparing CABG to PCI using drug-eluting stents were lacking.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial sought to assess the optimal revascularization strategy for patients with left main or three-vessel coronary artery disease.Patients: Eligible patients had three-vessel or left main coronary artery disease. Patients had to have 50% or more stenosis in the target vessels and either chest pain or evidence of myocardial ischemia. Exclusion criteria were previous PCI or CABG, acute myocardial infarction or the need for concomitant cardiac surgery.Baseline characteristics: The trial randomized 1,800 patients – 903 randomized to PCI and 897 to CABG.The average age of patients was 65 years and 78% were men. The average body mass index was 28 kg/m2. Approximately 67% had hypertension, 78% had hyperlipidemia, 25% had diabetes, 33% had prior myocardial infarction, 5% had congestive heart failure, and 20% were current smokers.The number of target lesions was approximately 4 in both groups. The SYNTAX score was 28.4 in the PCI group and 29.1 in the CABG group.Note to readers: The SYNTAX score is an anatomical score to grade the complexity of coronary artery disease with higher scores indicating more complex disease. A score of 22 or less is considered low whereas a score of 33 or more is considered high (this scoring was a prespecified secondary endpoint). Procedures: Patients were assigned in a 1:1 ratio to undergo CABG or PCI using Taxus Express paclitaxel-eluting stents (drug-eluting stent). Randomization was stratified by the presence or absence of left main disease and diabetes.The intent was to achieve complete revascularization in all coronary arteries of at least 1.5 mm diameter with 50% or more stenosis. The techniques for CABG and PCI and post procedural medications were chosen based on local practices.Endpoints: The primary endpoint was a composite of death from any cause, stroke, myocardial infarction, or repeat revascularization up to 12 months after randomization.Analysis was performed based on the intention-to-treat principle. The primary analysis was a non-inferiority analysis. The estimated sample size was 1800 patients assuming 13.2% event rate in the CABG group, 14.0% in the PCI group and 6.6% absolute risk difference non-inferiority margin. This sample size would provide 96% power at 5% one-sided alpha.Results: Revascularization was complete in 56.7% of the patients in the PCI group and 63.2% in the CABG group. In the CABG group, one or more arterial grafts were used in 97.3% of the patients. In the PCI group, the average number of stents implanted per patient was more than four.At 12 months, the primary outcome was lower in the CABG group (12.4% vs 17.8%, RR with PCI: 1.44, 95% CI: 1.15 – 1.81; p= 0.002). The absolute difference was 5.4% with an upper bounds of the 95% CI of 8.3%; thus not meeting non-inferiority. Stroke was lower with PCI (0.6% vs 2.2%; p= 0.003) while repeat revascularization was lower with CABG (5.9% vs 13.5%; p< 0.001). There was no significant difference in death from any cause (4.4% with PCI vs 3.5% with CABG; p= 0.37) or myocardial infarction (4.8% with PCI vs 3.3% with CABG; p= 0.11).There was a significant interaction based on the SYNTAX score where patients with high SYNTAX scores (>/=33) had significant benefit with CABG while patients with low or intermediate SYNTAX scores did not (14.7% with CABG vs 13.6% with PCI for low SYNTAX score, 12.0% with CABG vs 16.7% with PCI for intermediate SYNTAX score, and 10.9% with CABG vs 23.4% with PCI for high SYNTAX score; p for interaction= 0.01).In the subgroup of patients with left main disease, the rate of the primary outcome at 12 months was not significantly different between both treatment groups (13.7% with CABG vs 15.8% with PCI; p= 0.44). In patients with three-vessel but no left main disease, the primary outcome was significantly higher in the PCI group (19.2% vs 11.5%; p< 0.001).Stent thrombosis was 3.2% in the PCI group and graft occlusion was 3.1% in the CABG group.Conclusion: In patients with stable three-vessel or left main coronary artery disease, PCI did not meet non-inferiority compared to CABG in reducing the composite endpoint of death from any cause, stroke, myocardial infarction, or repeat revascularization over 12 months of follow up. The number of patients needed to treat with CABG to prevent one primary endpoint was approximately 19 patients, which was mainly accounted for by repeat revascularization. There was no significant difference in death or myocardial infarction and stroke was higher in the CABG group.The subgroup analysis based on SYNTAX score demonstrated a strong signal that CABG is more effective than PCI in patients with complex coronary artery disease. In patients with stable coronary artery disease, meeting the inclusion criteria of this trial, the risk of repeat revascularization with PCI should be carefully weighed against the increased stroke risk and invasiveness of CABG. Considerations regarding patient selection are crucial. It is reasonable to anticipate that less robust patients will have higher morbidity with CABG versus PCI.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

N Engl J Med 2023;389:2319-2330Background: Percutaneous coronary intervention (PCI) does not reduce mortality or myocardial infarction as seen in COURAGE, FAME 2, ISCHEMIA and ISCHEMIA-CKD. However, unblinded studies have indicated that revascularization may improve symptoms, which is a key factor in driving PCI decisions for many patients. ORBITA was the first blinded, placebo-controlled trial of PCI for stable angina and found no significant improvement in exercise time with PCI. The trial had a high use of anti-anginal medications, with an average of 3 medications per patient  pre-randomization. However, this level of medication use is not always achievable in clinical practice due to side effects and challenges with adherence.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The ORBITA-2 trial sought to test the hypothesis that PCI improves symptoms in patients with stable angina who are not receiving background antianginal medications.Patients: Eligible patients had angina or angina equivalent, severe coronary stenosis of 70% or more in at least one coronary artery and evidence of ischemia on non-invasive testing or by invasive pressure wire assessment.Main exclusion criteria were acute coronary syndrome within 6 months, previous CABG, left main disease, chronic total occlusion of target vessel, and left ventricular ejection fraction of 35% or less.Baseline characteristics: The trial randomized 301 patients – 151 randomized to PCI and 150 to placebo PCI.The average age of patients was 64 years and 79% were men. Approximately 63% had hypertension, 28% had diabetes, 72% had hyperlipidemia, and 62% were current or previous smokers. Left ventricular systolic function was normal in 96% of the patients.Angina class based on the Canadian Cardiovascular Society (CCS) angina grade was 2 in 58% of the patients and 3 in 39%. Approximately 80% had single vessel disease, 17% had 2-vessel disease and 2% had 3-vessel disease. Left anterior descending coronary artery was the target vessel in 55% of the patients.Procedures: Patients initially underwent coronary angiogram and invasive physiologic assessment was performed in each vessel with 50% or more stenosis. Patients underwent the coronary angiography while wearing headphones with music playing for auditory isolation throughout the procedure. Patients who had evidence of ischemia in at least one territory were then randomized in a 1:1 ratio to PCI or placebo PCI. Patients were sedated until they were unresponsive to verbal and tactile stimuli. In the PCI group, all target vessels were treated during the index procedure. Patients in the placebo group did not receive intervention and were kept sedated for at least 15 minutes after randomization.The recovery room staff and all subsequent medical providers were unaware of the treatment assignments. The operator and research staff who were present during the randomization procedure had no further contact with the patients.Anti-anginal medications were stopped at enrollment. Antihypertensive medications that has antianginal properties were replaced with different agents.Patients were followed up for 12 weeks during which they reported daily angina symptoms using a smart phone application. New anti-anginal medications or increase in the dose of anti-anginal medications were also tracked. At the end of the 12 weeks, patients completed symptom and quality-of-life questionnaires, had an assessment of CCS class, and underwent a treadmill exercise test and dobutamine stress echocardiography. After all of these were completed, patients and medical staff were unblinded.Endpoints: The primary endpoint was an angina symptom score calculated based on the number of angina episodes that a patient reported on a given day and the number of units of antianginal medication prescribed on that day. In this score, each episode of angina on a particular day counts as 1 point for a maximum of 6 points per day (0 points given to no angina), and each unit of anti-anginal medications counts as 7 points (0 points given for no antianginal medications prescribed that day). In supplement table 3, authors provided what counted as one unit of anti-anginal medications. For example, atenolol 25 mg counted as 1 unit and amlodipine 2.5 mg counted as one unit.Secondary endpoints included frequency of angina, use of ant-anginal medications, exercise time on treadmill test and symptoms questionnaires.Analysis was performed based on the intention-to-treat principle. The estimated sample size to achieve 80% power at 0.05 alpha was 284 patients. This is based on assumed standard deviation of 6 angina symptom score units and a difference of 2 units between PCI and placebo.Results: Data were available on 99.7% of the total patient-days.Compared to placebo, PCI reduced the mean angina symptom score (2.9 vs 5.6, OR: 2.2, 95% CI: 1.4 - 3.5; p

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N Engl J Med 2022;387:1351-1360Background: Systolic heart failure and obstructive coronary artery disease often coexist. Some patients show improvement in left ventricular systolic function after revascularization, which led to the development of the concept of myocardial hibernation. In this state, areas of the heart that are exposed to repetitive ischemia reduce their contractility to help facilitate their survival. Restoring blood flow to these hypocontractile yet viable segments could improve outcomes. Although observational studies supported this theory, large randomized trials were still lacking. Patients with severe left ventricular systolic dysfunction were generally excluded from the seminal trials of percutaneous coronary intervention (PCI) in stable coronary artery disease.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Revascularization for Ischemic Ventricular Dysfunction (REVIVED) trial sought to test the hypothesis that revascularization with PCI plus medical therapy is superior to medical therapy alone in patients with left ventricular systolic dysfunction, obstructive coronary artery disease and viable myocardium.Patients: Eligible patients had left ventricular ejection fraction of 35% or less, obstructive coronary artery disease, in addition to viability in at least four dysfunctional myocardial segments that are amenable to revascularization by PCI. Viability could be determined by any imaging modality and was adjudicated based on local experts.Major exclusion criteria were myocardial infarction within 4 weeks, sustained ventricular arrhythmias within 72 hours, acutely decompensated heart failure requiring inotropic support, invasive or non-invasive ventilation or mechanical circulatory support within 72 hours, glomerular filtration rate

The Lancet Volume 391, Issue 10115, 6–12 January 2018, Pages 31-40Background:  For decades, cardiologists commonly used percutaneous coronary intervention (PCI) for the relief of angina. It made sense because PCI resulted in near complete resolution of blood flow through a stenosed vessel. The problem facing evidence-based clinicians was that no previous trial had compared PCI to a placebo (sham) procedure. Instead, previous trials had compared PCI (a procedure) to tablets. In the absence of blinding, a procedure will exert a larger placebo effect than tablets.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 Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial was designed to assess the effect of PCI versus placebo on exercise time in patients with stable ischemic symptoms.ORBITA met ethical criteria because previous trials, primarily the COURAGE trial, had found that PCI in addition to medical therapy did not reduce hard outcomes, such as myocardial infarction or death due to cardiovascular causes, compared to medicine alone. In other words, PCI in patients with stable coronary artery disease was not a disease-modifying therapy; it was used to relieve symptoms.Patients:  Patients had to have single-vessel coronary artery disease (≥ 70% stenosis) that was appropriate for PCI and angina or equivalent symptoms. The authors published in the appendix pictures of every patient enrolled in the trial. Exclusion criteria included acute coronary syndrome, previous bypass surgery, left main stenosis, chronic total occlusions, severe valvular disease or left ventricular dysfunction, moderate or severe pulmonary hypertension, or life-expectancy less than 2 years.  Baseline Characteristics: The mean age of patients was 65 years. More than 79% were male. Almost 90% had normal left ventricular function. Canadian Cardiovascular Society class included about 60% with class 2 symptoms and nearly 40% with class 3 symptoms. Angina had been present for a mean of 9 months. Trial Procedures: ORBITA had two phases. First was a 6-week medical optimization phase wherein patients were optimally treated with medical therapy. They had a questionnaires, dobutamine stress echo, and a cardiopulmonary exercise test.  They then had the blinded procedure with either PCI or placebo.All PCI was done with drug-eluting stents. The procedure included measures to insure blinding, such as headphones during the procedure, sedation and a measure of hemodynamics such as fractional flow reserve. The second phase was a 6-week period of blanking in which patients underwent follow-up assessment. Testing procedures were similar to the pre-procedure protocol.At all times, the staff were blinded to the procedural data. This included procedural details as well as post-procedural assessment. The recovery staff were well rehearsed in their role of maintenance of blinding. Patients and subsequent medical caregivers were also blinded to treatment allocation. The study physicians present during the procedure had no further contact with the patient during the study.By the time of randomization, in the PCI group, 103 (98%) of 105 patients were taking aspirin, 103 (98%) were taking a second antiplatelet, and 99 (94%) were taking a statin, compared to 93 (98%), 94 (99%), and 91 (96%) of 95 patients, respectively, in the placebo group. At the same timepoint, in the whole study population, 156 (78%) of 200 patients were taking β blockers and 182 (91%) were taking calcium channel antagonists.The mean number of antianginal medications in the PCI group was 0·90 (SD 0·8) at enrollment, 2·8 (1·2) at pre-randomization, and 2·9 (1·1) at follow-up, compared to the placebo group in which the mean number of medications was 1·0 (0·9; p=0·357), 3·1 (0·9; p=0·097), and 2·9 (1·1; p=0·891), respectively.Endpoints: The primary endpoint of ORBITA was the difference between PCI and placebo groups in the change in treadmill exercise time. The power calculation relied on previous trials wherein PCI had resulted in a 48-55 second increase in exercise time over medicine. ORBITA authors designed the trial to detect a 30 second increase in exercise time.They estimated that a sample size of 100 patients per group had more than 80% power to detect a between-group difference in the increment of exercise duration of 30 seconds, at the 5% significance level, using the two-sample t test of the difference between groups. This calculation assumed a between-patient standard deviation of change in exercise time of 75 s. Since there had been no previous placebo-controlled trials of PCI, the authors initially allowed for a one-third dropout rate in the 6-week period of medical optimization between enrollment and randomization and therefore planned to enroll 300 patients. But the dropout rate was much lower, so only 230 patients had to be enrolled. The primary endpoint was continuous, and it was calculated as a difference between groups. They also measured secondary endpoints, including measures of angina severity and quality of life.Results: A total of 368 patients were screened for eligibility, and 200 were randomly assigned. Most were excluded from randomization because they declined to participate. There were 105 allocated to PCI (all but one had PCI) and 95 to placebo (4 patients had PCI due to a procedural complication).Across all patients, the mean area stenosis by quantitative coronary angiography was 84·4% (SD 10·2), mean FFR was 0·69 (0·16), and mean iFR was 0·76 (0·22). 57 (29%) patients had FFR greater than 0·80 and 64 (32%) had iFR greater than 0·89.The median length of stent implanted was 24 mm (IQR 18–33). After PCI, the mean FFR improved to 0·90 (SD 0·06; p

N Engl J Med 2020;382:1395-407 - ISCHEMIAN Engl J Med 2020;382:1608-16 - ISCHEMIA-CKDBackground: The COURAGE trial, published in 2007, represented a major reversal in cardiovascular medicine. In patients with stable CAD an initial strategy of revascularization plus medical therapy did not reduce the chance of dying or having a heart attack compared to an initial strategy of medical therapy alone. Prior to these results, patients with stable CAD were routinely managed with an initial invasive approach and the field of cardiology was intensely focused on finding coronary blockages and “fixing” them in symptomatic and asymptomatic patients alike. Thus, it's not surprising that following results from COURAGE, the practice continued to be vigorously defended and applied routinely in the management of patients with stable CAD.The first major attempt to reverse the results of COURAGE came from the FAME 2 trial, published in 2012, which tested the hypothesis that patients with stable CAD and an abnormal fractional flow reserve (FFR) in the cath lab would do better with an initial invasive strategy compared to medical therapy alone. The trial was stopped early for efficacy but the positive results were driven entirely by revascularization during follow up - not death or heart attack. The trial was criticized for being stopped inappropriately without providing an answer to whether an early invasive strategy improved hard endpoints compared to initial medical therapy alone. The concepts of “faith healing” and “subtraction anxiety” are useful for understanding the results and limitations of the FAME 2 trial.The ISCHEMIA trial which began enrolling patients in 2012 sought to overcome limitations of COURAGE and FAME. The investigative aim of the study was to test the hypothesis that in patients with stable CAD and moderate to severe ischemia on provocative testing, an initial invasive strategy reduced a composite of major cardiac events compared to initial medical therapy alone. The ISCHEMIA-CKD trial was performed in conjunction with the ISCHEMIA Research Group to address an important knowledge gap in managing patients with CAD. Patients with advanced chronic kidney disease (CKD) experience a higher rate of cardiac events than their counterparts without CKD; however, they are also at a higher risk of procedural complications. The standard of care at the time was generally to manage a patient with stable CAD and CKD like any other patient with CAD despite the fact that such patients were historically excluded from participation in clinical trials and thus, there was really no data from clinical trials to guide decision making.The ISCHEMIA-CKD investigators sought to test the hypothesis that in patients with advanced CKD and stable CAD and moderate to severe ischemia on stress testing, an initial invasive strategy reduced death or MI compared to initial 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: For the ISCHEMIA trial, eligible patients had to be at least 21 years of age or older with at least moderate ischemia on a qualifying stress test based on the following criteria:* Nuclear perfusion with SPECT or PET with >/= 10% ischemic myocardium* Echocardiography with >/= 3/16 segments with stress-induced severe hypokinesis or akinesis* Cardiac MRI with >/= 10% ischemic myocardium on perfusion imaging and/or >/= 3/16 segments with stress-induced severe hypokinesis or akinesis on wall motion assessment* Exercise treadmill test without imaging that met all 4 following criteria* clinical history of typical angina or typical angina during the stress test* absence of resting ST depression > 1.0 mm or confounders that render exercise EKG non-interpretable (LBBB, LVH with repolarization, pacemaker, etc.)* exercise-induced horizontal or downsloping ST depression >/= 1.5 mm in 2 leads or >/= 2.0 mm in any lead or ST elevation >/= 1.0 mm in a non-infarct territory* either of the following:* workload at which ST segment criteria are met is NOT to exceed completion of stage 2 of a standard Bruce protocol or 7 METS if a non-Bruce protocol is used* ST segment criteria are met at

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N Engl J Med 2012;367:991-1001Background: Percutaneous coronary intervention (PCI) did not improve the outcome of death or nonfatal myocardial infarction in stable coronary artery disease, as seen in the COURAGE trial. Nonetheless, some skepticism remained within the cardiology community regarding the results of the COURAGE trial, with the belief that revascularizing ischemia-causing lesions could improve clinical outcomes (ischemic testing was not required in all patients in the COURAGE trial). While there was data supporting this idea, large randomized trials providing conclusive evidence were still lacking.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.Fractional flow reserve (FFR) is a pressure-wire-based measurement performed during coronary angiography to evaluate whether a coronary stenosis is likely to be causing myocardial ischemia.The investigators of FAME 2 trial sought to test the hypothesis that FFR-guided PCI with drug-eluting stents plus optimal medical therapy (OMT) is superior to OMT alone in patients with stable coronary artery disease.Patients: Eligible patients had stable angina pectoris and stenosis of 50% or more in at least one major coronary artery that has a diameter of at least 2.5 mm and supplying a viable myocardium. Patients with atypical or no chest pain were included if they had documented ischemia on noninvasive testing. To evaluate the hemodynamic severity of each identified stenosis, FFR was measured using a coronary guidewire during adenosine-induced hyperemia. Patients with at least one stenosis in a major coronary artery with an FFR of 0.80 or less were randomized.Major exclusion criteria were: Bypass surgery felt to be the preferred treatment strategy, left main disease, myocardial infarction within a week, prior coronary artery bypass surgery, left ventricular ejection fraction