Lessons Learned From the COURAGE Trial: Generalizability, Limitations, and Implications

Percutaneous coronary intervention (PCI) is effective in reducing anginal symptoms in selected patients with coronary artery disease (CAD) and in reducing mortality in patients with ST-elevation acute myocardial infarction (AMI) who are emergently treated, as well as in those with high-risk acute coronary syndromes without ST-segment elevation.1–4 Such successes have often been promulgated to justify more widespread use of PCI in symptomatic and asymptomatic patients with stable CAD, presumably to reduce subsequent cardiac events. In 2004, more than 1 million coronary stent procedures were performed in the United States,5 and the vast majority of all PCIs ≈85%) were undertaken electively in patients with stable CAD.6 Although PCI is known to decrease mortality when performed to restore coronary blood flow during AMI, no study has examined the ability of PCI to improve outcomes over and above modern, optimal medical therapy in coronary patients with or without anginal symptoms. Yet, many patients (and physicians) believe that PCI and stenting as a first-line treatment strategy can reduce the risk of AMI, improve survival, or both. Recently, this question was addressed when the results of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial7 were presented at the American College of Cardiology 56th Annual Scientific Sessions in New Orleans, Louisiana. The study was simultaneously published in The New England Journal of Medicine and appeared in the April 12 print issue. Of 35,539 patients who were initially evaluated for eligibility in the trial, only 3071 (8.6%) met all inclusion criteria. Of these, 2287 (74%) patients with known CAD were enrolled at 50 US and Canadian hospitals/medical centers and randomized to 1 of 2 treatment groups: PCI and optimal medical therapy (PCI group; n=1149) or optimal medical therapy alone (medical therapy group; n=1138). Thus, both groups received aggressive medical therapy, which included an array of antiischemic and cardioprotective medications (ie, long-acting metoprolol, amlodipine, and isosorbide mononitrate, alone or in combination, along with either lisinopril or losartan, and simvastatin alone or in combination with ezetimibe) to relieve symptoms and achieve guideline-driven lipid/lipoprotein and blood pressure target levels, as well as lifestyle programs such as smoking cessation, exercise, weight management, and nutritional counseling. Patients undergoing PCI received aspirin and clopidogrel, in accordance with contemporary guidelines and established practice patterns. Enrolled patients had signs and/or symptoms of myocardial ischemia and a stenosis of at least 70% in one or more proximal epicardial coronary arteries; moreover, 69% had multivessel CAD. A majority of the patients in the trial were men (85%), including a predominantly white population (86%), and 38% of the subjects had experienced a previous myocardial infarction. Most exhibited several risk factors for CAD: 29% were smokers, 67% had hypertension, and 71% had an elevated cholesterol level. Approximately half of the patients met criteria for the metabolic syndrome. In contrast, patients with severe left ventricular dysfunction (eg, refractory heart failure, ejection fraction <30%), clinical instability (eg, cardiogenic shock, persistent Canadian Cardiovascular Society class IV angina), a markedly positive treadmill stress test (eg, significant ST-depression or exertional hypotension at a low metabolic workload [<5 metabolic equivalents or stage 1 of the Bruce protocol]), recent revascularization, and coronary anatomy not suitable for PCI were excluded. The primary outcome was a composite of death from any cause and nonfatal myocardial infarction. Secondary outcomes included a composite of death, myocardial infarction, stroke, and hospitalization for unstable angina. Over a median follow-up of 4.6 years, a total of 211 deaths or nonfatal myocardial infarctions (the primary focus of the COURAGE trial) occurred in the PCI group (19.0%), compared with 202 in the medical therapy group (18.5%), a statistically nonsignificant difference (Table I). When stroke was added to this composite end point, the cumulative event rates were nearly identical (no significant difference), 20.0%and 19.5% for the PCI and medical therapy groups, respectively. When outcomes were analyzed individually, there were no differences in rates of death, myocardial infarction, stroke, or hospitalization for acute coronary syndromes between the treatment groups. On the other hand, a higher percentage of the PCI group remained angina-free during the trial (Table II). Moreover, as compared with the PCI group, a greater percentage of the medically managed patients (32.6%vs 21.1%) went on to have either PCI or coronary artery bypass surgery (at the discretion of their physician) to alleviate worsening signs or symptoms of myocardial ischemia (Table I). Although there was no overall advantage of a particular treatment (PCI vs medical therapy) according to baseline characteristics (eg, age, sex, race, smoking, angina class, ejection fraction, previous coronary artery bypass surgery, health care system), women in the PCI group tended to do slightly better than those who received medical therapy alone. Among patients with multivessel CAD, previous myocardial infarction, and diabetes, the rate of the primary end point was similar for both groups. Body mass index for both treatment groups remained largely unchanged, whereas there were slight decreases and increases in the percentage of cigarette smokers and those engaged in regular physical activity, respectively. Despite the widespread belief that coronary revascularization may reduce the incidence of acute cardiac events, the findings of the COURAGE trial are understandable. In a study of patients who had undergone cardiac catheterization before and up to 1 month after AMI, the coronary artery that subsequently occluded had <50% stenosis on the first angiogram in 66% of patients.8 More recently, Falk and colleagues,9 consolidating the data from 4 different studies, demonstrated that nearly 90% of AMIs involve sites with <70% obstruction in the months to years before infarction (Figure 1). Collectively, these findings suggest a new paradigm for preventing initial and recurrent acute cardiac events (ie, aggressive lifestyle modification and cardioprotective drug therapy)10,11 and explain the inability to demonstrate reduced rates of subsequent myocardial infarction and death using PCI, as reported by the COURAGE investigators.7 These results are also concordant with a recent meta-analysis of 11 randomized trials comparing PCI with conservative medical treatment in patients with stable CAD.12 There was no significant difference between the 2 treatment strategies for any of the outcome variables tested (Figure 2); in fact, there was a trend for more cardiac deaths or AMIs, particularly nonfatal AMIs, in patients who underwent PCI. Stenosis severity and risk of associated myocardial infarction (MI). Nearly 90% of acute myocardial infarctions occur at sites without a significant stenosis (<70% obstruction) on a previous angiogram. Rupture of a vulnerable atherosclerotic plaque, characterized by a thin fibrous cap and a large low-density lipoprotein cholesterol-laden lipid core, is believed to be the triggering mechanism underlying rapid progression of mild to moderate lesions to severe stenosis or total coronary artery occlusion. Adapted from Falk et al.9 Meta-analysis of 11 randomized clinical trials comparing percutaneous coronary intervention (PCI) to conservative medical treatment in patients with stable coronary artery disease for death, cardiac death or myocardial infarction (MI), nonfatal MI, coronary artery bypass graft (CABG) surgery, and PCI during follow-up, with specific reference to the summary risk ratio and 95% confidence intervals (CIs). Adapted from Katritsis and Ioannidis.12 Would surgical revascularization have fared better than PCI relative to the primary outcomes evaluated? Tu and associates13 compared the medical outcomes of >230,000 elderly patients in the United States and Canada, each of whom had recent AMI. The US patients were ≈5 to 8 times more likely to undergo coronary angiography and revascularization procedures during the first 30 days after the index infarction (P<.001), a practice pattern that narrowed slightly but persisted through 180 days of follow-up, yet both groups had exactly the same survival rates 1 year later. Similarly, others have been unable to demonstrate the superiority of an early invasive strategy in patients with acute coronary syndromes and an elevated cardiac troponin T level but without ST-segment elevation.14 Do the COURAGE trial results apply to all coronary patients? Probably not. Were there limitations to the study methodology and potential confounding variables? Most definitely. The investigators acknowledged that the preponderance of male patients limited the generalizability of their findings, as did the lack of ethnic diversity (only 14% of the patients were nonwhite). In addition, unstable and extremely high-risk patients were excluded from participating in the trial. Generally, PCIs used bare-metal stents, primarily because the COURAGE trial was conducted mostly before drug-eluting stents were available. Nevertheless, recent reports suggest the results apply to coated stents, as bare-metal and drug-eluting devices have not shown a difference (either short-term or long-term) relative to the trial's major end points, that is, death and nonfatal myocardial infarction.15–17 During the study period, more aggressive clopidogrel regimens were adopted before and after PCI procedures, which may have influenced the frequency of periprocedural myocardial infarctions.18 Finally, a greater number of patients did, in fact, “cross over” from medical therapy to revascularization during the follow-up of 2.5 to 7.0 years (median, 4.6 years). Yet, this does not diminish the finding that initial PCI failed to prevent myocardial infarction and death in patients with stable CAD.18 Collectively, what do the results of the COURAGE trial and other recent studies really signify? According to Dr Steve Nissen, Director of Cardiology at the Cleveland Clinic, “… the results [of the COURAGE trial] suggest that its probably OK to defer angioplasty and give medical therapy a try—and you're not going to compromise your health.” Dr James Stein, Director of the Preventive Cardiology Program at the University of Wisconsin Hospital and Clinics, Madison, commented, “This study clearly shows something we all knew—but many did not want to believe—that angioplasties don't save lives, except in acutely ill patients, and [they] don't prevent heart attacks.” Moreover, recent studies suggest that there is no compelling reason to use PCI of an occluded infarct-related artery with late presenters (3–28 days after AMI), in that outcomes (including left ventricular function) do not appear to be favorably influenced over medical management alone.19,20 According to an accompanying editorial, the COURAGE trial should lead to changes in the initial treatment of many patients with stable CAD, with expected substantial health care savings.18 Nevertheless, established practice patterns, economic incentives, how cardiologists view the applicability of these results to their patients, and the common belief in a “magic bullet” (ie, PCI) may serve to attenuate the true impact of the COURAGE trial findings. In actuality, the results of the COURAGE trial serve to reinforce existing practice guidelines which state that PCI can be safely deferred in patients with stable CAD.21,22 Thus, it remains unclear to what extent patients and the medical community will embrace these sobering and provocative new findings.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.