Should Percutaneous Revascularization for Stable Coronary Artery Disease Be Performed Sooner or Later?*
Abhiram Prasad, MD, FRCP, FESC, FACC,
Bernard J. Gersh, MBChB, DPhil, FACC*
Division of Cardiovascular Diseases and Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
Key Words: stable angina • angioplasty • coronary artery disease • ischemia • clinical trial
Coronary artery disease (CAD) represents a spectrum that varies in severity from single- to triple-vessel disease with clinical presentation ranging from stable angina to an acute coronary syndrome (ACS) or sudden cardiac death. Management of the condition has evolved significantly during the last 3 decades as a consequence of the advances in medical therapy, a pivotal component of which is aggressive risk factor reduction, percutaneous coronary intervention (PCI), and cardiac surgery. Data from multiple clinical trials indicate that treatment, including the use of revascularization, needs to be individualized for each patient depending on the coronary anatomy, ischemic burden, left ventricular function, and the overall clinical milieu, including the impact of symptoms upon quality of life and the presence and severity of comorbidities. General agreement exists that PCI is beneficial, and the preferred strategy, in high-risk patients (ST-segment elevation myocardial infarction and higher-risk non–ST-segment elevation acute coronary syndromes) in whom it reduces morbidity and mortality (1,2). The role of PCI in lower-risk patients such as those with stable CAD is different and predominantly directed at the relief of symptoms and ischemia. The publication of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial has rekindled the debate over the relative merits of medical therapy versus PCI for stable CAD (3).
In this issue of the Journal, Nishigaki et al. (4) present data from the latest randomized trial to compare medical therapy with PCI in patients with stable CAD. The study is unique in that it was conducted among a non-Western population of 384 patients recruited from 78 centers in Japan. The choice of antianginal and secondary preventive therapies in both arms was at the discretion of the physicians and not mandated by the protocol. Thus, medical therapy in this trial reflected "real-world" practice as opposed to the case-management approach used in the optimal medical therapy strategy of the COURAGE trial (3). Inclusion criteria were the presence of a significant stenosis documented on a coronary angiogram in addition to either a history of angina or electrocardiographic evidence of ischemia. Those patients enrolled represented an exceedingly low-risk population with approximately two-thirds exhibiting single-vessel disease and none exhibiting triple-vessel disease.
Patients with a reduced ejection fraction, chronic total occlusions, vein graft lesions, and significant comorbid conditions including creatinine greater than 1.5 g/dl were excluded. This is reflected in the very low annual mortality rate of  1% (compared with 4% in the COURAGE trial) (3) and the fact that 90% of patients had either no or mild angina. Stent use (76%) was lower, whereas the use of balloon angioplasty alone (15%) and atherectomy was greater than one might expect in contemporary practice in the U.S.
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The PCI-related reduction in acute coronary syndromes
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The study was terminated prematurely after an interim analysis demonstrating reduced events in the PCI arm, although the composite end point used had not been selected a priori. As observed in previous randomized trials, there was no difference in the primary end point of all-cause mortality in the 2 groups, although the study was vastly underpowered to detect a reduction in death. It was found that PCI was associated with lower frequency of the primary end points of ACS (11.7% vs. 5.0%, p = 0.012) and emergency hospitalization.
Although it is generally accepted that PCI reduces recurrent ACS in patients with unstable disease, this finding has not been a consistent one in patients with stable CAD. Thus, the observed reduction in ACS with percutaneous revascularization in the study by Nishigaki et al. (4) is of interest. There are several important factors that must to be considered in interpreting their data. First, the reduction in the rate of ACS was exclusively due to the reduction in unstable angina (8.9% vs. 3.4%, p = 0.028) rather than myocardial infarction (3.8% vs. 1.6%, p = 0.20). Unstable angina was defined as "emergency admission for ischemic cardiac pain associated with electrocardiographic signs of myocardial ischemia and coronary stenosis of >90%" in the absence of a myocardial infarction. Despite the attempts to standardize the definition, it is well recognized that unstable angina is a subjective diagnosis and a weak end point for a clinical trial.
Second, the authors state that it is routine practice in Japan to perform coronary angiography 3 to 12 months after PCI. Follow-up angiography also was recommended within 1 to 2 years in the medically treated patients by the protocol. Thus, there is the distinct possibility that knowledge of the angiographic findings by the participants and physicians, who were not blinded, may have been a source of bias. Third, data regarding periprocedural myocardial infarction were not provided and, therefore, one cannot assess whether incorporating clinically significant events at the time of the PCI might have reduced the net benefit from PCI.
Fourth, the frequency of smokers, who are at greater risk for ACS, was 2-fold greater in the medical arm. Finally, there was suboptimal therapy of hyperlipidemia in both groups, with a mean low-density lipoprotein of 106 mg/dl at 3 years with a trend toward less statin use in the medical arm (55.9% vs. 65.4%, p = 0.14). Thus, PCI appeared to reduce the rate of unstable angina, an observation that may have resulted from systematic bias, as well as differences between the groups with regard to baseline characteristics and medical therapy.
However, the reduction in unstable angina by PCI may have been due to better relief of ischemia. Indeed, the findings are consistent with those reported in the TIME (Trial of Invasive versus Medical therapy in Elderly patients) study (5), in which continued medical management alone was associated with an approximate 50% probability of hospitalization and revascularization over the subsequent 1 year. Patients enrolled in that study were more symptomatic and at much greater risk with almost a 10-fold greater annual mortality.
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Use of PCI and symptom relief
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The second RITA (Randomized Intervention Treatment of Angina-2) trial was among the earliest studies to demonstrate that PCI is more effective than medical therapy in relieving angina, a finding that has been replicated in subsequent studies (6). Nishigaki et al. (4) once again report this benefit of PCI in the stent era. Although the reduction in the severity of angina was modest, it was apparent immediately after revascularization and persisted for the entire duration of follow-up (median 3.3 years). This reduction was accompanied by a reduction in the need for nitrate therapy. The results are consistent with the data from the COURAGE trial in which an initial PCI strategy was superior to optimal medical therapy alone with regard to quality of life and symptom control, though the benefit diminished over time (7). It is worth noting that the benefit of PCI, with regard to the relief of ischemia, may have been underestimated due to the fact that 36.5% of patients in the medical arm crossed over to elective revascularization.
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Use of PCI and ischemic burden
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The efficacy of PCI in relieving ischemia and the potential for improving outcomes in selected patients with stable CAD is supported by a substudy of the COURAGE trial among 314 patients who had documented ischemia at baseline on myocardial perfusion stress testing and underwent repeat assessment at 6 to 18 months after assignment to treatment (8). The patients in the PCI and optimal medical therapy groups were well matched in terms of severity of angina, severity of CAD, and ejection fraction. Patients in the PCI arm were far more likely (33.3% vs. 19.8%, p = 0.004) to have a reduction in ischemic burden of  5% of the myocardium compared with those patients treated with optimal medical therapy alone. Importantly, patients in whom there was a reduction in ischemic burden had lower rates of death or myocardial infarction. This benefit was greatest in patients who had moderate to severe ischemia at baseline. There was no death or myocardial infarction in patients who had no residual ischemia at follow-up, compared with a rate of 39.3% among those who had 10% of the myocardium with residual ischemia.
These data suggest that PCI relieves angina to a greater extent and that less residual ischemia is associated with better outcomes. Nonetheless, although this is an interesting substudy, it should be emphasized that in the overall COURAGE trial there was no reduction in death or myocardial infarction with PCI. Treatment strategies based on relieving ischemic burden have not been formally tested in stable CAD and should be considered in the design of future trials.
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Conclusions
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The use of PCI is very effective and superior to medical therapy for reducing or abolishing angina and improving functional status. However, revascularization must be considered an adjunct, rather than an alternative, to optimal medical therapy. An initial medical strategy is suitable for many patients, though at least one-third will cross over to revascularization. Thus, sooner or later, PCI is required for a significant proportion of patients, regardless of the initial strategy. Nonetheless, the major lessons of almost 3 decades of trials of revascularization versus medical therapy in patients with chronic stable angina and preserved left ventricular systolic function need to be reinforced. There is no difference in the "hard" end points of death and myocardial infarction with either strategy. The high incidence of crossover from medical therapy to revascularization is not a limitation of the trials but represents the realities of clinical practice.
However, what is reassuring is that the price to be paid for revascularization "later rather than sooner" is not that of death or myocardial infarction. These trials help us as clinicians to make a rational choice for the individual patient. There are no lack of data—the onus is on us to integrate the information appropriately. It is critical not to extrapolate the data from the recent trials to patients with stable CAD who have not had angiography or those with severe symptoms as they were not included. Issues that need to be evaluated in future research include the impact of drug-eluting stents on the durability of the benefit from PCI, developing strategies based on ischemic burden and complete revascularization to maximize the potential benefit of PCI on outcomes, and further assessing the impact of improved approaches to secondary prevention.
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Footnotes
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Dr. Gersh is a member of Advisory Boards for CV Therapeutics, Boston Scientific, and Abbott Laboratories.
* Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology. 
* Reprint requests and correspondence: Dr. Bernard J. Gersh, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905 (Email: gersh.bernard{at}mayo.edu).
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Percutaneous Coronary Intervention Plus Medical Therapy Reduces the Incidence of Acute Coronary Syndrome More Effectively Than Initial Medical Therapy Only Among Patients With Low-Risk Coronary Artery Disease: A Randomized, Comparative, Multicenter Study
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J. Am. Coll. Cardiol. Intv. 2008 1: 469-479.
[Abstract]
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