infarctions, but fewer nonprocedural infarctions during follow‐up. The incidence of death from any cause was low and similar in the two groups. These data suggest that an ischemic burden based strategy for revascularization is not superior medical therapy[15]. However, this conclusion needs to be interpreted in light of the facts that the statistical power of the trial was decreased due to lower than planned recruitment and lower event rates than expected, duration of follow‐up was relatively short, high‐risk patients with significant left main disease (on CT angiography), low ejection fraction, severe heart failure, or severe symptoms despite optimal medical interventions were excluded.
Measurement of fractional flow reserve (FFR) appears to be beneficial in the triage of patients with an intermediate stenosis who have not had a stress test prior to the angiogram. In the DEFER trial, patients with single vessel disease and an intermediate stenosis, an FFR ≥0.75 identified a low risk group of patients who did not benefit from angioplasty at a follow‐up of five years. In the more recent Fractional Flow Reserve vs Angiography for Multivessel Evaluation 2 (FAME 2) trial, the clinical utility of FFR measurement in patients with stable coronary artery disease being angiographically evaluated for PCI was assessed [16]. FFR was measured across all lesions with a ≥50% diameter reduction in a major native epicardial coronary artery with a diameter of at least 2.5 mm and supplying viable myocardium. Patients with at least one stenosis with an FFR of ≤0.80 were randomized to FFR‐guided PCI of all stenoses with FFR ≤0.80 with DES plus optimal medical therapy, or optimal medical therapy alone. The primary endpoint was a composite of death, myocardial infarction, or unplanned hospitalization leading to urgent revascularization at 24 months. The study was stopped prematurely by the data and safety monitoring board. After a mean duration of follow‐up of 213 days, after randomization of 888 of the planned 1632 patients, the primary endpoint occurred in 4.3% who had PCI compared to 12.7% who were managed medically (hazard ratio [HR] 0.32, 95% CI 0.19–0.53). The difference persisted at 2‐year follow‐up. The reduction was driven by a lower rate of urgent revascularization in the PCI group. Though “urgent revascularization” is considered a “soft” endpoint, the definition used to define the events met criteria for an acute coronary syndrome and 50% of the patients had objective evidence of ischemia. Limitations of the FAME 2 include the premature termination of the trial, lack of non‐invasive stress test documentation of ischemia prior to angiography, and the absence of double blinding of the assigned strategy such that the results of FFR measurement in the medical arm may have biased the patient’s and/or physician’s decision for preceding with crossover to PCI. Nevertheless, the findings of FAME 2 suggest that PCI is appropriate in patients with functionally significant stenosis involving a moderate or greater myocardial territory, and this is reflected in current guidelines (Table 11.2). Most interventionist use a FFR‐guided strategy for intermediate (50–70% diameter stenosis) lesions in the absence of objective documentation of at least moderate ischemic burden in the coronary territory of interest or unclear results from stress testing.
The Medicine, Angioplasty, or Surgery Study (MASS) and MASS II trials have compared medical therapy with PCI and CABG in stable angina. The MASS trial enrolled patients with single vessel disease (>80% proximal left anterior descending artery stenosis) [17]. While balloon angioplasty and medical therapy were associated with greater need for revascularization, there was no difference in rate of death or myocardial infarction in the three groups during follow‐up. The trial was conducted in the pre‐stent era without modern medical therapy which limits the applicability of the findings to contemporary practice. The MASS II trial, however, was conducted in patients with multivessel disease, and had a similar design except that PCI was performed with bare metal stents in most patients, and more contemporary medical therapy was implemented. At five years, the results were similar to the MASS trial in that there was no difference in death or myocardial infarction between the three treatment strategies, but the need for revascularization for refractory angina during follow‐up was much higher with medical therapy and PCI [18].
The ORBITA trial randomized 230 patients with CCS class II and III angina and single‐vessel disease (≥70% stenosis) to PCI or a sham procedure. The placebo procedure in the control arm and blinding of patients as well as the care team following the procedure are unique features of this trial. At six weeks follow‐up, there was no difference between the groups for the primary end point of exercise time increment (28.4 versus 11.8 seconds, p = 0.2), though the trend favored PCI. Other exercise variables and angina severity also was not different. The very small sample size, surrogate endpoints, exceedingly short duration of follow‐up, and exclusion of patients with complex disease are major limitations of the trial [19].
A significant number of patients with CAD have asymptomatic or “silent” ischemia which is associated with an increased risk of cardiovascular events. The Asymptomatic Cardiac Ischemia Pilot (ACIP) study investigated the efficacy of three treatment strategies among patients with stable disease who had angina or silent ischemia from single or multivessel disease. Patients were randomized to angina‐guided medical therapy, angina plus ischemia‐guided medical therapy, or revascularization by either balloon angioplasty or CABG. At two years following randomization, revascularization was associated with a lower mortality and a reduction in the composite endpoint of death, myocardial infarction, and recurrent hospitalization [20]. An important study that evaluated treatment of silent ischemia is the Swiss Interventional Study on Silent Ischemia Type II (SWISSI II) trial which compared medical therapy with balloon angioplasty among patients who had suffered a myocardial infarction, and had one or two vessel disease [21]. A surprising finding was that cardiac death and myocardial infarction were significantly lower in the group randomized to balloon angioplasty. While the findings of the ACIP and SWISSI II trials are significant, they need to be interpreted with the knowledge that both enrolled relatively small number of patients and that optimal medical therapy, as defined in the COURAGE trial, was not implemented.
The studies to date have had significant crossover to revascularization in those originally randomized to medical therapy and hence have been trials of “initial treatment strategies” rather than specific treatments. Thus, based on the evidence from the COURAGE trial and the preceding randomized clinical trials, it is reasonable to conclude that medical therapy is an appropriate initial strategy for a substantial proportion of patients with mild to moderately severe stable angina. PCI is suitable for those patients who are significantly symptomatic despite optimal medical therapy, or as initial strategy for those with a positive stress test at low workload, or have a large ischemic territory. Aggressive secondary prevention is essential regardless of the treatment strategy utilized. The findings of the Atorvastatin versus Revascularization Treatment (AVERT) trial showed that PCI in combination with inadequate lipid lowering therapy is associated with worse outcomes in patients with angina when compared with a strategy of optimal lipid management and medical therapy alone [11].
In BARI 2D, 2368 patients with type 2 diabetes mellitus and stable coronary artery disease (defined as either a ≥50% stenosis of a major epicardial artery with a positive stress test or ≥70% stenosis and classic angina) were randomized to either revascularization (CABG or PCI) within 4 weeks together with intensive medical therapy or to intensive medical therapy alone [22]. The decision regarding CABG versus PCI was based on clinical judgment, and made prior to randomization. At five years, there was no difference in the primary endpoints of the rates of survival (88.3% vs 87.8%) or freedom from the composite of death, myocardial infarction, and stroke (77.2% vs 77.7%). In the PCI stratum, there was no significant difference in primary endpoints between the revascularization group compared to the medical‐therapy only group. However, in the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group. Patients selected for CABG had higher angiographic and clinical risk scores than those selected for PCI, and it was those with the highest clinical and angiographic risk profile who seemed to derive a benefit from CABG.
In a meta‐analysis from 12 randomized clinical trials with 37 548 patient‐years of follow‐up demonstrated that PCI compared with medical therapy alone was associated with a statistically significant 24% relative reduction in the risk of spontaneous non‐procedural myocardial infraction
