Previous studies have suggested that percutaneous coronary intervention (PCI) decreases long-term mortality in patients with silent myocardial ischemia (SMI), but whether PCI specifically decreases mortality when added to intensive medical therapy is unknown. We performed a post hoc analysis of clinical outcomes in patients in the COURAGE trial based on the presence or absence of anginal symptoms at baseline. Asymptomatic patients were classified as having SMI by electrocardiographic ischemia at rest or reversible stress perfusion imaging (exercise-induced or pharmacologic). Study end points included the composite primary end point (death or myocardial infarction [MI]); individual end points of death, MI, and hospitalization for acute coronary syndrome; and need for revascularization. Of 2,280 patients 12% (n = 283) had SMI and 88% were symptomatic (n = 1,997). There were no between-group differences in age, gender, cardiac risk factors, previous MI or revascularization, extent of angiographic disease, or ischemia by electrocardiogram or imaging. Compared to symptomatic patients, those with SMI had fewer subsequent revascularizations (16% vs 27%, p <0.001) regardless of treatment assignment and fewer hospitalizations for acute coronary syndrome (7% vs 12%, p <0.04). No significant differences in outcomes were observed between the 2 treatment groups, although there was a trend toward fewer deaths in the PCI group (n = 7, 5%) compared to the optimal medical therapy (OMT) group (n = 16, 11%, p = 0.12). In conclusion, addition of PCI to OMT did not decrease nonfatal cardiac events in patients with SMI but showed a trend toward fewer deaths. Although underpowered, given similar outcomes in other small studies, these findings suggest the need for an adequately powered trial of revascularization versus OMT in SMI patients.
Silent myocardial ischemia (SMI)—objective evidence of myocardial ischemia without symptoms of angina—occurs in up to 25% of patients with coronary artery disease (CAD). Previous evidence from 2 small studies (Asymptomatic Cardiac Ischemia Pilot and Swiss Interventional Study on Silent Ischemia Type II ) has suggested that treatment of SMI with anti-ischemic medication and in particular revascularization may improve outcomes, but these studies were conducted before contemporary optimal medical therapy (OMT). Because these 2 studies have provided suggestive evidence that patients with SMI might benefit more from revascularization than medical therapy, we sought to test the hypothesis that percutaneous coronary intervention (PCI) would have a beneficial impact on clinical outcomes in asymptomatic patients with SMI enrolled in the Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation (COURAGE) trial and who received aggressive medical therapy.
Methods
The COURAGE study design (clinical trial number NCT00007657 ) has been described previously. The trial included 2,287 patients with chronic stable angina pectoris and anatomic CAD who met an American College of Cardiology/American Heart Association class I/IIa indication for PCI with ≥70% stenosis in ≥1 proximal epicardial coronary artery combined with objective evidence of ischemia or, in patients with recently stabilized Canadian Cardiovascular Society class III/IV symptoms who did not undergo provocative testing, ≥80% stenosis was required for study enrollment. Thus, patients with objective evidence of myocardial ischemia and significant angiographic CAD were included in the trial with or without angina. Patients were randomized to 1 of 2 initial management strategies, OMT alone or OMT + PCI, and followed for clinical outcomes from 2.5 to 7 years (median 4.6 years).
In brief, exclusion criteria included persistent Canadian Cardiovascular Society class IV angina pectoris, a markedly positive stress test result (substantial ST-segment depression or hypotensive response during stage 1 of the Bruce protocol), refractory heart failure or cardiogenic shock, ejection fraction <30%, revascularization within the previous 6 months, and coronary anatomy not suitable for PCI. Presence of SMI was defined by 1 of the following criteria in the absence of symptoms of angina or angina equivalents: (1) new ischemic ST-T changes at rest on 12-lead electrocardiogram (≥1 mm in ≥2 contiguous leads), (2) exercise-induced ischemic electrocardiographic changes (≥1 mm horizontal or downsloping ST-segment depression 80 ms beyond the J point), and/or (3) reversible myocardial perfusion imaging defects during exercise or pharmacologic vasodilator stress.
All patients received antiplatelet therapy with aspirin (81 to 325 mg/day) or clopidogrel 75 mg/day if aspirin allergy/intolerance was present. Patients undergoing PCI received aspirin and clopidogrel in accordance with existing clinical practice guidelines and established treatment standards. Medical anti-ischemic therapy in the 2 groups included long-acting metoprolol, amlodipine, and isosorbide mononitrate, alone or in combination. Lisinopril or losartan was used for blood pressure control and as secondary prevention in patients with heart failure or decreased systolic function. All patients received aggressive therapy to lower low-density lipoprotein cholesterol levels (simvastatin alone or in combination with ezetimibe) with a target level of 60 to 85 mg/dl (1.55 to 2.20 mmol/L). After this treatment target was achieved, secondary lipid targets were addressed to increase the level of high-density lipoprotein cholesterol to a level >40 mg/dl (1.03 mmol/L) and decrease triglyceride levels to <150 mg/dl (1.69 mmol/L) with diet, exercise, extended-release niacin, and fibrates—alone or in combination. Overall, excellent adherence to intensive OMT was maintained in all randomized patients throughout the duration of the trial.
This was a post hoc analysis of the SMI subgroup. Comparisons of baseline characteristics and clinical outcomes were made between patients with SMI and those with angina irrespective of treatment allocation. Similar comparisons were made between patients with SMI randomized to PCI + OMT versus OMT alone. Predefined statistical analyses were conducted for the following outcomes (time to first event): primary composite end point of death or myocardial infarction (MI); death alone; hospitalization for acute coronary syndrome; composite of death, MI, or hospitalization for acute coronary syndrome; composite of death, MI, or stroke; composite of death, MI, or hospitalization for acute coronary syndrome; and need for subsequent revascularization. Spontaneous MI was defined as creatine kinase-MB ≥1.5 times the upper normal limit or troponin ≥2.0 times the upper normal limit, and periprocedural MI as a creatine kinase-MB ≥3.0 times the upper normal limit or troponin ≥5.0 times the upper normal limit with new ischemic symptoms.
Comparison of categorical variables was done with chi-square test or Wilcoxon rank-sum test, and Student’s t test was used for continuous variables. Overall event rates were assessed using chi-square tests. Treatment effects (unadjusted and adjusted for diabetes and family history) for outcomes in the SMI cohort were assessed using Cox proportional hazards models. Because multiple comparisons were made, statistical significance was defined as a nominal p value <0.01 as it was for the subgroup comparisons in the trial proper. An exploratory pooled analysis was also undertaken that included COURAGE SMI data and results of the Asymptomatic Cardiac Ischemia Pilot study and Swiss Interventional Study on Silent Ischemia Type II trial for the end points of death or MI and death alone. A random effects model was used to calculate relative risk decreases for the above end points, and hazard ratios and 95% confidence intervals were constructed to express between-group result differences and treatment effect.
Results
For the study population as a whole, 2,280 patients could be accurately classified at baseline as having symptomatic versus silent ischemia. Of this total, 283 patients (12.4%) had SMI. Baseline clinical characteristics for the symptomatic versus SMI groups are listed in Table 1 . Patients with SMI were comparable to symptomatic patients in age, gender, ethnicity, diabetes and other cardiac risk factors, previous cardiac disease, and previous revascularization. There were no significant differences in the frequency of electrocardiographic abnormalities at rest in patients with SMI compared to those with angina pectoris ( Table 2 ).
| Characteristic | AP at Baseline | SMI at Baseline |
|---|---|---|
| (n = 1,997, 88% of total) | (n = 283, 12% of total) | |
| Age (years) | 62 | 62 |
| Men | 85% | 84% |
| White | 86% | 83% |
| Nonwhite | 14% | 13% |
| Diabetes mellitus | 33% | 34% |
| Hypertension | 67% | 62% |
| Family history of coronary artery disease | 48% | 48% |
| Previous myocardial infarction | 38% | 42% |
| Previous percutaneous coronary intervention | 16% | 13% |
| Previous coronary bypass | 12% | 14% |
| AP at Baseline | SMI at Baseline | |
|---|---|---|
| Electrocardiographic abnormalities at rest | ||
| Patients | 1,821 | 259 |
| ST-segment depression >0.5 mm | 274 (15%) | 41 (16%) |
| T-wave abnormalities | 278 (15%) | 50 (19%) |
| Either | 426 (23%) | 68 (26%) |
| Extent of ischemic myocardium on myocardial perfusion imaging ⁎ | ||
| Patients | 1,287 | 205 |
| 0–5% | 262 (20%) | 50 (25%) |
| 5–10% | 637 (49%) | 94 (46%) |
| >10% | 388 (30%) | 61 (30%) |
⁎ Percent ischemic myocardium = (stress total perfusion defect minus total perfusion defect at rest).
Although objective evidence of ischemia (electrocardiographic or stress perfusion imaging) was required for entry into COURAGE, not every patient had a baseline stress test or underwent perfusion imaging; 205 patients (72.4%) in the SMI group underwent stress myocardial perfusion imaging compared to 1,287 (64.4%) in the group with baseline angina. There was no difference between groups in extent of ischemia as detected by perfusion scintigraphy ( Table 2 ). Compared to symptomatic patients, patients with SMI had less frequent subsequent hospitalizations for acute coronary syndrome and less frequent subsequent revascularizations after the initial hospitalization ( Table 3 ). Overall, however, there was no difference in the primary outcome or any secondary outcome between the groups with or without angina at baseline.
| Outcome | AP at Baseline | SMI at Baseline | p Value |
|---|---|---|---|
| (n = 1,997) | (n = 283) | ||
| Death or myocardial infarction | 369 (18%) | 46 (16%) | 0.52 |
| Death alone | 156 (8%) | 23 (8%) | 0.64 |
| Myocardial infarction alone | 248 (12%) | 26 (9%) | 0.18 |
| Hospitalization for acute coronary syndrome | 239 (12%) | 21 (7%) | 0.04 |
| Subsequent revascularization | 532 (27%) | 46 (16%) | <0.001 |
| Death/myocardial infarction/stroke | 389 (19%) | 48 (17%) | 0.46 |
| Death/myocardial infarction/acute coronary syndrome | 540 (27%) | 62 (22%) | 0.13 |
Of the 283 patients with SMI at baseline, 135 were randomized to PCI + OMT and 148 patients to OMT alone; of patients with SMI randomized to PCI + OMT, 24% had diabetes at baseline compared to 43% who were assigned to OMT alone (p = 0.001). Prevalence of hypertension, previous MI, and previous revascularization (bypass surgery and/or PCI) did not differ between patients with SMI randomized to PCI + OMT and those on OMT alone ( Table 4 ). The 2 randomized groups had a similar distribution of 1-, 2-, and 3-vessel CAD at baseline ( Table 4 ).
| Characteristic | PCI + OMT | OMT |
|---|---|---|
| (n = 135) | (n = 148) | |
| Diabetes ⁎ | 24% | 43% |
| Hypertension | 61% | 63% |
| Family history of coronary artery disease † | 56% | 41% |
| Myocardial infarction | 42% | 42% |
| Percutaneous coronary intervention | 14% | 11% |
| Coronary bypass | 5% | 5% |
| Number of coronary arteries narrowed ≥70% | ||
| 1 | 27% | 32% |
| 2 | 44% | 39% |
| 3 | 27% | 29% |
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