In the Occluded Artery Trial (OAT), percutaneous coronary intervention (PCI) of an infarct-related artery on days 3 to 28 after acute myocardial infarction was of no benefit compared to medical therapy alone. The present analysis was conducted to determine whether PCI might provide benefit to the subgroup of higher risk patients with a depressed ejection fraction (EF). Of 2,185 analyzed patients (age 58.6 ± 11.0 years) with infarct-related artery occlusion on days 3 to 28 after acute myocardial infarction in the Occluded Artery Trial, 1,094 were assigned to PCI and 1,091 to medical therapy. The primary end point was a composite of death, reinfarction, and New York Heart Association class IV heart failure. The outcomes were analyzed by EF (first tertile, EF ≤44%, vs second and third tertiles combined, EF >44%). Interaction of the treatment effect with EF on the study outcomes were examined using the Cox survival model. The 5-year rates of the primary end point (death, reinfarction, or New York Heart Association class IV heart failure) were not different in either subgroup (PCI vs medical therapy, hazard ratio 1.25, 99% confidence interval 0.83 to 1.88, for EF ≤44%; hazard ratio 0.98, 99% confidence interval 0.64 to 1.50, for EF >44%). However, in patients with an EF >44%, PCI reduced the rate of subsequent revascularization (p = 0.004, interaction p = 0.05). In conclusion, optimal medical therapy remains the overall treatment of choice for stable patients with a persistent total occlusion of the infarct-related artery after acute myocardial infarction, irrespective of the baseline EF. In patients with normal or moderately impaired left ventricular contractility, PCI reduced the need for subsequent revascularization but did not otherwise improve outcomes.
After acute myocardial infarction (AMI), left ventricular (LV) systolic dysfunction is a key predictor of subsequent morbidity and mortality. Because of the progressive nature of LV remodeling, it remains a hazard during long-term follow-up. Previous reports have suggested that delayed percutaneous coronary intervention (PCI) of the infarct-related artery (IRA) might preserve LV function and improve the clinical outcomes in patients with impaired LV systolic function. The benefits of PCI might be expected to be greater in those with poor LV function. The Occluded Artery Trial (OAT) was a controlled, randomized study of PCI of the IRA versus medical therapy alone after AMI. Although an ancillary study did demonstrate modest improvements in LV geometry in patients assigned to PCI, no reduction in death, reinfarction, or heart failure was identified during an average of 3 years of follow-up for PCI relative to a conservative medical approach. We hypothesized that a clinical benefit attributable to PCI might be more apparent in patients with a depressed baseline ejection fraction (EF). Therefore, we incorporated this as a prespecified analysis in the OAT protocol. In the present analysis, we examined whether the clinical effects of the study intervention (PCI of IRA vs medical therapy alone) were related to the baseline EF.
Methods
The design and methods of the OAT have been previously described. In brief, OAT was a randomized multicenter, controlled, unblinded study of patients sustaining an AMI who were found to have a persistently occluded infarct artery at diagnostic cardiac catheterization on calendar days 3 to 28 (minimum of 24 hours after symptom onset) after the index event. To be eligible, patients had to be clinically stable with either a large area of affected myocardium (i.e., proximal occlusion of a major epicardial vessel) or a baseline EF of <50%. Of the 2,201 patients, 1,101 were randomly assigned to PCI with stent placement and optimal medical therapy (PCI group) and 1,100 were randomly assigned to optimal medical therapy alone (medical group). These patients included 2,166 who were enrolled between February 2000 and December 2005 in the main OAT and 35 patients who were enrolled in the extension phase of the OAT-Nuclear (NUC) substudy in 2006. All patients were to receive optimal medical therapy, including aspirin, anticoagulation, if clinically indicated, an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, a β blocker, and lipid-lowering therapy, unless contraindicated. Thienopyridine therapy was to be initiated before PCI and continued for ≥2 to 4 weeks in patients undergoing PCI, with consideration of 1 year of therapy for both groups beginning in 2003. The Agency for Healthcare Research and Quality guidelines were to be followed for treating patients in heart failure with LV systolic dysfunction. The major exclusion criteria included New York Heart Association class III or IV heart failure, shock, serum creatinine concentration ≥2.5 mg/dl (221 μmol/L), angiographically significant left main or 3-vessel coronary artery disease, angina at rest, and severe ischemia on stress testing.
The baseline EF was available for 1,094 patients in the PCI group and 1,091 in the medical group. Left ventriculography was to be performed during baseline angiography unless contraindicated or if a qualifying coronary angiogram was obtained without LV angiography before transfer to the OAT Center. The EF was assessed by the Angiography Core Laboratory on a routine basis for 1,723 patients. In the cases for which no core laboratory data were available, the site-determined LVEF (as determined by echocardiography radionuclide ventriculography or LV angiogram) was used (n = 462) for the present analysis.
The institutional review boards at the participating centers approved the study protocol. All patients provided written informed consent.
The primary end point was the first occurrence of death from any cause, reinfarction, or New York Heart Association class IV heart failure resulting in hospitalization or admission to a short-stay unit. The secondary end points included the incidence of the individual components of the primary end point (i.e., New York Heart Association class III or IV heart failure, death, or reinfarction), stroke, revascularization, and the presence of angina symptoms. In addition to these prespecified end points, we analyzed the composite of death or New York Heart Association class IV heart failure, which was of particular interest in relation to the EF.
The study end points were adjudicated by an independent committee unaware of the treatment assignments. The definition of reinfarction has been previously provided.
The intent of the present analysis was to evaluate the relationships among the EF, PCI, and outcomes. Patients were divided by baseline EF into 2 groups, one group consisted of patients in the lowest tertile of EF (“low EF,” defined as EF of ≤44%) and the second consisted of patients in the second and third tertiles (“higher EF,” defined as EF >44%). Analyses of the interactions between the study treatment and EF were prespecified in the OAT protocol, and the tertile-based thresholds of EF were prespecified before the present analyses. Continuous variables are presented as the median with the interquartile ranges and were compared using the Wilcoxon nonparametric test. Categorical variables were compared using the chi-square test. The association of the EF and the study outcomes was analyzed using Cox regression models. Multivariate Cox models included all baseline clinical and angiographic characteristics with <10% missing data. The interaction of the study treatment and the outcomes was assessed with the EF stratified into the 2 EF subgroups, as described. In addition, the interaction between the study treatment and outcomes was modeled with LVEF as a continuous function. Hazard ratios for the study treatment within the EF-based subgroups were adjusted for the baseline variables predictive of the primary outcome on multivariate analysis. All α values are 2 sided, and all analyses were by intention to treat. To control for the type I error rate, it was prespecified by the study protocol that a p value of ≤0.01 would be considered evidence of differences in the secondary analyses, and a p value >0.01 to <0.05 would be evidence of a trend toward a difference. The Statistical Analysis Systems, version 9.1.3 (SAS Institute, Cary, NC) software, was used for the statistical analyses.
Results
The baseline EF was available for 2,185 (99.3%) of the 2,201 patients enrolled in the OAT. Of these patients, 1,170 (53.5%) had an EF <50%. For 92 of these 1,170 patients, the sole high-risk criterion of an EF <50% (and no proximal occlusion of a large vessel) was sufficient for enrollment in the study. The EF ranged from 10% to 82%. The median EF was 48% (interquartile range 40% to 55%); 449 patients (20.6%) had an EF <40% and 134 (6.1%) had an EF <30%.
A comparison between the low (≤44%) and higher (>44%) EF groups with respect to the baseline clinical and angiographic characteristics, medications, and procedural outcomes for those treated invasively is provided in Tables 1 and 2 . Clopidogrel use at 1 year did not differ between the low and higher EF groups (14.9% vs 14.8%, respectively, p = 0.95), nor did it differ between those randomized to PCI in the low and higher EF groups (18.1% vs 17.6%, respectively, p = 0.86).
| Variable | Low EF (≤44%; n = 743) | Higher EF (>44%; n = 1,442) | p Value |
|---|---|---|---|
| Ejection fraction (%) | 37.0 (31–41) | 53.0 (49–58) | |
| Age (10 years) | 5.9 (5.1–6.7) | 5.8 (5–6.7) | 0.07 |
| Men | 577 (77.7%) | 1,125 (78.0%) | 0.85 |
| White | 574 (77.3%) | 1,175 (81.5%) | 0.02 |
| Diabetes mellitus | 204 (27.5%) | 247 (17.1%) | <0.0001 |
| Angina pectoris | 174 (23.4%) | 317 (22.0%) | 0.45 |
| Myocardial infarction | 106 (14.3%) | 137 (9.5%) | 0.0008 |
| Hypertension | 373 (50.2%) | 689 (47.8%) | 0.28 |
| New York Heart Association >1 before index acute myocardial infarction or at randomization | 213 (28.7%) | 243/1,441 (16.9%) | <0.0001 |
| Cerebrovascular disease | 20 (2.7%) | 61 (4.2%) | 0.07 |
| Peripheral vascular disease | 30 (4.0%) | 53/1,440 (3.7%) | 0.68 |
| Renal insufficiency | 12 (1.6%) | 17 (1.2%) | 0.40 |
| Congestive heart failure | 34 (4.6%) | 18/1,440 (1.3%) | <0.0001 |
| Percutaneous coronary revascularization | 47 (6.3%) | 58 (4.0%) | 0.02 |
| Hypercholesterolemia ⁎ | 372/742 (50.1%) | 758 (52.6%) | 0.28 |
| Family history of coronary disease before age 55 in first-degree relative | 280 (37.7%) | 599 (41.5%) | 0.08 |
| Current cigarette smoker | 275 (37.0%) | 578 (40.1%) | 0.16 |
| Killip class >1 | 213/741 (28.7%) | 200/1,435 (13.9%) | <0.0001 |
| Heart rate † (10 beats/min) | 7.5 (6.7–8.2) | 7.0 (6.2–7.7) | <0.0001 |
| Systolic blood pressure † (10 mm Hg) | 11.8 (10.6–13) | 12.0 (11–13) | 0.0003 |
| Diastolic blood pressure † (10 mm Hg) | 7.0 (6.2–8) | 7.0 (6.4–8) | 0.12 |
| Pulse pressure † (10 mm Hg) | 4.5 (4.0–5.5) | 5.0 (4–5.8) | 0.0003 |
| Glomerular filtration rate † (10 ml/min/1.73 m 2 ) | 7.8 (6.5–9.1) | 7.9 (6.7–9.3) | 0.03 |
| Glucose † (10 mg/dl) | 11.2 (9.7–14.2) | 10.5 (9.4–12.4) | <0.0001 |
| Body mass index † (10 kg/m 2 ) | 2.8 (2.5–3.1) | 2.8 (2.5–3.1) | 0.88 |
| Index event | |||
| Rales | 77 (10.4%) | 59/1,438 (4.1%) | <0.0001 |
| New Q waves | 526 (70.8%) | 941 (65.3%) | 0.009 |
| ST elevation | 555/723 (76.8%) | 843/1,387 (60.8%) | <0.0001 |
| ST elevation or new Q waves | 659 (88.7%) | 1,171 (81.2%) | <0.0001 |
| Thrombolytic in first 24 hours | 169 (22.7%) | 248/1,441 (17.2%) | 0.002 |
| Interval to index acute myocardial infarction (days) | 9 (5–17) | 8.0 (5–16) | 0.43 |
| Culprit left anterior descending artery | 436 (58.7%) | 351 (24.3%) | <0.0001 |
| Any collaterals | 623/734 (84.9%) | 1,287/1,423 (90.4%) | 0.0001 |
| Multivessel coronary disease | 162/737 (22.0%) | 212/1,430 (14.8%) | <0.0001 |
| Medications at hospital discharge | |||
| Long-acting nitrate | 159 (21.4%) | 338 (23.4%) | 0.28 |
| Sublingual nitrate | 197 (26.5%) | 450 (31.2%) | 0.02 |
| β Blocker | 655 (88.2%) | 1,263 (87.6%) | 0.70 |
| Calcium channel blocker | 40 (5.4%) | 89 (6.2%) | 0.46 |
| Aspirin | 706 (95.0%) | 1,384 (96.0%) | 0.30 |
| Ticlopidine or clopidogrel | 454 (61.1%) | 866 (60.1%) | 0.64 |
| Warfarin (Coumadin) | 139 (18.7%) | 75 (5.2%) | <0.0001 |
| Digoxin | 51 (6.9%) | 10 (0.7%) | <0.0001 |
| Diuretics | 216 (29.1%) | 153 (10.6%) | <0.0001 |
| Spironolactone | 78 (10.5%) | 46 (3.2%) | <0.0001 |
| Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker | 662 (89.1) | 1,096 (76.0) | <0.0001 |
| Insulin | 71 (9.6%) | 66 (4.6%) | <0.0001 |
| Oral hypoglycemic | 136 (18.3%) | 160 (11.1%) | <0.0001 |
| Lipid-lowering agent | 572 (77.0%) | 1,202 (83.4%) | 0.0003 |
| Antiarrhythmic agent | 51 (6.9%) | 31 (2.1%) | <0.0001 |
⁎ Hypercholesterolemia defined as previous diagnosis of hypercholesterolemia or previously treated with lipid-lowering agent or having fasting low-density lipoprotein cholesterol ≥130 mg/dl or total cholesterol ≥200 mg/dl.
† Missing values for continuous variables include glomerular filtration rate, 40 patients; glucose, 67 patients; heart rate, 3 patients; systolic blood pressure, 2 patients; diastolic blood pressure, 2 patients; pulse pressure, 2 patients; body mass index, 16 patients.
| Variable | EF | p Value | |
|---|---|---|---|
| ≤44% (n = 390) | >44% (n = 704) | ||
| Infarct-related artery | <0.0001 | ||
| Left anterior descending | 215 (55.1%) | 168 (23.9%) | |
| Circumflex | 57 (14.6%) | 118 (16.8%) | |
| Right | 118 (30.3%) | 418 (59.4%) | |
| Pre-PCI TIMI grade flow | 0.18 | ||
| 0 | 317/386 (82.1%) | 578/698 (82.8%) | |
| 1 | 64/386 (16.6%) | 118/698 (16.9%) | |
| 2 | 3/386 (0.8%) | 2/698 (0.3%) | |
| 3 | 2/386 (0.5%) | 0/698 (0.0%) | |
| Post-PCI TIMI grade flow | 0.0002 | ||
| 0 | 54/379 (14.2%) | 50/690 (7.2%) | |
| 1 | 12/379 (3.2%) | 16/690 (2.3%) | |
| 2 | 27/379 (7.1%) | 30/690 (4.3%) | |
| 3 | 286/379 (75.5%) | 594/690 (86.1%) | |
| 2 or 3 | 313/379 (82.6%) | 624/690 (90.4%) | 0.0002 |
| Collaterals | |||
| Any collaterals | 320/385 (83.1%) | 628/695 (90.4%) | 0.0005 |
| 0 | 65/385 (16.9%) | 67/695 (9.6%) | <0.0001 |
| 1 | 280/385 (72.7%) | 494/695 (71.1%) | |
| 2 | 40/385 (10.4%) | 134/695 (19.3%) | |
Periprocedural complications were uncommon. A total of 7 reinfarctions and 5 deaths occurred, with a similar distribution between the EF subgroups.
Overall, the cumulative 5-year composite primary event rate was 17.5%. The rates of the components of the primary end point were as follows: death 11.7%, repeat myocardial infarction 6.0%, and New York Heart Association class IV heart failure 4.6%. The rates of the primary outcome and each of its components were greater among patients with a lower baseline EF. Detailed data on the frequency of the study end points within the lower and higher EF subgroups are listed in Table 3 .
| Variable | EF | Hazard Ratio (99% Confidence Interval) | ||||
|---|---|---|---|---|---|---|
| ≤44% (n = 743) | >44% (n = 1,442) | Unadjusted | p Value | Adjusted ⁎ | p Value | |
| Composite (primary) outcome | 26.3% | 13.2% | 2.33 (1.74–3.13) | <0.0001 | 1.97 (1.46–2.67) | <0.0001 |
| Death | 18.4% | 8.5% | 2.44 (1.66–3.57) | <0.0001 | 2.00 (1.35–2.97) | <0.0001 |
| Fatal or nonfatal reinfarction | 6.7% | 5.7% | 1.33 (0.80–2.23) | 0.15 | 1.18 (0.69–2.00) | 0.42 |
| NYHA IV heart failure | 8.9% | 2.6% | 3.86 (2.17–6.86) | <0.0001 | 3.0 (1.66–5.42) | <0.0001 |
| NYHA III/IV HF | 11.8% | 3.1% | 3.99 (2.42–6.55) | <0.0001 | 3.21 (1.93–5.35) | <0.0001 |
| Death or nonfatal reinfarction | 23.1% | 12.7% | 2.05 (1.49–2.81) | <0.0001 | 1.72 (1.24–2.39) | <0.0001 |
| Death or NYHA IV HF | 22.2% | 9.7% | 2.68 (1.91–3.74) | <0.0001 | 2.19 (1.55–3.09) | <0.0001 |
| Stroke | 1.9% | 1.8% | 1.06 (0.42–2.64) | 0.88 | 0.99 (0.39–2.53) | 0.98 |
| Revascularization | 20.7% | 20.6% | 1.04 (0.79–1.38) | 0.72 | 1.03 (0.77–1.36) | 0.82 |
| Angina pectoris | 43.7% | 39.6% | 1.11 (0.91–1.35) | 0.19 | 1.08 (0.88–1.32) | 0.32 |
In the multivariate models adjusting for independent predictors of the primary outcome (glomerular filtration rate, days from qualifying AMI to randomization, history of peripheral vascular disease, congestive heart failure, diabetes, rales on examination) or death (glomerular filtration rate, days from qualifying AMI to randomization, history of angina, cerebrovascular disease, congestive heart failure, Killip class 2 to 4 at presentation), a low EF was independently associated with excess risk of the primary outcome, death and heart failure ( Table 3 ).
No interaction was found between the baseline EF and treatment effect for the composite outcome or any of its components, using either EF modeled as a continuous function or when EF was divided into low versus higher subgroups ( Table 4 and Figure 1 ).
| Variable | Low EF (≤44%) | Higher EF (>44%) | Interaction p Value | ||||||
|---|---|---|---|---|---|---|---|---|---|
| PCI (n = 390) | MED (n = 353) | HR (99% CI) | p Value | PCI (n = 704) | MED (n = 738) | HR (99% CI) | p Value | ||
| Composite (primary) outcome | 28.8% | 23.5% | 1.25 (0.83–1.88) | 0.17 | 13.7% | 12.9% | 0.98 (0.64–1.50) | 0.92 | 0.30 |
| Death | 19.3% | 17.5% | 1.11 (0.66–1.87) | 0.62 | 7.6% | 9.3% | 0.81 (0.46–1.43) | 0.35 | 0.30 |
| Fatal or nonfatal reinfarction | 8.8% | 4.5% | 2.02 (0.85–4.80) | 0.04 | 6.1% | 5.4% | 1.06 (0.56–2.01) | 0.82 | 0.12 |
| NYHA IV HF | 9.5% | 8.1% | 1.10 (0.55–2.18) | 0.73 | 2.5% | 2.6% | 0.75 (0.29–1.92) | 0.43 | 0.40 |
| NYHA III/IV HF | 12.9% | 10.5% | 1.19 (0.66–2.15) | 0.44 | 2.2% | 4.0% | 0.54 (0.23–1.26) | 0.06 | 0.05 |
| Death or nonfatal reinfarction | 25.3% | 20.6% | 1.33 (0.84–2.10) | 0.11 | 12.8% | 12.6% | 0.98 (0.63–1.54) | 0.93 | 0.23 |
| Death or NYHA IV HF | 23.7% | 20.5% | 1.11 (0.71–1.74) | 0.55 | 9.5% | 9.9% | 0.85 (0.51–1.40) | 0.40 | 0.38 |
| Stroke | 1.2% | 2.7% | 0.46 (0.09–2.21) | 0.20 | 1.9% | 1.6% | 1.14 (0.39–3.35) | 0.75 | 0.22 |
| Revascularization | 22.3% | 19.1% | 1.05 (0.67–1.66) | 0.77 | 17.8% | 23.3% | 0.69 (0.50–0.96) | 0.004 | 0.05 |
| Angina pectoris | 41.5% | 46.0% | 0.83 (0.60–1.14) | 0.12 | 35.2% | 43.9% | 0.74 (0.59–0.93) | <0.001 | 0.46 |
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