HIGHLIGHTS
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Beta-blockers are often prescribed after-MI, but no specific one has been favored.
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This study compares metoprolol versus carvedilol in an after-MI cohort.
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The study showed similar overall survival between carvedilol and metoprolol.
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Improved survival with carvedilol vs metoprolol was noted in the ejection fraction ≤40% subgroup.
Beta-blockers are typically prescribed following myocardial infarction (MI), but no specific beta-blocker is recommended. Of 7,057 patients enrolled in the OBTAIN multi-center registry of patients with acute MI, 4142 were discharged on metoprolol and 1487 on carvedilol. Beta-blocker dose was indexed to the target daily dose used in randomized clinical trials (metoprolol-200 mg; carvedilol-50 mg), reported as %. Beta-blocker dosage groups were >0% to12.5% (n = 1,428), >12.5% to 25% (n = 2113), >25% to 50% (n = 1,392), and >50% (n = 696). The Kaplan-Meier method was used to calculate 3-year survival. Correction for baseline differences was achieved by multivariable adjustment. Patients treated with carvedilol were older (64.4 vs 63.3 years) and had more comorbidities: hypertension, diabetes, prior MI, congestive heart failure, reduced left ventricular ejection fraction, and a longer length of stay. Mean doses for metoprolol and carvedilol did not significantly differ (37.2 ± 27.8% and 35.8 ± 31.0%, respectively). The 3-year survival estimates were 88.2% and 83.5% for metoprolol and carvedilol, respectively, with an unadjusted HR = 0.72 (p <0.0001), but after multivariable adjustment HR = 1.073 (p = 0.43). Patients in the >12.5% to 25% dose category had improved survival compared with other dose categories. Subgroup analysis of patients with left ventricular ejection fraction ≤40%, showed worse survival with metoprolol versus carvedilol (adjusted HR = 1.281; 95% CI: 1.024 to 1.602, p = 0.03). In patients with left ventricular ejection fraction >40%, there were no differences in survival with carvedilol versus metoprolol. In conclusion, overall survival after acute MI was similar for patients treated with metoprolol or carvedilol, but may be superior for carvedilol in patients with left ventricular ejection fraction ≤40%.
Beta-blocker therapy after myocardial infarction (MI) improves survival and is a cornerstone of after-MI management. Multiple randomized clinical trials and observational studies supported the use of beta-blocker therapy after-MI, leading to the recommendation of beta-blocker therapy for the majority of patients following acute non-ST elevation MI and ST-elevation MI without any contraindication. The most prescribed beta-blocker after-MI varies from region to region, but the 2 most prescribed are metoprolol and carvedilol. In the OBTAIN (Outcomes of Beta-blocker Therapy After myocardial INfarction) registry, metoprolol and carvedilol were the 2 most common beta-blocker prescribed, accounting for 93% of all beta-blockers. Metoprolol is a primarily ß1-adrenergic receptor blocker, while carvedilol is a ß1-, ß2-, and α1- adrenergic receptor blocker which also has pleiotropic anti-oxidant and vasodilatory effects. Both metoprolol , and carvedilol have been reported to improve survival after-MI but little information is available comparing the relative benefits of these agents following acute myocardial infarction. , This report from the OBTAIN registry study compares the effect of carvedilol and metoprolol on survival following acute MI.
METHODS
This is a sub-study from the OBTAIN registry. Full details are provided in the original report. There were 25 United States sites and 1 Canadian site which enrolled a total of 7,057 patients with acute MI. Only patients discharged on metoprolol or carvedilol were included in this report. The study was approved by each site’s Institutional Review Board with a waiver of consent for registry enrollment. Participating centers and study committees and personnel are listed in the original report.
Acute MI was diagnosed by: (1) either creatine kinase elevation >2 times or troponin elevation >3 times the upper limit of normal established at each site and (2) chest pain (or equivalent symptoms suggestive of MI) or electrocardiographic changes consistent with MI. Important information concerning type of MI, complications of MI, hospitalization course, reperfusion therapy, length of stay, and discharge medications were recorded in the registry in addition to basic demographics and past medical history. All data were collected at the sites, and de-identified patient information was entered into a web-based electronic data capture system.
The managing physician chose the type and dose of beta-blockers. Beta-blocker dose was indexed (administered/target dose) to the target dose used in the randomized clinical trials that established efficacy, metoprolol 200mg/day , and carvedilol 50mg/day (carvedilol controlled-release equivalent dose-80 mg/day). Beta-blocker dose was classified into 4 pre-specified groups: >0% to 12.5%, >12.5% to 25%, >25% to 50%, and >50% of the target dose.
The pre-specified end point for this study was time to all-cause mortality with survival censored at 3 years. Follow-up vital status was assessed by either chart review, the Social Security Administration Death Master File, or direct communication with the patient/family, as previously reported(5).
Differences in patient characteristics were compared using t-test or non-parametric Wilcoxon test for continuous variables or chi-square tests for categorical variables. The Kaplan-Meier method was used to calculate 3-year survival for the 2 beta-blocker groups and construct survival curves. Proportional hazards frailty regression with patients nested by hospital was used to calculate hazard ratios and confidence intervals, test for the independent effects on survival, and to test interactions with metoprolol versus carvedilol. Cox proportional hazards regression was used to test for the independent effects of beta-blocker dosing on survival. We also performed an interaction test for the difference in metoprolol and carvedilol effects on survival in patients with left ventricular ejection fraction ≤40% and >40%. Adjustment for baseline differences among groups was achieved by multivariable adjustment with the variables listed in Table 1 . All tests were 2-tailed and a conventional 5% significance level was used.
| Variable | Beta-Blocker at Discharge | p-value | |
|---|---|---|---|
| Carvedilol | Metoprolol | ||
| (n= 1,487) | (n=4,142 ) | ||
| Age (years) | 64.4±13.5 | 63.3±13.5 | 0.004 |
| Men | 981 (66%) | 2889 (70%) | 0.007 |
| White | 1125 (76%) | 3313 (80%) | 0.0005 |
| Black | 187 (13%) | 434 (11%) | 0.03 |
| Asian | 32 (2.2%) | 104 (2.5%) | 0.44 |
| Indian | 11 (0.7%) | 13 (0.3%) | 0.03 |
| Pacific | 5 (0.3%) | 7 (0.2%) | 0.32 |
| Unknown | 130 (8.7%) | 274 (6.6%) | 0.006 |
| Mixed | 3 (0.2%) | 3 (0.1%) | 0.19 |
| Hispanic | 157 (11%) | 259 (6.7%) | <0.0001 |
| Body mass index (kg/m 2 ) | 29.±6.6 | 29.2±6.5 | 0.72 |
| Diabetes mellitus | 94 (40%) | 1233 (30%) | <0.0001 |
| Hypertension | 1058 (71%) | 2753 (67%) | 0.0007 |
| Hyperlipidemia | 798 (54%) | 2248 (54%) | 0.72 |
| Previous myocardial infarction | 343 (23%) | 818 (20%) | 0.006 |
| Congestive heart failure history | 274 (19%) | 317 (7.7%) | <0.0001 |
| Chronic obstructive pulmonary disease | 171 (12%) | 392 (10%) | 0.02 |
| Coronary artery bypass graft surgery | 259 (18%) | 474 (11%) | <0.0001 |
| End stage renal disease | 61 (4.1%) | 126 (3.0%) | 0.05 |
| Cerebrovascular accident/Transient ischemic attack | 171 (12%) | 413 (10%) | 0.01 |
| Current smoker | 450 (31%) | 1406 (34%) | 0.008 |
| Implanted cardioverter-defibrillator * | 112 (7.5%) | 88 (2.1%) | <0.0001 |
| Myocardial infarction characteristics | |||
| ST-segment elevation myocardial infarction | 715 (48%) | 1792 (43%) | 0.001 |
| Non-ST segment elevation myocardial infarction | 770 (52%) | 2349 (57%) | 0.001 |
| Anterior | 332 (46%) | 515 (29%) | <0.0001 |
| Inferior/Posterior | 278 (39%) | 985 (55%) | <0.0001 |
| Thrombolytic therapy | 98 (6.6%) | 315 (7.6%) | 0.2 |
| Primary percutaneous coronary intervention | 919 (62%) | 2485 (60%) | 0.21 |
| In-hospital revascularization (nonprimary percutaneous coronary intervention and coronary artery bypass graft surgery) | 351 (24%) | 1082 (26%) | 0.06 |
| Diagnostic angiography | 150 (10%) | 415 (10%) | 0.94 |
| Admission resting systolic blood pressure (mmHg) | 139.6±30.1 | 141.4±29.5 | 0.04 |
| Admission heart rate (beats/min) | 85.9±22.1 | 82.3±20.9 | <0.0001 |
| Left ventricular ejection fraction (%) | 39.9±13.7 | 48.7±11.7 | <0.0001 |
| Troponin (ng/ml) | 11.7 (3-42.5) | 6.9 (1.9-25.6) | <0.0001 |
| Length of stay (days) | 6 (4-9) | 5 (3-7) | <0.0001 |
| Discharge Medication | |||
| Beta-blocker dose(%) | 35.8±31.0 | 37.2±27.8 | 0.128 |
| Aspirin | 1367 (92%) | 3890 (94%) | 0.008 |
| Angiotensin converting enzyme inhibitor /Angiotensin receptor blocker | 1009 (68%) | 2804 (68%) | 0.91 |
| Statin | 1214 (82%) | 3716 (90%) | <0.0001 |
| Clopidogrel | 1014 (68%) | 3053 (74%) | <0.0001 |
| Dual antiplatelet | 956 (64%) | 2935 (71%) | <0.0001 |
| Mortality | |||
| 1 year ( Kaplan-Meier %) | 141 (9.5%) | 293 (7.1%) | 0.003 |
| 2 years ( Kaplan-Meier %) | 219 (15%) | 435 (11%) | <0.0001 |
| 3 years ( Kaplan-Meier %) | 245 (17%) | 489 (12%) | <0.0001 |
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