Author + information
- Received August 12, 2003
- Revision received September 19, 2003
- Accepted September 23, 2003
- Published online May 19, 2004.
- Steven J Kernis, MD*,* (, )
- Kishore J Harjai, MD, FACC*,
- Gregg W Stone, MD, FACC†,
- Lorelei L Grines, PhD*,
- Judith A Boura, MS*,
- William W O'Neill, MD, FACC* and
- Cindy L Grines, MD, FACC*
- ↵*Reprint requests and correspondence:
Dr. Steven J. Kernis, William Beaumont Hospital Cardiology, 28829 West King William, Farmington Hills, Michigan 48331, USA.
Objectives We sought to determine if beta-blocker therapy improves clinical outcomes of acute myocardial infarction (AMI) after successful primary percutaneous coronary intervention (PCI).
Background We have shown that pre-treatment with beta-blockers has a beneficial effect on short-term clinical outcomes in patients undergoing primary PCI for AMI. It is unknown if beta-blocker therapy after successful primary PCI improves prognosis of AMI.
Methods We analyzed clinical, angiographic, and outcomes data in 2,442 patients who underwent successful primary PCI in the Primary Angioplasty in Acute Myocardial Infarction-2 (PAMI-2), PAMI No Surgery-on-Site (PAMI noSOS), Stent PAMI, and Air PAMI trials. We classified patients into beta group (those who received beta-blockers after successful PCI, n = 1,661) and no-beta group (n = 781). We compared death and major adverse cardiac events (MACE) (death, reinfarction, and ischemia-driven target vessel revascularization) at six months between groups receiving and not receiving beta-blockers.
Results At six months, beta patients were less likely to die (2.2% vs. 6.6%, p < 0.0001) or experience MACE (14 vs. 17%, p = 0.036). In multivariate analysis, beta-blockers were independently associated with lower six-month mortality (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.26 to 0.73, p = 0.0016). Beta-blocker therapy was an independent predictor of lower six-month events in high-risk subgroups: ejection fraction ≤50% (death: OR 0.34, 95% CI 0.19 to 0.60, p = 0.0002) or multi-vessel coronary artery disease (CAD) (death: OR 0.26, 95% CI 0.14 to 0.48, p < 0.0001; MACE: OR 0.57, 95% CI 0.41 to 0.80, p = 0.0011).
Conclusions Treatment with beta-blockers after successful primary PCI is associated with reduced six-month mortality, with the greatest benefit in patients with a low ejection fraction or multi-vessel CAD.
The American College of Cardiology/American Heart Association guidelines recommend routine use of beta-blockers after acute myocardial infarction (AMI) (1). This recommendation is based on results of studies performed in the pre-fibrinolytic era (2–6)and in patients treated with thrombolytics (7–11). In the era of primary angioplasty, no clinical trials have examined the independent impact of beta-blockers on clinical outcomes after successful primary percutaneous coronary intervention (PCI) for AMI. Recently, we reported improved short-term clinical outcomes when beta-blockers are given for AMI before primary PCI (12). We believe that the benefit from pre-treatment with beta-blockers is likely due to attenuation of the harmful enhanced sympathetic drive that causes tachycardia, hypertension, and increased myocardial stress during AMI. It is less clear, however, if beta-blockade after successful primary PCI improves prognosis. To address this hypothesis, we analyzed patients enrolled in the Primary Angioplasty in Acute Myocardial Infarction-2 (PAMI-2), No Surgery-on-Site (noSOS), Stent PAMI, and Air PAMI trials.
We pooled clinical, angiographic, and clinical outcome data from 2,442 patients who underwent successful primary PCI in the PAMI-2 (13,14), noSOS (15), Stent-PAMI (16,17), and Air-PAMI trials (18)(Table 1). The PAMI studies without data on post-PCI beta-blocker use were not included. Successful PCI was defined as achievement of Thrombolysis In Myocardial Infarction (TIMI) 3 flow and final residual stenosis <50% in the infarct-related artery (IRA). Left ventricular ejection fraction (LVEF) was determined by left ventriculography at the time of emergent cardiac catheterization. We excluded 475 patients with unsuccessful PCI from the analysis. A total of 1,661 patients received post-procedural beta-blockers, and 781 patients did not.
PAMI study protocol
All patients enrolled presented within 12 h of onset of chest pain and electrocardiographic changes (ST elevation in two contiguous leads or left bundle branch block). The trials excluded patients presenting with cardiogenic shock, those with high bleeding risk, and those who did not give informed consent. Before PCI, patients received 325 mg chewable aspirin, a 5,000- to 10,000-U bolus of heparin, and nitroglycerin. Intravenous beta-blockers were recommended for all patients without contraindications in all studies. Patients were taken emergently to the cardiac cath lab for coronary angiography and possible intervention. Those patients deemed unlikely to benefit from primary PCI (IRA with ≤70% stenosis or supplying a small area of myocardium) were treated medically without mechanical intervention. Patients found to have unprotected left main stenosis >60% or severe proximal three-vessel coronary artery disease (CAD) and spontaneous reperfusion were referred for coronary artery bypass grafting (CABG). In the absence of these contraindications, patients underwent PCI. Patients undergoing PCI were given heparin to achieve an activated clotting time between 350 and 400 s. Study monitors recorded in-hospital and six-month follow-up events at each center from review of patient medical records and, if indicated, telephone contact with the patient or family.
We classified patients into beta group (those who received beta-blockers after successful PCI, n = 1,661) and no-beta group (those who did not receive beta-blockers after PCI, n = 781). We compared baseline clinical and angiographic characteristics of both groups and assessed the incidence of death and major adverse cardiac events (MACE) (death, reinfarction, and ischemic-driven target vessel revascularization) at six months.
Statistical analyses were completed on the categorical variables using a chi-square test where appropriate (expected frequency ≥5); otherwise a Fisher exact test was used. Continuous variables were examined using a Wilcoxon rank test. This is a nonparametric approximation of the ttest. Kaplan-Meier survival curves were created for the cumulative incidence for death at six months comparing beta versus no-beta groups with a log-rank test.
A propensity score was derived using step-down logistic regression analyses to determine predictors of beta-blocker use after successful PCI. It adjusted for variables including age >70, history of peripheral vascular disease (PVD), final IRA percent stenosis, prior CABG, and having a right coronary artery (RCA) infarct. This score was included along with beta-blocker use in further multivariate analyses to adjust for the likelihood that a given patient would receive beta-blockers post-PCI. The SAS version 8.0 (Cary, North Carolina) was used for all analyses.
To determine the independent correlation of beta-blocker use with death and MACE at six months, we performed step-down logistic regression analyses. Clinical and angiographic differences (age, gender, current smoker, history of diabetes, PVD or chronic obstructive lung disease, prior angina, PCI, stent or CABG, Killip class >1, multi-vessel CAD, EF ≤50% [operator defined], final residual stenosis, systolic blood pressure <100, or IRA in the left circumflex or RCA; p < 0.10) and the propensity score were used as potential covariates in the models. Similar analyses were performed in the following subgroups: LVEF ≤50%, n = 1,361; multi-vessel CAD, n = 1,124; and those who survived index hospitalization without MACE, n = 2,323.
Of the 2,442 patients who had successful primary PCI, 1,661 patients (68%) were given beta-blockers after PCI. Across the four PAMI studies, the percent of patients given beta-blockers post-PCI ranged from 53% (Air PAMI) to 82% (NoSOS).
Beta patients were younger; they less frequently had a history of prior angina, CABG, PCI, diabetes, chronic obstructive lung disease (COPD), PVD, or admission Killip class >1; and they were more likely to be taking beta-blockers before emergent cardiac catheterization (Table 2). Patients receiving beta-blockers less com-monly had in-hospital sustained hypotension (4% in beta group vs. 8% in no-beta group, p = 0.0004) and in-hospital Killip class >1 (7% in beta group vs. 10% in no-beta group, p = 0.039), although in-hospital bradycardia occurred with equal frequencies in both groups (2.6% in beta group vs. 2.4% in no-beta group). Angiographically, the beta group had a slightly lower final diameter stenosis and the IRA was the RCA more frequently (Table 3).
The relation of beta-blocker use with six-month clinical outcomes
Patients receiving beta-blocker therapy after primary PCI had lower six-month mortality (2.2% vs. 6.6%, p < 0.0001) and MACE (14% vs. 17%, p = 0.036) compared with patients without beta-blocker use (Fig. 1and Table 4) . In survival analysis, six-month death and MACE were lower in the beta group (log-rank p < 0.0001 for death, p = 0.12) (Fig. 2). After adjusting for baseline clinical and angiographic differences and propensity score, step-down multivariate Cox regression analyses showed that beta-blocker use was a significant independent predictor of lower six-month mortality (OR 0.43, 95% CI 0.26 to 0.73, p = 0.0016), but not MACE (OR 0.87, 95% CI 0.66 to 1.13, p = 0.29). Other variables independently associated with increased six-month mortality included EF ≤50%, multi-vessel CAD, age, history of PVD, Killip class >1, and a non-RCA (Fig. 3).
The protective effect of post-procedural beta-blocker therapy was seen in patients with low EF (death: 2.6% vs. 8.2%, p < 0.0001; MACE: 15% vs. 19%, p = 0.12) and those with multi-vessel CAD (death: 2.7% vs. 10%, p < 0.0001; MACE: 14% vs. 22%, p = 0.0003), but not in those with EF >50% (death: 1.3% vs. 1.5%, p = 1.00; MACE: 11% vs. 11%, p = 0.95) or single-vessel CAD (death: 1.8% vs. 2.9%, p = 0.20; MACE: 14% vs. 11%, p = 0.28) (Fig. 1). After excluding patients with in-hospital MACE beta group, n = 1,562; no-beta group, n = 727), beta patients (all patients included) were less likely to die at six months (1.0% vs. 2.1%, p = 0.042) and had a trend toward lower MACE (9% vs. 11%, p = 0.10) (Fig. 1). Patients receiving beta-blockers had higher survival and MACE-free survival at six months (Fig. 2).
In patients with EF ≤50%, beta-blockers were significant independent predictors of lower six-month mortality (OR 0.34, 95% CI 0.19 to 0.60, p = 0.0002) but not MACE (OR 0.80, 95% CI 0.58 to 1.10, p = 0.17). In patients with multi-vessel CAD, beta-blockers were significant independent predictors of lower six-month mortality (OR 0.26, 95% CI 0.14 to 0.48, p < 0.0001) and MACE (OR 0.57, 95% CI 0.41 to 0.80, p = 0.0011). Beta-blocker therapy had a modest but nonsignificant independent effect on six-month clinical outcomes in patients who survived the index hospitalization without MACE (death: OR 0.58, 95% CI 0.29 to 1.17, p = 0.13; MACE: OR 0.80, 95% CI 0.59 to 1.10, p = 0.17).
Beta-blocker therapy imparts a significant six-month mortality benefit when given to AMI patients after successful primary PCI. Beta-blockade was associated with an absolute risk reduction of 4.4% in six-month mortality (2.2% in beta group vs. 6.6% in no-beta group); indicating that treating 23 patients prevented one death at six months. Previous large-scale trials have also demonstrated reductions in mortality with beta-blocker therapy before and after primary fibrinolysis in the management of AMI. Teo et al. (7)reported a 1.2% absolute risk reduction (5.4% with beta-blockers vs. 6.6% without beta-blockers), which translates into one life saved per 83 patients treated. In multivariate analyses, beta-blockers were independently associated with lower mortality. We believe that our study is the first to show significant benefit from beta-blocker therapy even after successful primary angioplasty.
Further analyses revealed that two patient subgroups drove this benefit: patients with EF ≤50% and patients with multi-vessel CAD. Six-month mortality and MACE were lower in beta patients in each of these subgroups. In patients with low EF an absolute risk reduction of 5% for six-month mortality and 4% for six-month MACE was seen from beta-blocker therapy. In patients with multi-vessel CAD, absolute risk reductions of 7.3% for six-month mortality and 8% for six-month MACE were observed from beta-blocker therapy. Interestingly, these are larger reductions than the 3.8% absolute risk reduction in one-year mortality reported in a recent meta-analysis of beta-adrenergic blocker therapy for New York Heart Association functional class II and III congestive heart failure patients (19).
This significant mortality reduction in patients with either reduced EF or multi-vessel CAD is not surprising. Multiple large trials, including the meta-analysis by Brophy et al. (19), have documented improvement in clinical outcomes seen with beta-adrenergic blockade in patients with left ventricular systolic dysfunction, with or without congestive heart failure (11,20). The data on beta-blockers in patients with multi-vessel versus single-vessel CAD, however, are less well established. Given their well-documented anti-ischemic and antiarrhythmic properties, beta-blockers might be expected to improve clinical outcomes across all these subgroups, especially with multi-vessel CAD where untreated coronary lesions in non-infarct-related arteries remain.
Patients with normal EF and those with single-vessel CAD showed no statistically significant reduction in six-month mortality or MACE with post-PCI beta-blockade, although mortality reduction may be clinically significant in patients with single-vessel CAD (1.8% vs. 2.9%). Given the wealth of data supporting beneficial effects of beta-blockers on long-term clinical outcomes, this observation may be at odds with intuitive expectation. However, no previous similar studies analyzed this large subgroup of AMI patients treated successfully with primary PCI. It is enticing to speculate that complete and successful primary revascularization early in the course of AMI in patients with normal LVEF reduces their future risk of cardiac events to a point where chronic beta-blockade becomes unnecessary. Although our retrospective study does not allow such a conclusion to be made definitively, we find this possibility intriguing.
It is possible that the improved prognosis seen in beta patients was in large part due to a selection bias favoring use of beta-blockers in healthier patients (those with less frequent histories of CAD, chronic obstructive lung disease, and diabetes). Patients with sustained hypotension, CHF, and bradycardia during the index hospitalization, for example, are generally not treated with beta-blockers. In fact, we did find that a lower percentage of patients in the beta group experienced in-hospital sustained hypotension and Killip class >1, although both groups had equal incidences of in-hospital bradycardia. We minimized this selection bias by performing a subgroup analysis on patients without in-hospital MACE. This analysis showed that even in patients without in-hospital MACE, those receiving beta-blockers were less likely to die at six months. In multivariate analysis of patients without in-hospital MACE, beta-blockers were associated with a nonsignificant yet modest independent effect on six-month mortality. The OR of 0.58 in this subset is quite similar to the OR of 0.43 for the entire population. Hence, lack of statistical significance is likely secondary to fewer patients and fewer events in this subgroup.
Our study has the usual limitations inherent to retrospective analyses; for example, selection bias may have led healthier patients to receive beta-blockers. Further, our results cannot be extrapolated to patients with cardiogenic shock, as the PAMI studies excluded these patients. Our results may be less representative of contemporary practice because of lower rates of glycoprotein IIb/IIIa and thienopyridine medications and lower stent use in the PAMI studies. We have no data on the specific beta-blocker used, the dose employed, or whether adequate beta-blockade was achieved.
We have shown that AMI patients receiving beta-blockers after primary PCI have lower six-month mortality and MACE. Beta-blockade is independently associated with reduced six-month mortality, but not MACE. This benefit is driven by patients with reduced EF or multi-vessel CAD.
Our conclusions support the current American College of Cardiology/American Heart Association guidelines recommending beta-blocker therapy for secondary prevention after AMI. Whether beta-blockers are necessary after successful primary PCI for AMI in patients with normal EF or single-vessel CAD is a question that needs to be answered by future prospective clinical trials.
The authors thank the people and institutions that participated in the PAMI trials.
- acute myocardial infarction
- coronary artery bypass grafting
- coronary artery disease
- infarct-related artery
- ischemia driven target vessel revascularization
- left ventricular ejection fraction
- major adverse cardiac events
- Primary Angioplasty in Acute Myocardial Infarction
- percutaneous coronary intervention
- peripheral vascular disease
- right coronary artery
- Thrombolysis in Myocardial Infarction
- Received August 12, 2003.
- Revision received September 19, 2003.
- Accepted September 23, 2003.
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