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Prognostic Impact of Acute Beta-Blocker Therapy on Top of Aspirin and Angiotensin-Converting Enzyme Inhibitor Therapy in Consecutive Patients With ST-Elevation Acute Myocardial Infarction
Prognostic Impact of Acute Beta-Blocker Therapy on Top of Aspirin and Angiotensin-Converting Enzyme Inhibitor Therapy in Consecutive Patients With ST-Elevation Acute Myocardial Infarction Harm Wienbergen, MD*, Uwe Zeymer, MD, Anselm Kai Gitt, MD, Claus Juenger, MD, MPH, Rudolf Schiele, MD, Tobias Heer, MD, Frank Towae, MD, and Jochen Senges, MD, for the MITRA PLUS Study Group The prognostic effect of -blocker treatment on ST-elevation acute myocardial infarction (STEMI) is controversially discussed in the era of reperfusion therapy. From the German multicenter registry Maximal Individual Therapy of Acute Myocardial Infarction PLUS (MITRA PLUS), 17,809 consecutive patients with STEMI treated with a guideline-recommended therapy with aspirin and an angiotensin-converting enzyme inhibitor were investigated; the prognostic effect of additional acute -blocker treatment was analyzed. Patients with cardiogenic shock were excluded. Of included patients, 77.6% received additional acute -blocker treatment and 22.4% did not. Patients with -blocker treatment were younger and more often received reperfusion therapy. Acute -blocker treatment was associated with a lower hospital mortality (univariate analysis 4.9% vs 10.8%, p <0.001; multivariate analysis odds ratio [OR] 0.70, 95% confidence interval [CI] 0.61 to 0.81). Acute  blockade was significantly associated with a lower hospital mortality in patients without (OR 0.66, 95% CI 0.56 to 0.79) and with (OR 0.76, 95% CI 0.60 to 0.98) reperfusion therapy. The greatest benefit of acute -blocker treatment, measured by the number needed to treat to save 1 life, was found in patients with anterior MI, a heart rate >80 beats/min, no reperfusion therapy, female gender, and age >65 years. In conclusion, acute -blocker therapy in the clinical practice of treating patients with STEMI, in addition to aspirin and angiotensin-converting enzyme inhibitor therapy, was independently associated with a significant decrease in hospital mortality in patients with and without reperfusion therapy. High-risk patients with STEMI, such as elderly patients and patients without reperfusion therapy, showed a greater benefit of acute -blocker therapy than low-risk patients with STEMI. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1208 –1211) There is strong evidence of lower mortality and reinfarction rates with long-term -blocker use in patients who have recovered from acute myocardial infarction (MI).1,2 The effect of -blocker treatment on the acute phase of MI is still unclear. Data before the reperfusion era have shown a decrease in infarction mortality by acute -blockade treatment.1,3 More recent studies have controversially discussed the routine use of acute  blockers.4 – 8 In the recent Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study (COMMIT-CCS-II), acute treatment with metoprolol (up to 15 mg intravenously and then 200 mg/day orally) did not decrease in-hospital mortality, but the rate of reinfarction and ventricular fibrillation was sig-
Herzzentrum Ludwigshafen, Institut für Herzinfarktforschung, Ludwigshafen, Germany. Manuscript received September 13, 2006; revised manuscript received and accepted December 7, 2006. The MITRA PLUS study was supported by the Landesversicherungsanstalt, Rheinland Pfalz, Germany; the Ministerium für Arbeit, Soziales und Gesundheit, Rheinland-Pfalz, Germany; MSD Sharp & Dohme, Haar, Germany; Bristol-Myers Squibb, München, Germany; Aventis Pharma, Bad Soden, Germany; AstraZeneca, Wedel, Germany; Pfizer, Karlsruhe, Germany; and Abbott, Ludwigshafen, Germany. *Corresponding author: Tel: 01149-621-503-4000; fax: 01149-621503-4044. E-mail address: [email protected] (H. Wienbergen). 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.12.036
nificantly decreased. Beta blockade increased the rate of cardiogenic shock, especially the first day after admission.7,8 In the present study, acute -blocker treatment was investigated in consecutive patients with ST-elevation acute MI (STEMI) by analyzing data from the German registry Maximal Individual Therapy of Acute Myocardial Infarction PLUS (MITRA PLUS). We investigated the effect of  blockers in addition to that of a guideline-recommended medical standard therapy with aspirin and oral angiotensinconverting enzyme (ACE) inhibitors. Methods and Results The MITRA PLUS is a German prospective, multicenter, observational data pool of current treatments of acute coronary syndromes. Since 1994, ⬎45,000 consecutive patients in 390 hospitals have been registered prospectively in the MITRA PLUS registry. The MITRA PLUS registry consists of consecutive subregistries that have been previously described in detail, i.e., the 60 Minutes Myocardial Infarction Project (60 minutes MIP),9 Maximal Individual Therapy in Acute Myocardial Infarction (MITRA),10 Myocardial Infarction Registry (MIR),11 and Acute Coronary Syndromes Registry (ACOS).12 In the present analysis of the MITRA PLUS registry, we exclusively analyzed patients with STEMI (non–ST-elevation www.AJConline.org
Coronary Artery Disease/Beta Blockers in Acute Myocardial Infarction
1209
Table 1 Univariate and multivariate analyses of hospital outcome with respect to acute -blocker therapy (n ⫽ 17,809 patients with ST-elevation acute myocardial infarction receiving aspirin and angiotensin-converting enzyme inhibitor treatment) Variable
Mortality Nonfatal reinfarction Nonfatal stroke
Acute -Blocker Therapy Yes
No
4.9% 3.4% 0.6%
10.8% 4.0% 0.7%
p Value, Univariate
OR (95% CI), Multivariate*
⬍0.001 0.09 0.56
0.70 (0.61–0.81) 0.86 (0.70–1.05) 1.09 (0.68–1.76)
* Adjustment for age, gender, previous MI, diabetes mellitus, renal failure, initial heart rate, chronic obstructive pulmonary disease, hypertension, and reperfusion therapy.
acute coronary syndromes were excluded) and acute medical treatment with aspirin and ACE inhibitors. Patients with cardiogenic shock as an absolute contraindication for acute -blocker treatment were excluded. In the resulting group of 17,809 patients with STEMI, we investigated the additional effect of acute -blocker treatment on outcome. The decision of whether -blocker treatment was indicated or contraindicated for any patient was made by the treating physicians. STEMI was diagnosed in the presence of the 2 following criteria: persistent angina pectoris for ⱖ20 minutes and ST-segment elevation ⱖ1 mm in ⱖ2 standard leads or ⱖ2 mm in ⱖ2 contiguous precordial leads, or the presence of left bundle branch block. Diagnosis was later confirmed by increased cardiac enzymes to ⬎2 times the upper limit of normal. Acute -blocker treatment was defined as -blocker treatment during the first 48 hours after hospital admission (intravenous or oral). Thrombolysis In Myocardial Infarction (TIMI) risk score for patients with STEMI was calculated using the score parameters as published by Morrow et al.13 Patients were recruited from hospitals in Germany, including community hospitals and tertiary centers. Study protocols, including definitions and information on data documentation, were distributed to the participating study centers before data collection. On admission, data on patient characteristics and on symptoms and prehospital delay were recorded. During hospital stay, data on electrocardiographic findings, biochemical markers, and treatment were documented. At discharge, outcome and major cardiovascular and cerebrovascular adverse events were recorded as were risk assessment and medication at discharge. Data were collected on record forms by treating physicians. All data sheets were sent to the central data processing center (Institut für Herzinfarktforschung, Ludwigshafen, Germany) for uniform monitoring and analysis. Absolute numbers, percentages, medians, and 25% and 75% quartiles were computed to describe the patient population. Categorical variables were compared by using chisquare or Fisher’s exact test and calculating the odds ratio [OR] and 95% confidence interval [CI]. Multiple logistic regression was used to compare clinical outcomes in patients with and without -blocker treatment; adjustment was performed for age, gender, previous MI, diabetes mellitus,
Figure 1. Subgroup analysis of hospital mortality with respect to acute -blocker treatment (n ⫽ 17,809 patients with STEMI receiving aspirin and ACE inhibitor treatment). Multivariate analysis adjusted for age, gender, previous MI, diabetes mellitus, renal failure, initial heart rate, chronic obstructive pulmonary disease, hypertension, and reperfusion therapy. bpm ⫽ beats per minute. Table 2 Benefit of acute -blocker treatment in a subgroup analysis (n ⫽ 17,809 patients with ST-elevation acute myocardial infarction receiving aspirin and angiotensin-converting enzyme inhibitor treatment) Variable Higher benefit Anterior MI Heart rate ⱖ80 beats/min TIMI risk score ⱖ4 points No reperfusion therapy Female gender Age ⱖ65 yrs Lower benefit Reperfusion therapy TIMI risk score 0–3 points Age ⬍65 yrs
No. Needed to Treat (to save 1 life in hospital) 13.4 14.4 15.0 15.1 15.8 17.3 37.0 55.8 71.7
renal failure, initial heart rate, chronic obstructive pulmonary disease, hypertension, and reperfusion therapy (Table 1). Infarction size was not documented during the entire study period, so we performed an additional logistic regression model with additional adjustment for infarction size. A subgroup analysis comparing subgroups of age, gender, heart rate, TIMI risk score for STEMI, and reperfusion therapy was performed with the same adjustment (Figure 1). The benefit of acute -blocker treatment was evaluated by an analysis of the number needed to treat to save 1 life in the hospital (Table 2). In all analyses, a p value ⬍0.05 was considered statistically significant. Tests were performed with SAS 8.02 (SAS Institute, Cary, North Carolina). In total, 17,809 patients with STEMI on acute aspirin and ACE inhibitor treatment were analyzed; 77.6% received additional acute -blocker treatment and 22.4% did not. Patients with acute -blocker treatment were younger (mean age 65.3 vs 72.0 years, p ⬍0.001) and more often men compared with patients without -blocker treatment. Patients with acute -blocker treatment more often received reperfusion therapy than patients without acute -blocker
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Table 3 Baseline characteristics and determinants of acute -blocker use (n ⫽ 17,809 patients with ST-elevation acute myocardial infarction with aspirin and angiotensin-converting enzyme inhibitor treatment) Acute -Blocker Therapy
Variable
Mean age (yrs) Age ⱖ65 yrs Women Previous MI Previous coronary intervention Diabetes mellitus Hypertension Chronic obstructive pulmonary disease Renal failure† Anterior MI Heart rate ⱖ80 beats/min Reperfusion therapy
Yes (n ⫽ 13,826)
No (n ⫽ 3,983)
65.3 50.9% 30.4% 15.2% 9.2% 24.0% 54.0% 2.6% 1.6% 53.1% 51.3% 66.0%
72.0 72.2% 40.0% 20.1% 8.2% 31.8% 50.5% 9.9% 4.1% 48.1% 53.1% 40.1%
p Value (univariate)
Determinants of -Blocker Use*
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.43 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.05 ⬍0.001
— 0.40 (0.37–0.43) 0.66 (0.61–0.71) 0.71 (0.65–0.78) 1.14 (0.83–1.55) 0.68 (0.63–0.73) 1.15 (1.07–1.23) 0.24 (0.21–0.28) 0.38 (0.31–0.46) 1.22 (1.13–1.32) 0.93 (0.87–1.00) 2.90 (2.69–3.11)
* OR (95% CI). Renal failure was defined as a creatinine level ⬎2 mg/dl.
†
treatment (Table 3). The strongest determinant for use of acute -blocker treatment was reperfusion therapy. Strong determinants against use of acute -blocker treatment were chronic obstructive pulmonary disease, renal failure, age ⱖ65 years, female gender, and diabetes mellitus (Table 3). Hospital mortality of patients with STEMI and acute  blockade was significantly lower than that of patients without acute  blockade (4.9% vs 10.8%, p ⬍0.001). No significant differences were found in the rate of nonfatal reinfarctions or strokes during the hospital course (Table 1). In a multivariate analysis adjusting for baseline characteristics and reperfusion therapy, acute -blocker treatment was independently associated with lower in-hospital mortality (OR 0.70, 95% CI 0.61 to 0.81; Table 1). In an additional logistic regression model with additional adjustment for infarction size (not documented during the entire study period), the significant association did not change (OR 0.72, 95% CI 0.62 to 0.83). The decrease in hospital mortality associated with acute  blockade was consistent across subgroups (Figure 1). Beta-blocker treatment was significantly associated with a decrease in hospital mortality in patients without (OR 0.66, 95% CI 0.56 to 0.79) and with (OR 0.76, 95% CI 0.60 to 0.98) reperfusion therapy. A great benefit of acute -blocker treatment, measured by the number needed to treat to save 1 life, was found in subgroups with anterior MI, an initial heart rate ⱖ80 beats/ min, TIMI risk score for STEMI ⱖ4 points, no reperfusion therapy, female gender, and age ⱖ65 years (Table 2). The number needed to treat in these high-risk patients was smaller compared with low-risk patients (age ⬍65 years, TIMI risk score for STEMI of 0 to 3 points, or reperfusion therapy). Discussion In the present study, the effect of acute -blocker treatment (⬍48 hours after admission) in addition to a medical standard therapy with aspirin and ACE inhibitors in consecutive
patients with STEMI and without cardiogenic shock was investigated. A medical standard therapy with aspirin and oral ACE inhibitors is recommended in the American Heart Association/American College of Cardiology guidelines for management of patients with STEMI (class I recommendation consists of aspirin and oral ACE inhibitors in patients with anterior infarction, pulmonary congestion, or an ejection fraction ⬍0.40; class IIa recommendation consists of oral ACE inhibitors in patients without these criteria).1 We investigated the additional effect of acute -blocker therapy and its beneficial effect in subgroups in addition to medical therapy with aspirin and oral ACE inhibitors. We found a significant association of acute -blocker treatment with lower hospital mortality in univariate and multivariate analyses. The decrease in hospital mortality was found in patients with and without reperfusion therapy. The beneficial effects of -blocker treatment in acute STEMI, as prevention of ventricular tachycardia, ventricular fibrillation, recurrent ischemia, and cardiac rupture,8,14 obviously outweigh the harmful effects of -blocker treatment and lead to a lower mortality in patients with STEMI when using  blockers in addition to aspirin and ACE inhibitor treatment. The benefit of -blocker treatment, measured by the number needed to treat to save 1 life, was greater in patients without than in those with reperfusion therapy (Table 2). However, in actual clinical practice, acute -blocker treatment was predominantly used in patients with reperfusion therapy (Table 3). High-risk patients with STEMI with a TIMI risk score ⱖ4 points had a greater benefit of acute -blocker treatment than low-risk patients with a TIMI risk score of 0 to 3 points (Table 2). However, in clinical practice, high-risk patients (e.g., elderly patients, women, and diabetics) less often received -blocker treatment than low-risk patients (Table 3). One study limitation was that our study did not differentiate doses or generics of  blockers and intravenous or oral administration. In addition, in an observational study,
Coronary Artery Disease/Beta Blockers in Acute Myocardial Infarction
despite adjustment in multivariate analysis, unavoidable selection effects by confounding factors always have to be taken into account. Therefore, our results cannot be directly compared with those of randomized trials. However, our study reflects the way acute -blocker treatment is performed in actual clinical practice of patients with STEMI, including treatment of high-risk patients and individual dosages of -blocker treatment. 1. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, et al. ACC/ AHA guidelines for the management of patients with ST-elevation myocardial infarction. J Am Coll Cardiol 2004;44:671–719. 2. Yusuf S, Lessem J, Jha P, Lonn E. Primary and secondary prevention of myocardial infarction and strokes: an update of randomly allocated, controlled trials. J Hypertens 1993;11(suppl):S61–S73. 3. First International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. Lancet 1986;2:57– 66. 4. Harjai KJ, Stone GW, Boura J, Grines L, Garcia E, Brodie B, Cox D, O‘Neill WW, Grines C. Effects of prior beta-blocker therapy on clinical outcomes after primary coronary angioplasty for acute myocardial infarction. Am J Cardiol 2003;91:655– 660. 5. Pfisterer M, Cox JL, Granger CB, Brener SJ, Naylor CD, Califf RM, van de Werf F, Stebbins AL, Lee KL, Topol EJ, Armstrong PW. Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA (alteplase) for Occluded Coronary Arteries. J Am Coll Cardiol 1998;32:634 – 640. 6. Freemantle N, Cleland J, Young P, Mason J, Harrison J. -Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999;318:1730 –1737. 7. Second Chinese Cardiac Study (CCS-2) Collaborative Group. Rationale, design and organization of the Second Chinese Cardiac Study
8.
9.
10.
11.
12.
13.
14.
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(CCS-2): a randomized trial of clopidogrel plus aspirin, and of metoprolol, among patients with suspected acute myocardial infarction. J Cardiovasc Risk 2000;7:435– 441. COMMIT (Clopidogrel and Metoprolol In Myocardial Infarction Trial) Collaborative Group. Early intravenous then oral metoprolol in 45852 patients with acute myocardial infarction: randomised placebocontrolled trial. Lancet 2005;366:1622–1632. Rustige J, Schiele R, Burczyk U, Koch A, Gottwik M, Neuhaus KL, Tebbe U, Uebis R, Senges J. The 60 minutes myocardial infarction project. Treatment and clinical outcome of patients with acute myocardial infarction in Germany. Eur Heart J 1997;18:1438 –1446. Schuster S, Koch A, Burczyk U, Schiele R, Wagner S, Zahn R, Glunz HG, Heinrich F, Stuby K, Berg G, et al, for the MITRA Study Group. Therapy of acute myocardial infarction, impact of clinical trials on clinical practice: the MITRA pilot phase. Z Kardiol 1997; 86:273–283. Wagner S, Schneider S, Schiele R, Fischer F, Dehn H, Grube R, Becker G, Baumgärtel B, Altmann E, Senges J. Acute myocardial infarction in Germany between 1996 and 1998; therapy and intrahospital course: results of the Myocardial Infarction Registry (MIR) in Germany. Z Kardiol 1999;88:857– 867. Wienbergen H, Gitt AK, Schiele R, Juenger C, Heer T, Gottwik M, Manthey J, Hempel A, Bestehorn K, Senges J, Rauch B. Actual clinical practice of exercise testing in consecutive patients after non– ST-elevation myocardial infarction: results of the Acute Coronary Syndromes Registry. Eur J Cardiovasc Prev Rehabil 2006;13:457– 463. Morrow DA, Antman EM, Charlesworth A, Cairns R, Murphy SA, de Lemos JA, Giugliano RP, McCabe CH, Braunwald E. TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation. Circulation 2000;102:2031– 2037. Owen A. Intravenous beta-blockade in acute myocardial infarction. Should be used in combination with thrombolysis. BMJ 1998;317: 226 –227.
Herzzentrum Ludwigshafen, Institut für Herzinfarktforschung, Ludwigshafen, Germany. Manuscript received September 13, 2006; revised manuscript received and accepted December 7, 2006. The MITRA PLUS study was supported by the Landesversicherungsanstalt, Rheinland Pfalz, Germany; the Ministerium für Arbeit, Soziales und Gesundheit, Rheinland-Pfalz, Germany; MSD Sharp & Dohme, Haar, Germany; Bristol-Myers Squibb, München, Germany; Aventis Pharma, Bad Soden, Germany; AstraZeneca, Wedel, Germany; Pfizer, Karlsruhe, Germany; and Abbott, Ludwigshafen, Germany. *Corresponding author: Tel: 01149-621-503-4000; fax: 01149-621503-4044. E-mail address: [email protected] (H. Wienbergen). 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.12.036
nificantly decreased. Beta blockade increased the rate of cardiogenic shock, especially the first day after admission.7,8 In the present study, acute -blocker treatment was investigated in consecutive patients with ST-elevation acute MI (STEMI) by analyzing data from the German registry Maximal Individual Therapy of Acute Myocardial Infarction PLUS (MITRA PLUS). We investigated the effect of  blockers in addition to that of a guideline-recommended medical standard therapy with aspirin and oral angiotensinconverting enzyme (ACE) inhibitors. Methods and Results The MITRA PLUS is a German prospective, multicenter, observational data pool of current treatments of acute coronary syndromes. Since 1994, ⬎45,000 consecutive patients in 390 hospitals have been registered prospectively in the MITRA PLUS registry. The MITRA PLUS registry consists of consecutive subregistries that have been previously described in detail, i.e., the 60 Minutes Myocardial Infarction Project (60 minutes MIP),9 Maximal Individual Therapy in Acute Myocardial Infarction (MITRA),10 Myocardial Infarction Registry (MIR),11 and Acute Coronary Syndromes Registry (ACOS).12 In the present analysis of the MITRA PLUS registry, we exclusively analyzed patients with STEMI (non–ST-elevation www.AJConline.org
Coronary Artery Disease/Beta Blockers in Acute Myocardial Infarction
1209
Table 1 Univariate and multivariate analyses of hospital outcome with respect to acute -blocker therapy (n ⫽ 17,809 patients with ST-elevation acute myocardial infarction receiving aspirin and angiotensin-converting enzyme inhibitor treatment) Variable
Mortality Nonfatal reinfarction Nonfatal stroke
Acute -Blocker Therapy Yes
No
4.9% 3.4% 0.6%
10.8% 4.0% 0.7%
p Value, Univariate
OR (95% CI), Multivariate*
⬍0.001 0.09 0.56
0.70 (0.61–0.81) 0.86 (0.70–1.05) 1.09 (0.68–1.76)
* Adjustment for age, gender, previous MI, diabetes mellitus, renal failure, initial heart rate, chronic obstructive pulmonary disease, hypertension, and reperfusion therapy.
acute coronary syndromes were excluded) and acute medical treatment with aspirin and ACE inhibitors. Patients with cardiogenic shock as an absolute contraindication for acute -blocker treatment were excluded. In the resulting group of 17,809 patients with STEMI, we investigated the additional effect of acute -blocker treatment on outcome. The decision of whether -blocker treatment was indicated or contraindicated for any patient was made by the treating physicians. STEMI was diagnosed in the presence of the 2 following criteria: persistent angina pectoris for ⱖ20 minutes and ST-segment elevation ⱖ1 mm in ⱖ2 standard leads or ⱖ2 mm in ⱖ2 contiguous precordial leads, or the presence of left bundle branch block. Diagnosis was later confirmed by increased cardiac enzymes to ⬎2 times the upper limit of normal. Acute -blocker treatment was defined as -blocker treatment during the first 48 hours after hospital admission (intravenous or oral). Thrombolysis In Myocardial Infarction (TIMI) risk score for patients with STEMI was calculated using the score parameters as published by Morrow et al.13 Patients were recruited from hospitals in Germany, including community hospitals and tertiary centers. Study protocols, including definitions and information on data documentation, were distributed to the participating study centers before data collection. On admission, data on patient characteristics and on symptoms and prehospital delay were recorded. During hospital stay, data on electrocardiographic findings, biochemical markers, and treatment were documented. At discharge, outcome and major cardiovascular and cerebrovascular adverse events were recorded as were risk assessment and medication at discharge. Data were collected on record forms by treating physicians. All data sheets were sent to the central data processing center (Institut für Herzinfarktforschung, Ludwigshafen, Germany) for uniform monitoring and analysis. Absolute numbers, percentages, medians, and 25% and 75% quartiles were computed to describe the patient population. Categorical variables were compared by using chisquare or Fisher’s exact test and calculating the odds ratio [OR] and 95% confidence interval [CI]. Multiple logistic regression was used to compare clinical outcomes in patients with and without -blocker treatment; adjustment was performed for age, gender, previous MI, diabetes mellitus,
Figure 1. Subgroup analysis of hospital mortality with respect to acute -blocker treatment (n ⫽ 17,809 patients with STEMI receiving aspirin and ACE inhibitor treatment). Multivariate analysis adjusted for age, gender, previous MI, diabetes mellitus, renal failure, initial heart rate, chronic obstructive pulmonary disease, hypertension, and reperfusion therapy. bpm ⫽ beats per minute. Table 2 Benefit of acute -blocker treatment in a subgroup analysis (n ⫽ 17,809 patients with ST-elevation acute myocardial infarction receiving aspirin and angiotensin-converting enzyme inhibitor treatment) Variable Higher benefit Anterior MI Heart rate ⱖ80 beats/min TIMI risk score ⱖ4 points No reperfusion therapy Female gender Age ⱖ65 yrs Lower benefit Reperfusion therapy TIMI risk score 0–3 points Age ⬍65 yrs
No. Needed to Treat (to save 1 life in hospital) 13.4 14.4 15.0 15.1 15.8 17.3 37.0 55.8 71.7
renal failure, initial heart rate, chronic obstructive pulmonary disease, hypertension, and reperfusion therapy (Table 1). Infarction size was not documented during the entire study period, so we performed an additional logistic regression model with additional adjustment for infarction size. A subgroup analysis comparing subgroups of age, gender, heart rate, TIMI risk score for STEMI, and reperfusion therapy was performed with the same adjustment (Figure 1). The benefit of acute -blocker treatment was evaluated by an analysis of the number needed to treat to save 1 life in the hospital (Table 2). In all analyses, a p value ⬍0.05 was considered statistically significant. Tests were performed with SAS 8.02 (SAS Institute, Cary, North Carolina). In total, 17,809 patients with STEMI on acute aspirin and ACE inhibitor treatment were analyzed; 77.6% received additional acute -blocker treatment and 22.4% did not. Patients with acute -blocker treatment were younger (mean age 65.3 vs 72.0 years, p ⬍0.001) and more often men compared with patients without -blocker treatment. Patients with acute -blocker treatment more often received reperfusion therapy than patients without acute -blocker
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Table 3 Baseline characteristics and determinants of acute -blocker use (n ⫽ 17,809 patients with ST-elevation acute myocardial infarction with aspirin and angiotensin-converting enzyme inhibitor treatment) Acute -Blocker Therapy
Variable
Mean age (yrs) Age ⱖ65 yrs Women Previous MI Previous coronary intervention Diabetes mellitus Hypertension Chronic obstructive pulmonary disease Renal failure† Anterior MI Heart rate ⱖ80 beats/min Reperfusion therapy
Yes (n ⫽ 13,826)
No (n ⫽ 3,983)
65.3 50.9% 30.4% 15.2% 9.2% 24.0% 54.0% 2.6% 1.6% 53.1% 51.3% 66.0%
72.0 72.2% 40.0% 20.1% 8.2% 31.8% 50.5% 9.9% 4.1% 48.1% 53.1% 40.1%
p Value (univariate)
Determinants of -Blocker Use*
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.43 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.05 ⬍0.001
— 0.40 (0.37–0.43) 0.66 (0.61–0.71) 0.71 (0.65–0.78) 1.14 (0.83–1.55) 0.68 (0.63–0.73) 1.15 (1.07–1.23) 0.24 (0.21–0.28) 0.38 (0.31–0.46) 1.22 (1.13–1.32) 0.93 (0.87–1.00) 2.90 (2.69–3.11)
* OR (95% CI). Renal failure was defined as a creatinine level ⬎2 mg/dl.
†
treatment (Table 3). The strongest determinant for use of acute -blocker treatment was reperfusion therapy. Strong determinants against use of acute -blocker treatment were chronic obstructive pulmonary disease, renal failure, age ⱖ65 years, female gender, and diabetes mellitus (Table 3). Hospital mortality of patients with STEMI and acute  blockade was significantly lower than that of patients without acute  blockade (4.9% vs 10.8%, p ⬍0.001). No significant differences were found in the rate of nonfatal reinfarctions or strokes during the hospital course (Table 1). In a multivariate analysis adjusting for baseline characteristics and reperfusion therapy, acute -blocker treatment was independently associated with lower in-hospital mortality (OR 0.70, 95% CI 0.61 to 0.81; Table 1). In an additional logistic regression model with additional adjustment for infarction size (not documented during the entire study period), the significant association did not change (OR 0.72, 95% CI 0.62 to 0.83). The decrease in hospital mortality associated with acute  blockade was consistent across subgroups (Figure 1). Beta-blocker treatment was significantly associated with a decrease in hospital mortality in patients without (OR 0.66, 95% CI 0.56 to 0.79) and with (OR 0.76, 95% CI 0.60 to 0.98) reperfusion therapy. A great benefit of acute -blocker treatment, measured by the number needed to treat to save 1 life, was found in subgroups with anterior MI, an initial heart rate ⱖ80 beats/ min, TIMI risk score for STEMI ⱖ4 points, no reperfusion therapy, female gender, and age ⱖ65 years (Table 2). The number needed to treat in these high-risk patients was smaller compared with low-risk patients (age ⬍65 years, TIMI risk score for STEMI of 0 to 3 points, or reperfusion therapy). Discussion In the present study, the effect of acute -blocker treatment (⬍48 hours after admission) in addition to a medical standard therapy with aspirin and ACE inhibitors in consecutive
patients with STEMI and without cardiogenic shock was investigated. A medical standard therapy with aspirin and oral ACE inhibitors is recommended in the American Heart Association/American College of Cardiology guidelines for management of patients with STEMI (class I recommendation consists of aspirin and oral ACE inhibitors in patients with anterior infarction, pulmonary congestion, or an ejection fraction ⬍0.40; class IIa recommendation consists of oral ACE inhibitors in patients without these criteria).1 We investigated the additional effect of acute -blocker therapy and its beneficial effect in subgroups in addition to medical therapy with aspirin and oral ACE inhibitors. We found a significant association of acute -blocker treatment with lower hospital mortality in univariate and multivariate analyses. The decrease in hospital mortality was found in patients with and without reperfusion therapy. The beneficial effects of -blocker treatment in acute STEMI, as prevention of ventricular tachycardia, ventricular fibrillation, recurrent ischemia, and cardiac rupture,8,14 obviously outweigh the harmful effects of -blocker treatment and lead to a lower mortality in patients with STEMI when using  blockers in addition to aspirin and ACE inhibitor treatment. The benefit of -blocker treatment, measured by the number needed to treat to save 1 life, was greater in patients without than in those with reperfusion therapy (Table 2). However, in actual clinical practice, acute -blocker treatment was predominantly used in patients with reperfusion therapy (Table 3). High-risk patients with STEMI with a TIMI risk score ⱖ4 points had a greater benefit of acute -blocker treatment than low-risk patients with a TIMI risk score of 0 to 3 points (Table 2). However, in clinical practice, high-risk patients (e.g., elderly patients, women, and diabetics) less often received -blocker treatment than low-risk patients (Table 3). One study limitation was that our study did not differentiate doses or generics of  blockers and intravenous or oral administration. In addition, in an observational study,
Coronary Artery Disease/Beta Blockers in Acute Myocardial Infarction
despite adjustment in multivariate analysis, unavoidable selection effects by confounding factors always have to be taken into account. Therefore, our results cannot be directly compared with those of randomized trials. However, our study reflects the way acute -blocker treatment is performed in actual clinical practice of patients with STEMI, including treatment of high-risk patients and individual dosages of -blocker treatment. 1. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, et al. ACC/ AHA guidelines for the management of patients with ST-elevation myocardial infarction. J Am Coll Cardiol 2004;44:671–719. 2. Yusuf S, Lessem J, Jha P, Lonn E. Primary and secondary prevention of myocardial infarction and strokes: an update of randomly allocated, controlled trials. J Hypertens 1993;11(suppl):S61–S73. 3. First International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. Lancet 1986;2:57– 66. 4. Harjai KJ, Stone GW, Boura J, Grines L, Garcia E, Brodie B, Cox D, O‘Neill WW, Grines C. Effects of prior beta-blocker therapy on clinical outcomes after primary coronary angioplasty for acute myocardial infarction. Am J Cardiol 2003;91:655– 660. 5. Pfisterer M, Cox JL, Granger CB, Brener SJ, Naylor CD, Califf RM, van de Werf F, Stebbins AL, Lee KL, Topol EJ, Armstrong PW. Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA (alteplase) for Occluded Coronary Arteries. J Am Coll Cardiol 1998;32:634 – 640. 6. Freemantle N, Cleland J, Young P, Mason J, Harrison J. -Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999;318:1730 –1737. 7. Second Chinese Cardiac Study (CCS-2) Collaborative Group. Rationale, design and organization of the Second Chinese Cardiac Study
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