Lack of Effect of Beta-blocker Therapy in Patients with ST-elevation Acute Myocardial Infarction in PCI Era

Lack of Effect of Beta-blocker Therapy in Patients with ST-elevation Acute Myocardial Infarction in PCI Era B. Bao 1, N. Ozasa 1, T. Morimoto 2, Y. Furukawa 3, M. Shirotani 4, H. Ogawa 5, C. Tei 6, H. Fujiwara 7, K. Mitsudo 8, T. Kimura 1, on behalf of CREDO-Kyoto Registry Cohort2 investigators (1) Kyoto University Graduate School of Medicine, Department of Cardiovascular Medicine, Kyoto, Japan (2) Kyoto University Hospital, Kyoto, Japan (3) Kobe City Medical Center General Hospital, Kobe, Japan (4) Nara of Department of Medicine at Kinki University Hospital, Nara, Japan (5) Kumamoto University Hospital, Kumamoto, Japan (6) Kagoshima University, Kagoshima, Japan (7) Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan (8) Kurashiki Central Hospital, Cardiology Department, Kurashiki, Japan

Disclosures Nothing to disclosure

Background Beta-blocker therapy for patients with ST-elevation acute myocardial infarction (STEMI) is recommended by clinical guidelines. Class I 1. Patients receiving beta-blockers within the first 24 hours of STEMI without adverse effects should continue to receive them during the early convalescent phase of STEMI. (Level of Evidence: A) 2. Patients without contraindications to beta-blockers who did not receive them within the first 24 hours after STEMI should have them started in the early convalescent phase. (Level of Evidence: A) Antman EM, et al. Circulation. 2004;110(9):e82-292. However, the effect of beta blockers in STEMI patients who have undergone percutaneous coronary intervention (PCI) has not been adequately evaluated.

Beta Blocker Therapy was not Associated with Better 3-year Clinical Outcomes in J-Cypher Registry Ozasa N, et al. Am J Cardiol. 2010;106(9):1225-1233.

Beta Blocker Therapy was not Associated with Better 3-year Clinical Outcomes in J-Cypher Registry Ozasa N, et al. Am J Cardiol. 2010;106(9):1225-1233.

Methods

Study Patients The Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) AMI registry is a physician-initiated non-company sponsored multicenter registry enrolling consecutive AMI patients undergoing coronary revascularization within 7 days after the onset in 26 tertiary hospitals in Japan. Among 5429 patients enrolled in the CREDO-Kyoto AMI registry, we identified 3692 patients who have undergone PCI within 24 hours after the onset of STEMI and survived the index hospitalization.

Statistics The primary outcome measure for the current analyses was a composite endpoint of cardiac death and recurrent MI (cardiac death/mi). Cumulative incidences of clinical event rates were estimated by the Kaplan-Meier method. Multivariable Cox proportional-hazards model was developed by using beta-blocker therapy and 39 clinically relevant factors and then stratified by centers to estimate the hazard ratios (HR) of beta-blockers. Subgroup analyses were performed in patients with the preserved left ventricular ejection fraction (LVEF) and low LVEF.

Results

Study Flowchart median follow-up duration: 955 days; inter-quartile range: 693-1248 days

Baseline Clinical Characteristics Age (years) Age >=75 years Male BMI BMI <25.0 Onset-to-balloon time (hours) Onset-to-balloon times 6 hours Door-to-balloon time (hours) Anterior infarction Killip classification I II III IV Hypertension Diabetes mellitus on insulin therapy Current smoking beta group N = 1613 65.8±12.3 416 (26%) 1255 (78%) 23.5 (21.5-25.8) 1105 (69%) 2.4 (1.2-5.0) 987 (70%) 1.5 (1.0-2.2) 850 (53%) 1247 (77%) 133 (8%) 37 (2%) 197 (12%) 1384 (86%) 494 (31%) 58 (4%) 687 (43%) no-beta group N = 2077 68.0±12.1 667 (32%) 1498 (72%) 23.3 (21.3-25.2) 1531 (74%) 2.7 (1.3-5.6) 1237 (67%) 1.5 (1.0-2.2) 955 (46%) 1642 (79%) 168 (8%) 45 (2%) 223 (11%) 1519 (73%) 669 (32%) 93 (4%) 849 (41%) p value 0.001 0.06 0.24 0.53 0.3 0.17 0.29

Baseline Clinical Characteristics Heart failure Shock at presentation Multivessel disease MR grade 3/4 LVEF LVEF 40% Prior myocardial infarction Prior Stroke Peripheral vascular disease egfr <30, not on dialysis Dialysis Atrial fibrillation Anemia (Hb <11.0g/dl) Platelet <100*109/l COPD Liver cirrhosis Malignancy (Continue) beta group N=1613 451 (28%) 234 (15%) 814 (50%) 38 (2%) 52.4±12.6 229 (17%) 139 (9%) 164 (10%) 42 (3%) 51 (3%) 25 (2%) 163 (10%) 135 (8%) 28 (2%) 31 (2%) 44 (3%) 118 (7%) no-beta group N=2077 552 (27%) 271 (13%) 1048 (50%) 53 (3%) 54.3±12.1 222 (14%) 178 (9%) 235 (11%) 80 (4%) 71 (3%) 22 (1%) 171 (8%) 171 (8%) 27 (1%) 93 (4%) 46 (2%) 175 (8%) p value 0.34 0.2 0.99 0.2 0.04 0.95 0.26 0.03 0.66 0.18 0.04 0.88 0.27 0.31 0.21

Baseline Procedural Characteristics DES use Number of target lesions Target of proximal LAD Target of unprotected LMC Target of CTO Target of bifurcation Side-branch stenting Total number of stents Total stent length (mm) Total stent >28mm Minimum stent size (mm) Minimum stent size <3.0mm beta group N=1613 480 (30%) 1 (1-2) 947 (59%) 42 (3%) 51 (3%) 413 (26%) 45 (3%) 1 (1-2) 25 (18-43) 661 (44%) 3 (2.5-3.5) 479 (32%) no-beta group N=2077 613 (30%) 1 (1-1) 1057 (51%) 49 (2%) 58 (3%) 532 (26%) 62 (3%) 1 (1-2) 24 (18-42) 799 (42%) 3 (2.5-3.5) 584 (31%) p value 0.87 0.04 0.63 0.51 0.99 0.72 0.45 0.03 0.2 0.36 0.41

Baseline Medication Antiplatelet therapy Thienopyridine Ticlopidine Clopidogrel Aspirin Cilostazol Other medication Statins ACE-I/ARB Nitrates Calcium channel blockers Nicorandil Warfarin Proton pump inhibitors H2-blockers beta group N=1613 1564 (97%) 1424 (91%) 140 (9%) 1607 (99.6%) 541 (34%) 1033 (64%) 1339 (83%) 421 (26%) 333 (21%) 487 (30%) 237 (15%) 587 (36%) 533 (33%) no-beta group N=2077 1997 (96%) 1837 (92%) 159 (8%) 2063 (99.3%) 770 (37%) 1054 (51%) 1452 (70%) 695 (33%) 431 (21%) 599 (29%) 190 (9%) 695 (33%) 777 (37%) p value 0.18 0.02 0.02 0.21 0.02 0.93 0.37 0.06 0.006

Crude and Adjusted Cumulative Incidence Curves for Cardiac Death/MI among Patients Treated with or without Beta Blockers in the Entire Cohort

Crude and Adjusted Cumulative Incidence Curves for Cardiac Death/MI among Patients Treated with or without Beta Blockers in the Preserved-LVEF subgroup

Crude and Adjusted Cumulative Incidence Curves for Cardiac Death/MI among Patients Treated with or without Beta Blockers in the Low-LVEF subgroup

Discussions

Most of STEMI patients treated with PCI had preserved LVEF and the cardiac event rates after hospital discharge were relatively low. Beta-blocker prescription at discharge was not associated with better clinical outcomes but rather it was associated with worse 3-year cardiovascular outcomes. Trends for worse outcomes in the beta group were consistently seen regardless of LVEF.

Compare to Other Registry the Event Rates were Relatively Low Unadjusted 1-year mortality for patients prescribed beta blocker or not beta group no-beta group p value Cooperative Cardiovascular Project* Nonrevascularization Group 15.4% 29.4% <0.001 Cooperative Cardiovascular Project PTCA Group 4.6% 7.5% <0.001 CREDO-Kyoto AMI registry 3.5% 4.0% 0.18 *The Cooperative Cardiovascular Project (CCP) is a nationwide quality improvement project (quality indicator measurement, feedback, remeasurement) in Medicare AMI patients sponsored by the Health Care Financing Administration. In Maine, New Hampshire, and Vermont, 3,472 baseline records were abstracted from 76 hospitals from January 1994 to February 1995. Chen J, et al. Arch Intern Med. 2000;160(7):947-952.

The Mechanism of the Effects of Beta Blockers in Patients with STEMI Attenuation of the myocardial oxygen demand by decreases in heart rate, blood pressure, and myocardial contractility via an adenosine-dependent mechanism. Asanuma H, et al. Circulation 2004;109:2773-9. Beta blockers are also thought to be effective in reducing tachyarrhythmic events. Vitale C, et al. Angiology. 2010;61(8):763-767. However, the adverse effects of beta blockers such as hypotension, bradycardia, dizziness, depression, drug allergy, and metabolic disorders might overwhelm the benefit of beta blockers in STEMI patients who have undergone PCI and have no residual ischemia. Freemantle N, et al. Br Med J. 1999;318(7200):1730-1737.

Limitations We do not know whether the participants continued beta blockers after discharge. The current study did not have adequate power to assess outcomes in this small subgroup with low LVEF. Selection bias for use of beta blockers is inevitable in this type of observational study.

Conclusions In this large observational cohort study, oral beta-blocker therapy was associated with worse 3-year clinical outcomes in patients with STEMI who have undergone PCI. Large-scale randomized controlled trials are needed to evaluate the role of beta-blocker therapy in STEMI patients who have undergone PCI.

Acknowledgement Kyoto University Hospital Kishiwada City Hospital Tenri Hospital Hyogo Prefectural Amagasaki Hospital Kitano Hospital Koto Memorial Hospital Kokura Memorial Hospital Maizuru Kyosai Hospital Nara Hospital, Kinki University Faculty of Medicine Kobe City Medical Center General Hospital Nishi-Kobe Medical Center Kansai Denryoku Hospital Osaka Red Cross Hospital University of Fukui Hospital Shizuoka City Shizuoka Hospital Hamamatsu Rosai Hospital Shiga University of Medical Science Hospital Japanese Red Cross Wakayama Medical Center Shimabara Hospital Kagoshima University Medica and Dental Hospital Shizuoka General Hospital Kurashiki Central Hospital Mitsubishi Kyoto Hospital Kumamoto University Hospital Shimada Municipal Hospital Juntendo University Shizuoka Hospital