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Suboptimal use of evidence-based medical therapy in patients with acute myocardial infarction from the Korea Acute Myocardial Infarction Registry: Prescription rate, predictors, and prognostic value
Suboptimal use of evidence-based medical therapy in patients with acute myocardial infarction from the Korea Acute Myocardial Infarction Registry: Prescription rate, predictors, and prognostic value Jang Hoon Lee, MD, a Dong Heon Yang, MD, a Hun Sik Park, MD, a Yongkeun Cho, MD, a Myung Ho Jeong, MD, b Young Jo Kim, MD, c Kee-Sik Kim, MD, d Seung Ho Hur, MD, e In Whan Seong, MD, f Taek Jong Hong, MD, g Myeong Chan Cho, MD, h Chong Jin Kim, MD, i Jae-Eun Jun, MD, a Wee-Hyun Park, MD, a and Shung Chull Chae, MD a for the Korea Acute Myocardial Infarction Registry Investigators j Daegu, Gwangju, Daejeon, Pusan, Cheongju, and Seoul, Republic of Korea
Background Only limited data are available for the recent trend of optimal evidence-based medical therapy at discharge after acute myocardial infarction (AMI) in Asia. We evaluated the predictors for the use of optimal evidence-based medical therapy at discharge and the association between discharge medications and 6-month mortality after AMI. Methods Between November 2005 and January 2008, we evaluated the discharge medications among 9,294 post-MI survivors who did not have any documented contraindications to antiplatelet drugs, β-blockers, angiotensin-converting enzyme inhibitors (ACE-Is)/angiotensin II receptor blockers (ARBs), or statins in the Korea Acute Myocardial Infarction Registry. Optimal evidence-based medical therapy was defined as the use of all 4 indicated medications. Results Of these patients, 4,684 (50.4%) received all 4 medications at discharge. The discharge prescription rates of antiplatelet drugs, β-blockers, ACE-Is/ARBs, and statins were 99.0%, 72.7%, 81.5%, and 77.2%, respectively. In multivariate analysis, advanced age, lower systolic blood pressure, higher Killip class at admission, left ventricular systolic dysfunction, higher blood creatinine level, lower total cholesterol levels, and coronary artery bypass grafting during hospitalization were independently associated with less use of optimal evidence-based medical therapy. In contrast, patients who underwent percutaneous coronary intervention were more likely to use optimal medications. In Cox proportional hazards model, optimal evidence-based medical therapy was an independent predictor of 6-month mortality after adjusting clinical characteristics and angiographic and procedural data. Conclusions The optimal evidence-based medical therapy is prescribed at suboptimal rates, particularly in patients with high-risk features. New educational strategies are needed to increase the use of these secondary preventive medical therapies. (Am Heart J 2010;159:1012-9.)
From the aDepartment of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea, bDepartment of Internal Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea, cDepartment of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea, dDepartment of Internal Medicine, Daegu Catholic University Hospital, Daegu, Republic of Korea, eDepartment of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea, fDepartment of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea, gDepartment of Internal Medicine, Pusan National University Hospital, Pusan, Republic of Korea, hDepartment of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea, and iDepartment of Internal Medicine, Kyung Hee University East-West Neo Medical Center, Seoul, Republic of Korea. j A list of participating Korea Acute Myocardial Infarction Registry Investigators can be found in Am J Cardiol 2009;104:182-9. Submitted December 29, 2009; accepted March 4, 2010. Reprint requests: Shung Chull Chae, MD, Department of Internal Medicine, Kyungpook National University Hospital, 50 Samduk 2-Ga, Chung-Ku, Daegu 700-721, Republic of Korea. E-mail: [email protected] 0002-8703/$ - see front matter © 2010, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2010.03.009
The mortality after acute myocardial infarction (AMI) has continued to decline during past 30 years, most recently with the introduction of immediate reperfusion therapy with fibrinolytic and percutaneous coronary intervention (PCI) as well as the introduction of powerful medications for secondary prevention.1 Among the medications for long-term secondary intervention, antiplatelet drugs, β-blockers, angiotensin-converting enzyme inhibitors (ACE-Is)/angiotensin receptor blockers (ARBs), and lipid-lowering drugs (statins) were proven to be highly effective in reducing the risk of cardiovascular morbidity or mortality after AMI.2,3 Furthermore, when prescribed additively, they may be more effective and have synergistic benefits in eligible patients.4,5 Although current guidelines for management of AMI recommend this optimal evidence-based medical therapy
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Table I. Baseline clinical characteristics in patients receiving or not receiving optimal medical therapy at discharge Optimal medical therapy Variable Demographics Age (y) Male Initial presentation Systolic blood pressure (mm Hg) Heart rate (beat/min) ST elevation MI Anterior MI Killip class N1 History Coronary heart disease Hypertension Diabetes mellitus Hyperlipidemia Congestive heart failure Cerebrovascular disease LVEF Laboratory findings Serum creatinine level (mg/dL) Peak creatine kinase MB (ng/mL) Peak cardiac troponin I (ng/mL) Total cholesterol (mg/dL) Triglyceride (mg/dL) High-density lipoprotein cholesterol (mg/dL) Low-density lipoprotein cholesterol (mg/dL) Treatment strategies ST elevation MI Primary PCI Facilitated PCI Thrombolytic therapy Conservative treatment Non-ST elevation MI Early invasive therapy Early conservative therapy PCI at index hospitalization CABG at index hospitalization Coronary angiography findings Coronary artery disease Left main, isolated Left main, complex 1-vessel disease 2-vessel disease 3-vessel disease Infarct-related artery Left main stem Left anterior descending artery Left circumflex artery Right coronary artery Previous medication Antiplatelet drugs β-Blockers ACE-Is/ARBs Statins
Overall (n = 9294)
Yes (n = 4684)
No (n = 4610)
P
63.8 ± 12.5 6170 (72.2%)
62.9 ± 12.3 3414 (72.9%)
64.7 ± 12.7 3296 (71.5%)
b.001 .135
132.7 ± 25.3 78.9 ± 17.6 5556 (59.9%) 4978 (53.6%) 2233 (24.0%)
134.3 ± 25.5 78.6 ± 17.0 2892 (61.8%) 2521 (53.8%) 963 (20.6%)
131.1 ± 25.0 79.2 ± 18.2 2664 (58.0%) 2457 (53.3%) 1270 (27.5%)
b.001 .122 b.001 .612 b.001
1368 (14.8%) 4375 (47.5%) 2408 (26.3%) 897 (11.0%) 145 (1.6%) 530 (5.7%) 51.9 ± 14.2
604 (12.9%) 2246 (48.4%) 1216 (26.3%) 513 (12.4%) 54 (1.2%) 263 (5.6%) 52.4 ± 11.6
764 (16.7%) 2129 (46.7%) 1192 (26.3%) 384 (9.6%) 91 (2.0%) 267 (5.8%) 51.3 ± 16.5
b.001 .110 .934 b.001 .001 .713 b.001
1.00 ± 0.28 145.9 ± 307.0 47.0 ± 136.2 184.3 ± 43.7 127.6 ± 106.1 45.8 ± 20.2 118.6 ± 43.0
0.98 ± 0.27 146.01 ± 292.4 51.3 ± 170.0 188.2 ± 44.2 132.7 ± 117.2 45.9 ± 22.9 122.6 ± 42.2
1.02 ± 0.29 145.8 ± 321.1 42.3 ± 85.4 180.4 ± 42.9 122.2 ± 93.1 45.6 ± 16.9 114.4 ± 43.4
b.001 .972 .004 b.001 b.001 .518 b.001
(81.9%) (9.4%) (2.2%) (6.4%)
2447 (84.6%) 260 (9.0%) 56 (1.9%) 129 (4.5%)
2104 (79.0%) 263 (9.9%) 68 (2.6%) 229 (8.6%)
2848 (76.2%) 890 (23.8%) 7922 (85.3%) 170 (1.8%)
1462 (81.6%) 330 (18.4%) 4169 (89.1%) 37 (0.8%)
1386 (71.2%) 560 (28.8%) 3753 (81.6%) 133 (2.9%)
32 (0.4%) 206 (2.4%) 3669 (43.6%) 2576 (30.6%) 1932 (23.0%)
17 (0.4%) 109 (2.5%) 1933 (44.1%) 1350 (30.8%) 979 (22.3%)
15 (0.4%) 97 (2.4%) 1736 (43.1%) 1226 (30.4%) 953 (23.7%)
158 4183 1418 2654
(1.9%) (49.7%) (16.9%) (31.5%)
78 (1.8%) 2234 (50.8%) 731 (16.6%) 1355 (30.8%)
80 (2.0%) 1949 (48.5%) 687 (17.1%) 1299 (32.4%)
1282 734 884 590
(13.8%) (7.9%) (9.5%) (6.3%)
579 (12.4%) 364 (7.8%) 415 (8.9%) 288 (6.1%)0
703 (15.2%) 370 (8.0%) 469 (10.2%) 302 (6.6%)
b.001 4551 523 124 358
b.001
b.001 b.001 .692
.207
b.001 .649 .031 .426
Data are expressed as mean ± SD or number (percentage). LVEF, Left ventricular ejection fraction; MI, Myocardial infarction; PCI, Percutaneous coronary intervention; CABG, Coronary artery bypass graft; ACE-I, Angiotensin converting enzyme inhibitor; ARB, Angiotensin receptor blocker.
(OMT) for secondary prevention in patients with AMI,2,3 several previous studies have demonstrated that these drugs are underused for secondary prevention in Western countries.4-10 In Asia, however, only limited
data are available for the recent trend of OMT at discharge after AMI.11 Accordingly, we used data from the Korea AMI Registry (KAMIR) to determine the predictors for OMT at
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Figure 1
Figure 2
Use of each medication at discharge in overall patients and in patients not receiving optimal medical therapy (OMT). APA, Antiplatelet agents. Other abbreviations are as in Table I.
discharge and the association between the use of OMT and 6-month mortality after AMI.
Materials and methods Study design and patient population KAMIR is a Korean, prospective, open, observational, multicenter online registry of AMI with support of Korean Society of Cardiology (KSC) since November 2005. The 50 participating hospitals are capable of primary PCI. Details of the KAMIR have been published.12 Between November 2005 and January 2008, 14,871 patients suspected to have AMI at admission were enrolled in the KAMIR and 11,942 patients with a final diagnosis of AMI were analyzed in this study. Of these patients, baseline clinical data including age, sex, and medications at discharge were available in 10,909 patients. The in-hospital mortality was 4.7% (n = 517); thus, 10,392 patients with AMI survived to hospital discharge. The AMI was diagnosed by characteristic clinical presentation, serial changes on the electrocardiogram suggesting infarction or injury, and increase in cardiac enzymes.13 We analyzed baseline clinical characteristics, angiographic findings, procedural data, and discharge medications in hospital survivors.
Medication use We considered all patients to be eligible for antiplatelet/ anticoagulant therapy, unless they had a history of lifethreatening bleeding, coagulopathy, or thrombocytopenia. We defined contraindications to β-receptor blockers as significant bradycardia (heart rate b50 beat/min) or hypotension (systolic blood pressure b90 mm Hg). Contraindications to ACE-Is/ARBs were hypotension and severe renal dysfunction (serum creatinine level N2.5 mg/dL in men or N2.0 mg/dL in women). We considered all patients with AMI to be eligible for statins. In the present study, we excluded 1,098 patients (10.6%) with any
Use of each medication at discharge according to (A) age, (B) PCI, and (C) CABG. Abbreviations are as in Table I and Figure 1.
documented contraindications to antiplatelet/anticoagulant therapy, β-receptor blockers, or ACE-Is/ARBs. The contraindications to these medications are 568 hypotension (5.5%), 532 significant bradycardia (5.1%), 497 severe renal dysfunction (4.8%), and 41 major bleeding (0.4%). Therefore, the study
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Table II. Multivariate logistic regression analysis for predicting OMT at discharge OR (95% CI)
P
0.840 (0.756-0.934) 1.005 (1.003-1.007)
.001 b.001
1.046 0.771 0.890 0.850 0.806 0.717
(0.939-1.165) (0.684-0.869) (0.767-1.031) (0.566-1.278) (0.702-0.925) (0.600-0.857)
.414 b.001 .121 .435 .002 b.001
1.001 (1.000-1.001)
.059
1.003 (1.002-1.004)
b.001
1.390 (1.198-1.614) 0.281 (0.171-0.463)
b.001 b.001
Variable Age ≥70 Systolic blood pressure, per 1 mm Hg increase ST-segment elevation MI Killip class N1 at admission Previous coronary heart disease Previous congestive heart failure LVEF b40% Serum creatinine, per 1 mg/dL increase Peak cardiac troponin I, per 1 ng/mL increase Total cholesterol, per 1 mg/dL increase PCI at index hospitalization CABG at index hospitalization
Abbreviations are as in Table I and Figure 1.
cohort consisted of 9,294 patients with AMI who survived to hospital discharge. Mean follow-up duration was 180 ± 35 days. The primary endpoint was 6-month mortality including cardiac death and noncardiac death. Cardiac death was defined as death from pump failure, arrhythmia, or mechanical complications including ventricular septal rupture and free wall rupture. During the followup period, follow-up data were obtained by reviewing medical records and telephone interview with patients. All data were recorded on an electronic Web page-based case report form.
Statistical analyses Data are expressed as mean ± SD for continuous variables and percentages for categorical variables. All comparisons between baseline variables were assessed with the Student t test for continuous variables and the Pearson χ2 test for categorical variables. Univariate analyses were performed to determine the clinical predictors of OMT defined as the use of all 4 indicated discharge medications, an antiplatelet drug, a β-receptor blocker, and a statin, plus an ACE-I/ARB, and the prognostic significance of clinical variables for 6-month mortality among hospital survivors. Variables with P values of b.05 on univariate analysis were entered into multivariate logistic regression model and Cox proportional hazards model. A multivariate logistic regression model was used to determine independent predictors of OMT among hospital survivors. Cox proportional hazards model was used to determine independent predictors of 6-month mortality. Mortality rates according to the number of discharge medication were compared with a 2-sided log-rank test and were plotted with cumulative Kaplan-Meier survival curve. For all analyses, a 2-sided P b .05 was considered statistically significant. Statistical analysis was performed using SPSS version 15.0 for Windows (SPSS Inc, Chicago, IL). This study was carried out with the support of the KSC in the memorandum of the 50th anniversary of the KSC. The authors are solely responsible for the design and conduct of this study,
Table III. Univariate analysis for 6-month mortality Death
Variable
No (n = 8584)
Yes (n = 115)
Age ≥70 4079 (35.6%) 93 (67.0%) Male 6311 (72.2%) 80 (69.0%) Initial presentation Systolic blood pressure 132.7 ± 25.3 129.9 ± 25.1 (mm Hg) Heart rate (beat/min) 78.6 ± 17.4 88.4 ± 21.4 ST elevation MI 5165 (60.3%) 64 (55.7%) Anterior MI 4364 (50.9%) 89 (77.4%) Killip class N1 2003 (23.3%) 58 (50.4%) History Coronary heart disease 1243 (14.5%) 27 (23.7%) Hypertension 4023 (47.3%) 68 (60.2%) Diabetes mellitus 2213 (26.1%) 42 (37.2%) Hyperlipidemia 834 (11.1%) 8 (8.0%) Current smoker 3865 (45.4%) 45 (40.2%) Previous congestive 128 (1.5%) 3 (2.6%) heart failure Previous Cerebrovascular 484 (5.6%) 9 (7.8%) disease LVEF b40% 1376 (17.3%) 57 (52.8%) Laboratory findings Serum creatinine level 1.00 ± 0.28 1.17 ± 0.37 (mg/dL) Peak creatine kinase 148.5 ± 315.4 103.6 ± 149.9 MB (ng/mL) Peak cardiac troponin I 47.4 ± 139.7 46.9 ± 83.7 (ng/mL) Total cholesterol (mg/dL) 184.7 ± 43.7 174.6 ± 45.8 Triglyceride (mg/dL) 128.5 ± 105.7 107.1 ± 57.5 High-density lipoprotein 45.8 ± 20.5 44.6 ± 11.8 cholesterol (mg/dL) Low-density lipoprotein 119.0 ± 43.0 109.0 ± 36.3 cholesterol (mg/dL) Treatment strategies PCI at index hospitalization 7355 (85.8%) 78 (67.8%) CABG at index 166 (1.9%) 0 (0.0%) hospitalization Thrombolytic therapy 418 (8.3%) 7 (8.6%) Conservative treatment 973 (11.3%) 34 (29.6%) Coronary angiography findings Coronary artery disease Left main, isolated 26 (0.3%) 1 (1.1%) Left main, complex 184 (2.3%) 2 (2.2%) 1-vessel disease 3500 (44.5%) 22 (23.9%) 2-vessel disease 2400 (30.5%) 34 (37.0%) 3-vessel disease 1753 (22.3%) 33 (35.9%) Infarct-related artery Left main stem 140 (1.8%) 2 (2.2%) Left anterior 3867 (49.5%) 57 (62.0%) descending artery Left circumflex artery 1332 (17.1%) 10 (10.9%) Right coronary artery 2472 (31.6%) 23 (25.0%) Discharge medication Antiplatelet drugs 8498 (99.4%) 113 (98.3%) β-Blockers 6259 (72.9%) 64 (55.7%) ACE-Is/ARBs 7031 (81.9%) 89 (77.4%) Statins 6624 (77.2%) 81 (70.4%) OMT 4346 (50.6%) 40 (34.8%)
P b.001 .442 .252 b.001 .316 b.001 b.001 .006 .006 .008 .325 .271 .328 .313 b.001 b.001 .132 .972 .016 b.001 .541 .021
b.001 .131 .916 b.001
.215 .916 b.001 .183 .002 .784 .018 .116 .173 .105 b.001 .212 .088 .001
Data are expressed as mean ± SD or number (percentage). Abbreviations are as in Table I and Figure 1.
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all study analyses, the drafting and editing of the paper and its final contents.
Figure 3
Results The baseline characteristics of the overall study patients are shown in Table I. The mean age was 63.8 ± 12.5 years old, and 6,170 patients (72.2%) were men. Of the 9,294 patients with AMI, 326 (3.5%), 4,284 (46.1%), and 4,684 (50.4%) patients were discharged on b2 drugs, 2 to 3 drugs, and all 4 indicated drugs, respectively. The discharge prescription rates of antiplatelet agents, βreceptor blockers, ACE-Is/ARBs, and statins were 99.0%, 72.7%, 81.5%, and 77.2%, respectively (Figure 1). In patients not receiving OMT, the discharge prescription rates of antiplatelet agents, β-receptor blockers, ACE-Is/ ARBs, and statins were 97.9%, 44.9%, 62.8%, and 54.0%, respectively. The prescription rate of OMT, particularly βblockers and statins was significantly lower in the older patients (Figure 2, A). The discharge prescription rates of the OMT were significantly higher in patients who underwent PCI (P b .001), whereas those were significantly lower in patients who underwent coronary artery bypass grafting (CABG) (P b .001) (Figure 2, B and C). In multivariate logistic regression analysis, age ≥70 (odds ratio [OR] 0.840, 95% confidence interval [CI] 0.756-0.934, P = .001), systolic blood pressure (OR 1.005, 95% CI 1.003-1.007, P b .001), Killip class N1 (OR 0.771, 95% CI 0.684-0.869, P b .001), left ventricular injection fraction (LVEF) b40% (OR 0.806, 95% CI 0.702-0.925, P = .002), serum creatinine levels (OR 0.717, 95% CI 0.6000.857, P b .001), serum total cholesterol levels (OR 1.003, 95% CI 1.002-1.004, P b .001), PCI at index hospitalization (OR 1.390, 95% CI 1.198-1.614, P b .001), and CABG at index hospitalization (OR 0.281, 95% CI 0.171-0.463, P b .001) were independent predictors of OMT at discharge after adjusting baseline clinical characteristics (Table II). At 6 months after the index admission, 595 patients (6.4%) were lost to follow-up. There were no significant differences in baseline characteristics for risk stratification (GRACE score) and the use of OMT at discharge between the groups with and without 6-month follow-up data. During the follow-up period, there were 115 allcause death (1.3%) including 77 cardiac deaths (0.9%) and 38 noncardiac (0.4%) deaths. In univariate analysis, age ≥70, mean heart rate, anterior MI, Killip class N1, previous coronary heart disease, hypertension, diabetes mellitus, LVEF, serum creatinine level, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels were significantly associated with the risk of 6month death (Table III). The proportion of patients who underwent PCI was significantly lower in dead group (P b .001). In Kaplan-Meier survival curve, mortality rates differed significantly according to the number of discharge medication (0 or 1 drugs 3.4%, 2 or 3 drugs 1.6%, all 4 drugs 0.9%, P b .001) (Figure 3).
Kaplan-Meier survival curve showing 6-month mortality of the 3 patient groups.
In Cox proportional hazards model, OMT (hazards ratio 0.340, 95% CI 0.162-0.714, P = .004) in addition to age ≥70, heart rate, anterior MI, Killip class N1 at admission, LVEF b40%, and serum creatinine levels were independent predictors of 6-month mortality after adjusting baseline clinical characteristics in model 1 (Table IV). In model 2, OMT (hazards ratio 0.394, 95% CI 0.161-0.963, P = .041) in addition to age ≥70, anterior MI, Killip class N1 at admission, LVEF b40%, serum creatinine levels, and multivessel disease were also strong independent predictors of 6-month mortality after adjusting angiographic and procedural data in addition to clinical characteristics.
Discussion Medications such as antiplatelet drugs, β-blockers, ACE-Is/ARBs, and statins have been associated with significantly improved outcomes in patients presenting with AMI regardless of the geographic location.2,3 In the present study, even with the evidence of benefit, the prescription rates in eligible patients varied from 99% for use of antiplatelet drugs at discharge to 73% for βblockers at discharge in overall patients. Only half of the eligible patients received OMT at discharge. Our results suggest that recommended cardiac drugs are prescribed at suboptimal rates. Numerous studies from Western countries have reported underuse of proven medical therapies at discharge.4-10 However, little is known about the pattern of discharge medications in Asian population.13 Of the 4 drug classes, the prescription rates of βblockers and statins were particularly lower in our study compared with previous studies from Western countries. The lower prescription rates of β-blockers may be
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Table IV. Cox proportional hazards model for predicting 6-month mortality Model 1⁎
Variable Discharge medication 0 or 1 medication 2 or 3 medications OMT Age ≥70 Heart rate, per 10 beat/min increase Anterior MI Killip class N1 at admission Previous coronary heart disease Hypertension Diabetes mellitus LVEF b40% Serum creatinine level, per 1 mg/dL increase Total cholesterol ≥220 mg/dL PCI at index hospitalization Left anterior descending artery disease Multivessel disease
Model 2†
Hazards ratio (95% CI)
P
Hazards ratio (95% CI)
P
Reference 0.459 (0.225-0.938) 0.340 (0.162-0.714) 2.363 (1.529-3.652) 1.105 (1.008-1.211) 2.642 (1.643-4.251) 1.786 (1.170-2.725) 0.730 (0.456-1.170) 1.206 (0.792-1.836) 1.181 (0.767-1.817) 2.556 (1.661-3.932) 2.014 (1.145-3.542)
.033 .004 b.001 .033 b.001 .007 .192 .382 .450 b.001 .015
Reference 0.488 (0.205-1.165) 0.394 (0.161-0.963) 1.913 (1.185-3.088) 1.046 (0.930-1.178) 3.669 (1.971-6.831) 1.888 (1.172-3.041) 0.648 (0.382-1.100) 1.043 (0.654-1.665) 1.141 (0.703-1.850) 2.676 (1.643-4.360) 2.693 (1.409-5.147)
.106 .041 .008 .452 b.001 .009 .108 .859 .593 b.001 .003
0.764 (0.426-1.370)
.367
0.958 0.865 0.960 2.006
.892 .656 .877 .016
(0.514-1.786) (0.457-1.637) (0.571-1.612) (1.139-3.532)
⁎ Model 1 was adjusted for clinical characteristics. † Model 2 was adjusted for clinical characteristics, angiographic findings, and procedural data. Abbreviations are as in Table I and Figure 1.
related to racial differences. It has been known that the incidence of coronary artery spasm was relatively high in Asian population.14 These studies may have influenced on deciding discharge medication. The lower prescription rate of statin in our study may be related to unique National Health Insurance system in Korea. Among OMT, antiplatelet drugs, β-blockers, and ACE-Is/ARBs are routinely reimbursed in post-MI patients. However, the prescription of statin is reimbursed only in patients with a certain level of total cholesterol irrespective of underlying disease, even in patients with AMI. These results suggest that demographic or socioeconomic characteristics may be associated with the pattern of medication use at discharge. Previous studies have reported the determinants of an individual medication at discharge after AMI.5,6,15,16 Advanced age, female sex, hypertension, heart failure, renal dysfunction, presence of an initial non–Q-wave MI, development of atrial fibrillation during hospitalization, and CABG during hospitalization were independently associated with underuse of OMT. Conversely, history of dyslipidemia, presence of ST elevation and positive cardiac biomarkers, previous MI, previous PCI, and cardiology care at admission were significantly associated with use of OMT. In the present study, we also found these “OMT paradox” in the use of OMT at discharge in post-MI survivors. Although current guidelines for management of AMI recommend targeting medical therapies and invasive procedures for patients with high-risk features including signs of congestive heart failure, lower LVEF, renal insufficiency, and/or hemodynamic instability,2,3 these high-risk features were associated
with less use of medical therapies and procedures in this analysis. In general, high-risk clinical characteristics are clustered together, and general conditions of these patients are poor, so physicians may have been more reluctant to prescribe aggressive medical therapies and perform invasive procedures.16 Contemporary adherence to current guidelines for management of AMI appears to be strongly influenced by patient risk status.16,17 During the acute phase of MI, patients with high-risk features are more likely to have an adverse outcome and to have complications associated with medications. Thus, it is difficult to balance the risks and benefits of medical therapies and invasive procedures in short-term management of AMI. Compared with shortterm management of AMI, discharge medications may not be influenced by these safety concerns because invasive procedures have been completed and complications associated with medications are less prominent. However, persistent undertreatment of high-risk patients in the absence of known contraindications at discharge explains that these high-risk features may have influenced on discharge medication decision making. Although there have been conflicting data regarding the interaction between advanced age and OMT at discharge,5,15,18-20 advanced age was independently associated with the less use of OMT in our study. Although recent emerging evidence suggests that older patients can get a similar benefits from aggressive cardiac therapy and the absolute benefit-risk ratio is expected to be even more favorable among elderly “ideal candidates,”21-23 clinicians are usually reluctant to prescribe aggressive medical therapies to older patients because
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advance age may be associated with an increased prevalence of comorbidities and higher incidence of adverse drug effects. There was a strong positive relationship between PCI and the use of OMT at discharge in our study. Similar findings have been reported in previous observation studies examining treatment patterns in patients hospitalized for AMI.5,15,16,24 Patients who underwent PCI are more likely to receive aggressive medical therapies because patients deemed to be poor candidates for a procedure are often denied appropriate medical therapy as well. Coronary angiographic findings such as the location of culprit artery and the number of diseased vessels was not associated the use of OMT. Interestingly, there was a strong inverse relationship between inhospital CABG and OMT at discharge. Other studies have also demonstrated that patients who underwent inhospital CABG are less likely to receive aggressive medical therapies.8,9 This may be related to less recognition of the vital importance of OMT after revascularization among surgical care teams. In the present study, we demonstrated that OMT at discharge was independently associated with improved 6month mortality in patients with AMI. The 6-month mortality decreased progressively with increasing the number of indicated medications. In patients receiving OMT, there was a 68% reduction in mortality after adjustment for clinical characteristics. Furthermore, adjustment for clinical, angiographic, and procedural data did not significantly attenuate the strength of this association. There was a 61% reduction in mortality after adjustment for these compounding variables. Recent studies also have demonstrated that OMT at discharge leads to the relative reduction in 6-month mortality in patients with AMI.4,5
Study limitations There are several potential limitations of our study. First, we were unable to record the reasons for nonprescription of certain medications and details about medication doses. We were also unable to accurately exclude patients with contraindications from our analyses. If patients had previously experienced adverse reactions to specific medications, which were not documented, these patients might be included in our study. Consequently, we may have underestimated the prescription rates for the 4 drug classes studied. Second, we were unable to examine longterm adherence to specific medications prescribed at the time of hospital discharge. Finally, we were unable to control unmeasured factors such as the high cost of longterm medications, which may have influenced on discharge medication use in this observational study. Despite the limitations of our study, this should not undermine our assessment of discharge medication use among hospital survivors.
Conclusion This study provides useful information on the pattern of discharge medication use and clinical outcome at 6 months in patients receiving OMT in Asian populations. Despite strong benefits of recommended cardiac drugs, these pharmacologic agents are prescribed at suboptimal rates, particularly in patients with high-risk features who may derive the greater therapeutic benefits. New educational strategies and initiatives are needed to increase the use of these secondary preventive medical therapies in this area of world.
References 1. Tunstall-Pedoe H, Vanuzzo D, Hobbs M, et al. Estimation of contribution of changes in coronary care to improving survival, event rates, and coronary heart disease mortality across the WHO MONICA Project populations. Lancet 2000;355:688-700. 2. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/nonST elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148-e304. 3. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 2008;117:296-329. 4. Mukherjee D, Fang J, Chetcuti S, et al. Impact of combination evidence-based medical therapy on mortality in patients with acute coronary syndromes. Circulation 2004;109:745-9. 5. Yan AT, Yan RT, Tan M, et al. Optimal medical therapy at discharge in patients with acute coronary syndromes: temporal changes, characteristics, and 1-year outcome. Am Heart J 2007;154: 1108-15. 6. Granger CB, Steg PG, Peterson E, et al. Medication performance measures and mortality following acute coronary syndromes. Am J Med 2005;118:858-65. 7. Krumholz HM, Radford MJ, Ellerbeck EF, et al. Aspirin for secondary prevention after acute myocardial infarction in the elderly: prescribed use and outcomes. Ann Intern Med 1996;124:292-8. 8. Allison JJ, Kiefe CI, Weissman NW, et al. Relationship of hospital teaching status with quality of care and mortality for medicare patients with acute MI. JAMA 2000;284:1256-62. 9. Burwen DR, Galusha DH, Lewis JM, et al. National and state trends in quality of care for acute myocardial infarction between 1994-1995 and 1998-1999: the Medicare health care quality improvement program. Arch Intern Med 2003;163:1430-9.
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10. Chen J, Radford MJ, Wang Y, et al. Do “America's best hospitals” perform better for acute myocardial infarction? N Engl J Med 1999; 340:286-92. 11. Kohro T, Hayashi D, Okada Y, et al. Effects of medication on cardiovascular events in the Japanese coronary artery disease (JCAD) study. Circ J 2007;71:1835-40. 12. Lee JH, Park HS, Chae SC, et al. Predictors of six-month major adverse cardiac events in 30-day survivors after acute myocardial infarction (from the Korea Acute Myocardial Infarction Registry). Am J Cardiol 2009;104:182-9. 13. Alpert JS, Thygesen K, Antman E, et al. Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36: 959-69. 14. Pristipino C, Beltrame JF, Finocchiaro ML, et al. Major racial differences in coronary constrictor response between japanese and caucasians with recent myocardial infarction. Circulation 2000;101: 1102-8. 15. Spencer FA, Lessard D, Yarzebski J, et al. Decade-long changes in the use of combination evidence-based medical therapy at discharge for patients surviving acute myocardial infarction. Am Heart J 2005;150: 838-44. 16. Roe MT, Peterson ED, Newby LK, et al. The influence of risk status on guideline adherence for patients with non–ST-segment elevation acute coronary syndromes. Am Heart J 2006;151:1205-13. 17. Alexander KP, Roe MT, Chen AY, et al. Evolution in cardiovascular care for elderly patients with non–ST-segment elevation
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18.
19.
20.
21.
22.
23.
24.
acute coronary syndromes: results from the CRUSADE National Quality Improvement Initiative. J Am Coll Cardiol 2005;46: 1479-87. Yan RT, Yan AT, Tan M, et al. Age-related differences in the management and outcome of patients with acute coronary syndromes. Am Heart J 2006;151:352-9. Simpson E, Beck C, Richard H, et al. Drug prescriptions after acute myocardial infarction: dosage, compliance, and persistence. Am Heart J 2003;145:438-44. Rathore SS, Mehta RH, Wang Y, et al. Effects of age on the quality of care provided to older patients with acute myocardial infarction. Am J Med 2003;114:307-15. Krumholz HM, Radford MJ, Wang Y, et al. National use and effectiveness of beta-blockers for the treatment of elderly patients after acute myocardial infarction: National Cooperative Cardiovascular Project. JAMA 1998;280:623-9. Ray KK, Bach RG, Cannon CP, et al. Benefits of achieving the NCEP optional LDL-C goal among elderly patients with ACS. Eur Heart J 2006;27:2310-6. Shepherd J, Blauw GJ, Murphy MB, et al. PROspective Study of Pravastatin in the Elderly at Risk. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360: 1623-30. Bhatt DL, Roe MT, Peterson ED, et al. Utilization of early invasive management strategies for high-risk patients with non–ST-segment elevation acute coronary syndromes (results from the CRUSADE quality improvement initiative). JAMA 2004;292:2096-104.
Background Only limited data are available for the recent trend of optimal evidence-based medical therapy at discharge after acute myocardial infarction (AMI) in Asia. We evaluated the predictors for the use of optimal evidence-based medical therapy at discharge and the association between discharge medications and 6-month mortality after AMI. Methods Between November 2005 and January 2008, we evaluated the discharge medications among 9,294 post-MI survivors who did not have any documented contraindications to antiplatelet drugs, β-blockers, angiotensin-converting enzyme inhibitors (ACE-Is)/angiotensin II receptor blockers (ARBs), or statins in the Korea Acute Myocardial Infarction Registry. Optimal evidence-based medical therapy was defined as the use of all 4 indicated medications. Results Of these patients, 4,684 (50.4%) received all 4 medications at discharge. The discharge prescription rates of antiplatelet drugs, β-blockers, ACE-Is/ARBs, and statins were 99.0%, 72.7%, 81.5%, and 77.2%, respectively. In multivariate analysis, advanced age, lower systolic blood pressure, higher Killip class at admission, left ventricular systolic dysfunction, higher blood creatinine level, lower total cholesterol levels, and coronary artery bypass grafting during hospitalization were independently associated with less use of optimal evidence-based medical therapy. In contrast, patients who underwent percutaneous coronary intervention were more likely to use optimal medications. In Cox proportional hazards model, optimal evidence-based medical therapy was an independent predictor of 6-month mortality after adjusting clinical characteristics and angiographic and procedural data. Conclusions The optimal evidence-based medical therapy is prescribed at suboptimal rates, particularly in patients with high-risk features. New educational strategies are needed to increase the use of these secondary preventive medical therapies. (Am Heart J 2010;159:1012-9.)
From the aDepartment of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea, bDepartment of Internal Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea, cDepartment of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea, dDepartment of Internal Medicine, Daegu Catholic University Hospital, Daegu, Republic of Korea, eDepartment of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea, fDepartment of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea, gDepartment of Internal Medicine, Pusan National University Hospital, Pusan, Republic of Korea, hDepartment of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea, and iDepartment of Internal Medicine, Kyung Hee University East-West Neo Medical Center, Seoul, Republic of Korea. j A list of participating Korea Acute Myocardial Infarction Registry Investigators can be found in Am J Cardiol 2009;104:182-9. Submitted December 29, 2009; accepted March 4, 2010. Reprint requests: Shung Chull Chae, MD, Department of Internal Medicine, Kyungpook National University Hospital, 50 Samduk 2-Ga, Chung-Ku, Daegu 700-721, Republic of Korea. E-mail: [email protected] 0002-8703/$ - see front matter © 2010, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2010.03.009
The mortality after acute myocardial infarction (AMI) has continued to decline during past 30 years, most recently with the introduction of immediate reperfusion therapy with fibrinolytic and percutaneous coronary intervention (PCI) as well as the introduction of powerful medications for secondary prevention.1 Among the medications for long-term secondary intervention, antiplatelet drugs, β-blockers, angiotensin-converting enzyme inhibitors (ACE-Is)/angiotensin receptor blockers (ARBs), and lipid-lowering drugs (statins) were proven to be highly effective in reducing the risk of cardiovascular morbidity or mortality after AMI.2,3 Furthermore, when prescribed additively, they may be more effective and have synergistic benefits in eligible patients.4,5 Although current guidelines for management of AMI recommend this optimal evidence-based medical therapy
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Table I. Baseline clinical characteristics in patients receiving or not receiving optimal medical therapy at discharge Optimal medical therapy Variable Demographics Age (y) Male Initial presentation Systolic blood pressure (mm Hg) Heart rate (beat/min) ST elevation MI Anterior MI Killip class N1 History Coronary heart disease Hypertension Diabetes mellitus Hyperlipidemia Congestive heart failure Cerebrovascular disease LVEF Laboratory findings Serum creatinine level (mg/dL) Peak creatine kinase MB (ng/mL) Peak cardiac troponin I (ng/mL) Total cholesterol (mg/dL) Triglyceride (mg/dL) High-density lipoprotein cholesterol (mg/dL) Low-density lipoprotein cholesterol (mg/dL) Treatment strategies ST elevation MI Primary PCI Facilitated PCI Thrombolytic therapy Conservative treatment Non-ST elevation MI Early invasive therapy Early conservative therapy PCI at index hospitalization CABG at index hospitalization Coronary angiography findings Coronary artery disease Left main, isolated Left main, complex 1-vessel disease 2-vessel disease 3-vessel disease Infarct-related artery Left main stem Left anterior descending artery Left circumflex artery Right coronary artery Previous medication Antiplatelet drugs β-Blockers ACE-Is/ARBs Statins
Overall (n = 9294)
Yes (n = 4684)
No (n = 4610)
P
63.8 ± 12.5 6170 (72.2%)
62.9 ± 12.3 3414 (72.9%)
64.7 ± 12.7 3296 (71.5%)
b.001 .135
132.7 ± 25.3 78.9 ± 17.6 5556 (59.9%) 4978 (53.6%) 2233 (24.0%)
134.3 ± 25.5 78.6 ± 17.0 2892 (61.8%) 2521 (53.8%) 963 (20.6%)
131.1 ± 25.0 79.2 ± 18.2 2664 (58.0%) 2457 (53.3%) 1270 (27.5%)
b.001 .122 b.001 .612 b.001
1368 (14.8%) 4375 (47.5%) 2408 (26.3%) 897 (11.0%) 145 (1.6%) 530 (5.7%) 51.9 ± 14.2
604 (12.9%) 2246 (48.4%) 1216 (26.3%) 513 (12.4%) 54 (1.2%) 263 (5.6%) 52.4 ± 11.6
764 (16.7%) 2129 (46.7%) 1192 (26.3%) 384 (9.6%) 91 (2.0%) 267 (5.8%) 51.3 ± 16.5
b.001 .110 .934 b.001 .001 .713 b.001
1.00 ± 0.28 145.9 ± 307.0 47.0 ± 136.2 184.3 ± 43.7 127.6 ± 106.1 45.8 ± 20.2 118.6 ± 43.0
0.98 ± 0.27 146.01 ± 292.4 51.3 ± 170.0 188.2 ± 44.2 132.7 ± 117.2 45.9 ± 22.9 122.6 ± 42.2
1.02 ± 0.29 145.8 ± 321.1 42.3 ± 85.4 180.4 ± 42.9 122.2 ± 93.1 45.6 ± 16.9 114.4 ± 43.4
b.001 .972 .004 b.001 b.001 .518 b.001
(81.9%) (9.4%) (2.2%) (6.4%)
2447 (84.6%) 260 (9.0%) 56 (1.9%) 129 (4.5%)
2104 (79.0%) 263 (9.9%) 68 (2.6%) 229 (8.6%)
2848 (76.2%) 890 (23.8%) 7922 (85.3%) 170 (1.8%)
1462 (81.6%) 330 (18.4%) 4169 (89.1%) 37 (0.8%)
1386 (71.2%) 560 (28.8%) 3753 (81.6%) 133 (2.9%)
32 (0.4%) 206 (2.4%) 3669 (43.6%) 2576 (30.6%) 1932 (23.0%)
17 (0.4%) 109 (2.5%) 1933 (44.1%) 1350 (30.8%) 979 (22.3%)
15 (0.4%) 97 (2.4%) 1736 (43.1%) 1226 (30.4%) 953 (23.7%)
158 4183 1418 2654
(1.9%) (49.7%) (16.9%) (31.5%)
78 (1.8%) 2234 (50.8%) 731 (16.6%) 1355 (30.8%)
80 (2.0%) 1949 (48.5%) 687 (17.1%) 1299 (32.4%)
1282 734 884 590
(13.8%) (7.9%) (9.5%) (6.3%)
579 (12.4%) 364 (7.8%) 415 (8.9%) 288 (6.1%)0
703 (15.2%) 370 (8.0%) 469 (10.2%) 302 (6.6%)
b.001 4551 523 124 358
b.001
b.001 b.001 .692
.207
b.001 .649 .031 .426
Data are expressed as mean ± SD or number (percentage). LVEF, Left ventricular ejection fraction; MI, Myocardial infarction; PCI, Percutaneous coronary intervention; CABG, Coronary artery bypass graft; ACE-I, Angiotensin converting enzyme inhibitor; ARB, Angiotensin receptor blocker.
(OMT) for secondary prevention in patients with AMI,2,3 several previous studies have demonstrated that these drugs are underused for secondary prevention in Western countries.4-10 In Asia, however, only limited
data are available for the recent trend of OMT at discharge after AMI.11 Accordingly, we used data from the Korea AMI Registry (KAMIR) to determine the predictors for OMT at
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Figure 1
Figure 2
Use of each medication at discharge in overall patients and in patients not receiving optimal medical therapy (OMT). APA, Antiplatelet agents. Other abbreviations are as in Table I.
discharge and the association between the use of OMT and 6-month mortality after AMI.
Materials and methods Study design and patient population KAMIR is a Korean, prospective, open, observational, multicenter online registry of AMI with support of Korean Society of Cardiology (KSC) since November 2005. The 50 participating hospitals are capable of primary PCI. Details of the KAMIR have been published.12 Between November 2005 and January 2008, 14,871 patients suspected to have AMI at admission were enrolled in the KAMIR and 11,942 patients with a final diagnosis of AMI were analyzed in this study. Of these patients, baseline clinical data including age, sex, and medications at discharge were available in 10,909 patients. The in-hospital mortality was 4.7% (n = 517); thus, 10,392 patients with AMI survived to hospital discharge. The AMI was diagnosed by characteristic clinical presentation, serial changes on the electrocardiogram suggesting infarction or injury, and increase in cardiac enzymes.13 We analyzed baseline clinical characteristics, angiographic findings, procedural data, and discharge medications in hospital survivors.
Medication use We considered all patients to be eligible for antiplatelet/ anticoagulant therapy, unless they had a history of lifethreatening bleeding, coagulopathy, or thrombocytopenia. We defined contraindications to β-receptor blockers as significant bradycardia (heart rate b50 beat/min) or hypotension (systolic blood pressure b90 mm Hg). Contraindications to ACE-Is/ARBs were hypotension and severe renal dysfunction (serum creatinine level N2.5 mg/dL in men or N2.0 mg/dL in women). We considered all patients with AMI to be eligible for statins. In the present study, we excluded 1,098 patients (10.6%) with any
Use of each medication at discharge according to (A) age, (B) PCI, and (C) CABG. Abbreviations are as in Table I and Figure 1.
documented contraindications to antiplatelet/anticoagulant therapy, β-receptor blockers, or ACE-Is/ARBs. The contraindications to these medications are 568 hypotension (5.5%), 532 significant bradycardia (5.1%), 497 severe renal dysfunction (4.8%), and 41 major bleeding (0.4%). Therefore, the study
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Table II. Multivariate logistic regression analysis for predicting OMT at discharge OR (95% CI)
P
0.840 (0.756-0.934) 1.005 (1.003-1.007)
.001 b.001
1.046 0.771 0.890 0.850 0.806 0.717
(0.939-1.165) (0.684-0.869) (0.767-1.031) (0.566-1.278) (0.702-0.925) (0.600-0.857)
.414 b.001 .121 .435 .002 b.001
1.001 (1.000-1.001)
.059
1.003 (1.002-1.004)
b.001
1.390 (1.198-1.614) 0.281 (0.171-0.463)
b.001 b.001
Variable Age ≥70 Systolic blood pressure, per 1 mm Hg increase ST-segment elevation MI Killip class N1 at admission Previous coronary heart disease Previous congestive heart failure LVEF b40% Serum creatinine, per 1 mg/dL increase Peak cardiac troponin I, per 1 ng/mL increase Total cholesterol, per 1 mg/dL increase PCI at index hospitalization CABG at index hospitalization
Abbreviations are as in Table I and Figure 1.
cohort consisted of 9,294 patients with AMI who survived to hospital discharge. Mean follow-up duration was 180 ± 35 days. The primary endpoint was 6-month mortality including cardiac death and noncardiac death. Cardiac death was defined as death from pump failure, arrhythmia, or mechanical complications including ventricular septal rupture and free wall rupture. During the followup period, follow-up data were obtained by reviewing medical records and telephone interview with patients. All data were recorded on an electronic Web page-based case report form.
Statistical analyses Data are expressed as mean ± SD for continuous variables and percentages for categorical variables. All comparisons between baseline variables were assessed with the Student t test for continuous variables and the Pearson χ2 test for categorical variables. Univariate analyses were performed to determine the clinical predictors of OMT defined as the use of all 4 indicated discharge medications, an antiplatelet drug, a β-receptor blocker, and a statin, plus an ACE-I/ARB, and the prognostic significance of clinical variables for 6-month mortality among hospital survivors. Variables with P values of b.05 on univariate analysis were entered into multivariate logistic regression model and Cox proportional hazards model. A multivariate logistic regression model was used to determine independent predictors of OMT among hospital survivors. Cox proportional hazards model was used to determine independent predictors of 6-month mortality. Mortality rates according to the number of discharge medication were compared with a 2-sided log-rank test and were plotted with cumulative Kaplan-Meier survival curve. For all analyses, a 2-sided P b .05 was considered statistically significant. Statistical analysis was performed using SPSS version 15.0 for Windows (SPSS Inc, Chicago, IL). This study was carried out with the support of the KSC in the memorandum of the 50th anniversary of the KSC. The authors are solely responsible for the design and conduct of this study,
Table III. Univariate analysis for 6-month mortality Death
Variable
No (n = 8584)
Yes (n = 115)
Age ≥70 4079 (35.6%) 93 (67.0%) Male 6311 (72.2%) 80 (69.0%) Initial presentation Systolic blood pressure 132.7 ± 25.3 129.9 ± 25.1 (mm Hg) Heart rate (beat/min) 78.6 ± 17.4 88.4 ± 21.4 ST elevation MI 5165 (60.3%) 64 (55.7%) Anterior MI 4364 (50.9%) 89 (77.4%) Killip class N1 2003 (23.3%) 58 (50.4%) History Coronary heart disease 1243 (14.5%) 27 (23.7%) Hypertension 4023 (47.3%) 68 (60.2%) Diabetes mellitus 2213 (26.1%) 42 (37.2%) Hyperlipidemia 834 (11.1%) 8 (8.0%) Current smoker 3865 (45.4%) 45 (40.2%) Previous congestive 128 (1.5%) 3 (2.6%) heart failure Previous Cerebrovascular 484 (5.6%) 9 (7.8%) disease LVEF b40% 1376 (17.3%) 57 (52.8%) Laboratory findings Serum creatinine level 1.00 ± 0.28 1.17 ± 0.37 (mg/dL) Peak creatine kinase 148.5 ± 315.4 103.6 ± 149.9 MB (ng/mL) Peak cardiac troponin I 47.4 ± 139.7 46.9 ± 83.7 (ng/mL) Total cholesterol (mg/dL) 184.7 ± 43.7 174.6 ± 45.8 Triglyceride (mg/dL) 128.5 ± 105.7 107.1 ± 57.5 High-density lipoprotein 45.8 ± 20.5 44.6 ± 11.8 cholesterol (mg/dL) Low-density lipoprotein 119.0 ± 43.0 109.0 ± 36.3 cholesterol (mg/dL) Treatment strategies PCI at index hospitalization 7355 (85.8%) 78 (67.8%) CABG at index 166 (1.9%) 0 (0.0%) hospitalization Thrombolytic therapy 418 (8.3%) 7 (8.6%) Conservative treatment 973 (11.3%) 34 (29.6%) Coronary angiography findings Coronary artery disease Left main, isolated 26 (0.3%) 1 (1.1%) Left main, complex 184 (2.3%) 2 (2.2%) 1-vessel disease 3500 (44.5%) 22 (23.9%) 2-vessel disease 2400 (30.5%) 34 (37.0%) 3-vessel disease 1753 (22.3%) 33 (35.9%) Infarct-related artery Left main stem 140 (1.8%) 2 (2.2%) Left anterior 3867 (49.5%) 57 (62.0%) descending artery Left circumflex artery 1332 (17.1%) 10 (10.9%) Right coronary artery 2472 (31.6%) 23 (25.0%) Discharge medication Antiplatelet drugs 8498 (99.4%) 113 (98.3%) β-Blockers 6259 (72.9%) 64 (55.7%) ACE-Is/ARBs 7031 (81.9%) 89 (77.4%) Statins 6624 (77.2%) 81 (70.4%) OMT 4346 (50.6%) 40 (34.8%)
P b.001 .442 .252 b.001 .316 b.001 b.001 .006 .006 .008 .325 .271 .328 .313 b.001 b.001 .132 .972 .016 b.001 .541 .021
b.001 .131 .916 b.001
.215 .916 b.001 .183 .002 .784 .018 .116 .173 .105 b.001 .212 .088 .001
Data are expressed as mean ± SD or number (percentage). Abbreviations are as in Table I and Figure 1.
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all study analyses, the drafting and editing of the paper and its final contents.
Figure 3
Results The baseline characteristics of the overall study patients are shown in Table I. The mean age was 63.8 ± 12.5 years old, and 6,170 patients (72.2%) were men. Of the 9,294 patients with AMI, 326 (3.5%), 4,284 (46.1%), and 4,684 (50.4%) patients were discharged on b2 drugs, 2 to 3 drugs, and all 4 indicated drugs, respectively. The discharge prescription rates of antiplatelet agents, βreceptor blockers, ACE-Is/ARBs, and statins were 99.0%, 72.7%, 81.5%, and 77.2%, respectively (Figure 1). In patients not receiving OMT, the discharge prescription rates of antiplatelet agents, β-receptor blockers, ACE-Is/ ARBs, and statins were 97.9%, 44.9%, 62.8%, and 54.0%, respectively. The prescription rate of OMT, particularly βblockers and statins was significantly lower in the older patients (Figure 2, A). The discharge prescription rates of the OMT were significantly higher in patients who underwent PCI (P b .001), whereas those were significantly lower in patients who underwent coronary artery bypass grafting (CABG) (P b .001) (Figure 2, B and C). In multivariate logistic regression analysis, age ≥70 (odds ratio [OR] 0.840, 95% confidence interval [CI] 0.756-0.934, P = .001), systolic blood pressure (OR 1.005, 95% CI 1.003-1.007, P b .001), Killip class N1 (OR 0.771, 95% CI 0.684-0.869, P b .001), left ventricular injection fraction (LVEF) b40% (OR 0.806, 95% CI 0.702-0.925, P = .002), serum creatinine levels (OR 0.717, 95% CI 0.6000.857, P b .001), serum total cholesterol levels (OR 1.003, 95% CI 1.002-1.004, P b .001), PCI at index hospitalization (OR 1.390, 95% CI 1.198-1.614, P b .001), and CABG at index hospitalization (OR 0.281, 95% CI 0.171-0.463, P b .001) were independent predictors of OMT at discharge after adjusting baseline clinical characteristics (Table II). At 6 months after the index admission, 595 patients (6.4%) were lost to follow-up. There were no significant differences in baseline characteristics for risk stratification (GRACE score) and the use of OMT at discharge between the groups with and without 6-month follow-up data. During the follow-up period, there were 115 allcause death (1.3%) including 77 cardiac deaths (0.9%) and 38 noncardiac (0.4%) deaths. In univariate analysis, age ≥70, mean heart rate, anterior MI, Killip class N1, previous coronary heart disease, hypertension, diabetes mellitus, LVEF, serum creatinine level, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels were significantly associated with the risk of 6month death (Table III). The proportion of patients who underwent PCI was significantly lower in dead group (P b .001). In Kaplan-Meier survival curve, mortality rates differed significantly according to the number of discharge medication (0 or 1 drugs 3.4%, 2 or 3 drugs 1.6%, all 4 drugs 0.9%, P b .001) (Figure 3).
Kaplan-Meier survival curve showing 6-month mortality of the 3 patient groups.
In Cox proportional hazards model, OMT (hazards ratio 0.340, 95% CI 0.162-0.714, P = .004) in addition to age ≥70, heart rate, anterior MI, Killip class N1 at admission, LVEF b40%, and serum creatinine levels were independent predictors of 6-month mortality after adjusting baseline clinical characteristics in model 1 (Table IV). In model 2, OMT (hazards ratio 0.394, 95% CI 0.161-0.963, P = .041) in addition to age ≥70, anterior MI, Killip class N1 at admission, LVEF b40%, serum creatinine levels, and multivessel disease were also strong independent predictors of 6-month mortality after adjusting angiographic and procedural data in addition to clinical characteristics.
Discussion Medications such as antiplatelet drugs, β-blockers, ACE-Is/ARBs, and statins have been associated with significantly improved outcomes in patients presenting with AMI regardless of the geographic location.2,3 In the present study, even with the evidence of benefit, the prescription rates in eligible patients varied from 99% for use of antiplatelet drugs at discharge to 73% for βblockers at discharge in overall patients. Only half of the eligible patients received OMT at discharge. Our results suggest that recommended cardiac drugs are prescribed at suboptimal rates. Numerous studies from Western countries have reported underuse of proven medical therapies at discharge.4-10 However, little is known about the pattern of discharge medications in Asian population.13 Of the 4 drug classes, the prescription rates of βblockers and statins were particularly lower in our study compared with previous studies from Western countries. The lower prescription rates of β-blockers may be
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Table IV. Cox proportional hazards model for predicting 6-month mortality Model 1⁎
Variable Discharge medication 0 or 1 medication 2 or 3 medications OMT Age ≥70 Heart rate, per 10 beat/min increase Anterior MI Killip class N1 at admission Previous coronary heart disease Hypertension Diabetes mellitus LVEF b40% Serum creatinine level, per 1 mg/dL increase Total cholesterol ≥220 mg/dL PCI at index hospitalization Left anterior descending artery disease Multivessel disease
Model 2†
Hazards ratio (95% CI)
P
Hazards ratio (95% CI)
P
Reference 0.459 (0.225-0.938) 0.340 (0.162-0.714) 2.363 (1.529-3.652) 1.105 (1.008-1.211) 2.642 (1.643-4.251) 1.786 (1.170-2.725) 0.730 (0.456-1.170) 1.206 (0.792-1.836) 1.181 (0.767-1.817) 2.556 (1.661-3.932) 2.014 (1.145-3.542)
.033 .004 b.001 .033 b.001 .007 .192 .382 .450 b.001 .015
Reference 0.488 (0.205-1.165) 0.394 (0.161-0.963) 1.913 (1.185-3.088) 1.046 (0.930-1.178) 3.669 (1.971-6.831) 1.888 (1.172-3.041) 0.648 (0.382-1.100) 1.043 (0.654-1.665) 1.141 (0.703-1.850) 2.676 (1.643-4.360) 2.693 (1.409-5.147)
.106 .041 .008 .452 b.001 .009 .108 .859 .593 b.001 .003
0.764 (0.426-1.370)
.367
0.958 0.865 0.960 2.006
.892 .656 .877 .016
(0.514-1.786) (0.457-1.637) (0.571-1.612) (1.139-3.532)
⁎ Model 1 was adjusted for clinical characteristics. † Model 2 was adjusted for clinical characteristics, angiographic findings, and procedural data. Abbreviations are as in Table I and Figure 1.
related to racial differences. It has been known that the incidence of coronary artery spasm was relatively high in Asian population.14 These studies may have influenced on deciding discharge medication. The lower prescription rate of statin in our study may be related to unique National Health Insurance system in Korea. Among OMT, antiplatelet drugs, β-blockers, and ACE-Is/ARBs are routinely reimbursed in post-MI patients. However, the prescription of statin is reimbursed only in patients with a certain level of total cholesterol irrespective of underlying disease, even in patients with AMI. These results suggest that demographic or socioeconomic characteristics may be associated with the pattern of medication use at discharge. Previous studies have reported the determinants of an individual medication at discharge after AMI.5,6,15,16 Advanced age, female sex, hypertension, heart failure, renal dysfunction, presence of an initial non–Q-wave MI, development of atrial fibrillation during hospitalization, and CABG during hospitalization were independently associated with underuse of OMT. Conversely, history of dyslipidemia, presence of ST elevation and positive cardiac biomarkers, previous MI, previous PCI, and cardiology care at admission were significantly associated with use of OMT. In the present study, we also found these “OMT paradox” in the use of OMT at discharge in post-MI survivors. Although current guidelines for management of AMI recommend targeting medical therapies and invasive procedures for patients with high-risk features including signs of congestive heart failure, lower LVEF, renal insufficiency, and/or hemodynamic instability,2,3 these high-risk features were associated
with less use of medical therapies and procedures in this analysis. In general, high-risk clinical characteristics are clustered together, and general conditions of these patients are poor, so physicians may have been more reluctant to prescribe aggressive medical therapies and perform invasive procedures.16 Contemporary adherence to current guidelines for management of AMI appears to be strongly influenced by patient risk status.16,17 During the acute phase of MI, patients with high-risk features are more likely to have an adverse outcome and to have complications associated with medications. Thus, it is difficult to balance the risks and benefits of medical therapies and invasive procedures in short-term management of AMI. Compared with shortterm management of AMI, discharge medications may not be influenced by these safety concerns because invasive procedures have been completed and complications associated with medications are less prominent. However, persistent undertreatment of high-risk patients in the absence of known contraindications at discharge explains that these high-risk features may have influenced on discharge medication decision making. Although there have been conflicting data regarding the interaction between advanced age and OMT at discharge,5,15,18-20 advanced age was independently associated with the less use of OMT in our study. Although recent emerging evidence suggests that older patients can get a similar benefits from aggressive cardiac therapy and the absolute benefit-risk ratio is expected to be even more favorable among elderly “ideal candidates,”21-23 clinicians are usually reluctant to prescribe aggressive medical therapies to older patients because
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advance age may be associated with an increased prevalence of comorbidities and higher incidence of adverse drug effects. There was a strong positive relationship between PCI and the use of OMT at discharge in our study. Similar findings have been reported in previous observation studies examining treatment patterns in patients hospitalized for AMI.5,15,16,24 Patients who underwent PCI are more likely to receive aggressive medical therapies because patients deemed to be poor candidates for a procedure are often denied appropriate medical therapy as well. Coronary angiographic findings such as the location of culprit artery and the number of diseased vessels was not associated the use of OMT. Interestingly, there was a strong inverse relationship between inhospital CABG and OMT at discharge. Other studies have also demonstrated that patients who underwent inhospital CABG are less likely to receive aggressive medical therapies.8,9 This may be related to less recognition of the vital importance of OMT after revascularization among surgical care teams. In the present study, we demonstrated that OMT at discharge was independently associated with improved 6month mortality in patients with AMI. The 6-month mortality decreased progressively with increasing the number of indicated medications. In patients receiving OMT, there was a 68% reduction in mortality after adjustment for clinical characteristics. Furthermore, adjustment for clinical, angiographic, and procedural data did not significantly attenuate the strength of this association. There was a 61% reduction in mortality after adjustment for these compounding variables. Recent studies also have demonstrated that OMT at discharge leads to the relative reduction in 6-month mortality in patients with AMI.4,5
Study limitations There are several potential limitations of our study. First, we were unable to record the reasons for nonprescription of certain medications and details about medication doses. We were also unable to accurately exclude patients with contraindications from our analyses. If patients had previously experienced adverse reactions to specific medications, which were not documented, these patients might be included in our study. Consequently, we may have underestimated the prescription rates for the 4 drug classes studied. Second, we were unable to examine longterm adherence to specific medications prescribed at the time of hospital discharge. Finally, we were unable to control unmeasured factors such as the high cost of longterm medications, which may have influenced on discharge medication use in this observational study. Despite the limitations of our study, this should not undermine our assessment of discharge medication use among hospital survivors.
Conclusion This study provides useful information on the pattern of discharge medication use and clinical outcome at 6 months in patients receiving OMT in Asian populations. Despite strong benefits of recommended cardiac drugs, these pharmacologic agents are prescribed at suboptimal rates, particularly in patients with high-risk features who may derive the greater therapeutic benefits. New educational strategies and initiatives are needed to increase the use of these secondary preventive medical therapies in this area of world.
References 1. Tunstall-Pedoe H, Vanuzzo D, Hobbs M, et al. Estimation of contribution of changes in coronary care to improving survival, event rates, and coronary heart disease mortality across the WHO MONICA Project populations. Lancet 2000;355:688-700. 2. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/nonST elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148-e304. 3. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 2008;117:296-329. 4. Mukherjee D, Fang J, Chetcuti S, et al. Impact of combination evidence-based medical therapy on mortality in patients with acute coronary syndromes. Circulation 2004;109:745-9. 5. Yan AT, Yan RT, Tan M, et al. Optimal medical therapy at discharge in patients with acute coronary syndromes: temporal changes, characteristics, and 1-year outcome. Am Heart J 2007;154: 1108-15. 6. Granger CB, Steg PG, Peterson E, et al. Medication performance measures and mortality following acute coronary syndromes. Am J Med 2005;118:858-65. 7. Krumholz HM, Radford MJ, Ellerbeck EF, et al. Aspirin for secondary prevention after acute myocardial infarction in the elderly: prescribed use and outcomes. Ann Intern Med 1996;124:292-8. 8. Allison JJ, Kiefe CI, Weissman NW, et al. Relationship of hospital teaching status with quality of care and mortality for medicare patients with acute MI. JAMA 2000;284:1256-62. 9. Burwen DR, Galusha DH, Lewis JM, et al. National and state trends in quality of care for acute myocardial infarction between 1994-1995 and 1998-1999: the Medicare health care quality improvement program. Arch Intern Med 2003;163:1430-9.
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10. Chen J, Radford MJ, Wang Y, et al. Do “America's best hospitals” perform better for acute myocardial infarction? N Engl J Med 1999; 340:286-92. 11. Kohro T, Hayashi D, Okada Y, et al. Effects of medication on cardiovascular events in the Japanese coronary artery disease (JCAD) study. Circ J 2007;71:1835-40. 12. Lee JH, Park HS, Chae SC, et al. Predictors of six-month major adverse cardiac events in 30-day survivors after acute myocardial infarction (from the Korea Acute Myocardial Infarction Registry). Am J Cardiol 2009;104:182-9. 13. Alpert JS, Thygesen K, Antman E, et al. Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36: 959-69. 14. Pristipino C, Beltrame JF, Finocchiaro ML, et al. Major racial differences in coronary constrictor response between japanese and caucasians with recent myocardial infarction. Circulation 2000;101: 1102-8. 15. Spencer FA, Lessard D, Yarzebski J, et al. Decade-long changes in the use of combination evidence-based medical therapy at discharge for patients surviving acute myocardial infarction. Am Heart J 2005;150: 838-44. 16. Roe MT, Peterson ED, Newby LK, et al. The influence of risk status on guideline adherence for patients with non–ST-segment elevation acute coronary syndromes. Am Heart J 2006;151:1205-13. 17. Alexander KP, Roe MT, Chen AY, et al. Evolution in cardiovascular care for elderly patients with non–ST-segment elevation
Lee et al 1019
18.
19.
20.
21.
22.
23.
24.
acute coronary syndromes: results from the CRUSADE National Quality Improvement Initiative. J Am Coll Cardiol 2005;46: 1479-87. Yan RT, Yan AT, Tan M, et al. Age-related differences in the management and outcome of patients with acute coronary syndromes. Am Heart J 2006;151:352-9. Simpson E, Beck C, Richard H, et al. Drug prescriptions after acute myocardial infarction: dosage, compliance, and persistence. Am Heart J 2003;145:438-44. Rathore SS, Mehta RH, Wang Y, et al. Effects of age on the quality of care provided to older patients with acute myocardial infarction. Am J Med 2003;114:307-15. Krumholz HM, Radford MJ, Wang Y, et al. National use and effectiveness of beta-blockers for the treatment of elderly patients after acute myocardial infarction: National Cooperative Cardiovascular Project. JAMA 1998;280:623-9. Ray KK, Bach RG, Cannon CP, et al. Benefits of achieving the NCEP optional LDL-C goal among elderly patients with ACS. Eur Heart J 2006;27:2310-6. Shepherd J, Blauw GJ, Murphy MB, et al. PROspective Study of Pravastatin in the Elderly at Risk. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360: 1623-30. Bhatt DL, Roe MT, Peterson ED, et al. Utilization of early invasive management strategies for high-risk patients with non–ST-segment elevation acute coronary syndromes (results from the CRUSADE quality improvement initiative). JAMA 2004;292:2096-104.