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Long-term prognosis of patients with acute myocardial infarction in the era of acute revascularization (from the Heart Institute of Japan Acute Myocardial Infarction [HIJAMI] registry)
International Journal of Cardiology 159 (2012) 205–210
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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Long-term prognosis of patients with acute myocardial infarction in the era of acute revascularization (from the Heart Institute of Japan Acute Myocardial Infarction [HIJAMI] registry)☆ Narumi Okura a, Hiroshi Ogawa a,⁎, Johji Katoh b, Takao Yamauchi c, Nobuhisa Hagiwara a a b c
Tokyo Women's Medical University, Tokyo, Japan Shim-Matsudo-Chuo general hospital, Chiba, Japan Sagamino Hospital, Sagamihara, Kanagawa, Japan
a r t i c l e
i n f o
Article history: Received 23 May 2010 Received in revised form 27 January 2011 Accepted 25 February 2011 Available online 12 March 2011 Keywords: Acute myocardial infarction Coronary risk factors Long-term prognosis Prospective cohort study
a b s t r a c t Background: The long-term prognosis of patients with acute myocardial infarction (AMI) in the contemporary acute revascularization era is not fully understood. Methods: To clarify long-term prognosis and prognostic factors of AMI patients in a real-world setting, we consecutively registered 3021 patients with AMI (mean age 69 years, 70.7% male) who were admitted to 17 participating medical institutions and followed up prospectively. The outcome measure was death from any cause. Results: Among 3021 patients, 629 patients had non-ST elevation MI (non-STEMI). During the index hospitalization, coronary angioplasty and thrombolytic therapy were performed in 58.1% and 16.3% of patients, respectively. During hospitalization, 285 patients (9.4%) died. Among 2736 patients (90.6%) who were discharged alive and followed for a median of 4.3 years (follow-up rate, 97.1%), 434 patients (15.9%) died. Among them, 250 (57.6%) died from non-cardiac causes. Compared with STEMI patients, non-STEMI patients suffered significantly more adverse outcomes. Advanced age and non-STEMI disease were associated with poorer outcomes. Multivariate analysis revealed that diabetes mellitus, acute-phase heart failure (Killip functional class ≥ 2), higher serum creatinine level (≥ 1.2 mg/dl), and advanced age (≥ 70 years and ≥ 80 years) at the onset of the AMI were independent poor prognostic factors (hazard ratios, 1.07, 2.53, 1.89, 2.50, and 6.80 respectively). Conclusions: AMI patients in the era of acute revascularization have favorable long-term prognoses, and a large proportion of late deaths are non-cardiac in nature. The establishment of an optimal management strategy for elderly AMI patients, AMI patients with diabetes, and non-ST elevation AMI patients are essential. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Acute myocardial infarction (AMI) is the most common cardiovascular disorder and has a large potential for serious consequences. Improvements in pharmacologic and interventional treatments have made it possible to successfully treat patients with acute coronary syndrome (ACS) [1–4]. In particular, advances in the technology of percutaneous coronary intervention (PCI) are remarkable. In the Acute Myocardial Infarction in Switzerland (AMIS) Plus Registry [5], investigators demonstrated that increased rates of PCI were associated with both decreased development of cardiogenic shock during
☆ This study was funded by the Japan Research Promotion Society for Cardiovascular Disease, which had no role in conducting the study. ⁎ Corresponding author at. Department of Cardiology, The Heart Institute of Japan, Tokyo Women's Medical University, Tokyo, Japan. Tel.: +81 3 3353 8111; fax: +81 3 3356 0441. E-mail address: [email protected] (H. Ogawa). 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.02.072
hospitalization and decreased mortality among patients who experience cardiogenic shock. In the Global Registry of Acute Coronary Events (GRACE) [6], investigators also found an increase in interventional treatments with β-blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), and statins in ACS patients. Furthermore, these changes have been accompanied by significant decreases in the rates of in-hospital deaths, cardiogenic shock, and new MI among patients with non-ST-elevation myocardial infarction (non-STEMI). Primary PCI has been demonstrated to improve the prognosis of patients with STEMI and is recommended in the most recent guidelines for management of patients with ST-elevation myocardial infarction by the American College of Cardiology and the American Heart Association [7]. On the other hand, although an invasive approach is considered superior to medical therapy for treatment of non-STEMI patients [8,9], the optimal timing of these procedures remains to be established. Subsequently, the beneficial effects of acute reperfusion therapy are not established in all patients with AMI.
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In the contemporary acute revascularization era, a prospective cohort study (The Heart Institute of Japan Acute Myocardial Infarction: HIJAMI) was conducted with AMI patients at the Department of Cardiology, Heart Institute of Japan, Tokyo Women's Medical University and its related 17 institutions [10–12] to determine the pathologies of patients with AMI, status of treatment, and prognoses. The purpose of the present study was to determine the long-term prognoses of patients with AMI and determine which factors are associated with a worse prognosis so that treatment strategies may be developed to improve these factors. 2. Materials and methods Full details of the HIJAMI registry have been described previously [11]. In brief, HIJAMI is a multicenter prospective cohort of consecutive patients with AMI who were admitted within 48 h after the onset of symptoms. Between January 1999 and June 2001, 3021 consecutive patients from 17 participating hospitals in Japan were registered. As HIJAMI was meant for observational purposes, treatment strategies such as drug therapies and early reperfusion treatment were used at the discretion of the responsible physician at each hospital. Clinical and angiographic data, including the patients' demographics, coronary risk factors, therapeutic modalities, complications, number of diseased vessels, infarct-related arteries, PCI strategies, laboratory data, and outcomes, were prospectively collected using a standardized case report form. AMI was diagnosed when at least two of the following three criteria were met: (1) typical chest pain; (2) greater than two-fold elevation of levels of enzymes released from the cardiac muscle compared with normal levels; and (3) new appearance of abnormal Q waves, an elevation or reduction of ST segments, a typical change in T waves, or new appearance of the left bundle branch block [13]. Classification of STEMI and non-STEMI was determined by the treating physician and based on interpretation of the ECG assessment of the patient's clinical status. Diabetes mellitus was defined as fasting blood glucose level ≥126 mg/dl during index hospitalization or treatment with hypoglycemic agents at the time of onset of AMI. Hypertension was defined as systolic blood pressure ≥ 140 mm Hg, diastolic blood
pressure ≥ 90 mm Hg, or history of having received treatment for hypertension. Hypercholesterolemia was defined as total cholesterol level ≥ 220 mg/dl. Clinical follow-up data were obtained from outpatient records or by a trained clinical research assistant at each hospital who made telephone contact with patients on a yearly basis. Patients were questioned, using a standard format, about the recurrence of cardiac symptoms and the need for hospitalization related to heart disease. Family members of deceased patients were contacted to ascertain time of death. The outcome measure was death from any cause. Data were expressed as medians and interquartile ranges or means and standard deviations. For continuous variables, normality was confirmed, and then the Student t test or Mann–Whitney U test was used to compare the STEMI and non-STEMI groups. For discontinuous variables, the chi-square test or Fisher's exact probability test was used. The cumulative probabilities of the event-free curves were estimated with the Kaplan–Meier method. The Cox proportional hazards model was used to evaluate the independent contribution of baseline clinical factors to the development of endpoint after adjustment for age, gender, systemic hypertension, diabetes, hypercholesterolemia, previous myocardial infarction, the number of diseased vessels, acute revascularization, Killip functional class, peak creatine kinase concentration, and medication use at discharge (aspirin, βblocker, calcium channel blocker, ACE inhibitor, and ARB). The proportional hazards assumption was confirmed by the log (− log survival function). The influence of profile, interaction, and collinearity in the generalized linear model was examined using regression diagnostic analysis. Two-tailed p-values b 0.05 were considered statistically significant. All analyses were performed using STATA statistical software (version 10.0, STATA Corp, College Station, TX).
3. Results The median observation period and the follow-up rate were 4.3 years and 97.1%, respectively. Table 1 shows patients' backgrounds. Among 3021 consecutive AMI patients, 629 patients had non-STEMI and 2392 had STEMI disease. Patients with non-STEMI disease were significantly more likely to be older and female, were
Table 1 Baseline characteristics. Variables
Overall (n = 3021)
Non-STEMI (n = 629)
STEMI (n = 2392)
p-value
Onset to admission (h) Women (%) Age (year) Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min.) Left ventricular ejection fraction (%)⁎
3.3 (1.7–9.0) 885 (29.3) 68.1 ± 12.2 23.5 ± 3.5 133.5 ± 28.0 77.7 ± 17.3 78.5 ± 20.3 52.7 ± 12.9 1379 (45.6) 1205 (39.9)
4.5 (2.1–12.5) 205 (32.6) 71.3 ± 11.5 23.4 ± 3.6 138.4 ± 28.1 77.8 ± 15.9 82.9 ± 22.8 51.9 ± 13.8 200 (31.8) 282 (44.8)
3.2 (1.7–7.9) 680 (28.4) 67.3 ± 12.3 23.5 ± 3.4 132.2 ± 27.8 77.7 ± 17.6 77.4 ± 19.5 53.0 ± 12.6 1179 (49.3) 923 (38.6)
b0.001 0.041 b0.001 0.37 b0.001 0.88 b0.001 0.097 b0.001 0.004
2410 (79.8) 228 (7.5) 200 (6.6) 183 (6.1) 1661 (55.0) 1155 (38.2) 1102 (36.5) 1620 (53.6) 407 (13.5) 489 (16.2) 40 (1.3) 255 (8.4) 63 (2.1) 2113 (1034–4000) 0.3 (0.1–0.9) 60.1 ± 21.2 6.1 ± 1.5 193 ± 42 101 (69–147) 47 ± 14 122 ± 37 21 (15–29)
417 (66.3) 68 (10.8) 108 (17.2) 36 (5.7) 368 (58.5) 260 (41.3) 250 (39.7) 310 (49.3) 86 (13.7) 175 (27.8) 16 (2.5) 88 (14.0) 35 (5.6) 1095 (663–2035) 0.3 (0.1–1.2) 53.8 ± 22.2 6.2 ± 1.4 195 ± 42 99 (68–149) 48 ± 15 124 ± 36 21 (14–32)
1993 (83.3) 160 (6.7) 92 (3.8) 147 (6.1) 1293 (54.1) 895 (37.4) 852 (35.6) 1310 (54.8) 321 (13.4) 314 (13.1) 24 (1.0) 167 (7.0) 28 (1.2) 2462 (1241–4437) 0.3 (0.1–0.8) 61.8 ± 20.6 6.1 ± 1.5 192 ± 42 101 (70–147) 47 ± 14 122 ± 37 21 (15–29)
0.046 0.072 0.056 0.014 0.869 b0.001 0.003 b0.001 b0.001 b0.001 0.014 b0.001 0.047 0.079 0.75 0.717 0.208 0.352
Anterior MI (%) Preinfarction angina (%) Killip functional class (%) I II III IV Hypertension (%) Hypercholesterolemia (%) Diabetes mellitus (%) Smoker (%) Family history (%) Previous MI (%) Hemodialysis (%) Previous PCI (%) Previous CABG (%) Peak creatine kinase (mg/dl) C-reactive protein (mg/dl) Estimated GFR (ml/min/1.73 m2) HbA1c, % Total-cholesterol (mg/dl) Triglyceride (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Length of hospital stay (days)
CABG: coronary artery bypass graft; CAD: coronary artery disease; GFR: glomerular filtration rate; Hb: hemoglobin; HDL: high-density lipoprotein; LDL: low-density lipoprotein; MI: myocardial infarction; PCI: percutaneous coronary intervention; and STEMI: ST-elevation myocardial infarction. Values are mean ± S.D. (indicated by ±) or median (interquartile range) unless otherwise noted. ⁎ Determined by contrast ventriculography, radionuclide ventriculography, or echocardiography.
N. Okura et al. / International Journal of Cardiology 159 (2012) 205–210
significantly less likely to be current smokers, and were significantly more likely to have hypertension, impaired renal function, and a history of coronary artery disease. The levels of Killip functional class among patients in the non-STEMI group were significantly higher compared with the STEMI group. Patients in the non-STEMI group had significantly longer intervals from symptom onset to admission compared with patients in the STEMI group. The prevalence of hypercholesterolemia and diabetes did not differ significantly between these two groups. Angiographic findings and therapeutic modalities are shown in Table 2. Of the 3021 patients, 72.1% underwent coronary angiography in the acute phase, 58.1% underwent PCI, and 16.3% received coronary thrombolysis. Acute revascularization was performed in 72.5% of STEMI patients and 36.6% of non-STEMI patients. Among patients who underwent revascularization within 24 h after the onset of AMI, 201 (87.3%) of non-STEMI and 1576 (90.8%) of STEMI patients achieved TIMI flow grade 3. During hospitalization of STEMI patients, PCI or coronary artery bypass graft (CABG) surgery was performed in 75.3% and 3.4%, respectively; these rates were significantly higher than those in non-STEMI patients. Treatment with PCI during index hospitalization was performed significantly less frequently (p b 0.001) in non-STEMI patients compared with STEMI patients (52.6% and 75.3%, respectively; Table 2). During hospitalization, 285 patients (9.4%) died. As a result, 2736 patients (90.6%) were discharged from the hospital and followed up for an average of 4.3 years. At discharge, aspirin was administered to 2431 patients (88.9%). Calcium antagonists and nitrates were administered to 845 (30.9%) and 1677 patients (61.3%), respectively. ACE inhibitors and β-blockers were administered to 1563 (57.1%) and 880 patients (32.2%), respectively. Compared with STEMI patients, non-STEMI patients received significantly less pharmacotherapy with aspirin and ACEinhibitors (Table 3). Among 2736 patients (90.6%) who were discharged alive and followed for a median of 4.3 years (follow-up rate, 97.1%), 434 patients (15.9%) died. Among them, 250 (57.6%) died from non-cardiac causes. Compared with STEMI patients, non-STEMI
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Table 3 Medications at discharge (n = 2736). Non-STEMI
STEMI
Total
2736
Overall (%)
549
(%)
2187
(%)
p-value
Aspirin Antiplatelet agents Nitrates ACE inhibitors ARBs Calcium channel blockers LLDs Beta blockers
2431 1440 1677 1563 183 845 628 880
(88.9) (52.6) (61.3) (57.1) (6.7) (30.9) (23.0) (32.2)
458 324 393 263 30 236 131 185
(83.4) (59.0) (71.6) (47.9) (5.5) (43.0) (23.9) (33.7)
1973 1116 1284 1300 153 609 497 695
(90.2) (51.0) (58.7) (59.4) (7.0) (27.8) (22.7) (31.8)
b0.0001 0.001 b0.0001 b0.0001 0.235 b0.0001 0.611 0.418
ACE = angiotensin-converting enzyme, ARB = angiotensin receptor blocker; and LLD = lipid-lowering drug.
patients suffered significantly more adverse outcomes during hospitalization and after hospital discharge (Table 4). At a median follow-up of 4.3 years, 23.8% of patients had died. Among AMI patients, the total mortality rate after the onset of AMI at 1 month, 6 months, 1 year, 2 years, 3 years, or 4 years was 7.9%, 12.3%, 14.4%, 17.4%, 19.9%, or 22.5%, respectively. Among AMI patients who were discharged alive after the index hospitalization, the total mortality rate at 6 months, 1 year, 2 years, 3 years, or 4 years was 3.7%, 5.7%, 9.0%, 11.8%, or 14.3%, respectively. Among them, 250 (57.6%) died from non-cardiac causes. (Fig. 1, Table 4). Advanced age and non-STEMI were associated with poorer outcomes (Figs. 2 and 3). We conducted multivariate analyses using factors such as patient background, acute-phase treatment, and prescription at discharge to examine the relationships between those factors and late prognosis (Table 5). The results of the analysis demonstrated that poor late prognoses were significantly associated with diabetes mellitus, acutephase heart failure, higher serum creatinine level (≥1.2 mg/dl), and advanced age at the onset of AMI (hazard ratio = 1.07 for diabetes, 2.53 for Killip functional class ≥ 2, 1.89 for higher serum creatinine
Table 2 Angiographic findings and invasive approach. Variables Coronary angiography Within 24 h (%) During hospitalization (%) Infarct related artery (%) Right coronary artery Left main trunk Left anterior descending Left circumflex Graft vessels Undefined Number of diseased vessel (%) 0 1 2 3 Undefined Revascularization Within 24 h (%) Onset to revascularization (h) Admission to revascularization (h) Thrombolysis (%) PCI (%) CABG (%) TIMI flow grade 3 (%) During hospitalization PCI (%) CABG (%)
Overall (n = 3021)
Non-STEMI (n = 629)
STEMI (n = 2392)
p-value
2178 (72.1) 2659 (88.0)
307 (48.8) 496 (78.9)
1871 (78.2) 2163 (90.4)
b0.001 b0.001
915 (30.3) 48 (1.6) 1208 (40.0) 409 (13.5) 18 (0.6) 423 (14.0)
95 (15.1) 19 (3.0) 140 (22.3) 207 (32.9) 9 (1.4) 159 (25.3)
820 (34.3) 29 (1.2) 1068 (44.6) 202 (8.4) 9 (0.4) 264 (11.0)
58 (1.9) 1239 (41.0) 588 (19.5) 293 (9.7) 843 (27.9)
12 (1.9) 114 (18.1) 97 (15.4) 84 (13.4) 322 (51.2)
46 1125 491 209 521
(1.9) (47.0) (20.5) (8.7) (21.8)
1965 (65.0) 4.5 (3.1–7.5) 1.6 (1.2–2.1) 491 (16.3) 1755 (58.1) 27 (0.9) 1777 (58.8) 2337 (77.4) 2133 (70.6) 137 (4.5)
230 (36.6) 6.6 (4.0–12.2) 2.1 (1.4–3.8) 30 (4.8) 206 (32.8) 12 (1.9) 201 (32.0) 375 (59.6) 331 (52.6) 55 (8.7)
1735 4.4 1.5 461 1549 15 1576 1962 1802 82
(72.5) (3.0–7.0) (1.2–2.0) (19.3) (64.8) (0.6) (65.9) (82.0) (75.3) (3.4)
CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention; and TIMI: Thrombolysis in Myocardial Infarction. Values are mean ± S.D. (indicated by ±) or median (interquartile range) unless otherwise noted.
b0.001
b0.001
b0.001 b0.001 b0.001 b0.001 b0.001 0.002 b0.001 b0.001 b0.001
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Table 4 Clinical outcome. Variables
Overall (n = 3021)
Non-STEMI (n = 629)
STEMI (n = 2392)
p-value
In-hospital complications (%) Heart failure Free wall rupture Interventricular septum rupture Acute mitral regurgitation Reinfarction Ventricular tachycardia or fibrillation Post infarction angina In-hospital mortality Follow-up Follow-up period (year) Lost to follow-up (%) Long-term outcome (%) Total death Cardiac death Non-cardiac death Death from CAD or non-fatal MI Fatal MI or non-fatal MI Major adverse cardiac events Hospitalization for ischemia Hospitalization for heart failure Revascularization Sudden death
1197 (39.6) 464 (15.4) 54 (1.8) 18 (0.6) 11 (0.4) 78 (2.6) 192 (6.4) 137 (4.5) 285 (9.4)
293 164 4 0 3 21 30 55 80
904 (37.8) 300 (12.5) 50 (2.1) 18 (0.8) 8 (0.3) 57 (2.4) 162 (6.8) 82 (3.4) 205 (8.6)
b0.001 b0.001 0.014 0.029 0.598 0.179 0.067 b0.001 0.002
4.3 (3.0–5.1) 89 (2.9) 719 422 297 527 163 998 331 285 347 37
(46.6) (26.1) (0.6) (0.0) (0.5) (3.3) (4.8) (8.7) (12.7)
4.1 (1.7–5.0) 15 (2.4)
(23.8) (14.0) (9.8) (17.4) (5.4) (33.0) (11.0) (9.4) (11.5) (1.2)
215 120 95 149 49 260 76 96 78 10
(34.2) (19.1) (15.1) (23.7) (7.8) (41.3) (12.1) (15.3) (12.4) (1.6)
4.3 (3.3–5.1) 74 (3.1) 504 (21.1) 302 (12.6) 202 (8.4) 378 (15.8) 114 (4.8) 738 (30.9) 255 (10.7) 189 (7.9) 269 (11.2) 27 (1.1)
b0.001 b0.001 b0.001 b0.001 0.003 b0.001 0.31 b0.001 0.419 0.35
CAD: coronary artery disease; MI: myocardial infarction. Values are mean ± S.D. (indicated by ±) or median (interquartile range) unless otherwise noted.
level, 2.50 for age ≥ 70 years, and 6.80 for age ≥ 80 years, p b 0.001 for all comparisons). 4. Discussion The present study revealed that aggressive acute-phase reperfusion therapy was associated with relatively favorable long-term prognoses, but the prognoses of elderly AMI patients and non-STEMI patients were poor. Among AMI patients who were discharged alive, more than half of them died later from non-cardiovascular causes. In a recent meta-analysis [14], the beneficial effects of primary PCI for AMI patients on 30 day mortality were not influenced by age. Subsequently, the investigators concluded that age should not be considered an exclusion criterion for the use of primary PCI. However, most randomized trials exclude patients with several comorbidities, including renal impairment [15]. Patients with advanced age frequently suffered from renal insufficiency. In the present study, we registered all patients with AMI within 48 h after AMI onset, which led to a higher patient age than that seen in some studies and a decrease in the rate of acute reperfusion therapy; these factors may
have decreased the beneficial effects of acute revascularization on long-term survival of AMI patients (Table 5). These limitations in a real-world setting may correlate with an unfavorable prognosis of AMI in elderly patients. In a recent cohort study [16], Chan et al. demonstrated that nonSTEMI disease was associated with a higher risk of long-term mortality than STEMI disease among MI patients who underwent catheterization. They also found that early revascularization was associated with a lower adjusted risk of mortality for both STEMI and non-STEMI disease. In the present study, non-STEMI patients tended to be late presenters, older, and have a lower rate of acute revascularization compared with STEMI patients. Consequently, nonSTEMI patients may have poorer long-term outcome than STEMI patients. Roger et al. [17] found that the modification of MI definition, especially the introduction of cardiac troponin, caused a rapid increase of non-STEMI disease and that non-STEMI disease now constitutes the majority of MIs. In the present study, we diagnosed MI based on creatine kinase level and its MB fraction as markers of myocardial injury. This may have lead to a lower incidence of nonSTEMI disease in this study. In the Japanese acute coronary syndrome
100
Survival (%)
95
Cardiac
90
Non-cardiac
85
All cause of death 80
75 0
1
2
3
4
5
Years since hospital discharge Fig. 1. Kaplan–Meier curves of vital prognoses of patients who were discharged alive in the HIJAMI registry (n = 2736).
Fig. 2. Kaplan–Meier curves of life prognoses of AMI patients who were discharged alive by age at AMI onset (n = 2736).
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prognosis among AMI patients. Further prospective studies are necessary to evaluate the relationship between these risk factors and prognosis of AMI patients. Studies show that due to the recent development of therapeutic modalities for patients with heart failure, about a half of all deaths among these patients are non-cardiovascular in nature [33]. The results of the present study support these findings. These results highlight the heterogeneity of patients with cardiovascular disease and have implications for the design and interpretation of results of clinical trials aimed at reducing mortality in cardiovascular disease. 5. Limitations
Fig. 3. Kaplan–Meier survival curves of STEMI vs. non-STEMI patients from time of AMI onset.
study [18], a multicenter observational cohort study conducted in the same period as the present study in Japan, the investigators reported that non-STEMI was diagnosed in 12% of 5325 consecutive AMI patients. Because most recurrences of AMI develop at sites remote from the initial infarction [19], prophylactic medical therapy has an important role in preventing further cardiovascular events and improving longterm outcome in AMI patients. Hypertension is an important risk factor for cardiovascular disease [20]. In Japan, advanced antihypertensive therapy has resulted in a reduction in cardiovascular deaths, such as cerebral hemorrhage [21]. Such advances in antihypertensive drugs have also contributed to a significant improvement in the life prognoses of hypertensive patients [22–24]. The mortality of diabetic patients due to coronary artery disease is reported to be approximately two- to four-fold higher than that of non-diabetic patients [25–27]. In recent years, treatment of diabetes mellitus has changed dramatically, and several different types of antidiabetic agents are currently available [28]. However, the evidence concerning the effects of specific glucose-lowering agents on macrovascular disease is limited and inconclusive [29]. The prognosis of diabetic patients with AMI was poorer than for their non-diabetic counterparts in the present study. Further improvement in therapy for diabetic patients with AMI is essential. In observational studies, paradoxical relationships have often been recognized between cardiovascular risk factors and prognosis of patients with cardiovascular disease [30–32]. In the present study, hypercholesterolemia and smoking were not associated with a poorer
Table 5 Cox proportional hazards models for all-cause mortality in all participants of the HIJAMI registry (n = 3021). Variables
p-value
Hazard ratio
95% CI
Female, gender Hypertension Smoking habit Diabetes mellitus Hypercholesterolemia Killip functional class ≥2 Creatinine level (≥1.2 mg/dl) Acute revascularization Age ≥70 years ≥ 80 years
0.18 0.60 0.48 b 0.0001 0.27 b 0.0001 b 0.0001 0.19 b 0.0001 b 0.0001
1.16 0.98 0.93 1.07 0.98 2.53 1.89 0.97 2.50 6.80
0.94–1.45 0.92–1.05 0.77–1.13 1.04–1.10 0.94–1.02 2.08–3.09 1.55–2.31 0.93–1.02 1.95–3.21 5.27–8.78
It is necessary to consider possible bias that may have affected the present findings. The most frequent limitation in the analysis of observational data is that inadequate comparability validity may lead to incorrect interpretations. Therefore, comparative analyses of various treatments will require appropriate risk adjustment. Observational data cannot provide definitive evidence that treatment improves survival, because observational studies cannot fully control for the distribution of important covariates among treatment groups. We cannot exclude possible unmeasured confounding by characteristics that were not examined. Furthermore, pharmacologic adherence was not assessed in this study. Other limitations included lack of precise information on the dose of each drug, drug compliance, duration of treatment, and insufficient safety data during the followup period. Despite these limitations, the results of the present study reflect the actual condition of AMI patients in the contemporary acute revascularization era, because the present study included all AMI patients who were admitted to hospitals, and 97% of participants were discharged alive and followed up for a median of 4.3 years. 6. Conclusions AMI patients treated with both acute revascularization and modern pharmacotherapy have favorable long-term prognoses, and a large proportion of late deaths are non-cardiac in nature. Opportunities exist to improve countermeasures against known coronary risk factors. In particular, the establishment of an optimal management strategy for elderly AMI patients, AMI patients with diabetes, and AMI patients with non-ST elevation are essential. Acknowledgments The authors of this manuscript certify that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [34]. References [1] Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988;2:349–60. [2] An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med 1993;329: 673–82. [3] Stone GW, Grines CL, Rothbaum D, et al. Analysis of the relative costs and effectiveness of primary angioplasty versus tissue-type plasminogen activator: the Primary Angioplasty in Myocardial Infarction (PAMI) trial. The PAMI Trial Investigators. J Am Coll Cardiol 1997;29:901–7. [4] Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock. N Engl J Med 1999;341:625–34. [5] Jeger RV, Radovanovic D, Hunziker PR, et al. Ten-year trends in the incidence and treatment of cardiogenic shock. Ann Intern Med 2008;149:618–26. [6] Fox KA, Steg PG, Eagle KA, et al. Decline in rates of death and heart failure in acute coronary syndromes, 1999–2006. JAMA 2007;297:1892–900. [7] Kushner FG, Hand M, Smith Jr SC, et al. Focused updates: ACC/AHA Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction (updating the 2004
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Contents lists available at ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Long-term prognosis of patients with acute myocardial infarction in the era of acute revascularization (from the Heart Institute of Japan Acute Myocardial Infarction [HIJAMI] registry)☆ Narumi Okura a, Hiroshi Ogawa a,⁎, Johji Katoh b, Takao Yamauchi c, Nobuhisa Hagiwara a a b c
Tokyo Women's Medical University, Tokyo, Japan Shim-Matsudo-Chuo general hospital, Chiba, Japan Sagamino Hospital, Sagamihara, Kanagawa, Japan
a r t i c l e
i n f o
Article history: Received 23 May 2010 Received in revised form 27 January 2011 Accepted 25 February 2011 Available online 12 March 2011 Keywords: Acute myocardial infarction Coronary risk factors Long-term prognosis Prospective cohort study
a b s t r a c t Background: The long-term prognosis of patients with acute myocardial infarction (AMI) in the contemporary acute revascularization era is not fully understood. Methods: To clarify long-term prognosis and prognostic factors of AMI patients in a real-world setting, we consecutively registered 3021 patients with AMI (mean age 69 years, 70.7% male) who were admitted to 17 participating medical institutions and followed up prospectively. The outcome measure was death from any cause. Results: Among 3021 patients, 629 patients had non-ST elevation MI (non-STEMI). During the index hospitalization, coronary angioplasty and thrombolytic therapy were performed in 58.1% and 16.3% of patients, respectively. During hospitalization, 285 patients (9.4%) died. Among 2736 patients (90.6%) who were discharged alive and followed for a median of 4.3 years (follow-up rate, 97.1%), 434 patients (15.9%) died. Among them, 250 (57.6%) died from non-cardiac causes. Compared with STEMI patients, non-STEMI patients suffered significantly more adverse outcomes. Advanced age and non-STEMI disease were associated with poorer outcomes. Multivariate analysis revealed that diabetes mellitus, acute-phase heart failure (Killip functional class ≥ 2), higher serum creatinine level (≥ 1.2 mg/dl), and advanced age (≥ 70 years and ≥ 80 years) at the onset of the AMI were independent poor prognostic factors (hazard ratios, 1.07, 2.53, 1.89, 2.50, and 6.80 respectively). Conclusions: AMI patients in the era of acute revascularization have favorable long-term prognoses, and a large proportion of late deaths are non-cardiac in nature. The establishment of an optimal management strategy for elderly AMI patients, AMI patients with diabetes, and non-ST elevation AMI patients are essential. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Acute myocardial infarction (AMI) is the most common cardiovascular disorder and has a large potential for serious consequences. Improvements in pharmacologic and interventional treatments have made it possible to successfully treat patients with acute coronary syndrome (ACS) [1–4]. In particular, advances in the technology of percutaneous coronary intervention (PCI) are remarkable. In the Acute Myocardial Infarction in Switzerland (AMIS) Plus Registry [5], investigators demonstrated that increased rates of PCI were associated with both decreased development of cardiogenic shock during
☆ This study was funded by the Japan Research Promotion Society for Cardiovascular Disease, which had no role in conducting the study. ⁎ Corresponding author at. Department of Cardiology, The Heart Institute of Japan, Tokyo Women's Medical University, Tokyo, Japan. Tel.: +81 3 3353 8111; fax: +81 3 3356 0441. E-mail address: [email protected] (H. Ogawa). 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.02.072
hospitalization and decreased mortality among patients who experience cardiogenic shock. In the Global Registry of Acute Coronary Events (GRACE) [6], investigators also found an increase in interventional treatments with β-blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), and statins in ACS patients. Furthermore, these changes have been accompanied by significant decreases in the rates of in-hospital deaths, cardiogenic shock, and new MI among patients with non-ST-elevation myocardial infarction (non-STEMI). Primary PCI has been demonstrated to improve the prognosis of patients with STEMI and is recommended in the most recent guidelines for management of patients with ST-elevation myocardial infarction by the American College of Cardiology and the American Heart Association [7]. On the other hand, although an invasive approach is considered superior to medical therapy for treatment of non-STEMI patients [8,9], the optimal timing of these procedures remains to be established. Subsequently, the beneficial effects of acute reperfusion therapy are not established in all patients with AMI.
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In the contemporary acute revascularization era, a prospective cohort study (The Heart Institute of Japan Acute Myocardial Infarction: HIJAMI) was conducted with AMI patients at the Department of Cardiology, Heart Institute of Japan, Tokyo Women's Medical University and its related 17 institutions [10–12] to determine the pathologies of patients with AMI, status of treatment, and prognoses. The purpose of the present study was to determine the long-term prognoses of patients with AMI and determine which factors are associated with a worse prognosis so that treatment strategies may be developed to improve these factors. 2. Materials and methods Full details of the HIJAMI registry have been described previously [11]. In brief, HIJAMI is a multicenter prospective cohort of consecutive patients with AMI who were admitted within 48 h after the onset of symptoms. Between January 1999 and June 2001, 3021 consecutive patients from 17 participating hospitals in Japan were registered. As HIJAMI was meant for observational purposes, treatment strategies such as drug therapies and early reperfusion treatment were used at the discretion of the responsible physician at each hospital. Clinical and angiographic data, including the patients' demographics, coronary risk factors, therapeutic modalities, complications, number of diseased vessels, infarct-related arteries, PCI strategies, laboratory data, and outcomes, were prospectively collected using a standardized case report form. AMI was diagnosed when at least two of the following three criteria were met: (1) typical chest pain; (2) greater than two-fold elevation of levels of enzymes released from the cardiac muscle compared with normal levels; and (3) new appearance of abnormal Q waves, an elevation or reduction of ST segments, a typical change in T waves, or new appearance of the left bundle branch block [13]. Classification of STEMI and non-STEMI was determined by the treating physician and based on interpretation of the ECG assessment of the patient's clinical status. Diabetes mellitus was defined as fasting blood glucose level ≥126 mg/dl during index hospitalization or treatment with hypoglycemic agents at the time of onset of AMI. Hypertension was defined as systolic blood pressure ≥ 140 mm Hg, diastolic blood
pressure ≥ 90 mm Hg, or history of having received treatment for hypertension. Hypercholesterolemia was defined as total cholesterol level ≥ 220 mg/dl. Clinical follow-up data were obtained from outpatient records or by a trained clinical research assistant at each hospital who made telephone contact with patients on a yearly basis. Patients were questioned, using a standard format, about the recurrence of cardiac symptoms and the need for hospitalization related to heart disease. Family members of deceased patients were contacted to ascertain time of death. The outcome measure was death from any cause. Data were expressed as medians and interquartile ranges or means and standard deviations. For continuous variables, normality was confirmed, and then the Student t test or Mann–Whitney U test was used to compare the STEMI and non-STEMI groups. For discontinuous variables, the chi-square test or Fisher's exact probability test was used. The cumulative probabilities of the event-free curves were estimated with the Kaplan–Meier method. The Cox proportional hazards model was used to evaluate the independent contribution of baseline clinical factors to the development of endpoint after adjustment for age, gender, systemic hypertension, diabetes, hypercholesterolemia, previous myocardial infarction, the number of diseased vessels, acute revascularization, Killip functional class, peak creatine kinase concentration, and medication use at discharge (aspirin, βblocker, calcium channel blocker, ACE inhibitor, and ARB). The proportional hazards assumption was confirmed by the log (− log survival function). The influence of profile, interaction, and collinearity in the generalized linear model was examined using regression diagnostic analysis. Two-tailed p-values b 0.05 were considered statistically significant. All analyses were performed using STATA statistical software (version 10.0, STATA Corp, College Station, TX).
3. Results The median observation period and the follow-up rate were 4.3 years and 97.1%, respectively. Table 1 shows patients' backgrounds. Among 3021 consecutive AMI patients, 629 patients had non-STEMI and 2392 had STEMI disease. Patients with non-STEMI disease were significantly more likely to be older and female, were
Table 1 Baseline characteristics. Variables
Overall (n = 3021)
Non-STEMI (n = 629)
STEMI (n = 2392)
p-value
Onset to admission (h) Women (%) Age (year) Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min.) Left ventricular ejection fraction (%)⁎
3.3 (1.7–9.0) 885 (29.3) 68.1 ± 12.2 23.5 ± 3.5 133.5 ± 28.0 77.7 ± 17.3 78.5 ± 20.3 52.7 ± 12.9 1379 (45.6) 1205 (39.9)
4.5 (2.1–12.5) 205 (32.6) 71.3 ± 11.5 23.4 ± 3.6 138.4 ± 28.1 77.8 ± 15.9 82.9 ± 22.8 51.9 ± 13.8 200 (31.8) 282 (44.8)
3.2 (1.7–7.9) 680 (28.4) 67.3 ± 12.3 23.5 ± 3.4 132.2 ± 27.8 77.7 ± 17.6 77.4 ± 19.5 53.0 ± 12.6 1179 (49.3) 923 (38.6)
b0.001 0.041 b0.001 0.37 b0.001 0.88 b0.001 0.097 b0.001 0.004
2410 (79.8) 228 (7.5) 200 (6.6) 183 (6.1) 1661 (55.0) 1155 (38.2) 1102 (36.5) 1620 (53.6) 407 (13.5) 489 (16.2) 40 (1.3) 255 (8.4) 63 (2.1) 2113 (1034–4000) 0.3 (0.1–0.9) 60.1 ± 21.2 6.1 ± 1.5 193 ± 42 101 (69–147) 47 ± 14 122 ± 37 21 (15–29)
417 (66.3) 68 (10.8) 108 (17.2) 36 (5.7) 368 (58.5) 260 (41.3) 250 (39.7) 310 (49.3) 86 (13.7) 175 (27.8) 16 (2.5) 88 (14.0) 35 (5.6) 1095 (663–2035) 0.3 (0.1–1.2) 53.8 ± 22.2 6.2 ± 1.4 195 ± 42 99 (68–149) 48 ± 15 124 ± 36 21 (14–32)
1993 (83.3) 160 (6.7) 92 (3.8) 147 (6.1) 1293 (54.1) 895 (37.4) 852 (35.6) 1310 (54.8) 321 (13.4) 314 (13.1) 24 (1.0) 167 (7.0) 28 (1.2) 2462 (1241–4437) 0.3 (0.1–0.8) 61.8 ± 20.6 6.1 ± 1.5 192 ± 42 101 (70–147) 47 ± 14 122 ± 37 21 (15–29)
0.046 0.072 0.056 0.014 0.869 b0.001 0.003 b0.001 b0.001 b0.001 0.014 b0.001 0.047 0.079 0.75 0.717 0.208 0.352
Anterior MI (%) Preinfarction angina (%) Killip functional class (%) I II III IV Hypertension (%) Hypercholesterolemia (%) Diabetes mellitus (%) Smoker (%) Family history (%) Previous MI (%) Hemodialysis (%) Previous PCI (%) Previous CABG (%) Peak creatine kinase (mg/dl) C-reactive protein (mg/dl) Estimated GFR (ml/min/1.73 m2) HbA1c, % Total-cholesterol (mg/dl) Triglyceride (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Length of hospital stay (days)
CABG: coronary artery bypass graft; CAD: coronary artery disease; GFR: glomerular filtration rate; Hb: hemoglobin; HDL: high-density lipoprotein; LDL: low-density lipoprotein; MI: myocardial infarction; PCI: percutaneous coronary intervention; and STEMI: ST-elevation myocardial infarction. Values are mean ± S.D. (indicated by ±) or median (interquartile range) unless otherwise noted. ⁎ Determined by contrast ventriculography, radionuclide ventriculography, or echocardiography.
N. Okura et al. / International Journal of Cardiology 159 (2012) 205–210
significantly less likely to be current smokers, and were significantly more likely to have hypertension, impaired renal function, and a history of coronary artery disease. The levels of Killip functional class among patients in the non-STEMI group were significantly higher compared with the STEMI group. Patients in the non-STEMI group had significantly longer intervals from symptom onset to admission compared with patients in the STEMI group. The prevalence of hypercholesterolemia and diabetes did not differ significantly between these two groups. Angiographic findings and therapeutic modalities are shown in Table 2. Of the 3021 patients, 72.1% underwent coronary angiography in the acute phase, 58.1% underwent PCI, and 16.3% received coronary thrombolysis. Acute revascularization was performed in 72.5% of STEMI patients and 36.6% of non-STEMI patients. Among patients who underwent revascularization within 24 h after the onset of AMI, 201 (87.3%) of non-STEMI and 1576 (90.8%) of STEMI patients achieved TIMI flow grade 3. During hospitalization of STEMI patients, PCI or coronary artery bypass graft (CABG) surgery was performed in 75.3% and 3.4%, respectively; these rates were significantly higher than those in non-STEMI patients. Treatment with PCI during index hospitalization was performed significantly less frequently (p b 0.001) in non-STEMI patients compared with STEMI patients (52.6% and 75.3%, respectively; Table 2). During hospitalization, 285 patients (9.4%) died. As a result, 2736 patients (90.6%) were discharged from the hospital and followed up for an average of 4.3 years. At discharge, aspirin was administered to 2431 patients (88.9%). Calcium antagonists and nitrates were administered to 845 (30.9%) and 1677 patients (61.3%), respectively. ACE inhibitors and β-blockers were administered to 1563 (57.1%) and 880 patients (32.2%), respectively. Compared with STEMI patients, non-STEMI patients received significantly less pharmacotherapy with aspirin and ACEinhibitors (Table 3). Among 2736 patients (90.6%) who were discharged alive and followed for a median of 4.3 years (follow-up rate, 97.1%), 434 patients (15.9%) died. Among them, 250 (57.6%) died from non-cardiac causes. Compared with STEMI patients, non-STEMI
207
Table 3 Medications at discharge (n = 2736). Non-STEMI
STEMI
Total
2736
Overall (%)
549
(%)
2187
(%)
p-value
Aspirin Antiplatelet agents Nitrates ACE inhibitors ARBs Calcium channel blockers LLDs Beta blockers
2431 1440 1677 1563 183 845 628 880
(88.9) (52.6) (61.3) (57.1) (6.7) (30.9) (23.0) (32.2)
458 324 393 263 30 236 131 185
(83.4) (59.0) (71.6) (47.9) (5.5) (43.0) (23.9) (33.7)
1973 1116 1284 1300 153 609 497 695
(90.2) (51.0) (58.7) (59.4) (7.0) (27.8) (22.7) (31.8)
b0.0001 0.001 b0.0001 b0.0001 0.235 b0.0001 0.611 0.418
ACE = angiotensin-converting enzyme, ARB = angiotensin receptor blocker; and LLD = lipid-lowering drug.
patients suffered significantly more adverse outcomes during hospitalization and after hospital discharge (Table 4). At a median follow-up of 4.3 years, 23.8% of patients had died. Among AMI patients, the total mortality rate after the onset of AMI at 1 month, 6 months, 1 year, 2 years, 3 years, or 4 years was 7.9%, 12.3%, 14.4%, 17.4%, 19.9%, or 22.5%, respectively. Among AMI patients who were discharged alive after the index hospitalization, the total mortality rate at 6 months, 1 year, 2 years, 3 years, or 4 years was 3.7%, 5.7%, 9.0%, 11.8%, or 14.3%, respectively. Among them, 250 (57.6%) died from non-cardiac causes. (Fig. 1, Table 4). Advanced age and non-STEMI were associated with poorer outcomes (Figs. 2 and 3). We conducted multivariate analyses using factors such as patient background, acute-phase treatment, and prescription at discharge to examine the relationships between those factors and late prognosis (Table 5). The results of the analysis demonstrated that poor late prognoses were significantly associated with diabetes mellitus, acutephase heart failure, higher serum creatinine level (≥1.2 mg/dl), and advanced age at the onset of AMI (hazard ratio = 1.07 for diabetes, 2.53 for Killip functional class ≥ 2, 1.89 for higher serum creatinine
Table 2 Angiographic findings and invasive approach. Variables Coronary angiography Within 24 h (%) During hospitalization (%) Infarct related artery (%) Right coronary artery Left main trunk Left anterior descending Left circumflex Graft vessels Undefined Number of diseased vessel (%) 0 1 2 3 Undefined Revascularization Within 24 h (%) Onset to revascularization (h) Admission to revascularization (h) Thrombolysis (%) PCI (%) CABG (%) TIMI flow grade 3 (%) During hospitalization PCI (%) CABG (%)
Overall (n = 3021)
Non-STEMI (n = 629)
STEMI (n = 2392)
p-value
2178 (72.1) 2659 (88.0)
307 (48.8) 496 (78.9)
1871 (78.2) 2163 (90.4)
b0.001 b0.001
915 (30.3) 48 (1.6) 1208 (40.0) 409 (13.5) 18 (0.6) 423 (14.0)
95 (15.1) 19 (3.0) 140 (22.3) 207 (32.9) 9 (1.4) 159 (25.3)
820 (34.3) 29 (1.2) 1068 (44.6) 202 (8.4) 9 (0.4) 264 (11.0)
58 (1.9) 1239 (41.0) 588 (19.5) 293 (9.7) 843 (27.9)
12 (1.9) 114 (18.1) 97 (15.4) 84 (13.4) 322 (51.2)
46 1125 491 209 521
(1.9) (47.0) (20.5) (8.7) (21.8)
1965 (65.0) 4.5 (3.1–7.5) 1.6 (1.2–2.1) 491 (16.3) 1755 (58.1) 27 (0.9) 1777 (58.8) 2337 (77.4) 2133 (70.6) 137 (4.5)
230 (36.6) 6.6 (4.0–12.2) 2.1 (1.4–3.8) 30 (4.8) 206 (32.8) 12 (1.9) 201 (32.0) 375 (59.6) 331 (52.6) 55 (8.7)
1735 4.4 1.5 461 1549 15 1576 1962 1802 82
(72.5) (3.0–7.0) (1.2–2.0) (19.3) (64.8) (0.6) (65.9) (82.0) (75.3) (3.4)
CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention; and TIMI: Thrombolysis in Myocardial Infarction. Values are mean ± S.D. (indicated by ±) or median (interquartile range) unless otherwise noted.
b0.001
b0.001
b0.001 b0.001 b0.001 b0.001 b0.001 0.002 b0.001 b0.001 b0.001
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Table 4 Clinical outcome. Variables
Overall (n = 3021)
Non-STEMI (n = 629)
STEMI (n = 2392)
p-value
In-hospital complications (%) Heart failure Free wall rupture Interventricular septum rupture Acute mitral regurgitation Reinfarction Ventricular tachycardia or fibrillation Post infarction angina In-hospital mortality Follow-up Follow-up period (year) Lost to follow-up (%) Long-term outcome (%) Total death Cardiac death Non-cardiac death Death from CAD or non-fatal MI Fatal MI or non-fatal MI Major adverse cardiac events Hospitalization for ischemia Hospitalization for heart failure Revascularization Sudden death
1197 (39.6) 464 (15.4) 54 (1.8) 18 (0.6) 11 (0.4) 78 (2.6) 192 (6.4) 137 (4.5) 285 (9.4)
293 164 4 0 3 21 30 55 80
904 (37.8) 300 (12.5) 50 (2.1) 18 (0.8) 8 (0.3) 57 (2.4) 162 (6.8) 82 (3.4) 205 (8.6)
b0.001 b0.001 0.014 0.029 0.598 0.179 0.067 b0.001 0.002
4.3 (3.0–5.1) 89 (2.9) 719 422 297 527 163 998 331 285 347 37
(46.6) (26.1) (0.6) (0.0) (0.5) (3.3) (4.8) (8.7) (12.7)
4.1 (1.7–5.0) 15 (2.4)
(23.8) (14.0) (9.8) (17.4) (5.4) (33.0) (11.0) (9.4) (11.5) (1.2)
215 120 95 149 49 260 76 96 78 10
(34.2) (19.1) (15.1) (23.7) (7.8) (41.3) (12.1) (15.3) (12.4) (1.6)
4.3 (3.3–5.1) 74 (3.1) 504 (21.1) 302 (12.6) 202 (8.4) 378 (15.8) 114 (4.8) 738 (30.9) 255 (10.7) 189 (7.9) 269 (11.2) 27 (1.1)
b0.001 b0.001 b0.001 b0.001 0.003 b0.001 0.31 b0.001 0.419 0.35
CAD: coronary artery disease; MI: myocardial infarction. Values are mean ± S.D. (indicated by ±) or median (interquartile range) unless otherwise noted.
level, 2.50 for age ≥ 70 years, and 6.80 for age ≥ 80 years, p b 0.001 for all comparisons). 4. Discussion The present study revealed that aggressive acute-phase reperfusion therapy was associated with relatively favorable long-term prognoses, but the prognoses of elderly AMI patients and non-STEMI patients were poor. Among AMI patients who were discharged alive, more than half of them died later from non-cardiovascular causes. In a recent meta-analysis [14], the beneficial effects of primary PCI for AMI patients on 30 day mortality were not influenced by age. Subsequently, the investigators concluded that age should not be considered an exclusion criterion for the use of primary PCI. However, most randomized trials exclude patients with several comorbidities, including renal impairment [15]. Patients with advanced age frequently suffered from renal insufficiency. In the present study, we registered all patients with AMI within 48 h after AMI onset, which led to a higher patient age than that seen in some studies and a decrease in the rate of acute reperfusion therapy; these factors may
have decreased the beneficial effects of acute revascularization on long-term survival of AMI patients (Table 5). These limitations in a real-world setting may correlate with an unfavorable prognosis of AMI in elderly patients. In a recent cohort study [16], Chan et al. demonstrated that nonSTEMI disease was associated with a higher risk of long-term mortality than STEMI disease among MI patients who underwent catheterization. They also found that early revascularization was associated with a lower adjusted risk of mortality for both STEMI and non-STEMI disease. In the present study, non-STEMI patients tended to be late presenters, older, and have a lower rate of acute revascularization compared with STEMI patients. Consequently, nonSTEMI patients may have poorer long-term outcome than STEMI patients. Roger et al. [17] found that the modification of MI definition, especially the introduction of cardiac troponin, caused a rapid increase of non-STEMI disease and that non-STEMI disease now constitutes the majority of MIs. In the present study, we diagnosed MI based on creatine kinase level and its MB fraction as markers of myocardial injury. This may have lead to a lower incidence of nonSTEMI disease in this study. In the Japanese acute coronary syndrome
100
Survival (%)
95
Cardiac
90
Non-cardiac
85
All cause of death 80
75 0
1
2
3
4
5
Years since hospital discharge Fig. 1. Kaplan–Meier curves of vital prognoses of patients who were discharged alive in the HIJAMI registry (n = 2736).
Fig. 2. Kaplan–Meier curves of life prognoses of AMI patients who were discharged alive by age at AMI onset (n = 2736).
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prognosis among AMI patients. Further prospective studies are necessary to evaluate the relationship between these risk factors and prognosis of AMI patients. Studies show that due to the recent development of therapeutic modalities for patients with heart failure, about a half of all deaths among these patients are non-cardiovascular in nature [33]. The results of the present study support these findings. These results highlight the heterogeneity of patients with cardiovascular disease and have implications for the design and interpretation of results of clinical trials aimed at reducing mortality in cardiovascular disease. 5. Limitations
Fig. 3. Kaplan–Meier survival curves of STEMI vs. non-STEMI patients from time of AMI onset.
study [18], a multicenter observational cohort study conducted in the same period as the present study in Japan, the investigators reported that non-STEMI was diagnosed in 12% of 5325 consecutive AMI patients. Because most recurrences of AMI develop at sites remote from the initial infarction [19], prophylactic medical therapy has an important role in preventing further cardiovascular events and improving longterm outcome in AMI patients. Hypertension is an important risk factor for cardiovascular disease [20]. In Japan, advanced antihypertensive therapy has resulted in a reduction in cardiovascular deaths, such as cerebral hemorrhage [21]. Such advances in antihypertensive drugs have also contributed to a significant improvement in the life prognoses of hypertensive patients [22–24]. The mortality of diabetic patients due to coronary artery disease is reported to be approximately two- to four-fold higher than that of non-diabetic patients [25–27]. In recent years, treatment of diabetes mellitus has changed dramatically, and several different types of antidiabetic agents are currently available [28]. However, the evidence concerning the effects of specific glucose-lowering agents on macrovascular disease is limited and inconclusive [29]. The prognosis of diabetic patients with AMI was poorer than for their non-diabetic counterparts in the present study. Further improvement in therapy for diabetic patients with AMI is essential. In observational studies, paradoxical relationships have often been recognized between cardiovascular risk factors and prognosis of patients with cardiovascular disease [30–32]. In the present study, hypercholesterolemia and smoking were not associated with a poorer
Table 5 Cox proportional hazards models for all-cause mortality in all participants of the HIJAMI registry (n = 3021). Variables
p-value
Hazard ratio
95% CI
Female, gender Hypertension Smoking habit Diabetes mellitus Hypercholesterolemia Killip functional class ≥2 Creatinine level (≥1.2 mg/dl) Acute revascularization Age ≥70 years ≥ 80 years
0.18 0.60 0.48 b 0.0001 0.27 b 0.0001 b 0.0001 0.19 b 0.0001 b 0.0001
1.16 0.98 0.93 1.07 0.98 2.53 1.89 0.97 2.50 6.80
0.94–1.45 0.92–1.05 0.77–1.13 1.04–1.10 0.94–1.02 2.08–3.09 1.55–2.31 0.93–1.02 1.95–3.21 5.27–8.78
It is necessary to consider possible bias that may have affected the present findings. The most frequent limitation in the analysis of observational data is that inadequate comparability validity may lead to incorrect interpretations. Therefore, comparative analyses of various treatments will require appropriate risk adjustment. Observational data cannot provide definitive evidence that treatment improves survival, because observational studies cannot fully control for the distribution of important covariates among treatment groups. We cannot exclude possible unmeasured confounding by characteristics that were not examined. Furthermore, pharmacologic adherence was not assessed in this study. Other limitations included lack of precise information on the dose of each drug, drug compliance, duration of treatment, and insufficient safety data during the followup period. Despite these limitations, the results of the present study reflect the actual condition of AMI patients in the contemporary acute revascularization era, because the present study included all AMI patients who were admitted to hospitals, and 97% of participants were discharged alive and followed up for a median of 4.3 years. 6. Conclusions AMI patients treated with both acute revascularization and modern pharmacotherapy have favorable long-term prognoses, and a large proportion of late deaths are non-cardiac in nature. Opportunities exist to improve countermeasures against known coronary risk factors. In particular, the establishment of an optimal management strategy for elderly AMI patients, AMI patients with diabetes, and AMI patients with non-ST elevation are essential. Acknowledgments The authors of this manuscript certify that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [34]. References [1] Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988;2:349–60. [2] An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med 1993;329: 673–82. [3] Stone GW, Grines CL, Rothbaum D, et al. Analysis of the relative costs and effectiveness of primary angioplasty versus tissue-type plasminogen activator: the Primary Angioplasty in Myocardial Infarction (PAMI) trial. The PAMI Trial Investigators. J Am Coll Cardiol 1997;29:901–7. [4] Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock. N Engl J Med 1999;341:625–34. [5] Jeger RV, Radovanovic D, Hunziker PR, et al. Ten-year trends in the incidence and treatment of cardiogenic shock. Ann Intern Med 2008;149:618–26. [6] Fox KA, Steg PG, Eagle KA, et al. Decline in rates of death and heart failure in acute coronary syndromes, 1999–2006. JAMA 2007;297:1892–900. [7] Kushner FG, Hand M, Smith Jr SC, et al. Focused updates: ACC/AHA Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction (updating the 2004
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