Abstract
Background:
Little is known about the threshold level of low‐density lipoprotein cholesterol (LDL‐C) for statin therapy in acute myocardial infarction (AMI).
Hypothesis:
The aim of this study was to investigate the short‐term benefit of the statin in post‐MI patients with low LDL‐C levels.
Methods:
Between November 2005 and January 2008, 6866 statin‐naive patients were selected from the Korea AMI registry. Major adverse cardiac event (MACE) was defined as a composite of death, recurrent MI, and revascularizations.
Results:
The 6‐month MACE and mortality showed a U‐shaped curve, with the lowest rate at 114–122 mg/dL. Propensity scores for statin use were calculated for patients with LDL‐C ≤ 113 mg/dL, and they were used to match the patients who received statin (statin user, n = 1031) with those who did not receive it (statin nonuser, n = 1031). The 6‐month MACE was not significantly different between statin users and statin nonusers (9.4% vs 11.0%; hazard ratio [HR]: 0.847, 95% confidence interval [CI]: 0.646‐1.111, P = 0.230), whereas the 6‐month mortality was significantly lower in statin users (7.2% vs 9.7%; HR: 0.728, 95% CI: 0.539–0.984, P = 0.039). However, when the analyses were repeated in the patients with LDL‐C ≤ 105 mg/dL, not only the 6‐month MACE (9.5% vs 9.9%; HR: 0.945, 95% CI: 0.700–1.277, P = 0.713) but also the 6‐month mortality (7.0% vs 8.7%; HR: 0.793, 95% CI: 0.566–1.111, P = 0.177) was not significantly different between statin users and statin nonusers (n = 876 in each group).
Conclusions:
The beneficial effects of statin therapy seem to vanish when LDL‐C is below a certain level in AMI patients. © 2011 Wiley Periodicals, Inc.
Jeong, Kim and Chae received funding from the Korean Society of Cardiology. J.H. Lee, Yang, H.S. Park and Chae received grants from GlaxoSmithKline and Pfizer.
Introduction
Numerous studies have demonstrated that statins reduce the risk of recurrent cardiovascular events and improve survival in patients with acute myocardial infarction (AMI).1, 2, 3, 4, 5 The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study reported that a statin, even in patients with lower low‐density lipoprotein cholesterol (LDL‐C), reduces recurrent ischemic events in the early period following AMI.5 Current guidelines recommend that statin therapy should be initiated soon after AMI, regardless of LDL‐C levels,6, 7, 8 with the target LDL‐C < 70 mg/dL. However, the population with LDL‐C < 100 mg/dL, which used to be the target LDL‐C, has never been specifically studied in these trials.
The AMI patients in the Asian population are known to have low LDL‐C, and they have not been included to a great extent in statin trials.9 The aim of this study is to investigate the “MIRACL‐like” short‐term benefit of the statin in post‐MI patients with low LDL‐C levels through analysis of the Korean AMI Registry (KAMIR).
Methods
Study Population
The KAMIR is a Korean, prospective, open, observational, multicenter, online registry of AMI with support of the Korean Society of Cardiology. Details of KAMIR have been published.10 Between November 2005 and January 2008, 14871 patients suspected of having AMI at admission were enrolled in the KAMIR, and 11942 patients with a final diagnosis of AMI were analyzed for this study. Among these patients, baseline clinical data of 10909 patients were available. Among them, 719 (6.7%) who had already received statin therapy before hospitalization were excluded from this study. Lipid levels were obtained within the first 24 hours of admission in 7002 patients. The LDL‐C levels were calculated by the Friedewald formula. Patients with a triglyceride level ≥400 mg/dL (n = 316) were excluded. Finally, 6866 patients were included in the analysis.
Acute MI was diagnosed by characteristic clinical presentation, serial changes on the electrocardiogram suggesting infarction or injury, and increase in cardiac enzymes.11
We analyzed baseline demographic characteristics, initial presentation, initial vital signs, electrocardiographic findings, results of laboratory tests, procedural data, and medications. Blood samplings for baseline laboratory tests, except for the lipid measurement, were collected at admission or before percutaneous coronary intervention (PCI). Overnight fasting blood was also sampled for lipid levels. Left ventricular ejection fraction was determined by 2‐dimensional echocardiography. In‐hospital complications and their management were also recorded.
The 6‐month major adverse cardiac events (MACE) were defined as death (cardiac death and noncardiac death), recurrent MI, and revascularizations (PCI and coronary artery bypass grafting). Follow‐up data were obtained by reviewing medical records and telephone interviews with patients. All data were recorded on an electronic Web page–based case‐report form.
Statistical Analyses
Data are expressed as mean ± standard deviation for continuous variables and as percentages for categorical variables. All comparisons between baseline variables were assessed with the Student t test for continuous variables and the Pearson χ 2 test for categorical variables. Patients were divided into 2 groups: those who received statin therapy and those who did not receive it during hospitalization and at discharge. Because the patients were not randomly assigned to statin therapy, propensity‐score (PS) matching, based on the probability of statin use, was performed to reduce the effect of treatment‐selection bias and potential confounding factors. For each patients, a PS, indicating the likelihood of statin use during hospitalization and at discharge, was calculated using a nonparsimonious multivariate logistic regression model.12 Goodness of fit of the PS was evaluated by the C statistic and the Hosmer‐Lemeshow test. In the PS‐matched cohort, the risks of each outcome were compared with the use of Cox regression models. The rate of MACE and mortality by statin use were compared by Kaplan‐Meier survival curves. Same statistical procedures were repeated for each LDL‐C decile to detect a possible threshold level of LDL‐C for beneficial effects of the statins. For all analyses, a 2‐sided P value <0.05 was considered statistically significant. Statistical analysis was performed using SAS software, version 9.1 (SAS Institute, Inc., Cary, NC).
Results
The prescription rate of statin therapy significantly decreased as LDL‐C levels decreased (data not shown). The rates of 6‐month MACE and mortality showed a U‐ shaped curve, with higher event rates in very low (<70 mg/dL) and very high LDL‐C levels (>166 mg/dL), and the lowest rate was at 114–122 mg/dL (Figure 1A,B). The rates of 6‐month MACE and mortality were significantly higher in patients with a LDL‐C level ≤105 mg/dL or >166 mg/dL, compared with those whose LDL‐C level ranged from 114 mg/dL to 122 mg/dL.
Figure 1.
The rate of 6‐month MACE (A) and 6‐month mortality (B) by deciles of LDL‐C levels. Abbreviations: LDL‐C, low‐density lipoprotein cholesterol; MACE, major adverse cardiac events.
Baseline characteristics and medications before and after PS matching are shown in Tables 1, 2, respectively. The mean age of the 2062 PS‐matched patients with a LDL‐C level ≤113 mg/dL was 66.6 ± 12.5 years, and 1521 (73.8%) of them were men. Before PS matching, statin nonusers were older and thinner. They were more likely to have higher Killip classes, cardiogenic shock, ventricular tachyarrhythmia, and heart failure. Cardiopulmonary resuscitation and mechanical ventilation were more frequently performed in statin nonusers, whereas PCI was more frequently performed in statin users. Antiplatelet agents, β‐blockers, and angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers were also more frequently prescribed in statin users during hospitalization and at discharge. After PS matching, all baseline covariates were balanced between statin users and statin nonusers. The mean LDL‐C was 84.0 ± 20.7 mg/dL (range, 45–113 mg/dL).
Table 1.
Baseline Characteristics by Statin Use Before and After PS Matching in Patients With LDL‐C Levels ≤113 mg/dL
| Statins Before PS Match | Statins After PS Match | |||||
|---|---|---|---|---|---|---|
| No, n = 1067 | Yes, n = 2296 | P Value | No, n = 1031 | Yes, n = 1031 | P Value | |
| Demographics | ||||||
| Age (y) | 67.0 ± 12.7 | 64.8 ± 12.4 | <0.001 | 66.7 ± 12.6 | 66.6 ± 12.3 | 0.824 |
| Male sex | 784 (73.5) | 1729 (75.3) | 0.256 | 766 (74.3) | 755 (73.2) | 0.582 |
| Height (cm) | 163.7 ± 8.4 | 164.0 ± 8.6 | 0.349 | 163.8 ± 8.4 | 163.8 ± 8.6 | 0.994 |
| Weight (kg) | 62.4 ± 11.1 | 63.9 ± 11.3 | 0.001 | 62.6 ± 11.0 | 62.5 ± 11.0 | 0.797 |
| BMI (kg/m2) | 23.2 ± 3.1 | 23.7 ± 3.2 | <.001 | 23.3 ± 3.1 | 23.2 ± 3.2 | 0.848 |
| Initial presentation | ||||||
| Prehospital resuscitation | 24 (2.3) | 37 (1.6) | 0.199 | 22 (2.1) | 21 (2.0) | 0.883 |
| Typical chest pain | 877 (84.1) | 1982 (87.4) | 0.009 | 860 (85.3) | 868 (86.0) | 0.650 |
| Dyspnea | 287 (28.2) | 595 (27.0) | 0.480 | 268 (27.2) | 275 (27.7) | 0.809 |
| Preinfarct angina pectoris | 406 (38.2) | 958 (42.0) | 0.037 | 397 (38.7) | 384 (37.5) | 0.602 |
| SBP (mm Hg) | 125.2 ± 28.3 | 127.0 ± 28.2 | 0.094 | 125.4 ± 28.1 | 125.6 ± 29.3 | 0.871 |
| Heart rate (bpm) | 77.8 ± 20.8 | 76.7 ± 19.8 | 0.136 | 77.3 ± 20.2 | 77.7 ± 21.4 | 0.671 |
| Killip class >1 | 330 (31.9) | 511 (22.9) | <0.001 | 306 (30.6) | 295 (29.6) | 0.633 |
| ECG on admission | ||||||
| STEMI | 626 (58.7) | 1465 (63.8) | 0.004 | 613 (59.5) | 612 (59.4) | 0.964 |
| Anterior MI | 436 (43.7) | 995 (45.0) | 0.516 | 424 (44.0) | 450 (45.5) | 0.526 |
| Inferior MI | 385 (38.6) | 869 (39.3) | 0.726 | 373 (38.7) | 363 (36.7) | 0.346 |
| Heart rhythm on admission | ||||||
| Sinus rhythm | 907 (87.8) | 2056 (91.3) | 0.002 | 886 (88.9) | 898 (88.6) | 0.828 |
| Atrial flutter/AF | 60 (5.8) | 96 (4.3) | 0.053 | 51 (5.1) | 58 (5.7) | 0.549 |
| VT/VF | 13 (1.3) | 15 (0.7) | 0.087 | 12 (1.2) | 11 (1.1) | 0.802 |
| History | ||||||
| Previous CHD | 170 (16.0) | 320 (14.0) | 0.124 | 161 (15.7) | 154 (15.0) | 0.675 |
| Hypertensiona | 517 (49.0) | 1085 (47.7) | 0.482 | 497 (48.7) | 489 (47.9) | 0.723 |
| DMb | 310 (29.5) | 621 (27.4) | 0.213 | 297 (29.3) | 298 (29.3) | 0.995 |
| Hyperlipidemiac | 42 (4.6) | 155 (7.8) | 0.002 | 41 (4.7) | 39 (4.4) | 0.795 |
| Current smoking | 443 (41.7) | 1034 (45.3) | 0.052 | 437 (42.6) | 440 (42.9) | 0.894 |
| Previous CHF | 24 (2.3) | 26 (1.1) | 0.010 | 18 (1.8) | 19 (1.9) | 0.892 |
| Previous CVD | 79 (7.7) | 136 (6.0) | 0.073 | 72 (7.2) | 74 (7.3) | 0.913 |
| Previous PVD | 10 (1.0) | 27 (1.2) | 0.576 | 9 (0.9) | 9 (0.9) | 1.000 |
| LVEF (%) | 51.0 ± 26.2 | 51.4 ± 12.3 | 0.680 | 51.2 ± 26.4 | 50.2 ± 12.7 | 0.341 |
| Laboratory findings | ||||||
| Glucose (mg/dL) | 170.0 ± 81.9 | 168.9 ± 81.9 | 0.718 | 169.8 ± 81.8 | 172.3 ± 83.7 | 0.499 |
| Serum Cr (mg/dL) | 1.29 ± 1.48 | 1.20 ± 1.49 | 0.089 | 1.28 ± 1.47 | 1.21 ± 1.15 | 0.199 |
| Peak CK‐MB (ng/mL) | 147.8 ± 349.2 | 149.8 ± 364.1 | 0.884 | 149.4 ± 354.2 | 159.5 ± 452.3 | 0.572 |
| Total cholesterol (mg/dL) | 150.2 ± 26.5 | 156.7 ± 25.8 | <0.001 | 151.0 ± 26.0 | 151.3 ± 27.3 | 0.744 |
| TG (mg/dL) | 110.5 ± 71.3 | 117.4 ± 73.6 | 0.010 | 111.4 ± 71.5 | 113.0 ± 73.5 | 0.626 |
| HDL‐C (mg/dL) | 44.5 ± 12.8 | 44.5 ± 12.8 | 0.923 | 44.6 ± 12.7 | 44.9 ± 13.4 | 0.566 |
| LDL‐C (mg/dL) | 83.6 ± 20.2 | 88.7 ± 19.7 | <0.001 | 84.1 ± 19.8 | 83.8 ± 21.5 | 0.777 |
| PCI at index hospitalization | 802 (75.2) | 1934 (84.2) | <0.001 | 796 (77.3) | 795 (77.1) | 0.926 |
| In‐hospital complication | ||||||
| Cardiogenic shock | 87 (8.5) | 108 (4.8) | <0.001 | 74 (7.5) | 69 (6.9) | 0.611 |
| New atrial flutter/AF | 17 (1.7) | 31 (1.4) | 0.529 | 16 (1.6) | 16 (1.6) | 1.000 |
| VT/VF during hospitalization | 62 (6.1) | 99 (4.4) | 0.041 | 59 (6.0) | 60 (6.0) | 0.979 |
| HF | 242 (23.7) | 441 (19.6) | 0.008 | 229 (23.1) | 238 (23.1) | 0.744 |
| Acute renal failure | 17 (1.7) | 20 (0.9) | 0.052 | 17 (1.7) | 15 (1.5) | 0.696 |
| CVA | 7 (0.7) | 12 (0.5) | 0.597 | 7 (0.7) | 9 (0.9) | 0.633 |
| Major bleeding | 11 (1.1) | 12 (0.5) | 0.085 | 8 (0.8) | 10 (1.0) | 0.654 |
| Management of in‐hospital complication | ||||||
| In‐hospital resuscitation | 50 (4.9) | 73 (3.2) | 0.020 | 47 (4.8) | 42 (4.2) | 0.539 |
| Defibrillation/cardioversion | 49 (4.8) | 78 (3.5) | 0.065 | 46 (4.6) | 46 (4.6) | 1.000 |
| Mechanical ventilator | 77 (7.6) | 92 (4.1) | <0.001 | 65 (6.5) | 65 (6.5) | 1.000 |
Abbreviations: AF, atrial fibrillation; BMI, body mass index; CHD, coronary heart disease; CHF, congestive heart failure; CK‐MB, creatine‐kinase MB; Cr, creatinine; CVA, cerebrovascular accident; CVD, cerebrovascular disease; DM, diabetes mellitus; ECG, electrocardiogram; HDL‐C, high‐density lipoprotein cholesterol; HF, heart failure; LDL‐C, low‐density lipoprotein cholesterol; MI, myocardial infarction; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; PS, propensity score; PVD, peripheral vascular disease; SBP, systolic blood pressure; STEMI, ST‐elevation myocardial infarction; TG, triglycerides; VF, ventricular fibrillation; VT, ventricular tachycardia.
Data are expressed as mean ± standard deviation or n (%).
Defined as previously diagnosed by a physician, receiving medication to lower blood pressure.
Defined as previously diagnosed by a physician, receiving medication to lower blood glucose.
Defined as previously diagnosed by a physician, receiving lipid‐lowering drugs.
Table 2.
Medications by Statin Use Before and After PS Matching in Patients With LDL‐C Levels ≤113 mg/dL
| Statins Before PS Match | Statins After PS Match | |||||
|---|---|---|---|---|---|---|
| No, n = 1067 | Yes, n = 2296 | P Value | No, n = 1031 | Yes, n = 1031 | P Value | |
| Previous medications | ||||||
| Antiplatelet agents | 139 (13.0) | 234 (10.2) | 0.015 | 130 (12.6) | 133 (12.9) | 0.843 |
| β‐Blockers | 78 (7.3) | 134 (5.8) | 0.102 | 72 (7.0) | 71 (6.9) | 0.931 |
| ACEIs/ARBs | 98 (9.2) | 141 (6.1) | 0.001 | 94 (9.1) | 91 (8.8) | 0.817 |
| CCBs | 101 (9.5) | 207 (9.0) | 0.674 | 99 (9.6) | 103 (10.0) | 0.767 |
| Diuretics | 59 (5.5) | 92 (4.0) | 0.047 | 50 (4.8) | 45 (4.4) | 0.599 |
| Nitrates | 67 (6.3) | 85 (3.7) | 0.001 | 59 (5.7) | 63 (6.1) | 0.709 |
| In‐hospital medications | ||||||
| Antiplatelet agents | 1050 (98.4) | 2284 (99.7) | <0.001 | 1026 (99.5) | 1022 (99.3) | 0.560 |
| β‐Blockers | 705 (66.1) | 1704 (74.3) | <0.001 | 693 (67.2) | 715 (69.5) | 0.268 |
| ACE‐Is/ARBs | 810 (75.9) | 1904 (83.1) | <0.001 | 793 (76.9) | 800 (77.7) | 0.653 |
| Heparin | 808 (75.7) | 1836 (80.1) | 0.004 | 785 (76.1) | 781 (75.9) | 0.898 |
| CCBs | 163 (15.3) | 277 (12.1) | 0.011 | 154 (14.9) | 150 (14.6) | 0.818 |
| Diuretics | 380 (35.6) | 686 (29.9) | 0.001 | 358 (34.7) | 368 (35.8) | 0.622 |
| Nitrates | 758 (71.0) | 1625 (70.9) | 0.933 | 737 (71.5) | 721 (70.1) | 0.480 |
| Discharge medications | ||||||
| Antiplatelet agents | 937 (97.3) | 2198 (99.1) | <0.001 | 929 (98.3) | 954 (97.9) | 0.561 |
| β‐Blockers | 643 (66.8) | 1577 (71.1) | 0.015 | 635 (67.2) | 671 (68.9) | 0.426 |
| ACEIs/ARBs | 737 (76.5) | 1862 (83.9) | <0.001 | 729 (77.1) | 742 (76.2) | 0.618 |
| CCBs | 130 (13.5) | 249 (11.2) | 0.071 | 124 (13.1) | 122 (12.5) | 0.696 |
| Diuretics | 244 (25.3) | 510 (23.0) | 0.153 | 238 (25.2) | 251 (25.8) | 0.769 |
| Nitrates | 496 (51.5) | 1050 (47.3) | 0.033 | 482 (51.0) | 491 (50.4) | 0.794 |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; LDL‐C, low‐density lipoprotein cholesterol; PS, propensity score.
Data are expressed as n (%).
Covariates included in the analysis are in Tables 2 and 3. During the follow‐up, 210 (10.2%) MACE occurred in the matched cohort with a LDL‐C level ≤113 mg/dL, including death, recurrent MI, and revascularization (Table 3). In the Cox proportional hazards model, there was no significant difference in the rate of 6‐month MACE between statin users (9.4%) and statin nonusers (11.0%; hazard ratio [HR]: 0.847, 95% confidence interval [CI]: 0.646–1.111, P = 0.230). The 6‐month mortality was significantly lower in statin users compared with statin nonusers (7.2% vs 9.7%; HR: 0.728, 95% CI: 0.539–0.984, P = 0.039). However, the difference of the rate of 6‐month MACE and mortality between statin users and statin nonusers decreased as baseline LDL‐C levels decreased. The reduction of 6‐month mortality was no longer significant in patients with LDL‐C levels of ≤105 mg/dL (mean, 79.8 ± 19.1 mg/dL; range, 43–105 mg/dL) between statin users (7.0%) and statin nonusers (8.7%; HR: 0.793, 95% CI: 0.566–1.111, P = 0.177) (Table 3). Kaplan‐Meier survival estimates for 6‐month MACE and mortality are in figures 2 and 3.
Table 3.
Hazard Ratios for 6‐Month Clinical Outcomes in the Matched Cohort for Each LDL‐C Cholesterol Decile
| Statins | Statins vs No Statins | |||
|---|---|---|---|---|
| Endpoint | Yes | No | Hazard Ratio (95% CI) | P Value |
| LDL‐C ≤ 113 mg/dL, n = 1031 | ||||
| Death, recurrent MI, or revascularization | 97 (9.4) | 113 (11.0) | 0.847 (0.646–1.111) | 0.230 |
| Death or recurrent MI | 85 (8.2) | 103 (10.0) | 0.814 (0.611–1.085) | 0.160 |
| Death from any cause | 74 (7.2) | 100 (9.7) | 0.728 (0.539–0.984) | 0.039 |
| Death from cardiac cause | 54 (5.2) | 74 (7.2) | 0.719 (0.506–1.021) | 0.066 |
| Death from noncardiac cause | 20 (1.9) | 26 (2.5) | 0.754 (0.421–1.351) | 0.343 |
| LDL‐C ≤ 105 mg/dL, n = 876 | ||||
| Death, recurrent MI, or revascularization | 83 (9.5) | 87 (9.9) | 0.945 (0.700–1.277) | 0.713 |
| Death or recurrent MI | 71 (8.1) | 79 (9.0) | 0.890 (0.646–1.226) | 0.476 |
| Death from any cause | 61 (7.0) | 76 (8.7) | 0.793 (0.566–1.111) | 0.177 |
| Death from cardiac cause | 44 (5.0) | 56 (6.4) | 0.777 (0.523–1.153) | 0.210 |
| Death from noncardiac cause | 17 (1.9) | 20 (2.3) | 0.838 (0.439–1.600) | 0.593 |
Abbreviations: CI, confidence interval; LCL‐C, low‐density lipoprotein cholesterol; MI, myocardial infarction.
Data are expressed as n (%).
Figure 2.
Kaplan‐Meier estimates of the rate of 6‐month MACE including death, recurrent MI, or revascularization by statins use in patients with LDL‐C ≤ 113 mg/dL (A) and ≤105 mg/dL (B). Abbreviations: LDL‐C, low‐density lipoprotein cholesterol; MACE, major adverse cardiac events; MI, myocardial infarction.
Figure 3.
Kaplan‐Meier estimates of 6‐month mortality by statins use in patients with LDL‐C ≤ 113 mg/dL (A) and ≤105 mg/dL (B). Abbreviations: LDL‐C, low‐density lipoprotein cholesterol.
Discussion
In this multicenter observational study, the main findings were that the rate of 6‐month MACE and mortality showed a U‐shaped curve with higher event rates at very low and very high LDL‐C levels, and statin therapy was not beneficial in reducing the rate of 6‐month MACE and mortality in patients with LDL‐C ≤ 105 mg/dL.
In epidemiological studies, LDL‐C levels and the risk of coronary heart disease (CHD) showed a log‐linear relationship; the risk of CHD rose steeply as LDL‐C levels increased.8, 13 In contrast, U‐shaped associations between total cholesterol levels and mortality have been consistently documented in dialysis patients, elderly individuals, and patients with heart failure or CHD.14, 15, 16 There are 2 plausible mechanisms that can explain the paradox: either reverse causation, in which advanced cardiovascular disease leads to inflammation and/or malnutrition and lower cholesterol levels, or a confounding effect of inflammation and/or malnutrition, which leads to lower cholesterol levels and higher mortality.17 In the present study, the rate of 6‐month MACE showed a U‐shaped curve. Patients with lower LDL‐C levels were older and thinner, and had more high‐risk features. The mechanisms mentioned above might also explain in part this relationship in our study.
Experimental studies have demonstrated that statin therapy decreases the extent of myocardial necrosis, preserves myocardial viability, and results in increased ventricular function in models of myocardial ischemia reperfusion injury.18, 19 Statins' cardioprotective effect after AMI during long‐term treatment can be partly explained by their pleiotropic effects, such as anti‐inflammatory, antiplatelet, and antithrombotic properties, and improvements in endothelial function.20, 21, 22, 23, 24 However, clinical data on the beneficial effects of statins in the acute phase of AMI have shown conflicting results. Observational studies on patients with AMI have suggested that early statin therapy is associated with reduced in‐hospital and 1‐year mortality.3, 4 In a placebo‐controlled randomized study (MIRACL trial), a high dose of atorvastatin reduced recurrent ischemic events in the first 16 weeks; however, they were mostly recurrent symptomatic ischemia requiring rehospitalization, and the reductions had only a marginal significance.5 On the other hand, a nonrandomized study on the early use of statins in patients with acute coronary syndrome (ACS) indicated no benefit in terms of death, MI, or recurrent ischemia at 90 days.25 Furthermore, as for the subset of patients with cholesterol levels below treatment guidelines, early statin therapy was associated with higher adjusted risk for death or MI.
Results of our study differ from the previous studies in several aspects. First, our study included patients with LDL‐C levels lower than the upper limit of inclusion criteria in previous statin studies.2, 5 For example, although the MIRACL study enrolled ACS patients with relatively low baseline LDL‐C, their mean LDL‐C level was 124 mg/dL, which is much higher than the mean LDL‐C level of our study (79.8 mg/dL). Furthermore, in the previous 2 observational studies that reported beneficial effects of early statin therapy, the cholesterol levels were not clearly stated.3, 4 Second, in the present study, both types of AMI were included and >75% of patients underwent PCI. In contrast, the MIRACL trial only enrolled medically treated patients with unstable angina and non–Q‐wave AMI. Accordingly, the results of the MIRACL trial cannot be applied to all AMI patients requiring interventional treatment or surgical revascularization in the real world. Finally, racial difference may also have contributed to observed differences.26, 27 The beneficial effect of statin therapy in Asian ACS patients with lower LDL‐C levels has not been clearly studied.2, 8 We could not see the short‐term benefit of statins in our patients with low LDL‐C (<105 mg/dL) as in the MIRACL study. Therefore, the current recommendation for the routine use of statins in ACS patients, which seems not to be based on solid evidence, should be further evaluated, at least in this region of the world.
Study Limitations
Our study has several potential limitations. First, because the KAMIR is an observational study, statin therapy was not randomly administered to patients during hospitalization or at discharge. Although propensity analysis was performed for a large number of confounding factors, a registry study cannot adjust for all confounders. Second, we could not examine the effects of specific types of statins or dosages on observed outcomes. Moreover, our data seem to be limited only to a standard low dose of statins. Our national medical insurance system used to reimburse only a standard low dose of statins, and this may have resulted in the low dosage. A high‐dose statin provided significant benefit compared with a low dose in a comparative study in ACS patients.2 However, this result also cannot be directly extrapolated to the low LDL‐C population, because the mean LDL‐C level of the study patients was also much higher than the mean LDL‐C, 79.8 mg/dL, of our patients. Third, data on adherence to statin therapy throughout the follow‐up period were not available. We were unable to determine whether patients who were discharged with a statin kept on taking it during the following months, and whether patients who were discharged without a statin started taking one afterward. Fourth, follow‐up lipid profiles were not available, and we could not ascertain whether the results were associated with changes in follow‐up lipid profile over time.
Conclusion
In conclusion, our study suggests possible existence of a threshold LDL‐C level for the short‐term benefit of statins in the patients with AMI, which should be confirmed in randomized trials including an adequate number of patients with lower levels of LDL‐C.
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