The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) reduce major adverse cardiac events (MACE) and mortality in patients with acute coronary syndrome. We investigated the effectiveness of statin therapy in reducing MACE in patients with acute myocardial infarction (AMI) and renal dysfunction (RD). In the present retrospective study of 12,853 patients with AMI, the patients were categorized into 4 groups: group I, statin therapy and no RD (estimated glomerular filtration rate ≥60 ml/min/1.73 m 2 ); group II, neither statin therapy nor RD; group III, statin therapy and RD; group IV, no statin therapy but RD. The primary end points were death and complications during the hospital course. The secondary end points were MACE during 1 year of follow-up after AMI. Significant differences in the composite MACE during 12 months of follow-up were observed among the 4 groups (group I, 11.7%; group II, 19.0%; group III, 26.7%; and group IV, 45.5%; p <0.001). In a Cox proportional hazards model, mortality at 12 months increased stepwise from group II to IV compared to group I. Moreover, MACE-free survival in the severe RD group (estimated glomerular filtration rate <30 mL/min/1.73 m 2 ) was also greater in the statin-treated group. In conclusion, statin therapy reduced MACE at 1 year of follow-up in patients with AMI regardless of RD.
Despite the evidence showing the benefit of statin therapy, several studies have revealed that statins are prescribed less frequently to those with renal impairment. In addition, the effect of statins on coronary artery disease in patients with renal dysfunction (RD) is still controversial. It has been recently reported that statin therapy in patients with acute myocardial infarction (AMI) with low-density lipoprotein cholesterol levels <70 mg/dl was associated with improved clinical outcomes. Therefore, we have investigated further the effects of statin use in patients with AMI and RD.
Methods
The Korea Acute Myocardial Infarction Registry (KAMIR) is a Korean retrospective multicenter on-line registry designed to describe the characteristics and clinical outcomes of Korean patients with AMI and reflect the current practice of management in Korea. The registry included 52 community and university hospitals for primary percutaneous coronary intervention, and enrollment of 13,901 patients. Data were collected at each site by a well-trained study coordinator using a standardized protocol. The ethics committee at each participating institution approved the study protocol.
The study included a retrospective cohort of 12,865 consecutive patients (age 64 ± 13 years; 70% men) who were admitted to the hospital from November 2005 to July 2008 and who had a discharge diagnosis of AMI as determined by cardiac enzyme measurements and electrocardiographic findings. A total of 3,256 patients with AMI and renal insufficiency were included in the present study.
The patients were categorized into 4 groups on the basis of the presence of statin therapy and RD (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m 2 ). Group I (n = 7,553) received statin therapy and had no RD (eGFR ≥60 ml/min/1.73 m 2 ); group II did not receive statin therapy and did not have RD (n = 2056); group III received statin therapy and had RD (n = 2,218); and group IV received no statin therapy but had RD (n = 1,038).
AMI was defined by clinical signs or symptoms, including increased cardiac biomarkers (creatine kinase-MB, troponin I, or troponin T) and 12-lead electrocardiographic findings. Among the patients with AMI, ST-segment elevation myocardial infarction was defined by the presence of a new ST-segment elevation of ≥1 mm (0.1 mV) in continuous leads or a new left bundle branch block on the index on electrocardiogram, and non–ST-segment elevation myocardial infarction was defined by the non–ST-segment elevation myocardial infarction elevations. The left ventricular ejection fraction was checked using 2-dimensional echocardiography. The primary end points were death and complications during the hospital course. The secondary end points were major adverse cardiac events (MACE) (cardiogenic death, myocardial infarction, or stroke) and the need for emergency or elective repeat revascularization or coronary artery bypass grafting during follow-up.
RD was defined as an eGFR of <60 ml/min/1.73 m 2 . The creatinine level was measured before angiography, and renal function was assessed using the eGFR and the abbreviated Modification of Diet in Renal Disease formula.
The baseline variables were age; gender; body mass index; coronary risk factors, including hypertension (defined as a history of hypertension, admission blood pressure >140 mm Hg systolic or >90 mm Hg diastolic), current smoking, history of ischemic heart disease, hyperlipidemia (defined as a history of hyperlipidemia, total cholesterol level 240 mg/dL, or low-density lipoprotein cholesterol level of >101 mg/dl), and diabetes mellitus (DM; defined as a history of DM or random blood glucose level of >200 mg/dl); clinical symptoms at admission (chest pain or dyspnea); and Killip class.
The use of certain medications (ie, aspirin, angiotensin-converting enzyme inhibitor, diuretics, statin, β blockers, vasopressors) was recorded on admission. The surgical interventions (coronary artery bypass grafting, thrombolysis, percutaneous coronary intervention) and coronary care unit stays were recorded.
All patients were regularly followed up at 1, 6, and 12 months after discharge from the hospital. No patient was lost to follow-up. Asymptomatic routine follow-up angiography was not mandatory. The primary end points were death and complications, including cardiogenic shock, ventricular tachycardia, and fibrillation (need for an antiarrhythmic agent and/or defibrillation), atrioventricular block (need for a pacemaker), recurrent ischemia and myocardial infarction, and cerebrovascular accident, major bleeding, or multiorgan failure during hospitalization. The secondary end points were MACE, including cardiac death, myocardial infarction, or stroke, and the need for emergency or elective repeat revascularization or coronary artery bypass grafting surgery during follow-up. Target lesion revascularization was defined as repeat intervention (surgical or percutaneous) driven by a lesion in the stent or within 5 mm of the stent borders.
Continuous variables with a normal distribution are expressed as the mean ± SD for the 4 groups and were compared using 1-way analysis of variance. Continuous data with a skewed distribution are presented as the median (25th and 75th percentiles) and were compared using the Kruskal-Wallis test. Categorical variables were compared using the chi-square test, as appropriate. All p values were 2-sided, and p <0.05 indicated statistical significance. Multivariate analyses were performed to determine the prognostic significance of clinical variables for long-term clinical end points. Cox proportional hazards modeling was used to examine the relation of survival with a prespecified list of risk factors, including kidney function on MACE. The analyses were adjusted for age, gender, Killip class 4 myocardial infarction, hypertension, DM, smoking, hyperlipidemia, percutaneous coronary intervention, high-sensitive C-reactive protein, and medication (β blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, calcium channel blockers, diuretics, and statins) during 1 year of follow-up. Statistical analysis was done using the Statistical Package for Social Sciences software, version 17.0, for Windows (SPSS, Chicago, Illinois).
Results
A total of 12,865 patients with AMI were included in the present study. The patients from groups I and II were younger than those from groups III and IV, had a greater proportion of men, had lower rates of previous hypertension and DM, had a lower prevalence of non–ST-segment elevation myocardial infarction and Killip class 4 myocardial infarction, and had reduced levels of N-terminal probrain natriuretic peptide and high-sensitive C-reactive protein ( Tables 1 and 2 ). However, groups I and II had greater rates of a history of smoking, greater systolic blood pressure, and an increased left ventricular ejection fraction. The level of total cholesterol and low-density lipoprotein cholesterol was greater in groups I and III relative to groups II and IV, respectively.
| Baseline Variable | Statin and No RD (n = 7,553) | No Statin and No RD (n = 2,056) | Statin and RD (n = 2,218) | No Statin but RD (n = 1,038) | p Value |
|---|---|---|---|---|---|
| Age (years) | 60.7 ± 12.4 | 62.5 ± 12.7 | 70.6 ± 10.7 | 71.0 ± 10.6 | 0.000 |
| Men | 5,740 (76%) | 1,550 (76%) | 1,177 (53%) | 583 (56%) | 0.001 |
| Body mass index (kg/m 2 ) | 24.2 ± 3.5 | 23.8 ± 3.6 | 23.7 ± 3.4 | 23.0 ± 3.4 | 0.000 |
| Hypertension | 3,209 (43%) | 868 (43%) | 1,494 (68%) | 661 (64%) | 0.000 |
| Diabetes mellitus | 1,706 (23%) | 487 (24%) | 921 (42%) | 446 (43%) | 0.000 |
| Smoking | 4,778 (64%) | 1,229 (61%) | 938 (43%) | 399 (39%) | 0.000 |
| Hyperlipidemia | 781 (10%) | 118 (6%) | 274 (12%) | 57 (6%) | 0.017 |
| Ischemic heart disease history | 1,019 (14%) | 298 (15%) | 523 (24%) | 227 (22%) | 0.000 |
| Systolic blood pressure (mm Hg) | 130 ± 27 | 127 ± 27 | 126 ± 33 | 118 ± 36 | 0.000 |
| Diastolic blood pressure (mm Hg) | 80 ± 16 | 79 ± 23 | 76 ± 19 | 73 ± 36 | 0.000 |
| ST-segment elevation myocardial infarction | 4,750 (63%) | 1,523 (61%) | 1,240 (56%) | 571 (55%) | 0.000 |
| Non–ST-segment myocardial infarction | 2,803 (37%) | 803 (39%) | 978 (44%) | 467 (45%) | 0.000 |
| Variable | Statin and No RD (n = 7,553) | No Statin and No RD (n = 2,056) | Statin and RD (n = 2,218) | No Statin but RD (n = 1,038) | p Value |
|---|---|---|---|---|---|
| Glomerular filtration rate (ml/min) | 87.6 ± 19 | 86.3 ± 19.7 | 42.9 ± 15.1 | 40.2 ± 15.7 | 0.000 |
| Creatinine (mg/dl) | 0.9 ± 0.2 | 0.9 ± 0.2 | 2.2 ± 3.7 | 2.3 ± 2.4 | 0.000 |
| Troponin I (ng/ml) | 21 (4–50) | 21 (4–50) | 17 (3–50) | 15 (3–50) | 0.701 |
| Creatine kinase-MB (U/L) | 83 (21–213) | 69 (16–197) | 47 (13–161) | 48 (13–163) | 0.000 |
| Total cholesterol (mg/dl) | 184 (158–212) | 172 (147–196) | 177 (147–209) | 161 (137–188) | 0.000 |
| Triglyceride (mg/dl) | 105 (71–157) | 97 (66–146) | 103 (72–148) | 95 (69–140) | 0.000 |
| High-density lipoprotein-cholesterol (mg/dl) | 44 (37–51) | 44 (37–52) | 41 (35–49) | 41 (33–49) | 0.003 |
| Low-density lipoprotein cholesterol (mg/dl) | 118 (96–143) | 103 (83–126) | 111 (87–140) | 96 (73–120) | 0.000 |
| High-sensitive C-reactive protein (mg/dl) | 0.8 (0.2–4.0) | 0.7 (0.2–3.8) | 1.8 (0.3–9.1) | 2.2 (0.4–9.7) | 0.000 |
| N-terminal probrain type natriuretic peptide (pg/ml) | 340 (85–1,187) | 448 (112–1,558) | 2,325 (520–7,896) | 3,000 (575–11,953) | 0.000 |
| Killip class 4 | 178 (2–4) | 116 (5–6) | 184 (8–3) | 161 (15–5) | 0.000 |
| Left ventricular ejection fraction (%) | 52.6 ± 11.7 | 51.5 ± 12 | 48.2 ± 13.5 | 46.3 ± 14.2 | 0.000 |
| Discharge medication | |||||
| Aspirin | 7,509 (99%) | 1,989 (97%) | 2,191 (99%) | 970 (93%) | 0.000 |
| Clopidogrel | 7,398 (98%) | 1,932 (94%) | 2,151 (97%) | 905 (87%) | 0.000 |
| β Blocker | 5,871 (78%) | 1,247 (61%) | 1,599 (72%) | 518 (50%) | 0.000 |
| Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker | 6,490 (86%) | 1,365 (66%) | 1,790 (81%) | 608 (59%) | 0.000 |
| Calcium channel blocker | 984 (13%) | 275 (13%) | 413 (19%) | 190 (18%) | 0.000 |
| Diuretics | 1,885 (25%) | 549 (27%) | 1,138 (51%) | 496 (48%) | 0.000 |
The angiographic and procedural results are listed in Table 3 . Groups I and II had more prevalent left anterior descending coronary artery lesions than groups III and IV, which had more prevalent right coronary artery lesions. The coronary care unit stay was shorter for groups I and II than in the 2 other groups.
| Variable | Statin and No RD (n = 7,553) | No Statin and No RD (n = 2,056) | Statin and RD (n = 2,218) | No Statin but RD (n = 1,038) | p Value |
|---|---|---|---|---|---|
| Primary percutaneous coronary intervention | 3,570 (47%) | 864 (42%) | 934 (42%) | 416 (40%) | NS |
| Thrombolysis | 421 (6%) | 122 (6%) | 65 (3%) | 31 (3%) | 0.000 |
| Conservative treatment group | 587 (8%) | 188 (9%) | 182 (8%) | 101 (10%) | NS |
| Facilitated percutaneous coronary intervention | 130 (2%) | 48 (2%) | 32 (1%) | 18 (2%) | 0.000 |
| Infarct-related artery (%) | |||||
| Left anterior descending artery | 3,386 (45%) | 871 (42%) | 764 (34%) | 343 (33%) | 0.000 |
| Left circumflex artery | 1,191 (16%) | 283 (14%) | 297 (13%) | 118 (11%) | 0.048 |
| Right coronary artery | 2,249 (30%) | 556 (27%) | 742 (34%) | 298 (33%) | 0.000 |
| Left main stem | 111 (2%) | 49 (2%) | 63 (3%) | 30 (3%) | 0.000 |
| Multivessel involvement | 3,750 (50%) | 991 (48%) | 1,311 (59%) | 573 (55%) | 0.000 |
| Complex lesion (type B2 or C) | 4,955 (66%) | 1,263 (61%) | 1,381 (62%) | 555 (54%) | 0.000 |
| Preprocedural Thrombolyis In Myocardial Infarction flow grade 0 | 2,980 (40%) | 694 (34%) | 766 (35%) | 345 (33%) | NS |
| Postprocedural Thrombolyis In Myocardial Infarction flow grade 3 | 5,995 (79%) | 1,451 (71%) | 1,504 (68%) | 567 (55%) | 0.000 |
| Stent length (mm) | 25.0 ± 6.4 | 24.7 ± 6.4 | 25.4 ± 6.7 | 25.2 ± 6.4 | 0.019 |
| Stent diameter (mm) | 3.2 ± 0.4 | 3.2 ± 0.4 | 3.1 ± 0.4 | 3.0 ± 0.4 | 0.000 |
| Implanted stents (n) | 1.51 ± 0.8 | 1.45 ± 0.8 | 1.62 ± 0.9 | 1.48 ± 0.8 | 0.001 |
| Coronary care unit stay (days) | 3.4 ± 3.1 | 3.6 ± 3.8 | 5.2 ± 6.6 | 5.2 ± 7.4 | 0.000 |
The in-hospital events and 1-month MACE incidence are listed in Table 4 . Death during hospitalization was greater in groups III and IV, especially group IV. The 1-month incidence of MACE was lower in groups I and III than in groups II and IV, respectively.
| Outcome | Statin and No RD (n = 7,553) | No Statin and No RD (n = 2056) | Statin and RD (n = 2,218) | No Statin but RD (n = 1,038) | p Value |
|---|---|---|---|---|---|
| In-hospital death | 112 (17%) | 122 (18%) | 172 (26%) | 262 (39%) | 0.000 |
| 1-mo major adverse cardiac event | 278 (4%) | 178 (9%) | 267 (12%) | 306 (30%) | 0.000 |
| Cardiac death | 144 (2%) | 131 (6%) | 198 (9%) | 269 (26%) | 0.000 |
| Noncardiac death | 23 (0.3%) | 12 (0.6%) | 30 (1.4%) | 25 (2.4%) | 0.000 |
| Myocardial infarction | 31 (0.4%) | 8 (0.4%) | 19 (0.9%) | 4 (0.4%) | NS |
| Re-percutaneous coronary intervention | 63 (0.8%) | 16 (0.8%) | 15 (0.7%) | 7 (0.7%) | NS |
| Coronary artery bypass graft | 17 (0.2%) | 11 (0.5%) | 5 (0.2%) | 1 (0.1%) | NS |
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