Relation of C-Reactive Protein and One-Year Survival After Acute Myocardial Infarction With Versus Without Statin Therapy
Article Outline
We evaluated the interaction between inflammation and survival benefit from statin therapy in patients who had acute myocardial infarction. Although 1-year mortality did not differ between patients who used statin therapy and those who did not, among patients who had C-reactive protein (CRP) concentrations in the lower 2 tertiles (<2.9 mg/L), 1-year mortality was higher in patients who used statin therapy than in those who did not within the highest CRP-defined tertile (≥2.9 mg/L). Statin therapy significantly decreased the hazard ratio for 1-year mortality in patients who had high CRP levels to approximately the hazard present for patients who had low CRP levels and did not receive statin therapy.
We hypothesized that statin therapy has favorable effects in patients who have acute myocardial infarction (AMI) and increased levels of C-reactive protein (CRP). This study investigated whether statin therapy was associated with a favorable 1-year mortality rate in patients who had AMI and determined whether statin therapy affected the association between CRP and 1-year mortality in these patients.
A detailed description of the Osaka Acute Coronary Insufficiency Study (OACIS) has been published elsewhere.1, 2, 3, 4 The OACIS is a prospective, multicenter observational study, in which 25 collaborating hospitals in Japan recorded demographic, procedural, and outcome data and collected blood samples from patients who had AMI. The registry was designed to collect uniform prospective data on patients who had AMI that could be used to assess clinical variables, therapeutic procedures, and clinical events,1, 2 and to collect DNA samples from these patients that could be used to investigate whether common genetic variations are involved in the pathogenesis of AMI.3, 4 This study protocol was approved by the ethics committee of each participating hospital. The diagnosis of AMI required the presence of 2 of the following 3 criteria: (1) a clinical history of central chest pressure, pain, or tightness lasting for ≥30 minutes; (2) typical electrocardiographic changes (i.e., ST-segment elevation >0.1 mV in ≥1 standard or ≥2 precordial leads, ST-segment depression >0.1 mV in ≥2 leads, abnormal Q wave, or T-wave inversion in ≥2 leads); and (3) an increase in serum creatine kinase activity to >2 times the normal laboratory value. All patients who presented within 1 week after the onset of AMI were registered prospectively as soon as the diagnosis of AMI had been made. Research cardiologists and specialized research nurses recorded data concerning sociodemographic variables, medical history, therapeutic procedures, and clinical events during the patient’s stay in the hospital. Information was obtained from hospital medical records and by direct interview with the patient, family members, and the treating physician. After written informed consent for entering the OACIS was obtained from the patient, all in-hospital data were transmitted to the data collection center in the Department of Internal Medicine and Therapeutics of Osaka University Graduate School of Medicine (Suita, Japan) for processing and analysis.
In patients who were discharged alive, we obtained follow-up clinical data at 3, 6, and 12 months after the onset of AMI and annually thereafter. We obtained data concerning subsequent cardiac events by visits to the research outpatient clinic or, in a few instances, by verbal or written contact with the patient’s physician, the patient, or the patient’s family members. Causes of death were determined by blinded review of the circumstances that surrounded each death by the principal investigator at each site. Before initiation of this study, a research cardiologist and a specialized research nurse at each site received a training manual that explained how to complete the case report form, defined each variable, and provided examples of correct responses. Double-key entry was used by the data collection center to add each case report form to the database. Audits were performed electronically to detect out-of-range variables, inconsistencies, errors, or omissions. Telephone contact was then made with the local research cardiologists and specialized research nurses for resolution of any problems. We registered 4,545 consecutive patients who had AMI in the OACIS from April 1998 to March 2003. Of these patients, 4,113 who were discharged alive were included in this study. One-year follow-up was completed in 4,099 study patients (99.7%); the other 14 were lost to follow-up within the year. Therefore, we studied 4,099 patients to evaluate the association between statin therapy and 1-year mortality in patients who had AMI.
In our registry, blood collection began April 1999. Therefore, we studied 2,391 patients who survived an AMI, were registered in the OACIS from April 1999 to March 2003, and consented to blood sampling to evaluate the interaction between inflammation and survival benefit from statin therapy in these patients. Venous blood samples were obtained during the stable phase (mean ± SD 21 ± 12 days after onset of AMI) and were immediately analyzed for CRP concentrations. Serum CRP concentrations were measured by a latex agglutination nephelometric assay (Eiken Chemical Co., Tokyo, Japan). The lower detection limit of this test was 0.3 mg/L. Laboratory analyses were carried out in a blinded fashion. After determination of baseline CRP concentration, the study population was divided into tertile by CRP level (first tertile <0.9 mg/L, second tertile 0.9 to 2.8 mg/L, third tertile ≥2.9 mg/L). To compare the influence of statin therapy in patients who had inflammation with that in patients who did not, we classified study participants into 2 groups. High CRP levels were defined as a value in the third tertile (≥2.9 mg/L) and low CRP levels were defined as a value in the lower 2 tertiles (<2.9 mg/L).
Continuous variables between groups were compared by t test. Categorical variables were compared by chi-square test. Variables that were incorporated into our analysis included characteristics previously identified as factors of well-known prognostic importance, including age, gender, body mass index, diabetes mellitus, hypertension, cholesterol level, smoking, previous myocardial infarction, previous cerebrovascular disease, Killip’s class, anterior wall myocardial infarction, revascularization, and medication at discharge (i.e., angiotensin-converting enzyme inhibitor, β blocker, or antiplatelet agent). Survival curves were constructed by the Kaplan-Meier method, and differences in survival were assessed with the log-rank test. Cox’s regression analysis was used to assess the relative hazard of events. Analyses of data were performed with SPSS 11.0 (SPSS Japan, Inc., Tokyo, Japan). For all analyses, statistical significance was defined as a p value <0.05.
One thousand one hundred ninety-one patients (29.1%) were treated with statins, including 222 patients who received atorvastatin, 593 who received pravastatin, 225 who received simvastatin, 94 who received fluvastatin, 27 who received cerivastatin, and 30 whose statin type was unknown. Table 1 lists the characteristics of the study populations that received statin therapy and those that did not. Patients who received statin therapy were younger and more likely to have hypertension; had a higher body mass index and higher levels of total cholesterol, triglycerides, and low-density cholesterol; had a higher rate of previous myocardial infarction and a lower rate of previous cerebrovascular disease; were in a lower Killip’s class; and were more likely to be treated with angiotensin-converting enzyme inhibitors, β blockers, antiplatelet agents, or reperfusion therapy than were those who did not received statin therapy. Figure 1 shows Kaplan-Meier survival curves for 1-year mortality in patients who received statin therapy versus those who did not. Patients who did not receive statin therapy had a significantly higher 1-year mortality rate than did those who did not receive statin therapy.
Table 1. Patient characteristics
| Characteristic | Statin Therapy | p Value | |
|---|---|---|---|
| 0 (n = 2,908) | + (n = 1,191) | ||
| Age (yrs) |  65.7 | 62.4 | <0.001 |
| Men | 76.7% | 74.1% | 0.088 |
| Body mass index (kg/m2) | 23.3 | 24.3 | <0.001 |
| Diabetes mellitus | 32.5% | 35.6% | 0.065 |
| Hypertension | 50.3% | 55.2% | 0.005 |
| Total cholesterol (mg/dl) (average) | 182 | 218 | <0.001 |
| High-density lipoprotein cholesterol (mg/dl) (average) | 47 | 48 | 0.149 |
| Triglycerides (mg/dl) (average) | 103 | 136 | <0.001 |
| Low-density lipoprotein cholesterol (mg/dl) (average) | 117 | 145 | <0.001 |
| Current smoker | 53.7% | 54.8% | 0.522 |
| Previous myocardial infarction | 11.9% | 15.4% | 0.003 |
| Previous cerebrovascular disease | 10.8% | 7.8% | 0.011 |
| Killip’s class | <0.001 | ||
| I | 83.5% | 90.3% | |
| II | 9.5% | 5.9% | |
| III | 3.0% | 1.8% | |
| IV | 4.0% | 2.0% | |
| Anterior wall myocardial infarction | 49.5% | 47.3% | 0.200 |
| Revascularization therapy | 86.4% | 91.0% | 0.001 |
| Thrombolysis | 10.2% | 11.3% | 0.331 |
| Percutaneous coronary intervention | 80.7% | 88.1% | <0.001 |
| Coronary artery bypass grafting | 3.3% | 0.6% | <0.001 |
| Medication at discharge | |||
| Angiotensin-converting enzyme inhibitor | 60.0% | 65.0% | 0.003 |
| β Blocker | 33.0% | 39.3% | <0.001 |
| Antiplatelet agent | 95.1% | 97.4% | 0.001 |
Figure 1.
Kaplan-Meier survival curves show that 1-year mortality rate was lower in patients who received statin therapy than in those who did not (1.4% vs 3.4%, log-rank test, p <0.001).
Table 2 lists causes of death in the first year after AMI according to whether a statin was prescribed. Deaths from pump failure and recurrent infarction showed lower frequency in patients who received statin therapy than in those who did not. In unadjusted Cox’s regression analysis, the hazard ratio (HR) for 1-year mortality was 0.41 (95% confidence interval 0.25 to 0.69). After adjustment for age, gender, body mass index, diabetes mellitus, hypertension, cholesterol level, current smoking, previous myocardial infarction, previous cerebrovascular disease, revascularization, Killip’s class ≥II, anterior wall myocardial infarction, and use of an angiotensin-converting enzyme inhibitor, β blocker, and/or antiplatelet agent, statin therapy remained predictive of a lower 1-year mortality rate (HR 0.43, 95% confidence interval 0.19 to 0.98).
Table 2. Causes of death in first year
| Causes of Death | Statin Therapy | p Value | |
|---|---|---|---|
| 0 (n = 2,908) | + (n = 1,191) | ||
| Cardiovascular death | 2.5% | 0.8% | 0.001 |
| Pump failure | 1.3% | 0.5% | 0.028 |
| Sudden death | 0.5% | 0.2% | 0.179 |
| Recurrent infarction | 0.4% | 0.1% | 0.089 |
| Cardiac rupture | 0.1% | 0.0% | 0.365 |
| Stroke | 0.2% | 0.0% | 0.117 |
| Cardiac procedure | 0.1% | 0.1% | 0.870 |
| Noncardiovascular death | 0.5% | 0.3% | 0.522 |
| Cancer | 0.3% | 0.1% | 0.184 |
| Other | 0.2% | 0.3% | 0.599 |
Figure 2 shows Kaplan-Meier survival curves for 1-year mortality according to high versus low CRP level and prescription versus nonprescription of a statin. Among patients who had low CRP levels, 1-year mortality did not differ between patients who received statin therapy and those who did not (Figure 2). However, among patients who had high CRP levels, 1-year mortality was significantly higher in patients who did not receive statin therapy than in those who did (Figure 2). To detect an inter-relation between inflammation and statin therapy, patients were categorized into 4 groups according to presence or absence of high CRP level and presence or absence of statin therapy. In contrast to patients who had low CRP levels and received statin therapy, those who had high CRP levels and did not receive statin therapy developed the highest risk of 1-year mortality (HR 7.0; Figure 3). Importantly, in the presence of statin therapy, the HR for 1-year mortality was significantly decreased among patients who had high CRP levels (HR 1.95) to about the same HR as among patients who had low CRP levels and did not receive statin therapy (HR 1.41; Figure 3). Further, in analyses stratified by presence or absence of statin therapy, the association between high CRP level and 1-year mortality was statistically significant in patients who did not receive a statin (HR 4.28, 95% confidence interval 1.69 to 10.8) but was attenuated and no longer significant in patients who received a statin (HR 1.28, 95% confidence interval 0.21 to 7.23).
Figure 2.
Kaplan-Meier survival curves for 1-year mortality rate according to prescription of statin by subgroup: (A) Serum CRP level <2.9 mg/L and (B) CRP level ≥2.9 mg/L.
Figure 3.
HRs for 1-year mortality after AMI according to high versus low CRP level and prescription versus nonprescription of a statin. Adjustments were made for age, gender, body mass index, diabetes mellitus, hypertension, cholesterol level, current smoking, previous myocardial infarction, previous cerebrovascular disease, revascularization, Killip’s class ≥II, anterior wall myocardial infarction, and use of angiotensin-converting enzyme inhibitors, β blockers, and antiplatelet agents.
The main findings of this study are that statin therapy was an independent predictor for a favorable 1-year mortality rate in patients who had AMI, and that statin therapy was associated with a particularly marked decrease in 1-year mortality among patients who had AMI and high CRP levels.
Using data from a primary prevention trial, Ridker et al5 demonstrated a marked benefit of lovastatin among patients who had high CRP levels but low cholesterol levels. In a study of patients who had a history of myocardial infarction, a relation between CRP and recurrent coronary events was present among patients who were not assigned to pravastatin treatment, but this association was attenuated if pravastatin was given.6 Likewise, in a percutaneous coronary intervention study, statin therapy attenuated the predictive value of CRP for major adverse cardiac events.7 Thus, statin therapy has been found to attenuate the increased risk for adverse cardiac events that is conferred by high CRP levels in primary and secondary prevention contexts; these contexts represented stable coronary artery disease.8 Recently, patients who developed low CRP levels after statin therapy were shown to have better clinical outcomes than were those who developed high CRP levels.9, 10 It was unclear that statin therapy was associated with a particularly marked decrease in mortality among patients who had AMI and high levels of CRP. Further, measurement of CRP had not yet been shown to potentially improve targeting of statin therapy that was initiated within the early period after an AMI. In our present study, we found that statin therapy was associated with a marked decrease in 1-year mortality among patients who had AMI and high CRP levels. To our knowledge, this study is the first to show such a CRP-related benefit of statin therapy in this context.
Acknowledgment
We thank Mariko Yoneda, Kana Sakatani, Nagisa Yoshioka, Miki Shinkura, Tomomi Miyai, Tomoko Inoue, Akiko Yamagishi, Chikayo Nihashi, Kaori Okada, Shigemi Kohara, and Etsuyo Naito for excellent assistance with data collection.
Appendix
OACIS Participating Institutions and Investigators
Sakurabashi Watanabe Hospital, Osaka, Japan: K. Fujii, H. Ito; Osaka Police Hospital, Osaka, Japan: K. Kodama, A. Hirayama; Kansai Rosai Hospital, Amagasaki, Japan: S. Nagata, S. Nanto, T. Morozumi; Ishinkai Yao General Hospital, Yao, Japan: Y. Matsu-ura; Osaka General Medical Center, Osaka, Japan: M. Fukunami; Osaka Rosai Hospital, Sakai, Japan: Y. Yamada, J. Tanouchi, M. Nishino; Kawachi General Hospital, Higashi-Osaka, Japan: M. Mishima, Y.J. Lim; Higashi-Osaka City General Hospital, Higashi-Osaka, Japan: Y. Kijima; Osaka National Hospital, Osaka, Japan: H. Kusuoka, Y. Koretsune, Y. Yasumura; Osaka Minami National Hospital, Kawachinagano, Japan: N. Kinoshita, K. Imai; Osaka Kosei Nenkin Hospital, Osaka, Japan: T. Sasaki; Kobe Ekisaikai Hospital, Kobe, Japan: T. Shimazu, H. Fuji; Yao Municipal Hospital, Yao, Japan: S. Hoshida, K. Umemoto; Osaka Railway Hospital of West Japan Railway Company, Osaka, Japan: A. Ezumi; Kaizuka City Hospital, Kaizuka, Japan: H. Morita, J.M. Lee; Kita-Osaka Hospital, Osaka, Japan: N. Ogitani, S. Ikeda; Teramoto Memorial Hospital, Kawachinagano, Japan: E. Hishida; Settsu Iseikai Hospital, Settsu, Japan: N. Akehi; Kashiwara Municipal Hospital, Kashiwara, Japan: M. Naka, T. Akashi; Osaka Seamens Insurance Hospital, Osaka, Japan: A. Kohama; Saiseikai Senri Hospital, Suita, Japan: T. Hayashi, Y. Nakatsuchi; Meiwa Hospital, Nishinomiya, Japan: M. Sugii; Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan: K. Yamamoto, S. Takashima, T. Minamino; Department of Medical Information Science, Osaka University Graduate School of Medicine, Suita, Japan: H. Takeda, Y. Matsumura.
References
- . Impact of high-sensitivity C-reactive protein on predicting long-term mortality of acute myocardial infarction . Am J Cardiol . 2003;91:931–935
- . Prognostic significance of atrial fibrillation/atrial flutter in patients with acute myocardial infarction treated with percutaneous coronary intervention . Am J Cardiol . 2003;92:1150–1154
- Identification of 187 single nucleotide polymorphisms (SNPs) among 41 candidate genes for ischemic heart disease in the Japanese population . Hum Genet . 2000;106:288–292
- . Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-alpha secretion in vitro . Nature . 2004;429:72–75
- . Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events . N Engl J Med . 2001;344:1959–1965
- . Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels . Circulation . 1998;98:839–844
- . Statin therapy, inflammation and recurrent coronary events in patients following coronary stent implantation . J Am Coll Cardiol . 2001;38:2006–2012
- . Inflammation and atherosclerosis . Circulation . 2002;105:1135–1143
- . Pravastatin or atorvastatin evaluation, infection therapy—Thrombolysis In Myocardial Infarction I. C-reactive protein levels and outcomes after statin therapy . N Engl J Med . 2005;352:20–28
- . Reversal of atherosclerosis with aggressive lipid lowering I. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease . N Engl J Med . 2005;352:29–38
This work was supported by a Grant-in-Aid for Scientific Research (C)(2) (no. 15590743) from the Japan Society for the Promotion of Science, Tokyo, Japan, and by research funds from the Japan Arteriosclerosis Prevention Fund, Tokyo, Japan.
PII: S0002-9149(05)00926-4
doi:10.1016/j.amjcard.2005.04.030
© 2005 Elsevier Inc. All rights reserved.
