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(Circulation. 2006;113:1086-1092.)
© 2006 American Heart Association, Inc.
Heart Failure |
From the Section of Cardiovascular Medicine, Department of Internal Medicine (J.M.F., R.S., D.G., H.M.K.), and Section of Health Policy and Administration, Department of Epidemiology and Public Health (H.M.K.), Yale University School of Medicine, New Haven, Conn; Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn (J.M.F., D.G., H.M.K.); West Haven Veterans Administration Medical Center, West Haven, Conn (J.M.F., R.S.); Colorado Foundation for Medical Care, Aurora (J.M.F., F.A.M., H.M.K.); Qualidigm, Middletown, Conn (J.M.F, H.M.K); Division of Cardiology, Department of Medicine, Denver Health Medical Center, Denver, Colo (F.A.M.); and Divisions of Cardiology and Geriatric Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver (F.A.M.).
Correspondence to JoAnne M. Foody, MD, Yale University School of Medicine, 333 Cedar St, Room 315B FMP, New Haven, CT 06520-8025. E-mail joanne.foody{at}yale.edu
Received October 3, 2005; revision received December 13, 2005; accepted December 21, 2005.
| Abstract |
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Methods and Results A nationwide sample of 61 939 eligible Medicare beneficiaries
65 years of age who were hospitalized with a primary discharge diagnosis of HF between April 1998 and March 1999 or July 2000 and June 2001 was evaluated. The analysis was restricted to patients with no contraindications to statins (n=54 960). Of these patients, only 16.7% received statins on discharge. Older patients were less likely to receive a statin at discharge. Patients with hyperlipidemia and those cared for by a cardiologist or cared for in a teaching hospital were more likely to receive a statin at discharge. In a Cox proportional hazards model that took into account demographic, clinical characteristics, treatments, physician specialty, and hospital characteristics, discharge statin therapy was associated with significant improvements in 1- and 3-year mortality (hazard ratio, 0.80; 95% CI, 0.76 to 0.84; and hazard ratio, 0.82; 95% CI, 0.79 to 0.85, respectively). Regardless of total cholesterol level or coronary artery disease status, statin therapy was associated with significant differences in mortality.
Conclusions Our data demonstrate that statin therapy is associated with better long-term mortality in older patients with HF. This study suggests a potential role for statins as an adjunct to current HF therapy. Randomized clinical trials are required to determine the role of these agents in improving outcomes in the large and growing group of patients with HF.
Key Words: heart failure mortality elderly statins survival
| Introduction |
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Clinical Perspective p 1092
| Methods |
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Of the 78 882 initially abstracted cases, we excluded patients who met the following criteria: were <65 years of age (n=6553); had HF readmissions (n=3726); were transferred out of the hospital, left against medical advice, or had unknown discharge disposition (n=1506); died during hospitalization (n=4223); had no date of death information available (n=915); were hospitalized outside the United States (n=1417); were discharged to hospice (n=1299); had contraindications to statin therapy, including statin allergy or liver dysfunction (n=4655); or had no medications recorded on discharge (n=1227). In total, 23 922 patients met
1 of the above exclusion criteria, leaving a final analysis cohort of 54 960 patients (Table 1).
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Additional Data Sources
Patient vital status within 1 year and 3 years after discharge was determined with the Medicare Enrollment Database.8 In addition, patient data were linked to attending physician characteristics, verified by linkage with the American Medical Association Physician Masterfile, and hospital characteristics, determined with American Hospital Association annual surveys.
Statistical Analysis
Descriptive statistics (means, medians, interquartile ratios, frequencies, and percentages) generated for baseline demographic and clinical characteristics included lipid values, treatments and procedure, and hospital characteristics. Comparisons of characteristics of those who received statin and those who did not receive a statin were made with either a t test for continuous variables or a
2 test for categorical data.
First, we assessed the association of statins prescription at time of discharge with 1- and 3-year all-cause mortality. Then, we generated Kaplan-Meier estimates for 1- and 3-year outcome rates. Unadjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for discharge HMG Co-A reductase inhibitor versus no HMG Co-A reductase inhibitor were determined. All calculations were performed with the log-rank test and involved 2-sided probability values with an
value of 0.001.
The following available variables were used to develop the Cox proportional hazards model: demographic, clinical, physician, hospital, and treatment. Demographic and clinical variables entered into the model included age, sex, race, history of myocardial infarction, CABG, PTCA, smoking status, congestive HF, diabetes, hypertension, coronary artery disease (CAD), stroke, chronic obstructive pulmonary diseases, and dementia. Physician specialty (cardiology) and type of hospital (CABG available) were also included in the model. Other in-hospital test/treatment variables included cardiac catheterization, stress test, CABG, and PTCA after admission but before discharge. Finally, medications used on discharge (aspirin, ß-blockers, and ACE inhibitors) also were included. In secondary analyses, the results were stratified on the basis of patient age and total cholesterol levels in those patients with available measures.
To account for the natural clustering of patients within hospitals, we used the Huber-White sandwich estimator of variance method to adjust the standard errors of covariates for clustering on hospitals.9 To assess model performance and to minimize misclassification, we also used the logistic regression modeling approach to calculate receiver-operating characteristics and r2 to access model discrimination. We calculated the Pearson residual to access lack of fit of residuals and used the Hosmer-Lemeshow goodness-of-fit test method to assess fitness of the models.10 The SAS system version 6.12 (SAS Institute, Inc) was used for all statistical analyses.
This study was approved by Yale University School of Medicine Institutional Review Board. The institutional review board waived the need for informed consent for these administrative data. The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
| Results |
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40%, whereas 52% had ejection fractions >40%. In addition, cardiology consultations were obtained for 47% of patients, and 35% of hospitalizations were teaching hospitals.
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Patterns of Statin Prescription
In this cohort, 16.7% of HF patients without contraindications for statins received a statin prescription at discharge. Displayed in Table 2 are the baseline characteristics of statin versus no-statin patients. There were significant differences between these groups: The group receiving statins at discharge were younger, were more often male, and had a higher rate of prior myocardial infarction histories, CABG, percutaneous coronary intervention, diabetes, hypertension, and CAD. There were also higher rates of cardiac catheterization and stress testing performed among this group. Similarly, they were more likely to be seen by a cardiologist, admitted to hospitals with a CABG facility, and receive a higher rate of concomitant aspirin, ß-blocker, and ACE inhibitor prescriptions on discharge (Table 2).
Mortality at 1 Year
Unadjusted and adjusted HRs are shown in Table 3. In unadjusted analyses, 1-year mortality rates were lower among statin than no-statin patients (HR, 0.62; 95% CI, 0.59 to 0.65). Although after adjustment for potential confounders, including demographic, clinical characteristics, treatment, physician specialty, and hospital characteristics, the observed association between statins and survival attenuated, significant differences for death remained between those patients receiving statins and those who did not (HR, 0.80; 95% CI, 0.76 to 0.84). Table 4 shows covariate-adjusted HRs for 1-year mortality for patients receiving statins compared with those who received no statins as a function of age, total cholesterol, and CAD status.
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Mortality at 3 Years
Overall, statin therapy was associated with significant 3-year survival, as shown in the Figure (P<0.0001). The 3-year crude mortality was 48.5% in the statin group compared with 62.2% in the no-statin group (P<0.0001). After adjustment for potential confounders, including demographic, clinical characteristics, treatments, physician specialty, and hospital characteristics, significant differences for death remained between patients receiving statin and those who did not (HR, 0.82; 95% CI, 0.79 to 0.85), as shown in Table 5. The 3-year adjusted HR is comparable to the 1-year adjusted HR, suggesting persistent benefits of statin therapy over years.
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Impact of Cholesterol Level, CAD, and Age on Survival
Statin use was associated with improved survival irrespective of cholesterol level, as shown in Table 4. Paradoxically, patients with the lowest cholesterol had the greatest benefit. Although patients with the highest total cholesterol trended toward lower mortality with statins, this was not statistically significant. Similarly, in an analysis of the impact of CAD on the association between discharge lipid lowering and clinical outcomes, results showed that although patients with CAD were much more likely to be on a statin at discharge, mortality benefits were seen regardless of CAD status.
There was no remarkable interaction effect of statin by age on mortality. The risk ratio of the interaction term was 1.00 (95% CI, 0.99 to 1.00) in both the 1- and 3-year models. When age was stratified into 3 groups (65 to 74, 75 to 84, and
85 years), the adjusted risk ratios of the 1-year mortality for patients with statin were 0.84 (95% CI, 0.77 to 0.91), 0.80 (95% CI, 0.75 to 0.86), and 0.78 (95% CI, 0.69 to 0.87) for the 3 age groups, respectively. The 3-year mortality survival followed the same pattern, with adjusted risk ratios for stain patients of 0.83 (95% CI, 0.78 to 0.88), 0.82 (95% CI, 0.78 to 0.86), and 0.83 (95% CI, 0.76 to 0.91), respectively.
The 1- and 3-year receiver-operating characteristics were 0.7312 and 0.7443; r2 was 0.1226 and 0.1392; mean Pearson residuals were 0 (SD, 0.99) and 0 (SD, 1.00); and probability values for goodness of fit were 0.7214 and 0.2724, respectively. These statistics show that the models have been fitted appropriately.
| Discussion |
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An emerging body of evidence suggests the potential value of statins in the management of patients with HF; however, patients with HF are excluded from most statin trials. Patients enrolled in the Cholesterol and Recurrent Events (CARE) trial with asymptomatic left ventricular dysfunction showed similar benefits of statin therapy compared with patients without left ventricular dysfunction.2 In a post hoc analysis of the Scandinavian Simvastatin Survival Study (4S), there was a significant reduction in the development of subsequent HF in patients with preserved ventricular function at the time of entry into the study. In this study, the mortality rate in patients developing congestive HF was 25.5% in the simvastatin group compared with 31.9% in the placebo group.12 Similarly, in the Evaluation of Losartan in the Elderly trial II (ELITE) study, in patients receiving statins at enrollment, mortality was lower (10.6%) compared with those who were not (17.6%).13 Statin therapy was also associated with a 48% lower risk of death in the subanalysis of the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, which included patients with severe HF of ischemic and nonischemic origins.14 In another small, single-site study of a cohort of 551 patients with left ventricular systolic dysfunction, statin use was associated with improved 1-year survival and reduced urgent transplantation in both nonischemic and ischemic HF patients (91% versus 72%, P<0.001; and 81% versus 63%, P<0.001, respectively).3 After multivariate adjustment, statin therapy remained an independent predictor of improved survival (HR, 0.41; 95% CI, 0.18 to 0.94). However, the small size and single-site nature of this study limited its generalizability. A recent retrospective Canadian study from the province of Ontario also showed beneficial association of statin therapy in HF, but its small size, combined with the data being from a single province again, limits validity.4 In addition, a single-site study with 137 patients also showed mortality benefit in patients with diastolic HF.5
There are several possible mechanisms by which statin therapy may produce a benefit. Statins reduce cardiovascular events in patients with CAD or at high risk for CAD presumably by reducing atherosclerotic progression and plaque rupture. Although the antiatherosclerotic effects of statins are well studied, several smaller studies have demonstrated that statins reduce myocardial necrosis and preserve myocardial viability and ventricular function.13,15 Most recently, statin use has been shown to be associated with a reduced incidence of atrial fibrillation,16 a prevalent condition in elderly and an independent risk factor for mortality in patients with HF.17 Statins have been demonstrated to have important roles in angiogenesis,18,19 ventricular remodeling,2023 angiotensin II signaling, sympathetic nervous system activation,2427 oxidative stress,28 inflammation,29 thrombofibrinolysis,30 and endothelial nitric oxide synthesis,3133 all of which have important implications in the HF patient.34 Short-term statin therapy also has been shown to improve endothelial function in chronic HF patients, even after adjustment for cholesterol level.35,36
Although this is the largest study to date to assess the impact of statin therapy in a nationally representative cohort of older patients hospitalized with HF, there are outstanding issues to consider. This study was an observational study and does not have the strength of a randomized clinical trial, so its conclusions should be handled with important reservations. Although we have made robust adjustments for demographic, clinical, physician, and hospital factors, we cannot adjust for all the potential residual confounding factors. We did calculate the Pearson residuals to assess the residuals, which suggest that the models have been fitted appropriately. In addition, younger and perhaps healthier older persons could have been prescribed statins more often, but in our analysis, there were no remarkable effects of statin and age interaction on mortalities. Finally, we were not able to account for medication dose or compliance.
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| Acknowledgments |
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Disclosures
Dr Foody has received honoraria from and served on the speakers bureaus of Pfizer and Merck. Dr Masoudi has received honoraria from and served on the speakers bureaus of Pfizer and AstraZeneca. The other authors report no conflicts.
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| Footnotes |
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