0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Statin Therapy and Risks for Death and Hospitalization in Chronic Heart Failure FREE

Alan S. Go, MD; Wendy Y. Lee; Jingrong Yang, MA; Joan C. Lo, MD; Jerry H. Gurwitz, MD
[+] Author Affiliations

Author Affiliations: Division of Research, Kaiser Permanente of Northern California, Oakland (Drs Go and Lo and Ms Yang); Departments of Epidemiology, Biostatistics, and Medicine, University of California, San Francisco (Dr Go); Department of Medicine, Tufts School of Medicine, Boston, Mass (Ms Lee); Division of Endocrinology, Department of Medicine, San Francisco General Hospital, University of California, San Francisco (Dr Lo); and Meyers Primary Care Institute, University of Massachusetts Medical School, Fallon Clinic Foundation and Fallon Community Health Plan, Worcester (Dr Gurwitz).

More Author Information
JAMA. 2006;296(17):2105-2111. doi:10.1001/jama.296.17.2105.
Text Size: A A A
Published online

Context Whether statin therapy has beneficial effects on clinical outcomes in patients with heart failure is unclear.

Objective To evaluate the association between initiation of statin therapy and risks for death and hospitalization among adults with chronic heart failure.

Design, Setting, and Patients Propensity-adjusted cohort study of adults diagnosed with heart failure who were eligible for lipid-lowering therapy but had no previous known statin use, within an integrated health care delivery system in northern California between January 1, 1996, and December 31, 2004. Statin use was estimated from filled outpatient prescriptions in pharmacy databases.

Main Outcome Measures All-cause death and hospitalization for heart failure during a median of 2.4 years of follow-up. We examined the independent relationships between statin therapy and risks for adverse events overall and stratified by the presence or absence of coronary heart disease after multivariable adjustment for potential confounders.

Results Among 24 598 adults diagnosed with heart failure who had no prior statin use, those initiating statin therapy (n = 12 648; 51.4%) were more likely to be younger, male, and have known cardiovascular disease, diabetes, and hypertension. There were 8235 patients who died. Using an intent-to-treat approach, incident statin use was associated with lower risks of death (age- and sex-adjusted rate of 14.5 per 100 person-years with statin therapy vs 25.3 per 100 person-years without statin therapy; adjusted hazard ratio, 0.76 [95% confidence interval, 0.72-0.80]) and hospitalization for heart failure (age- and sex-adjusted rate of 21.9 per 100 person-years with statin therapy vs 31.1 per 100 person-years without statin therapy; adjusted hazard ratio, 0.79 [95% confidence interval, 0.74-0.85]) even after adjustment for the propensity to take statins, cholesterol level, use of other cardiovascular medications, and other potential confounders. Incident statin use was associated with lower adjusted risks of adverse outcomes in patients with or without known coronary heart disease.

Conclusion Among adults diagnosed with heart failure who had no prior statin use, incident statin use was independently associated with lower risks of death and hospitalization among patients with or without coronary heart disease.

Figures in this Article

Randomized controlled trials have proven that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) are highly effective for prevention of atherosclerotic vascular events and death.14 However, patients with heart failure were largely excluded from these trials. Despite therapeutic advances, outcomes for the growing number of predominantly elderly patients with heart failure remain poor,5,6 and additional strategies are needed to reduce the high rate of death and morbidity in these patients.

Statins effectively lower low-density lipoprotein cholesterol level. However, increasing attention has focused on other potentially favorable “pleotropic” effects that may apply in the setting of heart failure.7 For example, statins may induce angiogenesis by recruiting bone marrow stem cells,8 reduce levels of inflammatory factors, and improve endothelial function.9,10 On the other hand, epidemiological studies have observed a higher risk of adverse events with low levels of low-density lipoprotein cholesterol in persons with heart failure.11,12 Statins may diminish the ability of lipoproteins to bind endotoxins leading to stimulation of proinflammatory cytokines13; reduce levels of coenzyme Q1014 and selenoproteins,15 which could adversely affect cardiac muscle and function; and have deleterious interactions with medications commonly used for heart failure, such as digoxin.16

Therefore, we examined the association of incident statin use on the risks of death and hospitalization within a large, diverse population of patients with heart failure who were considered eligible for lipid-lowering therapy.

Source Population

The Kaiser Permanente Chronic Heart Failure cohort included all adults (age ≥20 years) diagnosed with heart failure between January 1, 1996, and December 31, 2004, within Kaiser Permanente of Northern California, a large integrated health care delivery system. Using previously described methods,17 patients were included if they met 1 or more of the following criteria based on a diagnosis of heart failure found in health plan databases: 1 or more hospitalizations with a principal diagnosis of heart failure (International Classification of Diseases, Ninth Edition [ICD-9] codes 398.91, 402.01, 402.11, 402.91, 428.0, 428.1, or 428.9); 2 hospitalizations with a secondary diagnosis of heart failure in which the principal diagnosis is related to the disease (eg, coronary heart disease [CHD]); 3 or more hospitalizations with secondary diagnosis of heart failure; 2 or more outpatient diagnoses; 3 or more emergency department visit diagnoses; or 2 or more inpatient secondary diagnoses plus 1 outpatient diagnosis. The index date was assigned at the first qualifying diagnosis. Medical record review of 9533 patients meeting these criteria confirmed serial physician-assigned heart failure diagnoses in 97% of cases. We previously showed that 96% of patients with a primary discharge diagnosis of heart failure18 were confirmed by chart review using Framingham clinical criteria.19

Given concern for treatment selection bias with inclusion of prevalent statin users20 and those who did not meet criteria for lipid-lowering therapy, we focused on the association of incident statin use during follow-up with outcomes only in patients who were not receiving statin therapy at the study entry date and who were eligible for treatment based on national guidelines.21 The Kaiser Foundation Research Institute's institutional review board approved the study and waived the requirement for written informed consent.

Statin Therapy and Other Medication Exposure

Receipt of any statin during the 120 days before the index date and throughout follow-up was identified based on filled prescriptions found in pharmacy databases. We also controlled for use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, diuretics, β-blockers, calcium channel blockers, other lipid-lowering agents, spironolactone, direct vasodilators, and recombinant erythropoietin. Using previously described methods,17 longitudinal medication use was estimated from drug refill patterns using the calculated day supply for each prescription. For any 2 consecutive prescriptions, the patient was classified as continually taking the medication if the second prescription was filled within 30 days of the projected end date of the first. If the second prescription was filled more than 30 days after the projected end date of the first, the patient was classified as not taking the medication from day 31 until the start date of the next prescription. If 2 prescriptions for the same drug were filled on the same day, we used the prescription with the longest calculated day supply to determine the projected end date. If a nonfatal hospitalization occurred during follow-up, the length of stay (in days) was added to the estimated day supply for any prescription crossing that hospitalization because patients were unlikely to take their own medications while hospitalized.

Covariates

Age, sex, and self-reported race/ethnicity were identified from health plan databases. Race/ethnicity was included because studies suggest it may be associated with differential treatment or outcomes in cardiovascular diseases. Socioeconomic status was estimated from 2000 US Census data. Low education was defined as living in a census block where more than 25% of those aged 25 years or older had less than a 12th-grade education; low income was defined as living in a block where annual household income is less than $35 000 per year.22 We ascertained information on coexisting illnesses based on diagnoses or procedures using ICD-9 codes, laboratory results, or specific therapies from health plan hospitalization discharge, ambulatory visit, laboratory, and pharmacy databases; diabetes mellitus registry23; and regional cancer registry.24 This included baseline and follow-up diagnoses of CHD, cerebrovascular disease, peripheral arterial disease, diabetes, hypertension, malignancy, thyroid disease, liver disease, lung disease, human immunodeficiency virus infection, valvular disease, dementia, depression, ventricular arrhythmias, and atrial fibrillation/flutter (ICD-9 codes available on request).

We also identified outpatient measurements of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and hemoglobin17 from laboratory databases during the 12 months before study entry and throughout follow-up. We classified kidney function using the Modification of Diet in Renal Disease equation for estimated glomerular filtration rate based on outpatient determinations of serum creatinine.25,26 We categorized glomerular filtration rate (in units of mL/min per 1.73 m2) as 60 or greater, 45 to 59, 30 to 44, 15 to 29, less than 15 not requiring dialysis, and receiving maintenance dialysis.22 Categories of 60 mL/min per 1.73 m2 or greater were not delineated given the higher degree of error in estimating the glomerular filtration rate above this level.27,28

We ascertained information on systolic function status from health plan databases. If available, we used a previously described approach18 to define reduced systolic function as left ventricular ejection fraction of less than 40% or a qualitative description of moderate or severely reduced systolic function; preserved left ventricular systolic function was defined by left ventricular ejection fraction of 40% or higher or a qualitative description of normal or only mildly reduced systolic function.

Finally, as a proxy for intensity of care, we identified the number of visits to a cardiologist before study entry and during follow-up. Information on participation in heart failure case management programs was not available.

Outcomes

Patients were censored at health plan disenrollment or end of follow-up on December 31, 2004. Disenrollment was defined as a gap in membership of 90 days or longer. Primary outcomes included death from any cause and hospitalization for heart failure. Deaths were identified from health plan databases for proxy report and deaths that occurred in the emergency department or hospital, Social Security Administration files,29 and California mortality files30 through 2004, which were the most recent data available at the time of the analysis. Hospitalization for heart failure was based on primary discharge diagnoses (ICD-9 codes 398.91, 402.01, 402.11, 402.91, 428.0, 428.1, and 428.9) found in hospital discharge and billing claims databases.

Statistical Approach

Analyses were performed using SAS software version 9.13 (SAS Institute Inc, Cary, NC), and a 2-sided P value of less than .05 was considered significant. We compared baseline characteristics among all patients during follow-up using the t test or Wilcoxon rank sum test for continuous variables and the χ2 test for categorical variables. Age- and sex-adjusted rates of death and hospitalization were calculated using Poisson regression with generalized estimating equations to account for repeated measures within individuals.

We examined the independent association between incident statin use and outcomes using extended Cox regression with time-dependent covariates. Because certain patients may stop therapies toward the end of life, which could yield a potentially overly optimistic estimate of treatment effects using a time-varying definition of drug exposure, our primary approach was similar to the intent-to-treat method in which treatment-eligible persons who initiated statin therapy during follow-up were considered to always be taking statins through the follow-up period even if they did not refill prescriptions. A secondary analysis incorporated time-varying estimates of statin therapy and assigned exposure status at the time of an outcome event based on our medication exposure algorithm. Stratified models were also performed in patients with or without known CHD at study entry given the known benefit of statins for secondary prevention.

We also adjusted for the likelihood of receiving statin therapy by using a continuous propensity score.31,32 Our propensity score logistic model (c statistic = 0.79) considered candidate variables shown in Table 1, Table 2, and Table 3. Additional variables selected for the final models included those known to be associated with the outcomes of interest, as well as any covariates that differed between patients in the 2 treatment groups during follow-up at a P value of less than .05. In analyzing hospitalizations for heart failure, a robust sandwich variance estimator was applied in the calculation of the 95% confidence intervals (CIs) to account for multiple hospitalizations by the same individual.33

Table Graphic Jump LocationTable 1. Baseline Demographic Characteristics of 24598 Adults With Diagnosed Heart Failure and Eligible to Receive Lipid-Lowering Therapy
Table Graphic Jump LocationTable 2. Baseline Medical Characteristics of Adults With Diagnosed Heart Failure and Eligible to Receive Lipid-Lowering Therapy
Table Graphic Jump LocationTable 3. Baseline Laboratory Tests and Medication Use of Adults With Diagnosed Heart Failure and Eligible to Receive Lipid-Lowering Therapy
Study Population and Baseline Characteristics

We identified 24 598 adults with diagnosed heart failure who had no prior known statin use and were considered eligible for lipid-lowering therapy. During follow-up, 12 648 (51.4%) initiated statin therapy. Patients initiating statin therapy were more likely than those not initiating statin therapy to be younger and male, with no clinically relevant differences in the distribution of race/ethnicity, education, or income level (Table 1). The most notable differences in other baseline characteristics between patients who did or did not initiate statin therapy were a higher prevalence of known CHD, diabetes, and hypertension in those initiating statin therapy (Table 2). Patients initiating statin therapy were also more likely to undergo testing for left ventricular function but there was no significant difference in the prevalence of reduced systolic function among tested patients (Table 3). Those initiating statin therapy had more visits to a cardiologist before and after study entry and had higher levels of total cholesterol and low-density lipoprotein cholesterol but no clinically relevant differences in levels of high-density lipoprotein cholesterol or hemoglobin. Baseline use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, calcium channel blockers, β-blockers, other lipid-lowering drugs, vasodilators, and nitrates was higher among patients who initiated statin therapy (Table 3).

Statin Therapy and Rates of Death and Hospitalization

Median follow up was 2.4 years (interquartile range, 1.0-4.3 years), during which time there were 8235 patients who died and 9215 who were hospitalized for heart failure. The age- and sex-adjusted rate of death was lower with statin therapy (14.5 per 100 person-years) vs without statin therapy (25.3 per 100 person-years) (P<.001; Figure). The lower rate of death associated with statin therapy was observed in the presence or absence of known CHD. The age- and sex-adjusted rate of hospitalization for heart failure was also lower with statin therapy (21.9 per 100 person-years) vs without statin therapy (31.1 per 100 person-years; P<.001), and seen in the presence or absence of known CHD (Figure).

Figure. Age- and Sex-Adjusted Rates of Death From Any Cause and Hospitalization for Heart Failure by Incident Statin Exposure
Graphic Jump Location

Rates are during follow-up among cohort members with dyslipidemia eligible for lipid-lowering treatment as defined by National Cholesterol Education Panel Adult Treatment Panel III risk-based criteria who had no known prior statin use, overall, and stratified by the presence or absence of known coronary heart disease (CHD) at study entry. P<.001 for all comparisons of statin therapy vs no statin therapy. Error bars indicate 95% confidence intervals.

Multivariable Association Between Incident Statin Use and Outcomes

In our primary analysis using an intent-to-treat approach, incident statin use was associated with a 24% lower relative risk (RR) of death compared with not taking a statin, even after adjustment for sociodemographic characteristics, comorbidities, longitudinal use of other therapies, and propensity to take a statin (Table 4). In a secondary analysis, time-dependent exposure to statins was associated with an even lower adjusted risk of death compared with periods when not taking statins. The favorable association between time-varying statin use and death was observed among patients with known CHD (adjusted hazard ratio [HR] 0.66; 95% CI, 0.61-0.71) and in those without known CHD (HR, 0.60; 95% CI, 0.54-0.67) at study entry.

Table Graphic Jump LocationTable 4. Multivariable Association Between Incident Statin Therapy and Risk of Death and Hospitalization for Heart Failure Among Treatment-Eligible Patients With Heart Failure and No Previous Statin Use

Similarly, using an intent-to-treat approach, incident statin use was associated with a 21% lower adjusted RR of hospitalization for heart failure compared with no statin use; the effect size was greater when examining statin use as a time-varying exposure (Table 4). Time-varying statin use was also associated with lower adjusted risks of hospitalization in patients with known CHD (HR, 0.73; 95% CI, 0.67-0.78) and in those without known CHD (HR, 0.74; 95% CI, 0.66-0.83).

Statins are effective for primary and secondary prevention of atherosclerotic events in the general population.1 While alterations of lipoprotein levels are considered a major reason for this benefit, other non–lipid-related effects such as reducing levels of inflammatory factors and detrimental cytokines, improving endothelial function, and stabilizing coronary plaque may be particularly beneficial in patients with heart failure.7 On the other hand, theoretical downsides to statin use in the setting of heart failure include reductions in coenzyme Q1014 and selenoprotein15 levels, which could have adverse effects on myocyte structure and function, as well as decreased ability of lipoproteins to bind endotoxins leading to excessive inflammation.13 In the present study, we found that within a large population of adults with heart failure who were eligible for lipid-lowering therapy, initiation of statin therapy was associated with lower risks for death and hospitalization, even after adjusting for expected differences in patients taking or not taking a statin with regard to cholesterol levels, other potential confounders, concurrent therapies, and the propensity to take a statin. The observed beneficial associations were prominent among patients with or without known CHD.

A recent systematic review of observational studies suggested that receipt of statins is associated with lower mortality and morbidity in patients with heart failure in most published studies with a wide range of potential effectiveness.34 For example, among 28 282 patients hospitalized for heart failure, receipt of any statin within 90 days after discharge was associated with a 28% lower adjusted RR of a composite cardiovascular outcome.35 In a post hoc analysis of 1153 patients with severe systolic heart failure in the Prospective Randomized Amlopidine Survival Evaluation (PRAISE) trial,36 the adjusted RR of death was 48% lower in the 134 patients receiving statins at baseline or during follow-up. In addition, among 551 patients with advanced systolic heart failure referred to a tertiary heart failure clinic, statin users had a 57% lower RR of death or urgent transplant.37 However, these and other published observational studies largely focused on selected subgroups including patients who were hospitalized for heart failure, had advanced heart failure, and/or impaired systolic function. Additional limitations include inclusion of prevalent statin users, only cross-sectional data on statin exposure, limited or no information on patients' eligibility for lipid-lowering therapy, minimal ethnic diversity, and concerns about residual confounding and incomplete adjustment for the effects of concurrent treatments that may be differentially used.34

Toward that end, the present study attempts to overcome many of these methodological challenges. Our heart failure population was large and sociodemographically diverse and included patients diagnosed with heart failure in both ambulatory and hospital settings. Reliance on an insured population with equal access to care also removed an important confounder. Our ascertainment of hospitalizations for heart failure was 100% because the health plan was financially responsible for admissions to network and out-of-network facilities. Identification of deaths included use of health plan databases that recorded inpatient and proxy-reported outpatient deaths, state death files, and Social Security Administration vital status. Our primary analysis used an intent-to-treat approach that focused on the association between initiation of statin therapy and risk of clinical outcomes in the relevant subgroup of patients with heart failure who were all recommended to receive lipid-lowering therapy based on national guidelines.21 Secondary analyses that more accurately characterized the timing and duration of exposure to statins suggested even greater benefit. We also statistically adjusted for cholesterol levels, a broad set of potential confounding variables including socioeconomic status, time-updated comorbidity and longitudinal use of other cardiovascular medications, as well as the propensity31 to initiate statin therapy in an attempt to further reduce the impact of treatment selection bias. Finally, we conducted analyses stratified by the presence or absence of CHD at study entry, given that statins and other lipid-lowering medications are indicated for secondary prevention in the general population. Overall, statin therapy remained a robust predictor of improved outcomes. Yet, because of the observational design of our study and the possibility of residual confounding, the magnitude of potential benefit from statin therapy may be overestimated given the effect sizes demonstrated in randomized controlled trials of other therapies for heart failure.38

Our study had several limitations. As an observational study of clinical practice, we cannot completely exclude residual confounding or selection bias as an alternative explanation of our findings, although we were able to adjust for a wide range of clinical and sociodemographic patient characteristics and other therapies received when evaluating incident statin use20 in comparable patients recommended to receive statin therapy.21 Despite use of previously validated approaches for detection of heart failure and relevant comorbidity from our databases,17,18,2224 as well as laboratory measures (ie, levels of lipoproteins, hemoglobin, serum creatinine), and filled medication prescriptions, we cannot rule out possible misclassification for all coexisting illnesses. We did not have data on left ventricular function for all patients, and information on functional status and quality of life was not available. Our study could not address specific mechanisms through which statins exert a beneficial effect on outcomes. Finally, as our study was conducted among insured adults in northern California, our results may not be completely generalizable to uninsured persons and other health care or geographic settings.

Limited experimental data on the efficacy of statins are available in patients with heart failure, and existing randomized comparisons in relatively small samples have yielded mixed results for intermediate outcomes related to inflammatory markers, left ventricular ejection fraction and other echocardiographic parameters, heart rate variability and QT duration and variability.3942 Therefore, given the clinically relevant effect size associated with receipt of statins in our study, results from ongoing (Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA],43 Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca-Heart Failure [GISSI-HF]44) and future randomized controlled trials involving clinical outcomes—particularly among patients with nonischemic heart failure not otherwise recommended to receive lipid-lowering therapy—are needed to clarify the role of statins in the management of heart failure.

Corresponding Author: Alan S. Go, MD, Division of Research, Kaiser Permanente of Northern California, 2000 Broadway St, Third Floor, Oakland, CA 94612 (Alan.S.Go@kp.org).

Author Contributions: Dr Go had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Go, Lee, Yang, Gurwitz.

Acquisition of data: Go, Yang.

Analysis and interpretation of data: Go, Yang, Lo, Gurwitz.

Drafting of the manuscript: Go, Lee.

Critical revision of the manuscript for important intellectual content: Go, Lee, Yang, Lo, Gurwitz.

Statistical analysis: Go, Yang.

Obtained funding: Go.

Administrative, technical, or material support: Go.

Study supervision: Go.

Financial Disclosures: Dr Go and Ms Yang reported receiving research support for this study from Amgen Inc. Dr Go also reported receiving research support from Wyeth. Dr Lo reported receiving research support from Novartis. None of the other authors reported disclosures.

Funding/Support: The research for this article was funded by a grant from Amgen Inc.

Role of the Sponsor: Amgen Inc had no role in the design, collection, analysis, and interpretation of data; in the writing of the manuscript; or in the preparation or decision to submit the manuscript for publication.

Independent Statistical Analysis: All analyses were performed by Jingrong Yang, MA, a biostatistician and SAS analyst who works exclusively for the Kaiser Division of Research. She received statistical consultation from Lynn Ackerson, PhD, who also works exclusively for Kaiser's Division of Research.

Acknowledgment: We thank Lynn M. Ackerson, PhD, for her statistical input and Krista L. Lepper, BA, for her expert technical assistance. Both Dr Ackerson and Ms Lepper received research support from Amgen Inc for their work.

Wilt TJ, Bloomfield HE, MacDonald R.  et al.  Effectiveness of statin therapy in adults with coronary heart disease.  Arch Intern Med. 2004;164:1427-1436
PubMed   |  Link to Article
Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials.  BMJ. 2000;321:983-986
PubMed   |  Link to Article
LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials.  JAMA. 1999;282:2340-2346
PubMed   |  Link to Article
Baigent C, Keech A, Kearney PM.  et al.  Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.  Lancet. 2005;366:1267-1278
PubMed   |  Link to Article
American Heart Association.  Heart Disease and Stroke Statistics—2005 Update. Dallas, Tex: American Heart Association; 2005
Roger VL, Weston SA, Redfield MM.  et al.  Trends in heart failure incidence and survival in a community-based population.  JAMA. 2004;292:344-350
PubMed   |  Link to Article
Bohm M, Hjalmarson A, Kjekshus J, Laufs U, McMurray J, van Veldhuisen DJ. Heart failure and statins–why do we need a clinical trial?  Z Kardiol. 2005;94:223-230
PubMed   |  Link to Article
Urbich C, Dimmeler S. Risk factors for coronary artery disease, circulating endothelial progenitor cells, and the role of HMG-CoA reductase inhibitors.  Kidney Int. 2005;67:1672-1676
PubMed   |  Link to Article
Strey CH, Young JM, Molyneux SL.  et al.  Endothelium-ameliorating effects of statin therapy and coenzyme Q10 reductions in chronic heart failure.  Atherosclerosis. 2005;179:201-206
PubMed   |  Link to Article
Tousoulis D, Antoniades C, Bosinakou E.  et al.  Effects of atorvastatin on reactive hyperemia and inflammatory process in patients with congestive heart failure.  Atherosclerosis. 2005;178:359-363
PubMed   |  Link to Article
Rauchhaus M, Clark AL, Doehner W.  et al.  The relationship between cholesterol and survival in patients with chronic heart failure.  J Am Coll Cardiol. 2003;42:1933-1940
PubMed   |  Link to Article
Horwich TB, Hamilton MA, Maclellan WR, Fonarow GC. Low serum total cholesterol is associated with marked increase in mortality in advanced heart failure.  J Card Fail. 2002;8:216-224
PubMed   |  Link to Article
Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis.  Lancet. 2000;356:930-933
PubMed   |  Link to Article
Rundek T, Naini A, Sacco R, Coates K, DiMauro S. Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke.  Arch Neurol. 2004;61:889-892
PubMed   |  Link to Article
Moosmann B, Behl C. Selenoprotein synthesis and side-effects of statins.  Lancet. 2004;363:892-894
PubMed   |  Link to Article
Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions.  Circulation. 2004;109:(suppl)  III-50-III-57
PubMed   |  Link to Article
Go AS, Yang J, Ackerson LM.  et al.  Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study.  Circulation. 2006;113:2713-2723
PubMed   |  Link to Article
Lee WY, Capra AM, Jensvold NG, Gurwitz JH, Go AS. Gender and risk of adverse outcomes in heart failure.  Am J Cardiol. 2004;94:1147-1152
PubMed   |  Link to Article
McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham Study.  N Engl J Med. 1971;285:1441-1446
PubMed   |  Link to Article
Ray WA. Evaluating medication effects outside of clinical trials: new-user designs.  Am J Epidemiol. 2003;158:915-920
PubMed   |  Link to Article
Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)..  JAMA. 2001;285:2486-2497
PubMed   |  Link to Article
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.  N Engl J Med. 2004;351:1296-1305
PubMed   |  Link to Article
Selby JV, Ray GT, Zhang D, Colby CJ. Excess costs of medical care for patients with diabetes in a managed care population.  Diabetes Care. 1997;20:1396-1402
PubMed   |  Link to Article
Fireman BH, Fehrenbacher L, Gruskin EP, Ray GT. Cost of care for patients in cancer clinical trials.  J Natl Cancer Inst. 2000;92:136-142
PubMed   |  Link to Article
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation.  Ann Intern Med. 1999;130:461-470
PubMed   |  Link to Article
Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine.  J Am Soc Nephrol. 2000;11:155A
Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease.  Ann Intern Med. 2004;141:929-937
PubMed   |  Link to Article
Henke PK, Blackburn S, Proctor MC.  et al.  Patients undergoing infrainguinal bypass to treat atherosclerotic vascular disease are underprescribed cardioprotective medications: effect on graft patency, limb salvage, and mortality.  J Vasc Surg. 2004;39:357-365
PubMed   |  Link to Article
Newman TB, Brown AN. Use of commercial record linkage software and vital statistics to identify patient deaths.  J Am Med Inform Assoc. 1997;4:233-237
PubMed   |  Link to Article
Arellano MG, Petersen GR, Petitti DB, Smith RE. The California Automated Mortality Linkage System (CAMLIS).  Am J Public Health. 1984;74:1324-1330
PubMed   |  Link to Article
Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects.  Biometrika. 1983;70:41-55
Link to Article
Rubin DB. Estimating causal effects from large data sets using propensity scores.  Ann Intern Med. 1997;127:757-763
PubMed   |  Link to Article
Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. New York, NY: Springer; 2000
van der Harst P, Voors AA, van Gilst WH, Bohm M, van Veldhuisen DJ. Statins in the treatment of chronic heart failure: a systematic review.  PLoS Med. 2006;3:e333:
PubMed
Ray JG, Gong Y, Sykora K, Tu JV. Statin use and survival outcomes in elderly patients with heart failure.  Arch Intern Med. 2005;165:62-67
PubMed   |  Link to Article
Mozaffarian D, Nye R, Levy WC. Statin therapy is associated with lower mortality among patients with severe heart failure.  Am J Cardiol. 2004;93:1124-1129
PubMed   |  Link to Article
Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure.  J Am Coll Cardiol. 2004;43:642-648
PubMed   |  Link to Article
Hunt SA.Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure.  ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  J Am Coll Cardiol. 2005;46:e1-e82
PubMed   |  Link to Article
Bleske BE, Nicklas JM, Bard RL.  et al.  Neutral effect on markers of heart failure, inflammation, endothelial activation and function, and vagal tone after high-dose HMG-CoA reductase inhibition in non-diabetic patients with non-ischemic cardiomyopathy and average low-density lipoprotein level.  J Am Coll Cardiol. 2006;47:338-341
PubMed   |  Link to Article
Mozaffarian D, Minami E, Letterer RA, Lawler RL, McDonald GB, Levy WC. The effects of atorvastatin (10 mg) on systemic inflammation in heart failure.  Am J Cardiol. 2005;96:1699-1704
PubMed   |  Link to Article
Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure.  J Am Coll Cardiol. 2006;47:332-337
PubMed   |  Link to Article
Vrtovec B, Okrajsek R, Golicnik A, Ferjan M, Starc V, Radovancevic B. Atorvastatin therapy increases heart rate variability, decreases QT variability, and shortens QTC interval duration in patients with advanced chronic heart failure.  J Card Fail. 2005;11:684-690
PubMed   |  Link to Article
Kjekshus J, Dunselman P, Blideskog M.  et al.  A statin in the treatment of heart failure? Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA): study design and baseline characteristics.  Eur J Heart Fail. 2005;7:1059-1069
PubMed   |  Link to Article
Tavazzi L, Tognoni G, Franzosi MG.  et al.  Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of N-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure.  Eur J Heart Fail. 2004;6:635-641
PubMed

Figures

Figure. Age- and Sex-Adjusted Rates of Death From Any Cause and Hospitalization for Heart Failure by Incident Statin Exposure
Graphic Jump Location

Rates are during follow-up among cohort members with dyslipidemia eligible for lipid-lowering treatment as defined by National Cholesterol Education Panel Adult Treatment Panel III risk-based criteria who had no known prior statin use, overall, and stratified by the presence or absence of known coronary heart disease (CHD) at study entry. P<.001 for all comparisons of statin therapy vs no statin therapy. Error bars indicate 95% confidence intervals.

Tables

Table Graphic Jump LocationTable 1. Baseline Demographic Characteristics of 24598 Adults With Diagnosed Heart Failure and Eligible to Receive Lipid-Lowering Therapy
Table Graphic Jump LocationTable 2. Baseline Medical Characteristics of Adults With Diagnosed Heart Failure and Eligible to Receive Lipid-Lowering Therapy
Table Graphic Jump LocationTable 3. Baseline Laboratory Tests and Medication Use of Adults With Diagnosed Heart Failure and Eligible to Receive Lipid-Lowering Therapy
Table Graphic Jump LocationTable 4. Multivariable Association Between Incident Statin Therapy and Risk of Death and Hospitalization for Heart Failure Among Treatment-Eligible Patients With Heart Failure and No Previous Statin Use

References

Wilt TJ, Bloomfield HE, MacDonald R.  et al.  Effectiveness of statin therapy in adults with coronary heart disease.  Arch Intern Med. 2004;164:1427-1436
PubMed   |  Link to Article
Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials.  BMJ. 2000;321:983-986
PubMed   |  Link to Article
LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials.  JAMA. 1999;282:2340-2346
PubMed   |  Link to Article
Baigent C, Keech A, Kearney PM.  et al.  Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.  Lancet. 2005;366:1267-1278
PubMed   |  Link to Article
American Heart Association.  Heart Disease and Stroke Statistics—2005 Update. Dallas, Tex: American Heart Association; 2005
Roger VL, Weston SA, Redfield MM.  et al.  Trends in heart failure incidence and survival in a community-based population.  JAMA. 2004;292:344-350
PubMed   |  Link to Article
Bohm M, Hjalmarson A, Kjekshus J, Laufs U, McMurray J, van Veldhuisen DJ. Heart failure and statins–why do we need a clinical trial?  Z Kardiol. 2005;94:223-230
PubMed   |  Link to Article
Urbich C, Dimmeler S. Risk factors for coronary artery disease, circulating endothelial progenitor cells, and the role of HMG-CoA reductase inhibitors.  Kidney Int. 2005;67:1672-1676
PubMed   |  Link to Article
Strey CH, Young JM, Molyneux SL.  et al.  Endothelium-ameliorating effects of statin therapy and coenzyme Q10 reductions in chronic heart failure.  Atherosclerosis. 2005;179:201-206
PubMed   |  Link to Article
Tousoulis D, Antoniades C, Bosinakou E.  et al.  Effects of atorvastatin on reactive hyperemia and inflammatory process in patients with congestive heart failure.  Atherosclerosis. 2005;178:359-363
PubMed   |  Link to Article
Rauchhaus M, Clark AL, Doehner W.  et al.  The relationship between cholesterol and survival in patients with chronic heart failure.  J Am Coll Cardiol. 2003;42:1933-1940
PubMed   |  Link to Article
Horwich TB, Hamilton MA, Maclellan WR, Fonarow GC. Low serum total cholesterol is associated with marked increase in mortality in advanced heart failure.  J Card Fail. 2002;8:216-224
PubMed   |  Link to Article
Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis.  Lancet. 2000;356:930-933
PubMed   |  Link to Article
Rundek T, Naini A, Sacco R, Coates K, DiMauro S. Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke.  Arch Neurol. 2004;61:889-892
PubMed   |  Link to Article
Moosmann B, Behl C. Selenoprotein synthesis and side-effects of statins.  Lancet. 2004;363:892-894
PubMed   |  Link to Article
Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions.  Circulation. 2004;109:(suppl)  III-50-III-57
PubMed   |  Link to Article
Go AS, Yang J, Ackerson LM.  et al.  Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study.  Circulation. 2006;113:2713-2723
PubMed   |  Link to Article
Lee WY, Capra AM, Jensvold NG, Gurwitz JH, Go AS. Gender and risk of adverse outcomes in heart failure.  Am J Cardiol. 2004;94:1147-1152
PubMed   |  Link to Article
McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham Study.  N Engl J Med. 1971;285:1441-1446
PubMed   |  Link to Article
Ray WA. Evaluating medication effects outside of clinical trials: new-user designs.  Am J Epidemiol. 2003;158:915-920
PubMed   |  Link to Article
Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)..  JAMA. 2001;285:2486-2497
PubMed   |  Link to Article
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.  N Engl J Med. 2004;351:1296-1305
PubMed   |  Link to Article
Selby JV, Ray GT, Zhang D, Colby CJ. Excess costs of medical care for patients with diabetes in a managed care population.  Diabetes Care. 1997;20:1396-1402
PubMed   |  Link to Article
Fireman BH, Fehrenbacher L, Gruskin EP, Ray GT. Cost of care for patients in cancer clinical trials.  J Natl Cancer Inst. 2000;92:136-142
PubMed   |  Link to Article
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation.  Ann Intern Med. 1999;130:461-470
PubMed   |  Link to Article
Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine.  J Am Soc Nephrol. 2000;11:155A
Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease.  Ann Intern Med. 2004;141:929-937
PubMed   |  Link to Article
Henke PK, Blackburn S, Proctor MC.  et al.  Patients undergoing infrainguinal bypass to treat atherosclerotic vascular disease are underprescribed cardioprotective medications: effect on graft patency, limb salvage, and mortality.  J Vasc Surg. 2004;39:357-365
PubMed   |  Link to Article
Newman TB, Brown AN. Use of commercial record linkage software and vital statistics to identify patient deaths.  J Am Med Inform Assoc. 1997;4:233-237
PubMed   |  Link to Article
Arellano MG, Petersen GR, Petitti DB, Smith RE. The California Automated Mortality Linkage System (CAMLIS).  Am J Public Health. 1984;74:1324-1330
PubMed   |  Link to Article
Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects.  Biometrika. 1983;70:41-55
Link to Article
Rubin DB. Estimating causal effects from large data sets using propensity scores.  Ann Intern Med. 1997;127:757-763
PubMed   |  Link to Article
Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. New York, NY: Springer; 2000
van der Harst P, Voors AA, van Gilst WH, Bohm M, van Veldhuisen DJ. Statins in the treatment of chronic heart failure: a systematic review.  PLoS Med. 2006;3:e333:
PubMed
Ray JG, Gong Y, Sykora K, Tu JV. Statin use and survival outcomes in elderly patients with heart failure.  Arch Intern Med. 2005;165:62-67
PubMed   |  Link to Article
Mozaffarian D, Nye R, Levy WC. Statin therapy is associated with lower mortality among patients with severe heart failure.  Am J Cardiol. 2004;93:1124-1129
PubMed   |  Link to Article
Horwich TB, MacLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure.  J Am Coll Cardiol. 2004;43:642-648
PubMed   |  Link to Article
Hunt SA.Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure.  ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  J Am Coll Cardiol. 2005;46:e1-e82
PubMed   |  Link to Article
Bleske BE, Nicklas JM, Bard RL.  et al.  Neutral effect on markers of heart failure, inflammation, endothelial activation and function, and vagal tone after high-dose HMG-CoA reductase inhibition in non-diabetic patients with non-ischemic cardiomyopathy and average low-density lipoprotein level.  J Am Coll Cardiol. 2006;47:338-341
PubMed   |  Link to Article
Mozaffarian D, Minami E, Letterer RA, Lawler RL, McDonald GB, Levy WC. The effects of atorvastatin (10 mg) on systemic inflammation in heart failure.  Am J Cardiol. 2005;96:1699-1704
PubMed   |  Link to Article
Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure.  J Am Coll Cardiol. 2006;47:332-337
PubMed   |  Link to Article
Vrtovec B, Okrajsek R, Golicnik A, Ferjan M, Starc V, Radovancevic B. Atorvastatin therapy increases heart rate variability, decreases QT variability, and shortens QTC interval duration in patients with advanced chronic heart failure.  J Card Fail. 2005;11:684-690
PubMed   |  Link to Article
Kjekshus J, Dunselman P, Blideskog M.  et al.  A statin in the treatment of heart failure? Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA): study design and baseline characteristics.  Eur J Heart Fail. 2005;7:1059-1069
PubMed   |  Link to Article
Tavazzi L, Tognoni G, Franzosi MG.  et al.  Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of N-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure.  Eur J Heart Fail. 2004;6:635-641
PubMed
CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 110

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Clinical Scenario

Users' Guides to the Medical Literature
Statin Dosing and LDL Levels