STATE-OF-THE-ART PAPER
Experimental and Clinical Basis for the Use of Statins in Patients With Ischemic and Nonischemic Cardiomyopathy
Kumudha Ramasubbu, MD*,
Jerry Estep, MD*,
Donna L. White, PhD, MPH ,
Anita Deswal, MD, MPH*,, and
Douglas L. Mann, MD*,*
* Section of Cardiology and the Winters Center for Heart Failure Research, Department of Medicine, Baylor College of Medicine and The Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Texas
Houston Center for Quality of Care and Utilization Studies, Houston, Texas
Section of Cardiology, Michael E. DeBakey VA Medical Center, Houston, Texas.
Manuscript received July 2, 2007;
revised manuscript received October 1, 2007,
accepted October 2, 2007.
* Reprint requests and correspondence: Dr. Douglas L. Mann, Section of Cardiology, 1709 Dryden Road, BCM602, F.C. 9.83, Houston, Texas 77030. (Email: dmann{at}bcm.tmc.edu).
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Abstract
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Over the past 2 decades our understanding of the pathologic mechanisms that lead to heart failure (HF) has evolved from simplistic hemodynamic models to more complex models that have implicated neurohormonal activation and adverse cardiac remodeling as important mechanisms of disease progression. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have become a standard part of the armamentarium in the prevention and treatment of coronary artery disease. Apart from their lipid-lowering capabilities, statins seem to have non–lipid-lowering effects that impact neurohormonal activation and cardiac remodeling. This review will examine the potential benefits of statins in HF patients with ischemic and nonischemic cardiomyopathy as well as potential concerns regarding the use of statins in these patients.
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Abbreviations and Acronyms
| | CI = confidence interval | | CoQ10 = coenzyme Q10 | | eNOS = endothelial nitric oxide synthase | | EPC = endothelial progenitor cell | | HF = heart failure | | HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A | | HR = hazard ratio | | LV = left ventricular | | LVEDD = left ventricular end-diastolic dimension | | LVEF = left ventricular ejection fraction | | NADPH = nicotinamide adenine dinucleotide phosphate | | NO = nitric oxide | | NYHA = New York Heart Association | | PI3K/Akt = phosphatidylinositol-3 kinase-Akt |
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Statins lower plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway that is responsible for cholesterol synthesis. As illustrated in Figure 1, important intermediate products in the mevalonate pathway include the isoprenoids, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate (1,2). These intermediate products lead to activation of various downstream intracellular signaling molecules by prenylation of the guanosine triphosphate-binding proteins Rho, Ras, and Rac. The Rho signal transduction pathway is involved in the activation of inflammatory cytokines and chemokines. It also plays an important role in the formation and maintenance of the actin cytoskeleton and thereby affects intracellular transport, messenger ribonucleic acid (mRNA) stability, and gene transcription (3–5). The Ras proteins are responsible for cell proliferation and hypertrophy, and the Rac proteins are involved in the production of reactive oxygen species (5). Thus, inhibition of HMG-CoA reductase leads to a decrease in farnesylated and geranylgeranylated proteins and a subsequent dose-dependent reduction in the downstream signaling pathways mediated by Rho, Ras, and Rac (6).
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Figure 1 Cholesterol Biosynthesis and the Beneficial and Adverse Downstream Effects of Statin Treatment
Beneficial (gray background) and adverse (checkered background) downstream effects of statin treatment. eNOS = endothelial nitric oxide synthase; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LPS = lipopolysaccharide; NAD(P)H = nicotinamide adenine dinucleotide phosphate; NF B = nuclear factor kappa B; PI3 = phosphatidylinositol-3; PP = pyrophosphate; tRNA = transfer ribonucleic acid.
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Beneficial effects of statins
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Anti-Inflammatory Effects.
It is now well accepted that the syndrome of heart failure (HF) is associated with systemic inflammation characterized by increased activation of proinflammatory cytokines, cardiac auto-antibodies, cell adhesion molecules, and the complement system. In fact, elevated levels of proinflammatory markers including interleukin-6, tumor necrosis factor, and C-reactive protein predict increased cardiovascular morbidity and mortality in patients with HF (7–9). By decreasing the production of farnesylated and geranylgeranylated proteins, statins reduce the activation of the transcription factor nuclear factor kappa-B, which plays an important role in regulating genes encoding proinflammatory cytokines and adhesion molecules (3).
The reduction of inflammatory cytokines by statins has been convincingly demonstrated in clinical studies. Several small, prospective studies evaluated the effect of statin treatment on inflammatory markers in patients with left ventricular (LV) systolic dysfunction and New York Heart Association (NYHA) functional class II to IV HF symptoms (10–14). Most of these trials noted a significant decrease in concentrations of inflammatory markers after treatment with a statin for 16 weeks to 12 months in patients with ischemic and nonischemic cardiomyopathy. In contrast, 2 recent studies showed that high-dose atorvastatin and high-dose rosuvastatin were safe but had no effect on inflammatory biomarkers (10,15). Potential explanations are the type of statin used (with possible inherent differences in pleiotropic effects), dose of statin used (both studies used very high doses), and differences in background HF therapy. Moreover, both studies enrolled patients with relatively mild HF (NYHA functional class I to III), who likely had minimal activation of neurohormonal and inflammatory systems. Therefore, one would not have expected to observe striking changes in the biomarkers after statin treatment.
In inflammatory states, endothelial cells and leukocytes increase their expression of adhesion molecules, thereby triggering the migration of leukocytes and further promoting inflammation (16). Statins have been demonstrated to inhibit expression of intercellular adhesion molecule-1 in in vitro models and significantly decrease vascular cell adhesion molecule-1 levels in HF patients (13,17). Moreover, statins seem to have a direct effect on cellular components of inflammation, insofar as they inhibit the expression of major histocompatibility complex class II on endothelial cells and monocytes, resulting in inhibition of T-cell activation (18).
Antioxidant Effects.
Several experimental and clinical studies have suggested a causal role of increased oxidative stress in the development of HF and that oxidative stress might be an important determinant of prognosis (19,20). The enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is suspected to be 1 of the major sources of reactive oxygen species in HF (21). As described previously, intermediate products of the mevalonate pathway lead to activation of Rac1, a subunit of NADPH oxidase, and hence to the production of reactive oxygen species (5). Accordingly, statins reduce oxidative stress by inhibiting NADPH oxidase. In animal models, statins have been shown to attenuate oxidative stress, prevent progression of cardiac hypertrophy to HF, and improve LV function (22–25). In humans, Maack et al. (26) demonstrated in patients with advanced HF that atorvastatin and pravastatin significantly reduced NADPH oxidase activity and thus free radical production, presumably via inhibition of Rac1-guanosine triphosphatase activity.
Endothelial Function.
The relationship between the HF syndrome and impaired endothelial function has been shown repeatedly in experimental and clinical studies (27,28). Endothelial dysfunction is characterized by a reduction in endothelial cell-derived nitric oxide (NO), which leads to impaired vascular relaxation, platelet aggregation, and increased vascular smooth muscle cell proliferation and migration (29). In patients with HF, endothelial dysfunction seems to contribute to exercise intolerance, impaired myocardial perfusion, and LV remodeling (30,31).
It has been suggested that statins exert vasoprotective effects through cholesterol-dependent and -independent mechanisms. The latter involve enhanced NO production within vascular endothelial cells via 2 proposed pathways. The phosphatidylinositol-3 kinase-Akt (PI3K/Akt) pathway leads to phosphorylation and thus activation of endothelial NO synthase (eNOS), resulting in increased NO production. Statins seem to increase eNOS activity via post-translational activation of the PI3K/Akt pathway (32,33). In addition, activation of a second pathway, the AMP-activated protein kinase pathway, results in enhanced eNOS mRNA stability (34,35). In several clinical HF studies, statins have been shown to upregulate eNOS (36–38). In HF patients, Tousoulis et al. (13) demonstrated that atorvastatin significantly improved forearm vasodilatory response to reactive hyperemia, suggesting an improvement in endothelial function.
Effects on Angiogenesis.
Recent studies have demonstrated that levels of circulating endothelial progenitor cells (EPCs) are increased in patients with HF. Although the exact role of EPCs in the pathogenesis of HF is not clear, elevated EPC levels in patients with advanced HF have been shown to independently predict cardiovascular mortality (39). The EPCs can transdifferentiate into myocardial and vascular cells and thus contribute significantly to neoangiogenesis, endothelial repair, and possibly myocardial remodeling (40). Statins increase the number of circulating EPCs (41). The proposed mechanism involves statin-induced inhibition of the mevalonate pathway, which leads to activation of the PI3K/Akt pathway resulting in the induction of EPC differentiation, improved EPC survival by inhibiting apoptosis (42), and vascular endothelial growth factor–induced endothelial cell migration (43). No reports to date, however, have demonstrated an association between statin therapy and neoangiogenesis in patients with HF, and the clinical significance remains unknown. The risk of developing cancer has been a concern with agents promoting neoangiogenesis and has been much debated with statin therapy. Although multiple prospective randomized trials have not shown any increased risk for cancer with statin treatment, a recent analysis of 23 statin treatment trials showed a significant inverse association between cancer incidence and achieved low-density lipoprotein (LDL) cholesterol levels. Whereas a causal relationship cannot be inferred from this analysis, the potential role of statins in the development of cancer still remains to be clarified (44).
Cardiac Hypertrophy and LV Remodeling.
Left ventricular remodeling involves complex alterations in the biology of the cardiac myocyte as well as in the extracellular matrix (45). Ras, Rho, and Rac have been implicated in promoting LV hypertrophy (5,46). Statins seem to decrease myocyte hypertrophy and attenuate LV remodeling by suppressing Ras, Rho, and Rac activity (47–50). In addition to inhibiting myocyte hypertrophy, statins affect myocardial fibrosis. Martin et al. (51) showed that atorvastatin significantly reduces collagen synthesis, alpha(I)-procollagen mRNA expression, and gene expression of the profibrotic peptide connective tissue growth factor in cell cultures of rat and human cardiac fibroblasts. Additionally, in a rat model of cardiac hypertrophy, treatment with pitavastatin led to a decrease in the expression of hypertrophic and profibrotic genes that was accompanied by a significant decrease in interstitial fibrosis and collagen deposition. Interestingly, statin-treated rats also showed smaller left ventricular end-diastolic dimension (LVEDD), higher LV fractional shortening, and improved survival compared with the untreated rats (52). In a different rat model of HF, rosuvastatin significantly decreased Rac-1 expression and significantly improved left ventricular ejection fraction (LVEF), cardiac hypertrophy, and perivascular fibrosis (25).
In humans, in a prospective randomized study of 108 patients, those receiving atorvastatin had a significant decrease in LVEDD from 57.1 to 53.4 mm, whereas patients in the placebo group experienced an increase in LVEDD (56.1 to 60.3 mm) over a 12-month period (11). In another study, Node et al. (53) demonstrated a significant decrease in LV end-systolic volume and a nonsignificant decrease in LVEDD in 51 patients with symptomatic nonischemic cardiomyopathy treated with simvastatin for 14 weeks. In contrast, in the UNIVERSE (Rosuvastatin Impact on Ventricular Remodelling Lipids and Cytokines) trial, treatment with high-dose rosuvastatin (40 mg/day) did not result in a significant improvement in LVEF relative to placebo. Potential explanations for this discrepant finding remain uncertain but might be the inclusion of nonischemic as well as ischemic patients, background HF therapies, the short study duration, small sample size, and the fact that there were improvements in LVEF in the placebo group as well as in the treatment group (14).
Neurohormonal Activation.
Both the adrenergic and renin-angiotensin systems are activated in the setting of HF, and the magnitude of activation correlates with the severity of symptoms and prognosis in HF patients. Therapies aimed at attenuating these systems have resulted in significant clinical benefit in patients with HF. Statins have been demonstrated to modulate neurohormonal activation. Elevated cholesterol levels have been associated with overexpression of angiotensin II type 1 receptor (54). Treatment with statins, in turn, has been shown to decrease levels of these receptors, resulting in both decreased angiotensin II-mediated vasoconstriction and enhanced response to angiotensin receptor blocker drugs (55–57). Furthermore, statins have been shown to inhibit vascular endothelial growth factor-induced upregulation of angiotensin-converting enzyme (58). In addition, statins have been demonstrated to reduce expression of the endothelin type A-receptor, as well as beta1-receptor–stimulated apoptosis (2,59). However, the clinical significance of these observations in HF patients remains to be elucidated.
Autonomic Regulation.
The severity of autonomic dysregulation in HF correlates with disease severity and has been associated with adverse outcome in patients with HF (60,61). Statins have been proposed to modulate the autonomic nervous system by activating eNOS and increasing NO production. On the premise that NO has sympatho-inhibitory properties, statins might thus lower sympathetic outflow (62). In a recent report, Pliquett et al. (63) showed that pravastatin normalized sympathetic outflow and reflex regulation in rabbits with HF. In humans, however, Bleske et al. (10) demonstrated in a randomized, double-blind, placebo-controlled trial that high-dose atorvastatin therapy (80 mg/day) had no beneficial effect on heart rate variability in patients with nonischemic cardiomyopathy. This study, however, was limited by a small sample size (15 patients). Moreover, 80% of the patients studied had mild HF (NYHA functional class II) and might not have had significant autonomic dysfunction. In a separate study, Vrtovec et al. (64) randomized 80 HF patients to atorvastatin or placebo. After 3 months, patients treated with atorvastatin had a significantly higher heart-rate variability, lower QT variability, and shorter QTc interval, all indicators of improved autonomic function.
Potential Anti-Arrhythmic Effects.
There is emerging evidence that statins might have beneficial effects on atrial and ventricular arrhythmias in HF patients. Analysis of ADVANCEMENT, a multicenter registry of patients with LV systolic dysfunction, showed that the use of lipid-lowering drugs was associated with a significant reduction in the prevalence of atrial fibrillation (65). Secondary analyses of the MADIT (Multicenter Automatic Defibrillator Implantation Trial)-II, which included patients with ischemic cardiomyopathy, showed that the cumulative rate of defibrillation for ventricular arrhythmias or sudden cardiac death was significantly reduced in patients with higher statin usage (66). Given the high prevalence of coronary artery disease in these studies, the likely mechanism of arrhythmia reduction with statin therapy is plaque stabilization and thus reduction of ischemia-related tachyarrhythmias. However, even in nonischemic cardiomyopathy, a secondary analysis of the DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) trial demonstrated a significant reduction in mortality and in arrhythmic sudden death in patients taking statins (67). These findings suggest that the statins’ nonlipid-lowering effects might play a role in decreasing arrhythmias.
Apart from anti-ischemic properties of statins, other proposed mechanisms for the observed decreased incidence of atrial and ventricular arrhythmias in patients taking statins include potential membrane-stabilizing properties, improvement in autonomic function, and anti-inflammatory properties. Furthermore, statins seem to improve LV function and prevent remodeling and might thereby influence the generation of ventricular arrhythmias (68). More recently, experimental data suggest that Rac1 guanosine triphosphatase (GTPase) might contribute to the pathogenesis of atrial fibrillation (69). Statins, by inhibiting HMG-CoA reductase, suppress Rac activity and might thus attenuate arrhythmias.
In summary, statins seem to have pleiotropic effects that might be beneficial in HF. Moreover, the molecular effects of statins seem to overlap those of currently accepted HF therapies. Table 1
shows that statins also have several properties that are not shared by current medical therapies for HF, suggesting that this class of drugs might provide added benefit for patients with HF.
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Potential deleterious effects of statins
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Despite the multiple beneficial properties attributed to statins, there is some concern that statins might have unfavorable effects in HF patients. This concern stems largely from retrospective studies, which report that a lower total cholesterol is associated with higher mortality in patients with advanced HF. However, it remains to be determined whether low cholesterol is the cause for increased mortality or merely a reflection of more advanced disease. Three main hypotheses have been presented outlining pathways leading to potentially harmful effects of statins.
The Endotoxin–Lipoprotein Hypothesis.
Circulating cholesterol and triglyceride-rich lipoproteins have the capacity to detoxify bacterial lipopolysaccharide (endotoxin), which stimulate the release of inflammatory cytokines in patients with HF. On the basis of this, higher levels of cholesterol are believed to be beneficial in patients with HF, because serum lipoproteins can bind and inactivate lipopolysaccharide. Statin therapy might thus increase levels of circulating endotoxin, leading to increased systemic inflammation and disease progression (70).
The Ubiquinone Hypothesis.
Statins inhibit synthesis of ubiquinone (coenzyme Q10 [CoQ10]), a downstream product in the mevalonate pathway (Fig. 1). Ubiquinone is present in all cells and membranes and serves a central role in the mitochondrial respiratory chain (71). Potential adverse effects of CoQ10 reduction in the setting of HF are decreased electron transport via CoQ10 in the mitochondrial respiratory chain, leading to a reduction in adenosine triphosphate production, and inhibition of the antioxidant function of CoQ10, leading to a reduction in cellular protection from free radical injury with subsequent aggravation of HF (72). Statin-induced CoQ10 reduction is well documented in both animal and human studies (73). However, no studies to date have demonstrated that statin-induced reduction in CoQ10 tissue levels leads to adverse clinical outcomes in subjects with HF.
The Selenoprotein Hypothesis.
Selenoproteins play an important role in muscle metabolism (skeletal and cardiac). Selenoprotein dysfunction and selenium deficiency have been associated with myopathies. By inhibiting the mevalonate pathway, statins decrease isopentenyl-pyrophosphate, which is required in the activation of selenocysteine–transfer RNA (tRNA). Thus, statins decrease selenoprotein production, which theoretically could cause both skeletal and cardiac muscle myopathy (74).
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Clinical Experience With Statins
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Several retrospective analyses of clinical trials or observational databases have suggested that the use of statins in patients with coronary artery disease has either decreased the incidence of HF (75) or reduced mortality in patients with known HF (76). Smaller prospective trials assessing the effects of statins on nonmortality clinical end points and other surrogate end points (echocardiographic parameters and biomarkers of inflammation) also support the beneficial effects of statins in HF (11–13,50,77,78).
Retrospective trials.
Most of the data evaluating the clinical effect of statins in patients with HF have been garnered from retrospective analyses of clinical trial databases. All studies included patients with ischemic and nonischemic cardiomyopathy; the majority of patients had coronary artery disease. Inclusion criteria for these studies were symptomatic HF, LV dysfunction, or both. The main clinical outcome variable for all the studies was mortality. Treatment with statins consistently resulted in a significant decrease in mortality across multiple trials enrolling large numbers of patients. Given the high prevalence of ischemic heart disease in these HF trials, as well as the known salutary effects of statins on outcomes in coronary artery disease, these findings are not surprising. Furthermore, these are retrospective studies with inherent biases and confounders (79,80). Interestingly, retrospective analyses of trials enrolling patients with coronary artery disease but without prior history of HF demonstrated a reduction in the risk of development of HF and HF hospitalizations in patients taking statins (75,81,82). However, because all studies evaluated patients with coronary artery disease, the observed reduction in HF could simply be due to a reduction in the occurrence of ischemia/myocardial infarction.
Prospective trials.
Very few prospective trials of statin treatment in patients with HF have been published. Several small, placebo-controlled studies in patients with nonischemic cardiomyopathy and symptomatic systolic HF showed an improvement in symptoms in patients taking statins (53,77,78). The fact that the statin effect cannot be attributed to the lowering of cholesterol and reduction in ischemic events further emphasizes the role of pleiotropic effects of statins in HF. More recently, a small prospective trial randomized 110 patients with NYHA functional class III HF and EF <30% to either atorvastatin 10 mg/day or no statin. Approximately 60% of the patients had ischemic cardiomyopathy. At 1 year follow-up, a significantly lower mortality rate was noted in patients taking statins (16% versus 36% respectively, p = 0.017), which appeared to be driven by a decrease in the rate of sudden cardiac death (83).
The largest prospective randomized trial to date, CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), randomized 5,011 patients ( 60 years) with NYHA functional class II to IV heart failure of ischemic etiology to 10 mg rosuvastatin versus placebo (84). In this trial, treatment with rosuvastatin did not confer a significant benefit with respect to the primary end point (HR 0.92 [95% CI 0.83 to 1.02]; p = 0.12), which was a composite of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke, nor several secondary endpoints including all-cause mortality (Fig. 2) (HR 0.95 [95% CI 0.86 to 1.05]; p = 0.31) and coronary events (HR 0.92 [95% CI 0.82 to 1.04]; p = 0.18), despite a significant decrease in circulating levels of low-density lipoprotein cholesterol and C-reactive protein (CRP). These results were surprising considering the known salutary effects of statins on coronary events in patients with coronary artery disease. However, the rate of atherothrombotic events was relatively low in the CORONA study, and the majority of deaths were due to sudden death or worsening HF, which reflects the fact that the patient population was comprised of patients with symptomatic HF rather than symptomatic coronary artery disease. Thus, the primary composite end point of the CORONA study may not have captured the beneficial effects of rosuvastatin in this elderly group of patients with advanced HF. And indeed, treatment with rosuvastatin resulted in a significant decrease in HF hospitalizations, which was a pre-specified secondary end point in the CORONA study, thus refuting speculation that treatment with statins might lead to worsening HF. It also bears emphasis that there are differences between the CORONA study and previous prospective statin trials. For example, the CORONA study enrolled older patients with more advanced HF. Although statin use in elderly patients with coronary artery disease has been shown to be beneficial (85), elderly patients with coronary artery disease and HF may represent a sicker population with more comorbidities, in whom significant cholesterol lowering may no longer have a favorable impact on cardiovascular death because the atherosclerotic and/or myocardial disease is simply too advanced to modify. This is supported by the subgroup analysis demonstrating a trend towards improved outcomes with rosuvastatin in younger patients and patients with higher blood pressure and lower brain natriuretic peptide levels possibly reflecting a healthier baseline status. Secondly, the CORONA and UNIVERSE trials used rosuvastatin compared to previous clinical trials that employed more lipophilic statins (2), raising the question of whether the effect of statins in HF can or should be viewed as a class effect.
Several of the smaller, prospective clinical trials have also demonstrated a favorable effect of statins on measures of systolic function. Treatment with simvastatin (53) and atorvastatin (78) demonstrated a significant improvement in LVEF after 14 weeks to 6 months. Similarly, Sola et al. (11) reported a significant increase in LVEF (33% to 37%) in 46 patients treated with atorvastatin while the 43 patients in the placebo group experienced a decline (from a baseline of 33% to 31%) over 12 months. In contrast, patients with HF treated with rosuvastatin 40 mg showed no difference in LV function compared with the placebo group (14), and a further study with cerivastatin only showed a trend towards increased LVEF by radionuclear ventriculography (77). Possible explanations for these discrepant results include choice of statin, differences in statin dosage, and patient selection.
The data on the use of statins in patients with HF and preserved systolic function is limited. Fukuta et al. (86) performed a prospective observational study in 137 patients with HF and LVEF 50% for 21 ± 12 months (86). These authors demonstrated that statin treatment was associated with a substantial improvement in survival, whereas treatment with an angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, beta-blocker, or calcium channel blocker had no significant effect on survival. These results further support a potential niche for the use of statins in HF patients.
Meta-analysis.
We performed a meta-analysis to obtain a better estimate of the magnitude of survival benefit with statins in HF and to better compare the effects of statins in patients with HF of ischemic and nonischemic etiologies. For this analysis, the medical literature was searched using the following search terms: statins and heart failure, HMG-CoA reductase inhibitors and heart failure, statins and systolic dysfunction. Trials were included in the meta-analysis if the primary focus was the evaluation of the effect of statins on mortality in patients with HF. Only trials that reported results as an HR were included. The following studies were excluded: non-English publications, abstracts, and evaluation of statins in the prevention of HF.
For the meta-analysis, the effect measure of choice was the HR and associated 95% CI. Heterogeneity was evaluated with Higgins I (87), and a random effects meta-analysis was performed (88). The meta-analysis results are presented as forest plots with HRs and 95% CIs for all individual studies as well as the overall pooled estimator. We employed Egger’s regression test to assess if there was potential small study or publication bias (89). Finally, we performed a stratified meta-analysis to evaluate whether the overall effect of statin use on relative risk of mortality differed among subgroups of HF patients (i.e., HF of ischemic and nonischemic etiology). All analyses were conducted using STATA 9.0 (Stata Corp., College Station, Texas).
Thirteen studies met the inclusion criteria for this meta-analysis (Table 2) (79,80,84,85,90–97), of which 11 were retrospective analyses and 2 were prospective studies. Overall, the pooled estimator suggested that statin use among HF patients conveys a significant 26% decreased relative risk of mortality (HR = 0.74; 95% CI 0.68 to 0.8) (Fig. 3). Eight of the 13 studies presented HRs for HF of ischemic and nonischemic etiology separately, and these were used in a stratified analysis. Interestingly, the result of the stratified analysis demonstrated a similarly protective effect of statins among HF patients regardless of etiology (HRischemic = 0.73; 95% CI 0.65 to 0.82 vs. HRnonischemic = 0.73; 95% CI 0.61 to 0.87) (Fig. 4). Moreover, both the magnitude and precision of the observed statin benefit were similar in the overall analysis as well as in the subgroup analysis. Of note, the improved mortality was seen when statins were added to currently recommended therapy for HF. The pooled estimators were also calculated excluding the 2 prospective trials: no significant change was noted (overall HR = 0.72; 95% CI 0.66 to 0.78; HRischemic = 0.69; 95% CI 0.60 to 0.78; HRnonischemic = 0.73; 95% CI 0.61 to 0.87).
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Figure 4 Mortality Among Patients With Heart Failure: Ischemic and Nonischemic Etiology
(A) Adjusted mortality among patients with ischemic etiology (n = 62,273) using statins compared with those not using statins. (B) Mortality among patients with heart failure of nonischemic etiology (n = 31,551) using statins compared with those not using statins.
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One limitation of the present meta-analysis is that the majority of included studies were retrospective, due to the paucity of prospective data. Thus, the results of the meta-analysis suffer from the shortcomings of retrospective studies, including different baseline characteristics and nonrandomization of treatment allocation. Secondly, the heterogeneity concerns confronted in any meta-analysis also exist here, for example, variable length of follow-up, variable types of statins used, various dosages of statins used, and lack of individual patient data. Despite these limitations, the results do show a significant reduction in relative risk of mortality with use of statins among HF patients regardless of etiology.
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Conclusions: Statins in Perspective
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In this review we have outlined the theoretical and clinical benefits of statins in patients with HF. Statins have several properties that are not shared by current medical therapies for HF, suggesting that this class of drugs might result in added benefit for patients receiving current HF therapies. Further, the results of our meta-analysis suggests that statin therapy leads to a 26% reduction in the risk of mortality in HF patients. Moreover, the magnitude of benefit of statins in this meta-analysis was similar in patients with ischemic and nonischemic cardiomyopathy. Although the meta-analysis is based on retrospective, nonrandomized studies performed in patients receiving various background therapies, the reduction in mortality risk for statins is similar to that reported in clinical trials with angiotensin-converting enzyme inhibitors (18% to 44%) and beta-blocker drugs (23% to 35%) (98–102). As previously noted, the results of the meta-analysis are in disagreement with the results of the prospective CORONA study, which showed a nonsignificant (p = 0.31) 5% decrease in all-cause mortality in elderly patients with moderate to advanced heart failure. Whether the negative results of the CORONA study represent patient selection, the hydrophilic properties of rosuvastatin, or true lack of treatment benefit of statins in HF cannot be addressed at present. The ongoing prospective trial GISSI-HF (103), which is enrolling patients with ischemic and nonischemic HF, should provide additional insight into whether statins will add to currently recommended HF therapy. That said, given the conflicting results of the trials previously discussed, it is premature to recommend the routine use of statins for the treatment of patients with HF outside of current practice guidelines for the treatment of coronary artery disease.
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Abstract
Beneficial effects of statins
