Although more than 100,000 patients have been studied in clinical trials evaluating the efficacy of statin treatment compared to placebo in primary and secondary prevention of cardiovascular morbidity and mortality, this investigation has revealed that the vast majority of published statin trials excluded patients with LVEF below 40% or NYHA III/IV. In addition, we report that in CHF patients, instead of high-serum cholesterol levels, low-serum cholesterol levels have been consistently associated with increased mortality rates. Finally, this study has revealed that although most studies assessing the effect of statins in CHF are encouraging, they only report surrogate efficacy parameters or are based on secondary analyses.
Theoretical Considerations for Statin Treatment in CHF Patients
We conclude that statin treatment in CHF has never been assessed in a large clinical trial setting, which is the gold standard for clinical evidence (). In view of this, the question is to what extent can the results of studies performed in other patient groups be extrapolated to CHF populations?
There are several theoretical considerations that argue in favor or against statin treatment in CHF. The most relevant arguments against statin therapy are the endotoxin lipoprotein hypothesis, the coenzyme Q10
(ubiquinone) hypothesis, and the selenoprotein hypothesis. The endotoxin lipoprotein hypothesis is related to lower cholesterol levels and will be discussed below. The ubiquinone hypothesis reasons that the inhibition of mevalonate synthesis by statins decreases the production of ubiquinone (coenzyme Q10
). Ubiquinone is involved in the production of ATP and therefore in meeting the metabolic demands of cells [30
]. Another fundamental characteristic of ubiquinone is its antioxidant (free-radical-scavenging) properties. The selenoprotein hypothesis postulates that statins interfere with the enzymatic isopentenylation of selenocysteine tRNA and prevent its maturation to a functional tRNA molecule, resulting in a decrease in available selenoproteins [31
]. Individuals with statin-induced myopathy have clinical and pathological features similar to those of syndromes associated with severe selenoprotein deficiency [31
The potential beneficial effects of statin treatment in CHF include improved vascular function, improved neurohormonal status, and decreased development of left ventricular hypertrophy. Statin treatment has been shown to favorably affect endothelial function [29
], as well as increasing capillary density [32
] and circulating endothelial progenitor cells [33
], and slowing the progression of coronary atherosclerosis [34
]. In addition, statins also modify the major neurohormonal systems involved in CHF, decreasing responsiveness to angiotensin II, for example [35
]. Statins also inhibit the beta-adrenergic receptor activation of Rac1 and consequently apoptosis [36
]. Finally, by blocking the synthesis of mevalonate, statins reduce the development of left ventricular hypertrophy [37
Cholesterol in CHF
In middle-aged persons, hypercholesterolemia is a well-known risk factor predicting the development of CAD and long-term all-cause mortality. This association is, however, controversial in elderly patients and those with a wide range of chronic and acute diseases [38
]. In the Framingham study, dyslipidemia initially appeared to be a risk factor for the development of CHF [41
]. However, in a more detailed analysis of the same Framingham database, the association between total cholesterol and all-cause mortality was found to be positive at 40 y, negligible at 50–70 y, and negative at age 80 y and above [42
]. In this context, it is important to note that the incidence and prevalence of CHF rises steeply with age, and that almost 80% of CHF patients are over 65 y of age. Despite these observations, however, the evidence from clinical trials proves that statin treatment is effective in elderly patients [43
]. The Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) trial extended the clinical evidence supporting statin treatment to elderly patients (>70 y) at high risk of developing cardiovascular disease and stroke [10
Several studies have addressed the relation and relevance of serum cholesterol levels to outcome in CHF patients in particular, and the results consistently suggest that lower cholesterol is associated with increased mortality (). More specifically, for each millimoles/liter decrease in total cholesterol, mortality increases by 25% [23
]. This phenomenon of “reverse epidemiology” in CHF is not unique for cholesterol levels, and also exists for body mass index and blood pressure [44
]. Nevertheless, the above-mentioned studies are observational studies and therefore of limited value. Although most studies are corrected for several indicators, such as nutritional status and cachexia, they may have been inadequately adjusted for other confounders. Lower cholesterol may mark an end-stage disease epiphenomenon, due to reduced hepatic cholesterol synthetic capacity. The endotoxin lipoprotein hypothesis, however, offers a plausible explanation for the observed relationship. This hypothesis postulates that higher levels of cholesterol might be beneficial in CHF because of the ability of cholesterol to modulate inflammatory immune function [45
]. CHF patients have increased serum cytokine levels, which might be linked to increased endotoxin levels [46
]. Circulating cholesterol- and triglyceride-rich lipoproteins are natural nonspecific buffers of endotoxins. They have the capacity to bind and detoxify bacterial lipopolysaccharides. In parallel with raised lipopolysaccharide plasma concentrations, patients with edematous and severe CHF show substantial immune activation [46
]. Episodes of endotoxemia may occur, and reducing lipoproteins could adversely affect lipopolysaccharide bioactivity modification [45
Clinical Evidence Supporting Statin Therapy in CHF
Several post hoc subgroup analyses of data from large clinical statin trials have been published, and have examined the effects of statins in CHF or on the development of CHF [2
]. One recent study, the Treating to New Targets (TNT) study involving 10,001 CAD patients, investigated the efficacy of 80 mg versus 10 mg of atorvastatin (no placebo arm). In this study, high-dose statin therapy was associated with a 26% decrease in hospitalization for congestive heart failure, which was a predefined secondary efficacy outcome parameter (HR 0.74 [95%CI 0.59–0.96], p =
Statin therapy has been associated with reduced mortality in observational studies (). Nevertheless, the effects of statin use in CHF currently reported in the literature do not prove causality, and are susceptible to considerable confounders and biases. First, the single largest confounder in nonrandomized studies is probably the patient characteristics that are related to the physicians' decision to prescribe a statin. Second, some of these CHF studies were conducted at a time when beta-blockers and spironolactone were not generally used in severe heart failure. Third, most of the patients receiving statin treatment at discharge were on statin treatment before inclusion in the study, which further complicates the analyses. Finally, although statin therapy seems to reduce new onset of heart failure, this reduction could be related to effects on reduction of recurrent myocardial infarction and subsequent CHF, rather than the development of CHF without recurrent infarctions.
There are limited data on the effects of statin treatment in patients with established CHF (). At present, the available CHF trials appear encouraging, however, and their results warrant confirmation in large clinical trials.
Strengths and Limitations
This paper is the first, to our knowledge, to systematically review the available data on the use of statin treatment in CHF patients. Limitations of the current study include the potential publication biases of the retrieved studies. Observational studies and post hoc analyses of clinical trials investigating the correlation between cholesterol levels and outcome in patients with CHF are exploratory in nature and may be more likely to be published if an association is found. Likewise, the published small-scale prospective studies evaluating statins specifically in CHF patients might also have suffered from publication bias since negative studies might have been considered underpowered.
Despite widespread clinical use of statins for hypercholesterolemia and prevention of CAD, there is a paucity of data on the effects of statins on clinical outcome in CHF. Currently, the available experimental, post hoc, and observational data and theoretical considerations are conflicting. On the one hand, three lines of evidence point towards statins having a harmful effect in CHF. First, lower cholesterol levels have repeatedly been related to a poorer outcome in CHF patients. This may be related to the function of cholesterol as a scavenger for cardiodepressive and harmful endotoxins. Second, statins in CHF may adversely affect mitochondrial function through inhibition of ubiquinone. Third, statins may decrease selenoproteins, which could result in decreased myocardial function. On the other hand, evidence of beneficial effects of statin treatment in CHF is accumulating. First, beneficial effects of statins demonstrated in non-CHF conditions, e.g., on vascular function, atherosclerosis, and left ventricular hypertrophy, might also be beneficial in CHF. Second, clinical knowledge regarding statin treatment in CHF is generally favorable, although it is primarily based on retrospective post hoc studies performed within the scope of large clinical trials and on small prospective studies with surrogate endpoints.
Statin treatment in established CHF has never been formally assessed in a large clinical trial, the gold standard for clinical evidence. Therefore, there are currently no reliable clinical data on the efficacy of statins in CHF. Two large clinical trials are, however, now under way to clarify the effects of statin treatment in CHF [20
]. These two studies will provide a more definite answer to whether or not we should initiate statin treatment in patients with established CHF.