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Statin therapy in patients with heart failure

Statin therapy in patients with heart failure
Literature review current through: Jan 2024.
This topic last updated: Mar 22, 2023.

INTRODUCTION — Statin therapy is widely used for both the secondary and primary prevention of atherosclerotic cardiovascular disease. However, the randomized trials that have provided evidence of benefit have included few patients with heart failure (HF) [1,2]. However, two major randomized trials, CORONA and GISSI-HF, have directly addressed this issue in patients with systolic HF. In addition, HF management is potentially complicated by the observation that low serum cholesterol is associated with worse outcomes.

These issues will be reviewed here. The role of statin therapy in the broad group of patients with cardiovascular disease and the multiple mechanisms by which statins might act in addition to cholesterol lowering are discussed elsewhere. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Statins: Actions, side effects, and administration" and "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

SERUM CHOLESTEROL AND PROGNOSIS IN HF — A low serum cholesterol in patients with heart failure (HF) is associated with higher mortality [1,3,4]. The following observations illustrated the range of findings:

In a retrospective review of 1134 patients with advanced, chronic HF (almost all New York Heart Association [NYHA] class III or IV) (table 1), mean left ventricular ejection fraction [LVEF] 22 percent), the serum cholesterol was higher in survivors compared to non-survivors at one year [3]. Patients in the lowest quintile of serum cholesterol (<129 mg/dL [3.3 mmol/L]) had an adjusted relative mortality risk of 2.1 compared to those in the highest quintile (serum cholesterol >223 mg/dL [5.8 mmol/L]). Low cholesterol appeared to be a marker for more severe disease, since these patients also had other findings known to predict worse outcomes in patients with HF, including lower serum albumin, lower serum sodium, and lower LVEF. (See "Predictors of survival in heart failure with reduced ejection fraction" and "Prognosis of heart failure".)

A relationship between lower serum cholesterol levels (less than 200 mg/dL [5.2 mmol/L] and higher mortality was also found in a multivariable analysis of 114 patients with chronic HF [4]. The multivariable model was validated in a second group of 303 additional patients with HF. The findings were independent of the etiology of HF.

A similar relationship between lower serum cholesterol levels and higher mortality was also found in a multivariable analysis of almost 18,000 patients presenting with short-term (acute) heart failure exacerbations [5].

Whether low cholesterol has a causative role or is simply a marker of more severe debilitation (ie, cardiac cachexia, liver dysfunction, and inadequate nutrition), has not been determined. Thus, there is a theoretical concern that lipid lowering with statins may have an adverse effect.

POTENTIAL BENEFITS AND HARMS OF STATIN THERAPY IN HF — Statins have a variety of lipid-independent (pleiotropic) effects that could contribute to improved outcomes in patients with heart failure (HF) [6]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)

These include:

Antiatherogenic and plaque-stabilizing properties and improvement in endothelial function, which together reduce the risk of an acute coronary syndrome and the ischemic burden on the failing ventricle. However, the rates of myocardial infarction are low in patients with HF, making it more difficult to demonstrate benefit from statin therapy [7].

Inhibition of proinflammatory cytokine activity [8], favorable modulation of the autonomic nervous system, and an antiarrhythmic effect.

There are at least two mechanisms by which statin use might be harmful in patients with HF:

Lipoproteins may remove bacterial endotoxins (lipopolysaccharides) that enter the circulation. By lowering lipoprotein levels, statins might make HF patients more susceptible to infection [9].

Plasma levels of ubiquinone (coenzyme Q10) are reduced during treatment with statins. Ubiquinone is a coenzyme in mitochondrial respiration, and depletion might adversely affect cardiac muscle. Serum ubiquinone levels have been inversely related to mortality in patients with HF [10].

However, a 2014 meta-analysis of 15 studies of a total of 45,110 individuals with HF (including 22,471 patients treated with statin and 22,639 who were not on statin) showed that use of statins was associated with reductions in all-cause mortality and rehospitalization for HF in the patients included in the analyses despite receiving evidence-based therapy for HF [11]. The results of this meta-analysis differ from those of the prospective, randomized trials discussed above. Although the precise reason is not clear, it could be that the benefit of statin therapy might depend on the stage of HF at which statins are started. Additionally, the age of the patients enrolled could also influence the findings. The sensitivity analyses removed the CORONA and GISSI-HF studies and did not find statistically substantial change in their overall findings. Another reason for the difference in the findings of this meta-analysis might be related to the use of various statins in contrast to the CORONA and GISSI-HF trials where rosuvastatin was used. It is conceivable that certain statins (eg, atorvastatin) might provide beneficial effects due to the pleiotropic effects [1,2,11,12].

HFREF — Early evidence of the role of statins in patients with heart failure with reduced ejection fraction (HFrEF) came from observational studies and post-hoc subgroup analyses in statin trials for coronary disease, which tended to support benefit from statin use [6,12-15]. In addition, two small randomized trials that evaluated surrogate endpoints came to differing conclusions [8,16].

The best data on the role of statin therapy in patients with HFrEF comes from two large randomized trials published in 2007 and 2008 (CORONA and GISSI-HF), neither of which showed benefit.

CORONA trial — In the CORONA trial, 5011 patients (mean age 73 years) with New York Heart Association (NYHA) class II to IV (table 1) ischemic systolic HF (mean left ventricular ejection fraction [LVEF] 31 percent) were randomly assigned to rosuvastatin 10 mg daily or placebo [17]. At baseline, the mean serum LDL-cholesterol concentration was 137 mg/dL (3.55 mmol/L). An entry requirement was that the investigator thought that the patient did not need a cholesterol lowering drug.

The following findings were noted at a median follow-up of 33 months:

Compared with placebo, rosuvastatin reduced LDL levels (76 versus 138 mg/dL [1.96 versus 3.57 mmol/L]), and also had beneficial effects on HDL-C and triglycerides.

Despite these biochemical changes, there was no significant reduction in the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (11.4 versus 12.3 percent with placebo, hazard ratio [HR] 0.92, 95% CI 0.83-1.02), or secondary outcomes such as cardiovascular mortality (9.3 versus 9.6 percent, HR 0.97), or coronary events (9.3 versus 10.0 percent, HR 0.92).

A post-hoc, subset analysis of the 3664 patients in whom baseline N-terminal pro B-type brain natriuretic peptide (NT-proBNP) levels were available, compared outcomes in the statin and placebo groups by tertile [18]. Patients in the lowest tertile of NT-proBNP (less than 103 pmol/L [868 pg/mL]), which is a marker for a better prognosis, had a significantly lower primary composite end point with statin therapy (HR 0.65, 95% CI 0.47-0.88). (See "Natriuretic peptide measurement in heart failure", section on 'Plasma BNP in heart failure'.)

GISSI-HF trial — In the GISSI-HF trial, 4574 patients (mean age 68 years) with ischemic or nonischemic NYHA class II to IV HF (table 1) and a mean LVEF of 33 percent were randomly assigned to rosuvastatin 10 mg daily or placebo [19]. Serum LDL cholesterol fell from 122 to 89 mg/dL (3.16 to 2.31 mmol/L) after three years of rosuvastatin compared to no significant change with placebo.

At a median follow-up of 47 months, there was no significant difference in deaths from any cause (29 versus 28 percent with placebo), or in the combined end point of death or admission to the hospital for cardiovascular causes in both ischemic (HR 1.03) and nonischemic cardiomyopathy (HR 1.02).

Conclusions — The CORONA and GISSI-HF trials suggest that the initiation of statin therapy is not useful in patients with systolic HF with or without coronary artery disease. CORONA raised the possibility that statins might be beneficial in patients with ischemic systolic HF with NT-proBNP values in the lowest tertile [18]. In the absence of confirmatory data, we suggest not using statin therapy in such patients.

In addition, the following concerns have been raised with regard to whether the results can be generalized to all patients with systolic HF:

Patients enrolled had moderate to severe disease and were older [20].

Only one statin was tested and at a low to moderate dose [20].

Ischemic events occur less frequently in patients with HF and systolic dysfunction than in the broad population of patients with established cardiovascular disease [7]. As a result, it may be harder to demonstrate benefit from statin therapy.

The question of whether patients on statin therapy who develop HF benefit from continued therapy has not been addressed in clinical trials.

HFPEF — Initial observational data suggest that statins might be of benefit in patients with heart failure and preserved ejection fraction (HFpEF). This potential effect was illustrated in a report of 137 consecutive patients with HF and a left ventricular ejection fraction (LVEF) ≥50 percent who did not have known coronary heart disease, significant valvular disease, or end-stage kidney disease; one-half were treated with a statin at the discretion of the physician [21]. The patients treated with a statin had a higher baseline LDL-cholesterol concentration than those not treated but the post-therapy values were similar in the two groups. At a mean follow-up of 21 months, statin therapy was associated with a lower mortality after adjustment for differences in baseline variables (adjusted relative risk 0.20, 95% CI 0.06-0.62). This difference observed in mortality is greater than that seen with statin therapy in other groups of patients, which calls into question whether confounding factors contribute to the difference seen.

A 2014 meta-analysis evaluated the effects of statin therapy on mortality in patients with HFpEF [22]. This meta-analysis included 11 studies (mostly observational) and included 17,985 patients with HFpEF. Statin use was associated with a 40 percent reduction in mortality (RR 0.60, 95% CI 0.49-0.74) [22]. The sensitivity analyses confirmed the stability of results and also showed a trend for reduction in mortality rates for statin users from 2005 to 2013 [11]. Although these results are tantalizing, they are limited by the observational nature of studies.  

Randomized trials are required to confirm these observations, particularly with the apparent lack of benefit of initiating statin therapy in patients with HFrEF. (See 'HFrEF' above.)

SUMMARY AND RECOMMENDATIONS

In patients with more than mild heart failure (HF) and a left ventricular ejection fraction less than 35 percent due to either ischemic heart disease or a nonischemic cardiomyopathy, we recommend starting statin therapy if they have a clinical indication for lipid lowering (Grade 1B).

This recommendation includes patients with a nonischemic cardiomyopathy who would have otherwise met criteria for initiation of statin therapy for the purpose of primary prevention. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Indications for statin therapy'.)

Patients with mild heart failure and a left ventricular ejection fraction less than 35 percent should receive statin therapy according to standard indications. (See 'CORONA trial' above and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Summary and recommendations'.)

In patients already on a statin for another appropriate indication at the time they develop HF, we suggest continuing statin therapy (Grade 2B).

Any HF patient with who is an appropriate candidate for receiving statin therapy and is not on a statin should be started on the statin therapy. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

In patients with HF with preserved ejection fraction, the decision to start statin therapy should be based upon other indications, such as the presence of atherosclerotic cardiovascular disease or LDL-cholesterol levels above guideline cutoffs.

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