Editorials
Statins Beneficial for Heart Failure With Preserved Ejection Fraction But Not Heart Failure With Reduced Ejection Fraction?
2015 Volume 79 Issue 3 Pages 508-509
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2015 Volume 79 Issue 3 Pages 508-509
Evidence-based therapy has been defined for heart failure (HF) with reduced ejection fraction (EF) (HFrEF). Rigorously conducted placebo-controlled, blinded trials have demonstrated the effectiveness of drugs that reduce the effect of the renin-angiotensin-aldosterone system and the β-adrenergic system, as well as implantable defibrillators and cardiac resynchronization, in patients with left bundle branch block.1 However, the majority of patients with HF do not have a reduced EF but have a preserved EF >0.50 (HFpEF) and some of the pathophysiologic characteristics of HFpEF and HFrEF are different.2–5 None of the proven treatments for HFrEF have been clearly shown to be effective in HFpEF. Thus, effective therapy for patients with HFpEF is an important unmet need.
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Statins are a potential therapy for HF regardless of EF. Statins lower the level of low-density lipoprotein (LDL) cholesterol and are effective in the secondary and primary prevention of coronary artery disease.6 In addition, statins have pleiotropic effects that may be of benefit in HF patients, including antioxidant, antiinflammatory, and antihypertrophic effects (Figure).6 However, statins did not have a beneficial effect in 2 large randomized trials. In the CORONA trial more than 5,000 patients with ischemic HFrEF (EF <0.40) were randomized to rosuvastatin or placebo.7 There was no benefit on the primary endpoint of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. The second large trial was GISSI-HF,8 which randomized almost 5,000 patients with clinically apparent HF of any cause to rosuvastatin or placebo. Similar to the result of the CORONA trial, there was no benefit on the primary endpoints of all-cause death, and all-cause death or cardiovascular hospitalization. Additionally, there was no benefit in the 10% patients who were found to have a relatively preserved LVEF (>0.40).8 However, there were not enough patients with EF >0.50 to assess the effect in patients with HFpEF. It is important to recognize that both trials demonstrated that statins are safe in HF.
Potential effects of statins in heart failure. ACS, acute coronary syndrome; cGMP, cyclic guanosine monophosphate; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LDL-C, low-density lipoprotein cholesterol; LV, left ventricular; NO, nitric oxide, PKG, protein kinase G.
Despite the lack of benefit in HFrEF, an initial single-center, observational study by Fukuta et al9 suggested that statins improved the mortality rate in patients with HFpEF. A recently reported meta-analysis of Fukuta’s study, together with 10 other subsequent observational studies of the effect of statins on mortality rate in patients with HFpEF found that the use of statins was associated with statistically significant 40% lower mortality rate.10
Now, Nochioka et al11 report in this issue of the Journal their rigorous analysis of the effect of statins in more than 3,000 patients with HFpEF and more than 1,400 patients with HFrEF who were prospectively studied over 3 years in the Chronic Heart Failure Analysis and Registry in the Tohoku district-2 (CHART-2) project. Consistent with the randomized trials, they found no effect of statins on mortality rate in HFrEF patients. However, there was a clear mortality benefit in patients with HFpEF. Patients treated with statins had a substantial reduction in 3-year mortality (hazard ratio=0.74, 95% confidence interval, 0.58–0.94; P<0.001).The mortality benefit persisted after sophisticated corrections for potential confounding factors by propensity matching and inverse probability of treatment weighting. Importantly, the improved survival occurred because of a reduction in sudden death and noncardiovascular death. There was no effect on cardiovascular death or HF hospitalizations.
The benefit that Nochioka et al observed on sudden death is consistent with an analysis of the Multicenter Automatic Defibrillator Implantation Trial II.12 In those patients with EF <0.30, statin therapy reduced the occurrence of ventricular tachycardia and ventricular fibrillation. Statins may reduce sudden death by reducing the development of acute coronary syndromes producing ischemia induced-arrhythmias or it is possible they have direct electrophysiologic effects.
Why does the benefit of therapy differ in HFrEF and HFpEF? The mortality benefit of therapies (except implantable cardioverters) for HFrEF is associated with reversal of left ventricular remodeling. The absence of left ventricular dilation in HFpEF may account for the lack of benefit of therapies in HFpEF.13 In contrast to these proven therapies for HFrEF, statin therapy appears to benefit patients with HFpEF but not HFrEF. It is possible that the pleiotropic effect of statins has a greater effect on the pathophysiology of HFpEF than that of HFrEF.6 It is also possible that the benefit in HFpEF is related to an effect on the patient’s comorbidities. This latter possibility is supported by Nochioka et al’s observation that the largest benefit was on noncardiovascular mortality.11 This, together with the lack of effect on HF re-admissions, suggests that statins benefit patients with HFpEF, although the drugs may not have a direct effect on the HF.
In conclusion, Nochioka et al’s large, prospective, observational study provides additional support for the hypothesis that statins produce a substantial mortality benefit in patients HFpEF despite their apparent lack of benefit in HFrEF. Statins are the only therapy that appears to improve mortality in patients with HFpEF. Definitive evaluation of this hypothesis will require a randomized trial. However, statins have been proven to be safe in HF and many patients with HFpEF have other indications for statins. Thus, until more information is available, we use statins in many of our patients with HFpEF.
