Statins and Heart Failure

Juan J. Chillarón, David Benaiges, Elisenda Climent, Juana A. Flores-Le Roux, Juan Pedro-Botet

Juan J. Chillarón, David Benaiges, Elisenda Climent, Juan A. Flores-Le Roux, Juan Pedro-Botet, Department of Endocrinology and Nutrition, Hospital del Mar, Barcelona; Department of Medicine, Universitat Autònoma de Barcelona, Spain

Correspondence to: Juan Pedro-Botet, Professor, Department of Endocrinology and Nutrition, Hospital del Mar, Passeig Marítim, 25-29, E-08003 Barcelona, Spain.
Email: 86620@parcdesalutmar.cat
Telephone: +34-932483711
Fax: + 34-932483337
Received: May 26, 2015
Revised: June 21, 2015
Accepted: June 26, 2015
Published online: October 10, 2015


Heart failure (HF) is a major public health issue owing to its prognostic impact and high mortality rate. In the developed countries, the prevalence reaches 1-2% of the adult population, rising to over 10% in those over 70 years of age. 50-70% of patients with HF have hypercholesterolemia, and many do not achieve the therapeutic goals recommended by clinical practice guidelines. Although statin therapy has proved to have many cardiovascular benefits, patients with HF have been systematically excluded from clinical trials; thus, the use of statins in these patients remains controversial. Specifically in HF patients, two large studies with rosuvastatin (CORONA and GISSI-HF) and one with pitavastatin (PEARL) were conducted; no differences in mortality were observed, although pitavastatin therapy appeared to exert a beneficial effect in patients with left ventricular ejection fraction > 30%. The aim of this review was to provide an update on the role of statin therapy in the pathophysiology of HF and present the existing clinical trial data for statin use in HF.

Key words: Heart failure; Pitavastatin; Statins; Rosuvastatin; Treatment

© 2015 The Authors. Published by ACT Group Ltd.

Chillarón JJ, Benaiges D, Climent E, Flores-Le Roux JA, Pedro-Botet J. Statins and Heart Failure. Journal of Cardiology and Therapy 2015; 2(5): 405-409 Available from: URL: http://www.ghrnet.org/index.php/jct/article/view/1396


Heart failure (HF) is a major public health concern owing to its prognostic impact and high mortality rate. In developed countries, prevalence reaches 1-2% of the adult population, rising to over 10% in those over 70 years of age[1]. In Spain, the prevalence of HF is around 5%, and was the leading cause of death in 3% of men and 10% of women in 2010[2]. Furthermore, annual mortality in HF patients has been estimated to be almost 16 times higher in men and 15 times higher in women compared to those without HF[3]. While HF mortality has fallen slightly in recent years it remains very high despite available therapies[4]. In addition, HF is a major cause of hospital admissions, being the leading cause of hospitalization in patients over 65 years of age and currently accounting for 3% of all hospital admissions[2].

Hypercholesterolemia is very common in patients with HF. In the CARDIOPRES study conducted in patients with chronic HF managed in primary care, approximately 60% had hypercholesterolemia[5]. In the EPISERVE study which included outpatient HF patients treated by specialists in cardiology, internal medicine and family medicine, 50% had hypercholesterolemia. Interestingly, that study found that while only 20% of patients met the therapeutic goals, hypercholesterolemia was independently related to the adequacy of treatment[6]. In the MERICAP study on hypertensive women ≥ 65 years treated in primary care, 71% with unrecognized HF had dyslipidemia versus to 60% of those without HF[7].

Statins proved to reduce cardiovascular morbidity and mortality in primary and secondary prevention studies[8-11], and represent the main pharmacologic tool in cardiovascular prevention[12,13]. Findings of the different prospective meta-analyses of individual data of the Cholesterol Treatment Trialists (CTT) collaboration clarified the role of statin therapy in the prevention of cardiovascular events and have showed that the benefits of statin therapy outweighed any known risks. Nonetheless, the issue is less clear in HF patients since this specific population has been systematically excluded from most large cardiovascular outcome studies on statins. Furthermore, subsequent clinical data examining the effect of statins in HF were limited by several factors: the cross-sectional design in some cases, sample size, inclusion of patients with diverse ejection fractions and different HF etiologies, limited clinical follow-up and different doses and types of statin[14-16]. The purpose of this review was to provide an update on the role of statin therapy in the pathophysiology of HF and present the existing clinical trial data for statin use in HF.


Evidence from both preclinical and clinical research supports the view that statins have a variety of antiatherogenic and cardioprotective effects that go beyond their impact on lipid metabolism. These effects, which are largely mediated by the drugs’ability to block the synthesis of isoprenoid intermediates, have provided new insights into their therapeutic use. In this respect, experimental studies have shown that statins impede major causal factors in the development of HF, thereby determining a reduction in inflammation and improvement in endothelial function[17]. Statins have been shown to block the development of cardiac hypertrophy via Rho and Ras, inhibit the activation of metalloproteases, exert antifibrotic and anti-apoptotic effects, inhibit the induction of hypertrophy resulting from angiotensin II and promote the mobilization of progenitor cells, inducing angiogenesis[18]. Furthermore, statins increase endothelial nitric oxide (NO) production by stimulating and up-regulating endothelial NO synthase (eNOS) and restore eNOS activity in the presence of hypoxia and oxidized LDL, conditions which lead to endothelial dysfunction. Thus, if the ability of statins to increase the bioavailability of nitric oxide is added to these effects, they may also be expected to exert beneficial effects in the context of HF[19] (Figure 1).

On the other hand, three hypotheses for possible harmful effects of statin therapy may explain the negative effects observed in some studies: first, the endotoxin-lipoprotein hypothesis, linking elevated cholesterol levels by regulating the inflammatory state characteristic of HF[20]; second, the ubiquinol hypothesis, which relates inhibiting ubiquinone synthesis statins produced by a reduction in cellular energy production that can affect ventricular function and promote the development of myopathy and myalgias[21]; and finally, the selenoprotein hypothesis, which relates selenoprotein deficiency to myopathy, may also affect the myocardium and worsen ventricular function[22]. These possible side effects have to be balanced with the results obtained in clinical trials discussed below.


For primary HF prevention, epidemiologic studies suggest that statins may prevent the onset of HF in dyslipidemic patients without established cardiovascular disease[23]. For secondary prevention, several clinical trials have shown that statin therapy after acute coronary syndrome prevents the development of HF and is associated with better prognosis[24-27]. Before 2007, several randomized clinical trials on the use of statins in HF to reduce overall mortality and cardiovascular disease had appeared, with discordant results, since the type and number of patients and the types of statin used and outcomes were highly heterogeneous. In most of those studies, an increase in left ventricular ejection fraction (LVEF) and clinical improvement assessed in different ways were demonstrated (New York Heart Association [NYHA] class, BNP, 6-minute walking test, …)[14-16], although none included more than 110 patients. Given the heterogeneity of the results obtained, two trials with more than 4,500 patients were designed to evaluate the effects of rosuvastatin in chronic HF[28,29]. The CORONA study was conducted in patients with symptomatic ischemic HF and an LVEF ≤ 40% without statin treatment in whom rosuvastatin was administered. After 3 years of follow-up, no reduction in total mortality from any cause was detected, although the number of hospitalizations due to HF was lower[28]. CORONA patients had an average age of 72 years with a moderate to severe degree of HF; thus, the already advanced HF stage could explain these "negative" findings.

The GISSI-HF[29] was the second large-scale randomized clinical trial on almost 5,000 patients with symptomatic HF regardless of etiology and LVEF ≤ 40% or > 40% if HF had occurred in the previous year without pretreatment with statins. As in the CORONA study, rosuvastatin was administered and, after 5 years of follow-up, no beneficial effects on overall mortality, total and cardiovascular hospitalizations were observed. Neither was a clinical improvement observed in chronic HF. Additionally, no benefit was observed in the 10% of patients found to have a relatively preserved LVEF (> 0.40)[30]. However, the number of patients with LVEF > 0.50 was insufficient to assess the effect in HF patients with preserved EF. It should be emphasized that both trials demonstrated that statins were safe in HF.

A combined analysis of patients included in these two trials showed that, in patients with ischemic HF, rosuvastatin reduced the risk of new myocardial infarction episodes (hazard ratio: 0.81, 95% CI from 0.66 to 0.99, p <0.05), although there remained no differences in the mortality rate[31].

Finally, the results of the PEARL study[32], which evaluated the efficacy of pitavastatin in 574 patients with chronic HF functional class II-III NYHA not previously treated with statins and followed for 35 months, were reported in 2013. In the whole group no differences in primary outcome (HR: 0.922, 95% CI: 0.632-1.345, p=0.672), a composite of hospitalization and clinical symptoms including dyspnea, shortness of breath and peripheral edema, were observed, together with LV dysfunction by echocardiography according to the American Heart Association/American College of Cardiology guidelines. However, when only patients with LVFE ≥ 30%, which involved 72% of the sample was analyzed, a 48% risk reduction for the primary outcome in patients treated with pitavastatin (HR: 0.525, 95% CI: 0308-3896, p=0.018) was found; data were not previously demonstrated. The main differences between that study and the two discussed previously (Table 1) were the mean age of patients, 63 years versus 73 and 68 in the CORONA and GISSI-HF studies, respectively, the percentage of patients with NYHA class II, which was much higher in the PEARL study, which was conducted entirely in Japanese individuals, who are known to exhibit a superior response to statins probably genetic-based, so that the differences observed are not directly extrapolable to other ethnic groups. However, the main contribution of PEARL is the demonstration that pitavastatin treatment in early stages of chronic HF can have a beneficial effect on cardiac mortality and hospitalization for HF. Recent observational studies support this fact, especially with the reduced mortality due to sudden death (HR: 0.59; 95% CI: 0.36 to 0.98, p=0.041), infection and death (HR: 0.53; 95% CI: 0.35 to 0.77, p=0.001) only in patients with a preserved EF[33]. This study showed that statin therapy improved survival in patients with chronic HF, even in those without high cholesterol, but to a lesser degree. Another study based on the Swedish Heart Failure Registry that analyzed 21,864 patients with HF and depressed EF found a lower one-year mortality in patients who continued statin therapy (HR: 0.81; 95% CI: 0.76 to 0.86; p<0.001), especially those with HF of ischemic etiology[34]. It is noteworthy that, in this study, the percentage of patients with atrial fibrillation was higher than in the CORONA and GISSI studies (45% vs 19 and 24%, respectively).

However, some meta-analyses have shown the use of statins in patients with HF to be associated with reductions in mortality and re-hospitalization for HF[35,36]. These differences could be explained at least in part by two factors. Firstly, not all statins have the same effect in HF patients, and not all patients with HF are the same. The benefit of statins appears greater in patients with less advanced HF (lower levels of natriuretic peptides)[35-37] and preserved ejection fraction[38]. This implies that when therapy is started earlier in patients with HF and hypercholesterolemia, the benefit will be greater[39]. In addition, some studies have also shown that statins partially reduce inflammatory markers of HF[40] and may improve cardiac function, ventricular remodeling and symptoms[41,42]. In this respect, simvastatin was able to prevent diastolic dysfunction in an experimental model of hypercholesterolemia regardless of its lipid-lowering effect. This beneficial effect was, at least partially, due to a decrease in myocardial fibrosis and angiogenesis[43].


A high percentage of HF patients present alterations in their lipid profile, and many fail to achieve the therapeutic goals recommended by clinical practice guidelines. Studies with rosuvastatin in these patients showed no significant differences in terms of mortality rates or cardiovascular events; however, pitavastatin in the early stages of the disease appears to improve HF symptoms. Further controlled trials in the early stages of the disease are required to confirm these findings in other ethnic groups and clarify the mechanisms leading to this improvement.


We thank Miss Christine O’Hara for review of the English version of the manuscript.


There are no conflicts of interest with regard to the present study.


1 Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93: 1137-1146.

2 Sayago-Silva I, García-López F, Segovia-Cubero J. Epidemiology of heart failure in Spain over the last 20 years. Rev Esp Cardiol. 2013;66:649-656.

3 de Giuli F, Khaw KT, Cowie MR, Sutton GC, Ferrari R, Poole-Wilson PA. Incidence and outcome of persons with a clinical diagnosis of heart failure in a general practice population of 696,884 in the United Kingdom. Eur J Heart Fail. 2005;7:295-302.

4 Bueno H, Ross JS, Wang Y, Chen J, Vidán MT, Normand SL, et al. Trends in length of stay and short-term outcomes among Medicare patients hospitalized for heart failure, 1993-2006. JAMA. 2010;303:2141-2147.

5 Rodríguez Roca GC, Barrios Alonso V, Aznar Costa J, Llisterri Caro JL, Alonso Moreno FJ, Escobar Cervantes C, et al. Clinical characteristics of patients diagnosed of chronic heart failure attended in primary care. The CARDIOPRES study. Rev Clin Esp. 2007;207:337-340.

6 González-Juanatey JR, Alegría Ezquerra E, Bertoméu Martínez V, Conthe Gutiérrez P, de Santiago Nocito A, Zsolt Fradera I. Heart failure in outpatients: comorbidities and management by different specialists. The EPISERVE Study. Rev Esp Cardiol. 2008;61:611-619.

7 Barrios V, Escobar C, De la Sierra A, Llisterri JL, González-Segura D. Detection of unrecognized clinical heart failure in elderly hypertensive women attended in primary care setting. Blood Press. 2010;19:301-307.

8 Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, 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.

9 Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117-125.

10 Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681.

11 Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581-590.

12 Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al; European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG). European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2012;33:1635-1701.

13 Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889-2934.

14 Anker SD, Clark AL, Winkler R, Zugck C, Cicoira M, Ponikowski P, et al. Statin use and survival in patients with chronic heart failure--results from two observational studies with 5200 patients. Int J Cardiol. 2006;112:234-242.

15 Dobre D, Rossignol P, Murin J, Parkhomenko A, Lamiral Z, Krum H, et al. Statin therapy and clinical outcomes in myocardial infarction patients complicated by acute heart failure: insights from the EPHESUS trial. Eur J Heart Fail. 2013;15: 221-227.

16 Lewinter C, Bland JM, Crouch S, Cleland JG, Doherty P, LeWinter MM, et al. Impact of aspirin and statins on long-term survival in patients hospitalized with acute myocardial infarction complicated by heart failure: an analysis of 1706 patients. Eur J Heart Fail. 2014;16:95-102.

17 Tousoulis D, Antoniades C, Vassiliadou C, Toutouza M, Pitsavos C, Tentolouris C, et al. Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure. Eur J Heart F. 2005;7:1126-1132.

18 Badimon L, Vilahur G. Beneficio clínico de las estatinas: ¿hemos cubierto todo el espectro? Rev Esp Cardiol. 2011;11(Suppl.B):3-13.

19 Trochu JN, Mital S, Zhang X, Xu X, Ochoa M, Liao JK, et al. Preservation of NO production by statins in the treatment of heart failure. Cardiovasc Res. 2003;60: 250-258.

20 Rauchhaus M, Clark AL, Doehner W, Davos C, Bolger A, Sharma R, et al. The relationship between cholesterol and survival in patients with chronic heart failure. J Am Coll Cardiol. 2003;42:1933-1940.

21 Mortensen SA, Leth A, Agner E, Rohde M. Dose-related decreased of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med. 1997;18(Suppl):S137-S144.

22 Moosmann B, Behl C. Selenoprotein synthesis and side-effects of statins. Lancet. 2004;363:892-894.

23 Wojnicz R, Wilczek K, Nowalany-Kozielska E, Szygula-Jurkiewicz B, Nowak J, Polonski L, et al. Usefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levels. Am J Cardiol. 2006;97:899-904.

24 Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.

25 Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.

26 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.

27 Lewis SJ, Moye LA, Sacks FM, Johnstone DE, Timmis G, Mitchell J, et al. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial. Ann Intern Med. 1998;129:681-689.

28 Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JG, Cornel JH, et al; CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248-2261.

29 Gissi-HF Investigators, Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372: 1231-1239.

30 Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): A randomised, double-blind, placebo controlled trial. Lancet. 2008;372:1231-1239.

31 Feinstein MJ, Jhund P, Kang J, Ning H, Maggioni A, Wikstrand J, et al. Do statins reduce the risk of myocardial infarction in patients with heart failure? A pooled individual-level reanalysis of CORONA and GISSI-HF. Eur J Heart Fail. 2015;17: 434-441.

32 Takano H, Mizuma H, Kuwabara Y, Sato Y, Shindo S, Kotooka N, et al; PEARL Study Investigators. Effects of pitavastatin in Japanese patients with chronic heart failure: the Pitavastatin Heart Failure Study (PEARL Study). Circ J. 2013;77:917-925.

33 Nochioka K, Sakata Y, Miyata S, Miura M, Takada T, Tadaki S, et al; CHART-2 Investigators. Prognostic impact of statin use in patients with heart failure and preserved ejection fraction. Circ J. 2015;79:574-582.

34 Alehagen U, Benson L, Edner M, Dahlström U, Lund LH. Association between use of statins and outcomes in heart failure with reduced ejection fraction: prospective propensity score matched cohort study of 21 864 patients in the Swedish heart failure registry. Circ Heart Fail. 2015;8:252-260.

35 Wang JQ, Wu GR, Wang Z, Dai XP, Li XR. Long-term clinical outcomes of statin use for chronic heart failure: a meta-analysis of 15 prospective studies. Heart Lung Circ. 2014;23:105-113.

36 Zhang S, Zhang L, Sun A, Jiang H, Qian J, Ge J. Efficacy of statin therapy in chronic systolic cardiac insufficiency: a meta-analysis. Eur J Intern Med. 2011;22: 478-484.

37 Cleland JG, McMurray JJ, Kjekshus J, Cornel JH, Dunselman P, Fonseca C, et al; CORONA Study Group. Plasma concentration of amino-terminal pro-brain natriuretic peptide in chronic heart failure: prediction of cardiovascular events and interaction with the effects of rosuvastatin: a report from CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure). J Am Coll Cardiol. 2009;54: 1850-1859.

38 Liu G, Zheng XX, Xu YL, Ru J, Hui RT, Huang XH. Meta-analysis of the effect of statins on mortality in patients with preserved ejection fraction. Am J Cardiol. 2014;113:1198-1204.

39 Barrios V, Escobar C. Rosuvastatin and cardiovascular continuum. When time is important. J Am Coll Cardiol. 2010;55:1645-1646.

40 Zhang L, Zhang S, Jiang H, Sun A, Wang Y, Zou Y, et al. Effects of statin therapy on inflammatory markers in chronic heart failure: a meta-analysis of randomized controlled trials. Arch Med Res. 2010;41:464-471.

41 Zhang L, Zhang S, Jiang H, Sun A, Zou Y, Ge J. Effects of statin treatment on cardiac function in patients with chronic heart failure: a meta-analysis of randomized controlled trials. Clin Cardiol. 2011;34:117-123.

42 Indolfi C, Di Lorenzo E, Perrino C, Stingone AM, Curcio A, Torella D, et al. Hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibit p21ras activation. Circulation. 2002;106:2118-2124.

43 Mannheim D, Herrmann J, Bonetti PO, Lavi R, Lerman LO, Lerman A. Simvastatin preserves diastolic function in experimental hypercholesterolemia independently of its lipid lowering effect. Atherosclerosis. 2011;216:283-291.

Peer reviewers: Elio Venturini, Civic Hospital “Bassa val di Cecina”, U.O. Cardiologia-UTIC, Via Montanara, 39, 57023 Cecina (LI), Italy; Sita Ram Mittal, Department of Cardiology, Mittal Hospital & Research Centre, Pushkar Road, Ajmer, Rajasthan -305001, India.


  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.