- Open Access
Debate: Should statin be used in patients with heart failure?
Trials volume 2, Article number: 266 (2001)
Statins reduce mortality of patients with coronary artery disease (CAD). However, by protocol, trials have excluded patients with chronic heart failure. Since the prevalent etiology of heart failure is CAD, preventing CAD may prevent heart failure progression. Statins may have other beneficial effects besides cholesterol lowering, such as anti-inflammatory properties and improvement of endothelial function. On the contrary, high levels of cholesterol can be beneficial in heart failure patients on the basis of the ability of serum lipoproteins to modulate inflammatory response. Furthermore, statins affecting mitochondrial function can have a deleterious effect on skeletal or cardiac muscles. Despite all these conflicting data, there is no evidence from trials on the effects of statins in patients with heart failure. For this reason, the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI) investigators planned a controlled trial testing the effect of statins in patients with heart failure of different etiology.
Lipid-lowering treatment with statins clearly reduces morbidity and mortality of patients with documented CAD [1–3]. However, because these trial protocols excluded patients with chronic heart failure, information on the effect of statins in this clinical condition is incomplete.
Since the prevalent etiology of heart failure is CAD, its prevention may reduce heart failure progression. Consistent with this hypothesis, a subanalysis of the Scandinavian Simvastatin Survival Study showed that statin treatment could prevent the occurrence of overt heart failure in patients with CAD .
Furthermore, recent studies suggest that statin treatment may have other beneficial effects besides cholesterol lowering. It has been hypothesized that the inhibition of hydroxymethyl glutaryl coenzyme Areductase can interfere with the synthesis of anti-inflammatory components, thus downregulating cytokine and chemokine production, which is activated in patients with heart failure (due to any etiology) . Statin treatment can also improve endothelial function, largely compromised in patients with heart failure irrespective of the underlying etiology, and is considered responsible for multi-organ failure [6, 7].
Along with this encouraging evidence, there are some suggestions that low levels of circulating lipoproteins and cholesterol may be independent predictors of impaired outcome in patients with heart failure [8, 9]. An association between a cholesterol cutoff level below 5.2 mmol/L (according to the treatment guidelines of the American Heart Association) and impaired 1-year event free survival was found in a group of patients with heart failure . There are several possible explanations for this finding. High levels of cholesterol can be beneficial in heart failure patients; cholesterol-rich serum lipoproteins are able to modulate inflammatory immune function because they bind and detoxify bacterial lipopolysaccharide, whose production is increased in heart failure patients (endotoxin-lipoprotein hypothesis) . Lipopolysaccharide is a very strong stimulator of the release of proinflammatory cytokines that promote heart failure progression and death.
Statins also inhibit the synthesis of mevalonate, a precursor of ubiquinone, which is a central compound of the mitochondrial respiratory chain [11–13]. Statins thus affect mitochondrial function and can have deleterious effects on skeletal or cardiac muscles. This mechanism may also be the basis of the main adverse effect of statins, which is toxic myopathy, possibly related to mitochondrial dysfunction.
Besides heart failure syndrome, other evidence also discourages the use of lipid-lowering agents in elderly patients; and patients affected by heart failure are generally old. An analysis of the Framingham database showed that the relationship between total cholesterol levels and all-cause mortality was positive at age 40 years, negligible at 50–70 years old, and negative at age 80 years . For this reason, Kronmal et al. stated that physicians should be cautious about initiating cholesterol-lowering treatment in patients older than 70 years of age. They furthermore felt that only randomized clinical trials in older people could settle the debate over the efficacy of lipid-lowering interventions for reducing mortality and morbidity in elderly patients. In this context, it is important to remember that the mean age of patients with heart failure is approximately 65 years, as determined from trial databases, and the mean age is older than 70 years in community settings.
Even though there is both encouraging and discouraging scientific information, there is no direct evidence from randomized clinical trials on the effects of statins in patients with heart failure. Only post hoc analyses have been performed.
The Losartan Heart Failure Survival Study (ELITE II) showed a mortality reduction in patients with heart failure of any etiology treated with statins (nonrandomized comparison) . Of nearly 900 patients with left ventricular dysfunction/failure enrolled in the statin hypothesis of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione trial, no safety problems were observed in the patients allocated to pravastatin . Additionally, the favorable direction of the effect in terms of total mortality was similar among patients with and without left ventricular dysfunction and/or failure (unpublished data).
In conclusion, while there are no reliable clinical data on the benefit/risk profile of statins in heart failure, current knowledge is characterized by some suggestive observations supporting the benefit of statins but also by conflicting clinical and experimental evidence on their use. This can be considered the ideal scenario to formally test the hypothesis. For these reasons, the GISSI investigators planned a randomized clinical trial testing the effect of statins in patients with heart failure of any etiology. The main objective was to demonstrate whether long-term treatment with statins is able to reduce major clinical events such as all-cause mortality, and hospitalizations for any cause, that frequently affect this clinical condition.
= coronary artery disease.
- ELITE II:
= Losartan Heart Failure Survival Study
= Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico.
The 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. 10.1016/S0140-6736(94)90566-5.
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996, 335: 1001-1009. 10.1056/NEJM199610033351401.
LIPID Study Group: Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998, 339: 1349-1357. 10.1056/NEJM199811053391902.
Kjekshus J, Pedersen TR, Olsson AG, Faergeman O, Pyorala K: The effects of simvastatin on the incidence of heart failure with coronary heart disease. J Card Fail. 1997, 3: 249-254.
Vaughan CJ, Murphy MB, Buckley BM: Statins do more than just lower cholesterol. Lancet. 1996, 348: 1079-1082. 10.1016/S0140-6736(96)05190-2.
Koh KK: Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res. 2000, 47: 648-657. 10.1016/S0008-6363(00)00146-2.
Drexler H, Hornig BD: Endothelial dysfunction in human disease. J Mol Cell Cardiol. 1999, 31: 51-60. 10.1006/jmcc.1998.0843.
Vredevoe DL, Woo MA, Doering LV, Brecht ML, Hamilton MA, Fonarow GC: Skin test anergy in advanced heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1998, 82: 323-328. 10.1016/S0002-9149(98)00334-8.
Richardz BM, Radovancevic B, Frazier OH, Vaughn WK, Taegtmeyer H: Low serum cholesterol levels predict high peri-operative mortality in patients supported by a left-ventricular assist system. Cardiology. 1998, 89: 187-188.
Rauchhaus M, Coats AJS, Anker SD: The endotoxin-lipoprotein hypothesis. Lancet. 2000, 356: 930-933. 10.1016/S0140-6736(00)02690-8.
Marz W, Siekmeier R, Muller HM, Wieland H, Gross W, Olbrich HG: Effects of lovastatin and pravastatin on the survival of hamsters with inherited cardiomyopathy. J Cardiovasc Pharmacol Ther. 2000, 5: 275-279.
de Lorgeril M, Salen P, Bontemps L, Belichard P, Geyssant A, Itti R: Effects of lipid-lowering drugs on left ventricular function and exercise tolerance in dyslipidemic coronary patients. J Cardiovasc Pharmacol Ther. 1999, 33: 473-478. 10.1097/00005344-199903000-00018.
Permanetter B, Rossy W, Klein G, Weingartner F, Seidl KF, Blomer H: Ubiquinone (coenzyme Q10) in the long-term treatment of idiopathic dilated cardiomyopathy. Eur Heart J. 1992, 13: 1528-1533.
Kronmal RA, Cain KC, Ye Z, Omenn GS: Total serum cholesterol levels and mortality risk as a function of age. A report based on the Framingham data. Arch Intern Med. 1993, 153: 1065-1073. 10.1001/archinte.153.9.1065.
Segal R, Pitt B, Pode-Wilson P, Sharma D, Bradstreet DC, Ikeda LS, (on behalf of the ELITE II): Effects of HMG-COA reductase inhibitors (statins) in patients with heart failure [abstract]. Eur J Heart Fail. 2000, 2(suppl 2): 96-10.1016/S1388-9842(00)80342-6.
Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico: Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999, 354: 447-455. 10.1016/S0140-6736(99)07072-5.
About this article
Cite this article
Pietro Maggioni, A. Debate: Should statin be used in patients with heart failure?. Trials 2, 266 (2001). https://doi.org/10.1186/cvm-2-6-266
- clinical trials
- heart failure