REVIEWS Statin treatment for patients with heart failure W. H. Wilson Tang and Gary S. Francis abstract | Statins may be beneficial for the prevention and treatment of heart failure, as indicated by large observational studies, small prospective studies, and post hoc analyses of cardiovascular databases. Two large, prospective, controlled trials have, however, shown that rosuvastatin has neutral effects on the survival of patients with chronic heart failure. The benefits of statin treatment seem to mostly result from their ability to halt disease progression in heart failure, particularly in patients with coronary artery disease. Based on these results, statin treatment might only be useful for the prevention of heart failure, and possibly in patients with new-onset heart failure. This Review highlights data from observational data analyses as well as from the large prospective trials investigating the safety and efficacy of statins in patients with heart failure. The results from these studies and their implications for the timing of initiating statin therapy in this patient population are also discussed. Tang, W. H. W. & Francis, G. S. Nat. Rev. Cardiol. 7, 249–255 (2010); published online 16 March 2010; doi:10.1038/nrcardio.2010.29
Introduction
over the past decade, the role of statin therapy in patients with heart failure has been supported by favorable observa‑ tional studies.1 However, two large, randomized, controlled trials have directly challenged the wealth of mechanistic and observational information that has helped to build the statin hypothesis, which is the notion that the pleio‑ tropic effects of statin therapy may be beneficial for the treatment of heart failure. in this review, we examine why the results from these two trials may be inconsistent with earlier data, with particular emphasis on the differences in study design and treatments. we postulate that a key benefit of statin therapy is to prevent the development and progression of heart failure rather than salvaging or reversing the advanced stages of this condition.
Benefits of statin therapy
statins were originally designed to lower cholesterol in patients with cardiovascular disease, but it is increasingly recognized that these drugs also have a favorable effect on inflammation, oxidative stress, and vascular performance (Figure 1).
lipid-lowering effects Dyslipidemia is the primary indication for contempo‑ rary use of statin therapy, which is based on its ability to competitively inhibit 3‑hydroxy‑3‑methylglutaryl coenzyme a (HmG Coa) reductase. this enzyme is a rate‑limiting step in the mevalonate pathway of chol‑ esterol biosynthesis. Blocking HmG Coa reductase leads to a reduction in serum cholesterol levels, and a decrease in stroke and cardiovascular disease. competing interests W. H. W. Tang declares an association with the following companies: Abbott Laboratories and Merck. G. S. Francis declares an association with the following company: Merck. See the article online for full details of the relationships.
anti-inflammatory effects Coronary artery disease is a leading cause of heart failure, which is characterized by heightened inflamma‑ tion due to the activation of proinflammatory cytokines, the complement system, cell adhesion molecules, and cardiac autoantibodies.2 elevated levels of inflammatory mediators, such as interleukin 6, tumor necrosis factor (tnF), and C‑reactive protein, have also been reported in the setting of heart failure, and are associated with increased morbidity and mortality.3–5 interestingly, inflammatory manifestations mostly occur in advanced stages of heart failure. some studies have demonstrated that statins reduce inflammatory cytokines in patients with ischemic and nonischemic cardiomyopathy;6–10 however, others have found no evidence for this effect in similar populations.11,12 the precise mechanism of their anti‑inflammatory effects is not known, but statins may reduce the production of farnesylated and geranyl‑ geranylated proteins, which leads to a decrease in nuclear factor kappa B (nFκB) activation, a key regulator of pro‑ inflammatory cytokine and adhesion molecule expres‑ sion.13 statins may also inhibit naDPH oxidase activity in patients with advanced heart failure, thus reducing major sources of reactive oxygen species.14 Endothelial effects endothelial dysfunction is evident in animal models and in patients with heart failure.15 a characteristic feature of endothelial dysfunction is a reduction in endothelial‑ cell‑derived nitric oxide. the net result is impaired vascular relaxation, increased platelet aggregation, and smooth muscle cell proliferation with enhanced migration of vascular smooth muscle. 16 statins seem to increase endothelial nitric oxide synthase activity in patients with heart failure.17,18 Furthermore, statins may also enhance endothelial progenitor cell release.19 most evidence supports the possibility that statins improve endothelial function, potentially by inhibition of
nature reviews | cardiology
Department of Cardiovascular Medicine, Cleveland Clinic Heart and Vascular Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA (W. H. W. Tang). Cardiovascular Division, University of Minnesota Medical School, MMC 508, 420 Delaware Street, Minneapolis, MN 55455, USA (g. S. Francis). Correspondence to: W. H. W. Tang
[email protected]
volume 7 | maY 2010 | 249 © 2010 Macmillan Publishers Limited. All rights reserved
rEviEWS Key points ■ Statin therapy has been implicated in the prevention of adverse cardiovascular events, including new-onset heart failure ■ Several observational and post hoc analyses from large clinical trials have implied that statin therapy may provide benefit to patients with heart failure ■ Two large randomized, controlled trials demonstrated that rosuvastatin had neutral effects on long-term outcomes in patients with chronic systolic heart failure when added to standard neurohormonal antagonists ■ The discrepancy between observational data and randomized trials can be explained by study design, medications used, or patient selection criteria ■ Early enthusiasm for statins as a therapeutic strategy has been dampened following these trials
Coagulation and thrombosis
Inflammation and immunomodulation
Statin
■ Increases tissue-type plasminogen activator ■ Reduces tissue factor expression ■ Inhibits platelet aggregation ■ Increases nitric oxide and NFκB activation ■ Reduces endothelial cell activation, leukocyteendothelial cell adhesion and T-cell and monocyte activation ■ Reduces C-reactive protein
Oxidative stress
■ Inhibits NADPH oxidase and reduces superoxide formation ■ Reduces lipoprotein oxidation
Plaque stability
■ Reduces inflammatory cell infiltrate and macrophage matrix metalloproteinase synthesis ■ Increases collagen synthesis and vascular smooth muscle cell content
■ Improves bioavailability of nitric oxide by increasing endothelial nitric oxide synthase Endothelial function expression and angiogenesis ■ Reduces endothelin-1 expression ■ Promotes endothelialization and enhances endothelial progenitor cell mobilization
Figure 1 | The pleiotropic effects of statins. Abbreviations: NADPH, nicotinamide adenine dinucleotide phosphate; NFκB, nuclear factor kappa B.
leukocyte–endothelium interactions via downregulation of endothelial cell adhesion molecules.
Clinical studies of statin therapy
the pleiotropic effects of statin therapy suggest that patients with heart failure may benefit from treatment irrespective of their ability to improve lipid profiles. that statins have been used in variously designed studies of patients with heart failure is, therefore, not surprising (table 1). Despite the heterogeneity in their design, these observational studies have been consistently favorable.
Nonrandomized observational studies the earliest data regarding the potential role of statin therapy in heart failure came from post hoc analyses of large‑scale clinical trials. Kjekshus and colleagues examined whether simvastatin reduced the onset of heart failure during the 5‑year follow‑up of the 4s study (scandinavian simvastatin survival study).20 in this retro‑ spective analysis of 4,444 patients with coronary artery disease but no heart failure, more patients receiving placebo developed heart failure compared with patients administered simvastatin (10.3% versus 8.3%, P
