The role of statin therapy in the management of cardiomyopathies

The non-lipid-lowering or pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been hypothesized to beneficially alter mechanisms involved in heart failure. Retrospective analyses of heart failure trials as well as small prospective trials with nonmortality clinical and surrogate end points appeared to confirm this presumption. However, two recently published, large, prospective randomized trials did not demonstrate any significant clinical benefit of statins in heart failure patients. This review outlines the proposed biologic effects of statins in heart failure syndrome and clinical evidence of statin use in heart failure patients.     

Should a statin be prescribed to every patient with heart failure?

Chronic heart failure (HF) represents an emerging epidemic since its prevalence is continuously increasing despite advances in treatment. Many recent clinical studies have clearly demonstrated that statin therapy is associated with improved outcomes in HF irrespective of aetiology (ischaemic or not) or baseline cholesterol levels. Indeed, most of the conducted large statin trials and trials in HF have demonstrated a positive effect of statins in HF patients. Furthermore, the use of statins in HF seems to be safe as none of the recent trials has resulted in worse outcomes for HF patients treated with statins. Potential mechanisms through which statins could benefit the failing myocardium include non-sterol effects of statins, as well as effects on nitric oxide and endothelial function, inflammation and adhesion molecules, apoptosis and myocardial remodelling and neurohormonal activation. This review discusses the pathophysiological basis of statin effects on HF and focuses on clinical data for the benefit from statin use in this setting. Until today there are no official recommendations in both the American and the European guidelines regarding the use of statins in HF patients, as the available data come from small observational or larger but retrospective, non-randomised studies. Therefore, HF patients should be treated according to current lipid guidelines. Large randomised clinical trials are underway and will further delineate the role of statin therapy in HF patients. Until more data are available, we could not recommend statin use to every patient with HF irrespective of HF aetiology and baseline cholesterol levels.     

Observational studies of statins in systolic heart failure

This article reviews the results of observational statin use in clinical trials of patients who have systolic heart failure, in post-myocardial infarction with left ventricular dysfunction, and in cardiac device trials. This article shows a consistent benefit of statins on mortality (approximately 25%) in heart failure patients of both ischemic and nonischemic etiology. The benefit is not altered by concomitant heart failure medications or device therapy. The benefit of statins in heart failure is being investigated in large prospective trials in a broad range of heart failure patients.     

Observational studies of statins in heart failure with preserved systolic function

This article reviews the available evidence from observational studies concerning the effect of statin therapy in patients who have heart failure and a preserved ejection fraction (diastolic heart failure). Observational studies suggest that statin therapy is associated with lower mortality in patients who have diastolic heart failure. These results emphasize the need for a randomized study of the effect of statins in diastolic heart failure. Until the results of such studies are available, it is recommended to use statins in patients with diastolic heart failure who otherwise have an indication for statin therapy.     

Nonlipid-lowering effects of statins

Optional statement Statins have been shown to effectively reduce cardiovascular events in patients with hypercholesterolemia, diabetes, and coronary disease, and after an acute coronary syndrome in several large-scale clinical trials. Interestingly, numerous studies have suggested that statins exert potentially important effects independent of lipid lowering (ie, improve endothelial function, reduce oxidant stress), and have direct antiinflammatory, antithrombotic, and plaque-stabilizing effects. These beneficial effects may contribute to cardiovascular protection by statin therapy beyond low-density lipoprotein (LDL) cholesterol lowering. Therefore, it remains unclear at present to what extent the beneficial cardiovascular effects of statin treatment are dependent on LDL cholesterol lowering (ie, whether the same effect would be achieved by other modes of lipid lowering). Consequently, statins should be used as a first-line therapy for lipid lowering. Importantly, the observation of LDL cholesterol-independent effects of statins has stimulated clinical studies testing a wider use of statin treatment for diseases that are not thought to be related to increased LDL cholesterol levels, such as in patients with chronic heart failure (in particular dilated cardiomyopathy) and even in inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.     

Drug insight: statins for nonischemic heart failure--evidence and potential mechanisms

While 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, also known as statins, have a well-established in role in the treatment and prevention of ischemic coronary artery disease, their utility in the setting of heart failure (HF) and left ventricular (LV) dysfunction remains under investigation. Although a reduction in LDL is the major effect of statin therapy, pleiotropic effects have been demonstrated, which could be responsible for the reduction in morbidity and mortality seen with statin use in patients with HF. Patients with both ischemic and nonischemic HF have been shown to have improved survival with statin therapy, and patients receiving statin therapy are less likely to develop HF. Studies have demonstrated that statins reduce inflammation, improve endothelial function, decrease thrombogenicity, and improve LV and autonomic function. In this Review, we present the literature supporting the pleiotropic effects of statin therapy in patients with HF or LV dysfunction, and discuss the mechanisms by which statins might elicit the improvements in morbidity and mortality seen in these patients.     

Statin-Mediated Low-Density Lipoprotein Lowering in Chronic Congestive Heart Failure

Many theories and clinical trials have attempted to address the effect of low-density lipoprotein (LDL) lowering in chronic congestive heart failure (CHF). The current evidence suggests that there is no convincing reason for administering statins to patients with nonischemic heart failure. Although they do not reduce the mortality rate, statins reduce LDL cholesterol and may provide some benefit to patients with ischemic heart failure. in contrast, some authors believe that statin therapy may actually worsen outcomes in patients with CHF, especially if there is excessive reduction in LDL cholesterol. This review discusses the theories attempting to link the adverse effects of statin-mediated LDL lowering in CHF to increased levels of endotoxin or reduced levels of coenzyme Q10. In addition, the 2 largest randomized, double-blind, placebo-controlled clinical trials (CoRoNA and Gissi-HF) were discussed. it is clear that more trials are needed to definitely ascertain the effect of statins on CHF.     

Effects of statin therapy on the development and progression of heart failure: mechanisms and clinical trials

BackgroundStatin therapy has been shown to effectively lower low-density lipoprotein cholesterol levels and reduce cardiovascular events. Statins also appear to exert other favorable effects, including anti-inflammatory actions and improvement in endothelial function. Statin therapy may therefore yield important clinical benefits in patients with heart failure—a physiologic state characterized by systemic inflammation and endothelial dysfunction.Methods and ResultsThis review summarizes basic and clinical investigations regarding the role of statin therapy in heart failure, focusing on potential mechanisms and preliminary clinical data. There is now extensive evidence suggesting that statins improve endothelial function, inhibit neurohormonal activation, restore autonomic balance, reduce inflammation, and prevent ventricular remodeling. Retrospective and small-scale prospective studies suggest that statins prevent the development of heart failure and reduce mortality in patients with established HF.ConclusionPreliminary evidence supports a role for statins in improving surrogate markers and clinical outcomes in ischemic and nonischemic heart failure. Large-scale randomized clinical trials are needed to definitively address this important topic.     

Potential autonomic nervous system effects of statins in heart failure

Sympathetic nervous system activation in heart failure, as indexed by elevated norepinephrine levels, higher muscle sympathetic nerve activity and reduced heart rate variability, is associated with pathologic ventricular remodeling, increased arrhythmias, sudden death, and increased mortality. Recent evidence suggests that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy may provide survival benefit in heart failure of both ischemic and nonischemic etiology, and one potential mechanism of benefit of statins in heart failure is modulation of the autonomic nervous system. Animal models of heart failure demonstrate reduced sympathetic activation and improved sympathovagal balance with statin therapy. Initial human studies have reported mixed results. Ongoing translational studies and outcomes trials will help delineate the potentially beneficial effects of statins on the autonomic nervous system in heart failure.     

Do statins prevent heart failure in patients after myocardial infarction?

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, reduce morbidity and mortality in patients with coronary artery disease (CAD). Because CAD is the major cause of heart failure (HF) in developed countries, prevention of CAD may result in reduced HF. Evidence from randomized trials on lipid reduction (Cholesterol and Recurrent Events and the Scandinavian Simvastatin Survival Study) has shown statins to decrease progression to HF. Recently, many beneficial effects of statins have been demonstrated beyond cholesterol lowering. These agents improve endothelial function, exhibit anti-inflammatory properties, and prevent cardiac hypertrophy. Experimental studies have shown attenuation of left ventricular remodeling after myocardial infarction, possibly through reduced oxidative stress. However, no clinical evidence exists to support an effect on ventricular remodeling. Small, short-lasting clinical studies have also suggested that statin therapy might be associated with improved survival in ischemic and nonischemic HF.     

Effects of early statin treatment on symptomatic heart failure and ischemic events after acute myocardial infarction in Japanese

Statins have been shown to prevent coronary artery disease and to preserve left ventricular function in dilated cardiomyopathy. We hypothesized that early use of statins would decrease cardiovascular events, including heart failure in patients with acute myocardial infarction (AMI). To examine the effect of statins in Japanese patients with AMI, a prospective, randomized, open-label trial was conducted in 486 patients with normal total cholesterol levels. Patients were randomly assigned to receive any available statin (n = 241) within 96 hours of AMI onset or no statin (n = 245) and were followed for up to 24 months. The primary end point was a composite of cardiovascular death, nonfatal AMI, recurrent symptomatic myocardial ischemia, congestive heart failure, and stroke. Event rate for the primary end point was lower in the statin group than in the nonstatin group (6.1% vs 11.4%, p = 0.0433). The statin group had a lower risk of congestive heart failure and symptomatic myocardial ischemia (p = 0.0154 and 0.0264, respectively). In conclusion, early lipid-lowering therapy with statins decreases recurrent cardiovascular events, in particular, congestive heart failure.     

Statins, hormones, and women: Benefits and drawbacks for atherosclerosis and osteoporosis

Clinical trials have shown that 3-hydoxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, known as statins, significantly reduce the risk of both primary and secondary coronary heart disease events. Although these trials have included few women, the evidence suggests that statins are as effective in women as in men. The addition of hormone replacement therapy to statin therapy augments lowering of low-density lipoprotein cholesterol, but may not increase the favorable effects on clinical events achieved with statins alone. Finally, new data suggest that statins may also reduce the risk of osteoporotic fractures, a provocative finding still in need of verification by clinical trials.     

Early withdrawal of statin therapy in patients with non-ST-segment elevation myocardial infarction: national registry of myocardial infarction

BACKGROUND: There is increasing interest in the non-lipid-lowering effects of statins and their effect on outcomes in patients with acute coronary syndrome. It has been suggested that withdrawal of statin therapy during an acute coronary syndrome may attenuate any benefits of pretreatment, thereby providing indirect evidence of the importance of their non-lipid-lowering effects. METHODS: This observational study compared the demographic and clinical characteristics and hospital outcomes in patients with non-ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction 4. Comparison groups consisted of patients previously receiving statins who also received statins within 24 hours of hospital admission (n = 9,001), patients previously using statins in whom therapy was discontinued (n = 4,870), and patients who did not receive statins at any time before or during hospitalization (n = 54,635). RESULTS: Of 13,871 patients receiving statins before hospital admission, 35.1% had treatment withdrawn during the first 24 hours of hospitalization. These patients had increased hospital morbidity and mortality rates relative to patients in whom therapy was continued, with higher rates of heart failure, ventricular arrhythmias, shock, and death. In multivariate analyses, these patients were at statistically significant increased risk of hospital death compared with those continuing statin therapy and at similar risk compared with those not receiving statins before or during hospitalization. CONCLUSIONS: Withdrawal of statin therapy in the first 24 hours of hospitalization for non-ST-segment elevation myocardial infarction is associated with worse hospital outcomes. In the absence of data from randomized clinical trials, our findings suggest that statin therapy should be continued during hospitalization for myocardial infarction unless strongly contraindicated.     

Efficacy of statin therapy in chronic systolic cardiac insufficiency: a meta-analysis

Background

Conflicting results currently exist on the clinical use of statins in patients with chronic systolic heart failure (CHF). This study aimed to investigate the effect of statins on clinical outcomes of CHF by a meta-analysis based on randomized controlled trials (RCTs).

Methods

We searched PubMed, MEDLINE, EMBASE, and Cochrane databases through 2010 and renewed in February 2011. We included RCTs of subjects who underwent statin or placebo treatment for established CHF, and provided data on clinical outcomes. Risk ratios (RR) were calculated using a random effects model.

Results

Thirteen trials involving 10,447 CHF patients were included in the meta-analysis. The pooling analysis showed that statin treatment did not significantly reduce the risk of all-cause death (RR = 0.93, 95% CI: 0.81–1.07, p = 0.31), death for cardiovascular cause or pump failure (p > 0.10), and rehospitalization for heart failure (RR = 0.90, 95% CI: 0.78–1.04, p = 0.15). In addition, statin therapy had a non-significant trend towards reduced risk of nonfatal myocardial infarction (RR = 0.84, 95% CI: 0.68–1.02, p = 0.08). When restricted to various statins and patients' age, the analysis demonstrated that atorvastatin was associated with reduced all-cause mortality (p = 0.009) and readmission rate for heart failure (p = 0.005), and the superiority of statin therapy was significant in CHF patients less than 65 years (both p < 0.01).

Conclusions

Although statin has little impact on clinical outcomes in overall CHF patients, statin administration if needed is feasible to CHF patients, and the treatment might be effective when restricted to specific statins or populations.     

Impact of Statins on Arteriovenous Fistulas Outcomes: A Meta‐Analysis

Statins are effective lipid‐lowering drugs with beneficial pleiotropic effects for vascular remodeling processes, statins may have a beneficial effect on the function of arteriovenous fistulas (AVFs) in hemodialysis (HD) patients. Therefore, we performed this systematic review to assess the protective effects of statin therapy in HD patients. The randomized controlled trials (RCTs) or quasi‐RCTs and retrospective cohort studies (RCS) of statin therapy for the function of AVFs in HD patients were searched from multiple databases. Relevant studies were screened according to predefined inclusion criteria and then pooled‐analyses were performed using RevMan 5.2 software. One RCT and six RCS containing 20 246 HD patients were included in this meta‐analysis, of whom 9847 were treated with statins and 10 399 were treated with placebo. Our meta‐analysis showed that there was no significant difference between statins and placebo groups, with those who received statin therapy showing similar AVF failure rates compared to control (pooled risk ratio = 0.89; 95% CI, 0.70 to 1.12, P = 0.32), and there was obvious evidence of statistical heterogeneity (P = 0.005; I² = 68%). In addition, subgroup pooled analyses revealed that statin therapy did not ameliorate AVF failure in participants from the same racial background or similar sample size trials. There was no evidence that statins therapy could reduce the AVFs failure. However, due to methodological limitations and obvious statistical heterogeneity, high‐quality, long‐term and multicenter trials are required to fully elucidate the clinical value of statins administration for the outcomes of AVFs in HD patients.     

Low-density lipoprotein in the setting of congestive heart failure: Is lower really better?

Hypercholesterolemia is a risk factor for coronary artery disease (CAD), CAD mortality, and incident heart failure (HF). Lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been shown to reduce the risk of developing HF in patients with CAD. However, in patients with chronic established HF, hypercholesterolemia has not been associated with an increased risk of mortality. Several studies have demonstrated that higher lipid and lipoprotein levels, including total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides, are associated with significantly improved outcomes in HF of both ischemic and nonischemic etiologies. In light of the association between high cholesterol levels and improved survival in HF, statin or other lipid-lowering therapy in HF remains controversial. To date, large outcome trials of statin therapy in HF of multiple etiologies have not demonstrated mortality benefit.     

Statins in heart failure. Beyond the lipid lowering effect

Statins, the most widely prescribed medications in patients with hyperlipidemia and coronary heart disease, have a number of pleiotropic actions beyond cholesterol lowering. They improve endothelial function, they have antioxidant and anti-inflammatory effects, they regulate neovascularization and have immunomodulatory activities. Experimental evidence suggests that statins may be beneficial in heart failure as they can inhibit myocardial hypertrophy, reduce cardiomyocyte loss by apoptosis, reduce oxidative stress and restore neurohormonal imbalance. Furthermore small randomised clinical trials showed that short term statin administration may improve key pathophysiological aspects of this syndrome. Finally retrospective analyses of large statin trials imply a long term profit on clinical outcome in this group of patients. These results however need to be reviewed with caution as certain studies have demonstrated that low serum cholesterol is associated with worse prognosis in HF and that ubiquinone levels, a micronutrient with antioxidant actions, reduces significantly following statin administration. Large prospective randomised controlled trials are needed to confirm the beneficial effect of statins on cardiovascular outcome in HF patients and further elucidate the contributing mechanisms. Finally the statin dose and the interaction with co-administered drugs need to be studied.     

In-hospital initiation of statin therapy in acute coronary syndromes: maximizing the early and long-term benefits

Patients with acute coronary syndrome (ACS) are at high risk for recurrent coronary events, sudden death, and all-cause mortality. Conventional revascularization therapies reduce the risk of further ischemia but do not affect the underlying atherosclerotic disease. Statins have a proven record in the secondary prevention of coronary heart disease. Furthermore, statins have been shown to exert varying degrees of pleiotropic effects, which may stabilize vulnerable atherosclerotic plaques. A compelling body of evidence from randomized controlled trials demonstrates that high-dose, potent statin therapy initiated immediately after an acute coronary event can significantly reduce early as well as longer-term morbidity and mortality. Furthermore, high-dose, potent statin therapy displays a reasonable safety profile. National guidelines now recommend that in patients with ACS, statin therapy should be initiated in hospital prior to discharge, irrespective of baseline low-density lipoprotein cholesterol levels, to improve clinical outcomes. Every effort should be made to ensure all eligible patients with ACS are initiated and maintained on statin therapy.     

The benefits of statin therapy—what questions remain?

Early hydroxymethylglutaryl-CoA reductase inhibitor (statin) trials provided the first evidence of the benefits of statin therapy in secondary prevention of coronary heart disease (CHD). Outcomes data from more recent trials involving atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin, have since expanded the patient population shown to benefit from statin therapy. Current studies are evaluating the benefits of lowering lipid levels with statins to below current goals, as well as examining benefits in special patient populations and evaluating the value of surrogate markers of CHD. Early trials provided a solid foundation of knowledge on the efficacy and safety of statins. Recent and ongoing trials generate new data to resolve remaining questions in the fields of CHD prevention and lipidology.     

The use of statins in patients with heart failure: more questions than answers

The use of statins to treat patients with heart failure (HF) is controversial due to conflicting results from large, prospective, randomized, placebo-controlled trials and other smaller studies. A recent comprehensive, well-conducted meta-analysis from Preiss and colleagues sought to determine whether statin therapy had an effect on major HF outcomes such as hospitalization and death. Although the study demonstrated a significant effect of statin therapy on HF hospitalizations, several limitations involving the participant data and nature of statin used in the analyzed trials raise questions about the inferences that can be drawn from the study results.