The use of statins in optimising reduction of cardiovascular risk: focus on fluvastatin

Patients with widely differing degrees of cardiovascular risk can derive benefit from effective lipid-lowering therapy with statins, including patients with normal or low cholesterol levels. Clinical trials with fluvastatin have shown that it is effective in patients across a broad spectrum of cardiovascular risk. The lipid-lowering effects of fluvastatin are smaller than some statins, but major clinical outcome studies have consistently demonstrated morbidity and mortality benefits with reductions of low-density lipoprotein cholesterol of <30%. As treatment with statins is generally life-long and patients often receive multiple concomitant medications, optimal statin therapy should be well tolerated and serious consideration should be given to the avoidance of drug interactions. Although serious side-effects of statins are very rare, it is important that fluvastatin is less susceptible to drug interactions than other statins, because serious side-effects of statin therapy are generally associated with concomitant medications affecting statin metabolism. In addition, an extended-release formulation of fluvastatin has been developed to provide liver selectivity with a sustained exposure to the drug, thus improving its efficacy, and safety and tolerability profiles.     

Role of statin pleiotropism in acute coronary syndromes and stroke

Several landmark clinical trials have demonstrated the benefit of lipid-lowering with statins for the primary and secondary prevention of coronary heart disease. The clinical data in support of lowering cholesterol by statins are unequivocal. The established mechanism of action is via sterol regulatory element binding protein (SREBP) activation due to reduced hepatic cholesterol synthesis and secondary upregulation of the low-density lipoprotein (LDL)-receptor, leading to enhanced clearance of circulating cholesterol and lipids. Although it is widely accepted that most clinical benefit obtained with statins is a direct result of their lipid-lowering properties, there is still some debate as to whether the so-called 'pleiotropic effects' of statins contribute to the clinical outcome in vascular disease, or whether all the beneficial effects of statins are simply due to lipid-lowering. For example, these agents appear to display additional cholesterol-independent effects on various aspects of cardiovascular disease, including improving endothelial function, decreasing vascular inflammation and enhancing plaque stability. Thus, further studies are needed to understand the full impact of statin therapy on each of these processes and whether these effects contribute to the clinical benefits of statins in acute coronary syndromes and stroke.     

Management of dyslipidemia in patients after solid organ transplantation

The increase in organ transplantation has led to primary care physicians assuming a greater role in the provision of health care. Cardiovascular disease is the leading cause of mortality in transplant patients. The risk factors for cardiovascular disease do not differ from the nontransplant population, except that there is increased prevalence of these risk factors in the transplant population. Post-transplant hyperlipidemia is extremely prevalent, partly because of the underlying condition causing the need for transplantation and partly because of the side effects of immunosuppressant agents. Although there are no large, cardiovascular event outcome trials demonstrating a benefit for lipid-lowering therapy in the transplant population, there is robust literature supporting this treatment in the nontransplant population, and numerous smaller trials in transplant patients have demonstrated the safety and efficacy of lipid-lowering therapy. This article reviews the evidence and treatment options for currently available lipid-lowering therapy in solid-organ transplant patients.     

Lipid-lowering drug use and cardiovascular events after myocardial infarction

BACKGROUND: The benefits of lipid-lowering drug treatment for the secondary prevention of coronary heart disease have been well established by randomized, controlled trials. Nonetheless, the risk of events has not been compared directly for inhibitors of hydroxymethylglutaryl coenzyme A reductase (statins) and non-statin lipid-lowering drugs. Further, it remains uncertain whether patients in usual practice who are treated with lipid-lowering drugs after myocardial infarction (MI) gain a similar benefit with regard to the risk of cardiovascular events compared with patients in randomized, controlled trials. OBJECTIVE: To assess the association between lipid-lowering drug therapies in usual clinical practice and the risk of cardiovascular events in patients with a first MI who were discharged alive from the hospital. METHODS: An inception-cohort study was performed among 1956 enrollees of Group Health Cooperative who sustained an incident MI between July 1986 and December 1996 and survived for at least 6 months after hospitalization. Subjects with untreated low-density-lipoprotein cholesterol concentrations > 130 mg/dL or untreated total cholesterol concentrations >200 mg/dL were included. The median duration of follow-up after the first MI was 3.3 years. Medical record review was used to collect information on cardiovascular risk factors. Computerized pharmacy records were used to assess antihyperlipidemic drug use during the first 6 months after hospitalization. RESULTS: Compared with 1263 subjects who did not receive lipid-lowering drug treatment, 373 subjects who received statins had a lower risk of recurrent coronary events (relative risk [RR] 0.59; 95% CI 0.39 to 0.89), stroke (RR 0.82; 95% CI 0.35 to 1.95), atherosclerotic cardiovascular mortality (RR 0.49; 95% CI 0.21 to 1.13), and any atherosclerotic cardiovascular event (RR 0.63; 95% CI 0.40 to 0.98). Among 320 subjects who used non-statin drug therapies, the RRs were 0.66 (95% CI 0.45 to 0.97) for recurrent coronary events, 0.95 (95% CI 0.46 to 1.95) for stroke, 0.68 (95% CI 0.35 to 1.32) for cardiovascular mortality, and 0.77 (95% CI 0.53 to 1.11) for any atherosclerotic cardiovascular event, compared with untreated hyperlipidemic patients. CONCLUSIONS: In this study of MI survivors, the use of lipid-lowering drug therapies after hospitalization was associated with a reduced risk of cardiovascular events. These results emphasize the importance of lipid-lowering drug treatment in patients with hyperlipidemia who survive a first MI.     

Drug therapy for prevention of cardiovascular disease--should surrogate measures be abandoned?

It has been suggested that the most effective method of reducing cardiovascular disease (CVD) is to define overall CVD risk and apply fixed doses of anti-hypertensive, hypolipidaemic and anti-platelet therapies, using the evidence base from clinical outcome studies. Such studies have examined large numbers of patients with a wide representation of subgroups and demon-Welwyn strated equivalent benefits in all subsets. In so doing, there may be over-interpretation of the data leading to large-scale applicability of the findings to individuals who were not genuinely represented in the study populations. Most lipid-lowering studies have been unable to consider the possibility that optimal correction of dyslipidaemia would have been more effective than the use of a fixed dose of statins. Studies of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockade have produced contradictory findings regarding unique non-hypotensive beneficial CVD effects, and suboptimal control of mild hypertension was a frequent finding in the study populations. Scrutiny of concomitant therapy in studies that focus on a particular issue such as LDL (low-density lipoprotein) cholesterol or blood pressure supports the notion that benefits from the agent may be attenuated by other drugs. Widespread application of fixed doses of all these agents to at-risk cases will increase the incidence of inappropriate use and side effects. Clinical experience with modulators of the renin-angiotensin system in hypertensive diabetic renal disease confirms reduced efficacy, and more frequent deterioration of renal function than observed in clinical trials. Measurement of individual biomedical CVD risk factors along with overall risk estimation should continue to be the mainstay of clinical practice. This will allow appropriate case selection for different agents, optimisation of dosage or better assessment of compliance where treatment is less efficacious, and monitoring for adverse effects of therapy. Pragmatic individualisation of care should remain the basis for treating asymptomatic CVD risk factors.     

Identifying patients at risk for coronary heart disease: implications from trials of lipid-lowering drug therapy

Abnormal lipid levels contribute significantly to the risk of coronary heart disease (CHD), which is increased further in the presence of other risk factors. The association between elevated low-density lipoprotein (LDL) cholesterol and CHD risk is well established, and large primary and secondary prevention studies of HMG-CoA reductase inhibitors (statins) have shown conclusively that lowering LDL cholesterol levels reduces CHD events and total mortality. Regardless of the intervention used (diet, surgery, drugs), reduction of plasma cholesterol has consistently produced a reduction in cardiovascular risk. Absolute benefit is greatest in those who are at highest risk initially, and trial results suggest that the lower the LDL cholesterol level achieved, at least down to LDL of 3.0 mmol/l, then the lower is the CHD event risk. Epidemiological data also point to the negative impact of other lipids on CHD risk. Low levels of high-density lipoprotein (HDL) and high levels of triglycerides (particularly in conjunction with an LDL/HDL ratio >5) are particularly strong risk factors for CHD. Thus, although prevention trials to date have primarily assessed the impact of LDL lowering on CHD events, the initial assessment of CHD risk should consider a more detailed atherogenic profile including HDL and triglyceride levels. A general approach to preventing cardiovascular disease should include strategies to reduce the overall CHD risk by lifestyle modification and management of modifiable risk factors such as smoking, hypertension and diabetes. Based on data from recent prevention studies, and because they are the most potent lipid-lowering agents available for lowering LDL cholesterol, statins have appropriately become the drug of choice for most patients with hyperlipidaemia who require drug therapy.     

Effects of statins on renal function

Patients with chronic kidney disease (CKD) are much more likely to die of cardiovascular disease than end-stage renal disease. Dyslipidemia is highly prevalent in patients with CKD and may contribute to the elevated cardiovascular risk as well as CKD progression. Statins are lipid-lowering drugs that appear to protect the kidneys via cholesterol reduction as well as noncholesterol-mediated mechanisms. Subgroup analyses of major clinical studies and meta-analyses of smaller trials indicate that statin therapy slows the decline of the glomerular filtration rate. Additionally, statins appear to reduce proteinuria in patients with CKD. Statins are well recognized to reduce cardiovascular morbidity and mortality in patients with and without documented cardiovascular disease and in certain high-risk populations, such as persons with diabetes mellitus. However, conclusive evidence for improved cardiovascular outcomes with statin therapy for CKD is not yet available. Several ongoing studies are evaluating the effect of statins on cardiovascular end points in patients with CKD and may provide data needed to support adjunctive use of these agents in this high-risk population.     

Statin therapy in patients with chronic kidney disease: to use or not to use

Dyslipdemia is a common complication of chronic kidney disease (CKD) and contributes to high cardiovascular morbidity and mortality of CKD patients. Experimental studies have demonstrated that lipids induce glomerular and tubulointerstitial injury and that lipid-lowering treatments ameliorate renal injury. Therapy with statins not only has the potential to lower cardiovascular morbidity and mortality in patients with CKD but also to slow progression of renal disease. Whereas the guidelines for treatment of hyperlipidaemia in nonrenal patients are based on prospective, randomized, placebo-controlled mega-trials, such data are not available for CKD patients. This review outlines the limited information currently available on the effect of statins among patients with CKD and summarizes the ongoing randomized trials designed to address this question.     

Low density lipoprotein cholesterol lowering: are the treatment guidelines still appropriate?

The availability of treatment guidelines has revolutionised our approach to detection, evaluation and treatment of dyslipidaemias in adults. Such guidelines focus on lowering low-density lipoprotein-cholesterol (LDL-C), the primary risk factor for coronary heart disease, and provide physicians with specific goals to be attained by dietary and, if necessary, pharmacological therapy. However, the guidelines were published in 1993, which means that the pivotal findings from large intervention trials with statins were not included. This has led to calls for the guidelines to be amended to take into account the findings of these studies and other evolving issues such as the pathogenesis of the acute coronary event and the contribution of low HDL-C and other lipid parameters. More importantly, the mostly epidemiological basis of the guidelines has instilled the concept that the lower the LDL-C level after lipid-lowering intervention the better the result in terms of prevention of coronary events. Available data now refute this assumption. Indeed, maximal therapeutic benefit is already obtained with a decrease in LDL-C level of 20-30%, irrespective of baseline levels or LDL-C levels on treatment and, until now, there have been no data to suggest that decreases in LDL-C of > 30% give any additional benefit to patients in terms of improving their long-term outcome. The concept of absolute LDL-C treatment goals therefore needs to be revisited. A more appropriate goal of lipid-lowering therapy with statins is to ensure LDL-C levels are reduced by 20-30%, with statin dosages as used in the intervention trials. Furthermore, there are insufficient data to advise that LDL-C levels should be lowered to 2.6 mmol/l. This issue will be resolved only when the results of the appropriate intervention trials are published.     

Statins in the intensive care unit

PURPOSE OF REVIEW: Statins are effective lipid-lowering agents used extensively in medical practice. This review summarizes the evidence for statin treatment of cardiovascular patients in the intensive care unit and briefly discusses the role of statins in prevention and treatment of sepsis as a potential future application of statins in critical care. RECENT FINDINGS: Recent studies have extended the use of statin therapy to the acute manifestations of cardiovascular disease and have suggested cholesterol-independent therapeutic benefits, termed pleiotropic effects, which have added a wide scope of potential targets for statin therapy. SUMMARY: Statin therapy should be continued in intensive-care patients in whom statin therapy is warranted due to underlying cardiovascular disease or significant risk thereof. In acute coronary syndromes, statin therapy should be initiated within 24-96 h regardless of pretreatment cholesterol levels. Patients undergoing vascular surgery should receive peri-operative statin therapy. Placebo-controlled clinical trials are required to consolidate the experimental and observational evidence for prevention and treatment of sepsis.     

Does the blood pressure-lowering effect of statins contribute to their beneficial cardiovascular effects?

Not all cardiovascular protection provided by statins is explained by their beneficial effects on lipoproteins. Old (e.g., clofibrate) and new (e.g., torcetrapib and ezetimibe) agents, with similar or more intense beneficial effect over lipoproteins, do not reproduce the beneficial effects of statins. Besides their anti-inflammatory and other pleiotropic effects, a blood pressure-lowering effect could be an additional mechanism of cardiovascular protection of statins. Large trials of statins in the primary and secondary prevention of cardiovascular disease did not report an effect on blood pressure, but the use of blood pressure-lowering agents was left to the discretion of physicians during the trial. Post hoc analyses of small trials and a meta-analysis of some of them have suggested that statins could lower systolic blood pressure by approximately 4 mmHg, particularly in patients with high blood pressure. Most studies, however, had small samples and were not blinded. Others had a cross-over or observational design. The overall view of these studies rules out a substantial blood pressure-lowering effect of statins. An effect restricted to subjects with high blood pressure could ultimately derive from the anti-inflammatory effect of statins, since higher levels of C-reactive protein are associated with higher blood pressure. An unequivocal demonstration of an antihypertensive effect of statins, however, is still lacking, and a randomized trial with enough power to evaluate blood pressure variation in a large range of blood pressure values is required to demonstrate whether statins definitely have an antihypertensive effect.     

Opening a new lipid "apo-thecary": incorporating apolipoproteins as potential risk factors and treatment targets to reduce cardiovascular risk

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) represent the cornerstone of drug therapy to reduce low-density lipoprotein (LDL) cholesterol and cardiovascular risk. However, even optimal statin management of LDL cholesterol leaves many patients with residual cardiovascular risk, in part because statins are more effective in reducing LDL cholesterol than apolipoprotein B (Apo B). Apo B may be a better marker of atherogenic risk than LDL cholesterol because Apo B measures the total number of all atherogenic particles (total atherosclerotic burden), including LDL, very low-density lipoprotein, intermediate-density lipoprotein, remnant lipoproteins, and lipoprotein(a). To determine whether Apo B is a better indicator of baseline cardiovascular risk and residual risk after lipid therapy compared with LDL cholesterol, a MEDLINE search of the literature published in English from January 1, 1975, through December 1, 2010, was conducted. On the basis of data from most population studies, elevated Apo B was more strongly associated with incident coronary heart disease than similarly elevated LDL cholesterol. Apo B was also a superior benchmark (vs LDL cholesterol) of statins' cardioprotective efficacy in both primary-prevention and secondary-prevention trials. To minimize cardiovascular risk among persons with hypercholesterolemia or dyslipidemia, the best available evidence suggests that intensive therapy with statins should be initiated to achieve the lowest possible Apo B level (with adequate drug toleration) and then other therapies (eg, niacin, bile acid resins, ezetimibe) added to potentiate these Apo B-lowering effects. In future consensus lipid-lowering treatment guidelines, Apo B should be considered as an index of residual risk, a potential parameter of treatment efficacy, and a treatment target to minimize risk of coronary heart disease.     

Evolocumab for the treatment of hypercholesterolemia

Introduction: Evolocumab is a fully human monoclonal immunoglobulin G2 directed against human proprotein convertase subtilisin/kexin type 9 (PCSK9). It is administered by subcutaneous injection every 2 weeks or once monthly.

Area covered: Herein, the authors discuss the rationale for inhibiting PCSK9 and describe the pharmacodynamics, pharmacokinetics and clinical trials with evolocumab. Evolocumab reduces low density lipoprotein cholesterol (LDL-C) levels by 50 to 60% in most patients with and without background treatment with statins or other lipid lowering agents. The safety profile appears satisfactory from the completed clinical studies and concerns regarding the risk of neurocognitive events have largely been dispelled.

Expert opinion: The reduction of LDL-C with evolocumab to previously unattainable levels has resulted in a reduction in the composite cardiovascular event endpoint in the FOURIER trial and this is likely to impact on future lipid management guidelines. The clinical outcome data and excellent tolerability profile clearly support the use of evolocumab in patients at high cardiovascular risk, including those with heterozygous or homozygous familial hypercholesterolemia, who are unable to achieve LDL-C targets with statins with or without other lipid-lowering drugs. The high cost of evolocumab will restrict its use, however.     

Hypothesis: atorvastatin has pleiotropic effects that translate into early clinical benefits on cardiovascular disease

The results of numerous long-term, randomized trials show that statins significantly decrease the risks of myocardial infarction, stroke, and vascular death as well as total mortality. The benefits of statins on cardiovascular disease in patients who are not experiencing acute coronary syndromes generally become apparent only after about 2 years. In contrast, atorvastatin conferred an early clinical benefit in the lipid-lowering arm of the long-term Anglo Scandinavian Cardiac Outcomes Trial as well as early benefit on progression of atherosclerosis in the Reversal of Atherosclerosis with Aggressive Lipid Lowering trial. An unexpected finding at baseline in the prospective Interaction of Atorvastatin and Clopidogrel Study was that patients on atorvastatin had significantly decreased platelet activity compared with either patients on other statins or those taking no statins. Atorvastatin has protective effects against membrane lipid peroxidation at pharmacologic concentrations. These and other considerations contribute to the hypothesis that atorvastatin has pleiotropic effects that translate into early clinical benefits on cardiovascular disease.     

Lipid-lowering therapy and outcomes in heart failure

Lipid-lowering therapy, particularly with statins, reduces the risk of cardiovascular mortality; however, there is uncertainty about their efficacy in patients with heart failure, including those without coronary artery stenosis. A clinical database was studied to determine whether lipid-lowering therapy is associated with improved survival in persons with heart failure-with or without concomitant coronary artery stenosis. During an 8-year period, 6060 people with a history of heart failure underwent coronary angiography. At the time of angiography, 1216 received a lipid-lowering agent. During a median follow-up of 4.7 years, 7.1 deaths per 100 person-years occurred among users of lipid-lowering therapy, compared with 7.8 per 100 person-years among nonusers (adjusted hazard ratio 0.87, 95% confidence interval 0.77-0.97). Use of lipid-lowering therapy was associated with a reduced risk of death in patients with heart failure. Current evidence supports statin use in individuals with recognized heart failure and concomitant coronary heart disease, dyslipidemia, or diabetes mellitus. More data are needed before statins can be recommended in those with isolated heart failure.     

The care gap: underuse of statin therapy in the elderly

Atherosclerotic diseases are responsible for the majority of deaths in the elderly, and they can also increase the risk of disability. Statins are first-line therapies for lowering lipid levels and have been shown to reduce the risk of cardiovascular events in large-scale clinical trials. There is a growing body of evidence that statins are as efficacious at lowering lipid levels and reducing the risk of coronary heart disease (CHD) in elderly patients as in younger individuals. Furthermore, as this population is at a greater absolute risk of CHD, they may receive greater absolute benefits from treatment. However, despite these benefits, many elderly individuals at risk of CHD and stroke are not receiving adequate lipid-lowering therapy, which could help them to maintain their health and independence. Further, prospective randomised trials are required to guide physicians in the treatment of elderly patients at risk of atherosclerotic disease, thereby resolving the current undertreatment.     

Melanoma chemoprevention: a role for statins or fibrates?

Although numerous second-generation isoprenylation inhibitors are proposed or under investigation for the treatment and/or prevention of cancer (eg, R115777, SCH 66336, L-778,123, BMS-214662), the chemotherapeutic and chemopreventive potential of commonly prescribed first-generation isoprenylation inhibitors, the statins, and other classes of lipid-lowering medications, the fibrates, has yet to be seriously explored. Two lipid-lowering medications, lovastatin and gemfibrozil, have been associated with a decreased incidence of melanoma in large, prospective, randomized, double-blind, placebo-controlled clinical cardiology trials. This article reviews melanoma biology and the clinical evidence for the use of lipid-lowering medications for melanoma chemoprevention and/or adjuvant chemotherapy.     

Peroxisome proliferator-activated receptor agonists,hyperlipidaemia, and atherosclerosis

Dyslipidaemia is a major risk factor in the development of atherosclerosis, and lipid lowering is achieved clinically using fibrate drugs and statins. Fibrate drugs are ligands for the fatty acid receptor peroxisome proliferator-activated receptor (PPAR)alpha, and the lipid-lowering effects of this class of drugs are mediated by the control of lipid metabolism, as directed by PPARalpha. PPARalpha ligands also mediate potentially protective changes in the expression of several proteins that are not involved in lipid metabolism, but are implicated in the pathogenesis of heart disease. Clinical studies with bezafibrate and gemfibrozil support the hypothesis that these drugs may have a significant protective effect against cardiovascular disease. The thiazolidinedione group of insulin-sensitising drugs are PPARgamma ligands, and these have beneficial effects on serum lipids in diabetic patients and have also been shown to inhibit the progression of atherosclerosis in animal models. However, their efficacy in the prevention of cardiovascular-associated mortality has yet to be determined. Recent studies have found that PPARdelta is also a regulator of serum lipids. However, there are currently no drugs in clinical use that selectively activate this receptor. It is clear that all three forms of PPARs have mechanistically different modes of lipid lowering and that drugs currently available have not been optimised on the basis of PPAR biology. A new generation of rationally designed PPAR ligands may provide substantially improved drugs for the prevention of cardiovascular disease.     

Interaction between statins and clopidogrel: is there anything clinically relevant?

Since their introduction several years ago, the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors-the statins-have been widely used for hyperlipidemia and for the primary/secondary prevention of cardiovascular diseases. They have been shown to be safe as well as efficacious in a number of different clinical trials; however, studies have suggested that they can interact with other co-administered therapies. More recently, the thienopyridines have been successfully integrated with the conventional medical treatment of coronary disease as they showed effectiveness in reducing platelet activity both in stable and unstable settings. They also improve the outcome of patients treated with percutaneous coronary intervention. The potential interaction of statins and thienopyridines is a matter of concern. Despite some preclinical data suggesting an interaction between statins metabolized by the liver cytochrome P3A4-such as atorvastatin, lovastatin and simvastatin-and clopidogrel, there is no compelling clinical evidence to stop their co-administration.     

On statins, strokes, meta-analyses, competing risks, and the onward march of science

A comment on the conduct of a meta-analysis analyzing the effects of statins on cardiovascular and cerebrovascular outcomes is presented in this editorial. Competing risk and risk-stratified analysis models that may be more appropriate for the analysis of clinical trials in general and statin trials in particular are introduced. The avoidance of these more complicated models seems to be paradoxical when other models that clinicians have used for some time and are using today are seen to contain more patient variables than the proposed models. Certainly, one way these competing risk and general mathematical models will be used is to have the data readily available for other researchers to duplicate the calculations or use in entirely new ways. This aids in the learning process and helps students, reviewers, editors, and others who wish to research and judge the clinical trials.