Antilipemics and prevention of cerebrovascular accidents. Meta-analysis

BACKGROUND: Previous overviews have suggested that the HMG-CoA reductase inhibitors (statins), but not other lipid lowering therapies (LLTs), may reduce stroke incidence in coronary patients. Our objective was to investigate the amplitude and sources of heterogeneity of LLT effects on stroke prevention. METHODS: A literature search was performed from 1966-2001 to identify all English-language published trials testing LLT. We then conducted a meta-analysis including randomised primary and secondary coronary heart disease prevention trials, which tested statins, nonstatins, diet or other interventions, and providing data on stroke incidence. RESULTS: The overall meta-analysis (38 individual trials, 83,161 patients, mean follow-up of 4.7 years) showed a significant relative risk reduction (RRR) of strokes by LLTs of 17% (p < 0.001), without significant heterogeneity between trials and between subgroups according to either the type of prevention (primary or secondary prevention) or type of LLT. Most demonstrative effects was obtained however with statins (RRR = 26%). Effect model analysis showed that the treatment benefits appeared constant whatever the risk of stroke, suggesting that LLTs may be effective in a population with a higher risk of stroke. Weighted regression showed a significant correlation between the RRR of stroke and total cholesterol levels (baseline, final, and change). Only final cholesterol level allowed a clear separation between benefit (RRR > 0) and no effect (RRR < 0) of LLTs on stroke incidence, with a cut-off for benefit of 6.0 mmol/L. CONCLUSION: LLTs reduce stroke incidence in coronary patients, especially when total cholesterol is under 6.0 mmol/L, this explains the better results obtained with statins.     

Statins and stroke prevention

Over the past decade, statins have been proved to significantly decrease coronary events in the primary and secondary prevention of coronary artery disease. Recent clinical trials have indicated that statins significantly reduce stroke risk in patients with vascular disease. A meta-analysis of randomized trials of statins in combination with other preventive strategies, involving 165,792 individuals, showed that each 1-mmol/l (39 mg/dl) decrease in LDL-cholesterol equates to a reduction in relative risk for stroke of 21.1 (95% CI: 6.3–33.5; p = 0.009). It is not known whether these findings might be due to the cholesterol-reduction effect of statins or to the pleiotropic effects of statins, such as improved endothelial function, decreased platelet aggregability and reduced vascular inflammation. In the secondary prevention of stroke, The Stroke Prevention by Aggressive Reduction of Cholesterol Levels study found that treatment with atorvastatin reduced the risk of recurrent cerebrovascular events in patients with recent stroke or transient ischemic attack but no history of heart disease.     

Preventing ischemic stroke in the older adult

Stroke is a deadly and disabling disease that preferentially afflicts older adults. It shares common risk factors with myocardial infarction (MI), such as hypertension, diabetes, and hyperlipidemia. Blood pressure control, cholesterol reduction with statins, and glucose control reduce the risk for both stroke and MI. Additionally, management of atrial fibrillation with warfarin reduces stroke risk. Beyond risk factor reduction, antiplatelet therapy is an effective option for lowering the likelihood of stroke in at-risk patients. Among antiplatelet agents, aspirin has been shown effective for secondary stroke prevention as well as primary and secondary MI prevention; clopidogrel for secondary stroke and MI prevention; and both ticlodipine and dipyridamole for secondary stroke prevention. Combining antiplatelet agents is rational. Carotid endarterectomy should be considered for stroke prevention in patients with ischemic symptoms; for patients with asymptomatic stenosis, potential benefit must be balanced against surgical risk.     

Secondary prevention of stroke

Stroke and transient ischemic attacks result from a range of mechanisms. Secondary prevention includes both conventional approaches to vascular risk-factor management (blood pressure lowering, cholesterol reduction with statins, smoking cessation and antiplatelet therapy) and more specific interventions, such as carotid endarterectomy or anticoagulation for atrial fibrillation. The relative importance of even conventional risk factors in stroke differs from coronary artery disease. Large clinical trials produce information on most aspects of stroke prevention. Stroke and transient ischemic attacks are now recognized as medical emergencies, with a high early risk of recurrence, and evidence is accumulating to support the importance of immediate institution of secondary preventative treatments. We review current literature on the secondary prevention of stroke.     

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.     

The influence of statin characteristics on their safety and tolerability

The efficacy of the statins for both primary and secondary prevention has now been clearly established in patients across the spectrum of cardiovascular risk. In addition to their primary effect in reducing plasma cholesterol, the statins possess various 'pleiotropic' effects that may contribute to their clinical effectiveness in reducing cardiovascular events, e.g. improvement of endothelial function, reduction of low-density lipoprotein-cholesterol oxidation and stabilisation of atheromatous plaques. Although statins share similar chemical characteristics, they differ significantly in terms of their molecular synthesis, solubility and pharmacokinetic behaviour and metabolism. Side-effects secondary to longterm statin therapy are rare, but rhabdomyolysis may occur when statins are administered together with other drugs that have a direct toxic effect on muscle or which inhibit statin metabolism. Among the various statins, it would appear that fluvastatin has the lowest propensity to interact with other drugs and the least potential to induce myotoxicity.     

The need for increased utilization of statins after occlusive stroke

In registry data, among patients who have survived an occlusive stroke, only about half are treated with statins despite a large and persuasive totality of evidence, which includes large-scale randomized trials. In a comprehensive worldwide meta-analysis of 90,056 participants, statins conferred statistically significant and clinically important reductions in stroke and myocardial infarction, as well as cardiovascular and total mortality. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial of patients with prior stroke or transient ischemic attack, high-potency statins decreased risks of recurrent stroke and major cardiovascular events. In a nonrandomized subgroup analysis, patients who achieved a 50% or greater reduction in low-density lipoprotein cholesterol (LDL-C) compared to those who achieved <50% had a statistically significant 31% reduction in risk of stroke. Finally, in a comprehensive, worldwide meta-analysis of all trials of cardiovascular disease, patients treated with intensive compared with conventional statin therapy had significantly reduced risks of stroke and myocardial infarction as well as any cardiovascular event or death. Based on this totality of evidence the US federal guidelines as well as those of the American Heart Association/American Stroke Association have been revised to recommend that patients with a prior occlusive stroke should have an optional goal for LDL of 70 mg/dL. All these considerations pose important and timely clinical and public health challenges concerning the need for wider utilization of statins in the treatment of patients with stroke.     

Stroke prevention by statins

The correlation between stroke incidence and serum lipid level has been equivocal, and conventional lipid-lowering agents such as fibrates were ineffective for stroke prevention. Recent clinical trials for HMG-CoA reductase inhibitors(statins) have demonstrated 20-30% reduction in the risk of cerebrovascular events and mortality in the population with previous coronary heart disease(CHD). The beneficial effect of statins was most evident for thromboembolic stroke, and no significant increase in hemorrhagic events was noted. Equal reduction in stroke risk was observed between hyper- and normocholesterolemic populations, indicating the non-lipid mechanisms of statins. The efficacy and safety of statin treatment make it a promising approach for the management of both CHD and non-CHD patients at high risk of stroke, especially the elderly.     

The need for wider and appropriate utilization of aspirin and statins in the treatment and prevention of cardiovascular disease

There is an increasing burden of occlusive cardiovascular disease (CVD) in developed, as well as in developing, countries. In fact, the WHO has projected that CVD will become the leading cause of death in the world in the next 10 years. The proximate cause of virtually all occlusive vascular events is thrombosis and the principal underlying cause is atherosclerosis. Aspirin, which inhibits platelet-dependent cyclooxygenase for the entire life of the platelet, has clinically important antithrombotic effects. Statins, which principally decrease low-density lipoprotein cholesterol, triglycerides and increase high-density lipoprotein cholesterol, have clinically important antiatherogenic effects. In secondary prevention, in a wide range of patients who have survived a prior myocardial infarction (MI), occlusive stroke, transient ischemic attack, as well as other high-risk conditions, long-term use of aspirin confers statistically significant and clinically important reductions in MI, stroke and CVD death. In addition, aspirin confers similar benefits when administered during acute MI or acute occlusive stroke. In primary prevention, aspirin confers a statistically significant and clinically important reduction in risk of a first MI but the data on stroke and CVD death remain inconclusive, so aspirin should be prescribed on an individual basis by the healthcare provider who weighs this clear benefit against long-term side effects. In a meta-analysis of 14 randomized trials of 90,056 subjects treated for 5 years, statins confer statistically significant and clinically important reductions in MI, stroke, CVD death and total mortality. In a meta-analysis of randomized trials of statins, in which aspirin was used in varying frequencies, the combination of aspirin and statins conferred greater clinical benefits than either agent alone on MI, occlusive stroke and CVD death. At present, the wider and more appropriate use of aspirin and statins will reduce premature MI, stroke and CVD death.     

Impact of statins on cardiovascular outcomes in renal transplant recipients: a systematic review

Patients with chronic kidney disease including renal transplant recipients (RTRs) have a markedly higher prevalence of cardiovascular disease than the general population. Many trials have established the role of statins in the prevention of cardiovascular mortality, not only by decreasing the low density lipoprotein-cholesterol levels but also by their pleotropic effects. These data from the general population may not be applicable to RTRs as these patients have different cardiovascular risk profiles. Till date, only a few prospective, randomized trials have assessed the use of statins in RTRs with regards to cardiovascular outcomes. The Assessment of Lescol in Renal Transplant trial, the largest trial so far, suggested that dyslipidemia management with statins in RTRs is associated with a significant reduction in the incidence of cardiac death and nonfatal myocardial infarction (although differences in the combined primary end point were not statistically significant). The current guidelines from National Kidney Foundation for managing dyslipidemia in RTRs recommend managing all chronic kidney disease patients as a coronary heart disease equivalent. The task group for drafting these guidelines concluded that based on the currently available evidence, additional studies may be needed in RTRs to confirm and extend the results of Assessment of Lescol in Renal Transplant trial.     

Stroke: strategies for primary prevention

Stroke is a leading cause of morbidity and mortality in North America. Primary prevention of stroke includes lifestyle modifications and measures to control blood pressure, cholesterol levels, diabetes mellitus, and atrial fibrillation. Lowering blood pressure in patients with hypertension prevents both hemorrhagic and ischemic stroke (relative risk reduction, 35 to 45 percent). Observational studies suggest that higher cholesterol levels are associated with an increased risk of ischemic stroke, and treatment with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) may reduce the risk of fatal and nonfatal stroke by 25 percent. Although high-quality evidence linking tighter glucose control with stroke reduction is lacking, good glucose control and aggressive treatment of hypertension and hyperlipidemia in patients with diabetes mellitus are recommended. The risk of stroke in patients with atrial fibrillation and the role of anticoagulation depend on factors such as age and the presence of comorbid conditions. Controversy exists about the roles of angiotensin-converting enzyme inhibitors and aspirin in the primary prevention of stroke.     

Cholesterol lowering in the older population: time for reassessment?

Hypercholesterolaemia is an established major risk factor for coronary heart disease (CHD) in the general population. In the vast majority of studies that focused on this particular age group and carefully eliminated other confounding factors such as co-morbid conditions, hypercholesterolaemia was a risk factor for CHD in the older population. Because the prevalence of CHD increases with advancing age, studies that consider not only the relative risk attributed to cholesterol but also the absolute numbers of people affected, show hypercholesterolaemia to be an even stronger risk factor in the elderly. Large primary and secondary prevention studies of HMG-CoA reductase inhibitors (statins) in the elderly have shown a reduction in major coronary events similar to that observed in the younger age group. The role of hypercholesterolaemia as a risk factor for stroke is less clear, and a major limitation is the heterogeneous nature of the disease. Nevertheless, most studies that evaluated non-haemorrhagic strokes separately showed a positive association with cholesterol levels, and statin therapy is effective in preventing stroke. These data provide a rationale for treating older hypercholesterolaemic people with statins, not only to prevent CHD, but also to prevent stroke.     

Ezetimibe plus simvastatin cardiovascular outcomes study program

Ezetimibe is a drug that impairs intestinal cholesterol absorption and decreases blood cholesterol levels. It has been shown that added to statins it can achieve a further reduction of low-density lipoprotein-cholesterol of 18-20%, overcoming the increase in absorption that follow the reduction in cholesterol synthesis by statins. Four major outcome trials are underway to study the effect of ezetimibe plus simvastatin in different subsets of high-risk patients: familiar hypercholesterolemia, degenerative aortic stenosis, chronic kidney disease and acute coronary syndrome. Hopefully, in the next few years the information provided by these trials will allow us to further reduce the increasing burden of cardiovascular disease.     

Pharmacologic treatment of hyperlipidemia

Pharmacologic treatment of hyperlipidemia in conjunction with therapeutic lifestyle changes can be used for both primary and secondary prevention of cardiovascular disease. Statins have the most convincing data for primary prevention, especially for higher risk patients. Therefore, risk stratification is essential. Statin therapy is also recommended for secondary prevention in all patients with known cardiovascular disease or the risk equivalent. High-dose statins should be initiated in patients with acute coronary syndrome. Omega-3 fatty acids may be a good alternative after myocardial infarction for patients who cannot tolerate statins. Fibrates and niacin have not been shown to reduce all-cause mortality in secondary prevention, but may be useful adjuncts when statins alone cannot adequately control lipid levels. Other cholesterol-lowering medications used for primary or secondary prevention of cardiovascular disease have not been shown to consistently improve patient-oriented outcomes. There is good evidence for using statins in the secondary prevention of stroke and peripheral arterial disease.     

'Trig-onometry': non-high-density lipoprotein cholesterol as a therapeutic target in dyslipidaemia

Targeting elevations in low-density lipoprotein cholesterol (LDL-C) remains the cornerstone of cardiovascular prevention. However, this fraction does not adequately capture elevated triglyceride-rich lipoproteins (TRLs; e.g. intermediate-density lipoprotein, very low density lipoprotein) in certain patients with metabolic syndrome or diabetic dyslipidaemia. Many such individuals have residual cardiovascular risk that might be lipid/lipoprotein related despite therapy with first-line agents (statins). Epidemiological evidence encompassing > 100,000 persons supports the contention that non-high-density lipoprotein cholesterol (non-HDL-C) is a superior risk factor vs. LDL-C for incident coronary heart disease (CHD) in certain patient populations. In studies with clinical end-points evaluated in the current article, a 1:1 to 1:3 relationship was observed between reductions in non-HDL-C and in the relative risk of CHD after long-term treatment with statins, niacin (nicotinic acid) and fibric-acid derivatives (fibrates); this relationship increased to 1:5 to 1:10 in smaller subgroups of patients with elevated triglycerides and low HDL-C levels. Treatment with statin-, niacin-, fibrate-, ezetimibe-, and omega 3 fatty acid-containing regimens reduced non-HDL-C by approximately 9-65%. In a range of clinical trials, long-term treatment with these agents also significantly decreased the incidence of clinical/angiographic/imaging efficacy outcome variables. For patients with dyslipidaemia, consensus guidelines have established non-HDL-C treatment targets 30 mg/dl higher than LDL-C goals. Ongoing prospective randomised controlled trials should help to resolve controversies concerning (i) the clinical utility of targeting non-HDL-C in patients with dyslipidaemia; (ii) the most efficacious and well-tolerated therapies to reduce non-HDL-C (e.g. combination regimens); and (iii) associations between such reductions and clinical, angiographic, and/or imaging end-points.     

Coronary event secondary prevention with statins irrespective of LDL-cholesterol

OBJECTIVE: To review the evidence for statin secondary prevention of coronary artery disease in patients with near-optimal or optimal low-density lipoprotein cholesterol (LDL-C). DATA SOURCES: A MEDLINE search (1966-October 2003) was conducted using the search terms HMG-CoA reductase inhibitor, statins, coronary disease, post-myocardial infarction, and average cholesterol. DATA SYNTHESIS: Secondary prevention trials enrolling subjects with near-optimal (<130 mg/dL) or optimal (<100 mg/dL) baseline LDL-C were included. Early statin secondary prevention studies suggested attenuated benefit, but more recent trials challenge this finding. CONCLUSIONS: Statin secondary prevention of coronary artery disease in patients near goal LDL-C is controversial, but recent trial results show promise.     

The place of statins in acute coronary accidents

Statin therapy significantly decreases the rate of clinical events in secondary prevention, however their use in patients with the acute phase of acute coronary syndromes remains controversial. Their pleiotropic effects on thrombosis, inflammation, and endothelial dysfunction, might improve vascular healing. Although numerous observational studies have shown a significant reduction in mortality, one trial suggested that the statins may have a potentially harmful effect in patients with low cholesterol. However, randomised controlled trials have not demonstrated harmful effects. Of these trials, the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is the only trial with adequate statistical power to show a significant reduction in ischemic events at 16 weeks with a high dose of once daily atorvastatin 80 mg.     

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.     

High-dose statin therapy for secondary prevention of stroke: stroke prevention by aggressive reduction in cholesterol levels study review

It has been shown that HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) lower the incidence of a first stroke in patients with coronary heart disease, diabetes, or risk factors for cardiovascular disease. However, it is unknown whether statin therapy could reduce the incidence of a second stroke in patients without evidence of heart disease. This article reviews the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial, a prospective, randomized, multicentered, double-blind, placebo-controlled, international trial designed to examine the effect of high-dose atorvastatin on secondary stroke prevention. Trial participants (4,731) had experienced a stroke or transient ischemic attack within 1 to 6 months before randomization into the study. Over the 5-year follow-up period, incidence of second stroke or transient ischemic attack was significantly reduced in the atorvastatin treatment group compared with the placebo group. In addition, high-dose atorvastatin therapy significantly decreased major coronary artery and other negative cardiovascular events. The reduction in incidence of secondary stroke was specific to ischemic stroke as opposed to hemorrhagic stroke. Results of the trial are clinically significant and support extension of the latest secondary stroke prevention guidelines to include statin therapy for those patients without coronary heart disease.