Evidence for the benefit of early intervention with pravastatin for secondary prevention of cardiovascular events

Treatment with HMG-CoA reductase inhibitors (or statins) lowers total and LDL cholesterol and decreases the risk of cardiovascular events. The absolute benefits are greater in patients with a higher baseline cardiovascular risk, so statins are particularly suited to secondary prevention. Although three large studies have shown convincingly that, in patients with a history of cardiovascular disease, simvastatin or pravastatin treatment reduces the risk of further events and lowers overall mortality, those studies have not included patients in the period immediately after an acute coronary event. They are, therefore, of limited value in answering the question of when to start statin treatment. However, there are practical reasons for starting statin treatment as early as possible, and results of clinical studies have now shown this to be a safe option for pravastatin. Early treatment with pravastatin can stabilize coronary atherosclerosis and improve endothelial function. More importantly, there is also evidence that early treatment with pravastatin can produce a clinical benefit a few months after the initial coronary event.     

Early statin therapy in acute coronary syndromes

Patients who survive an acute coronary syndrome are at much higher risk of a recurrent event within the following year than patients with stable coronary syndromes. Risk factor modification, including statin therapy, lowers the risk of recurrent events over many years, but also to reduces the high risk of an another event within the weeks to months following the initial acute coronary syndrome. The mechanisms that contribute to this benefit are likely related to improvements in endothelial function, a decrease in vascular inflammation, and reduced prothrombotic factors. The effects of statins may be mediated by cholesterol reduction, cholesterol-independent effects (particularly by decreasing isoprenoids), and mechanisms that are independent of inhibiting HMG CoA reductase. Observational studies show an early reduction in mortality with statin therapy started before discharge from hospital after an acute coronary syndrome. Several randomized controlled trials also support a rapid reduction in the risk of recurrent events after starting statins during the hospital admission for an acute coronary syndrome. Early statin therapy is also related to improved compliance and use of statins several years after a coronary event. Thus early statin therapy may improve both early and long-term secondary prevention efforts.     

Lipid reduction in acute coronary syndrome: How much, when, and how?

The use of statins for secondary prevention after acute coronary syndrome is well established. In recent years, trials have investigated the dose of statins used and timing of administration. Initiation of statin therapy as early as 1 day after an acute coronary syndrome event has been shown to be effective in reducing major adverse cardiovascular events. The benefit of early statin use is linked to reduction in inflammation and increased compliance with therapy. In addition, intensive therapy further reduces events and inflammation, as reflected by decreased C-reactive protein. Given the findings of these recent studies, early and intensive lipid-lowering therapy with a statin is justified and safe.     

Early statin therapy in acute coronary syndromes

Patients who survive an acute coronary syndrome of unstable angina or myocardial infarction are at much higher risk of a recurrent event within the following year than patients with stable coronary syndromes. Statin therapy is justified for many of these patients, not only for long-term benefit but also to reduce the risk of recurrent events within weeks of the primary event. The mechanisms that underlie this benefit are probably related to improvements in endothelial function, a decrease in vascular inflammation, and reduced prothrombotic factors. The effects of statins may be mediated by cholesterol reduction, cholesterol-independent effects (particularly decreasing isoprenoids), and mechanisms that are independent of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Observational studies consistently show an early reduction in mortality with statin therapy started before discharge from hospital after an acute coronary syndrome. Several randomized controlled trials also support an early benefit of risk reduction from statins started during the hospital admission for an acute coronary syndrome. Early statin therapy is also related to improved compliance and use of statins several years after a coronary event. Thus, early statin therapy may improve both early and long-term secondary prevention efforts.     

The next step in cardiovascular protection

While aggressive interventional therapy and anti-thrombotic therapy have revolutionized the management of acute coronary syndromes (ACS), defined as acute myocardial infarction (MI) or unstable angina (UA), long-term event rates remain high. Elevated lipids, inflammation and infection have each been implicated as additional mechanisms contributing to instability of vulnerable plaques. The new frontier in ACS management has focussed on treatment of these components of vascular disease. Preliminary trials have shown that early treatment with statins after ACS reduces coronary events but additional studies are needed to confirm this benefit. Furthermore, it is not clear what degree of low-density lipoprotein cholesterol (LDL-C) lowering is needed to stabilize the ACS patient. Chlamydia pneumoniae has been implicated in the development of coronary heart disease (CHD) but the results of preliminary trials investigating anti-chlamydial antibiotics have been inconsistent. Therefore, the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT TIMI 22) trial has been designed specifically to determine whether standard LDL-C reduction (with pravastatin 40 mg) provides a similar clinical benefit to more aggressive LDL-C reduction (with atorvastatin 80 mg). In 4162 ACS patients over a 2-year period, this trial will also evaluate the long-term effect of the quinolone antibiotic, gatifloxacin, in reducing cardiovascular events.     

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 case for early statin therapy in acute coronary syndromes

Three large secondary prevention studies have shown that, in patients with a history of cardiovascular disease, statin treatment reduces the risk of further events and lowers overall mortality. In these studies, total mortality was reduced by as much as 30% in high-risk groups and 22% in average-risk groups. However, these studies did not include patients immediately after the coronary event. There are many benefits to early intervention with statin therapy in patients with acute coronary syndromes, including reduction of the risk of a subsequent event, which is highest immediately after the index event. Early treatment may reduce this likelihood in the first months after a coronary event by stabilizing atherosclerotic plaques and improving endothelial function in addition to lowering low-density lipoprotein cholesterol levels. This article reviews the case for early statin therapy in patients with a history of coronary heart disease. Results of clinical studies have now shown early statin therapy to be safe and cost-effective in reducing in-hospital and 6-month mortality.     

Value and role of lipid lowering therapy for cardiovascular prevention in the elderly

Most of elderly people die of coronary and cerebrovascular disease events or become disabled after non fatal stroke or dementia. Most of evidence of benefits shown in both primary and secondary prevention comes from randomized trials done on middle-aged men. The elderly population exposed to major cardiovascular events and dementia regularly increase due to the lengthening of life expectancy. If the benefit of anti-hypertensives agents is now well-established in isolated systolic hypertension in the elderly, evidence of efficacy with statins remained unclear and needed to be investigated. Observational studies and post-hoc analysis of randomized trials have raised the possibility that statins could reduce the rate of cardiovascular events and the rate of dementia in elderly individuals. In this setting occur the results of two recent trials investigated the effects of simvastatin in a high cardiovascular risk population of whom 30% were aged 70 or older (Heart Protection Study), or the effects of pravastatin for primary or secondary prevention in high risk elderly patients with a middle-age of 75 (Prosper). Major cardiovascular events are significantly reduced in both trials but the relative risk reduction is lower than in previous trials in middle-aged patients. In Prosper, the most beneficial group of patients are those with baseline HDL cholesterol under 0.40 g l-1 (1.1 mmol l-1); coronary heart disease events is the principal component of treatment benefit whereas cerebrovascular events are not significantly reduced at 3-years follow-up probably due to the short duration of the trial. The outcome do not provide evidence for benefit in dementia. However, there is a non significant trend to reduction of transient ischaemic attacks. Recent publications suggest that stroke benefit from statins does not begin to appear until after 3 years of treatment. Hence, those evidence suggests that the strategy for vascular risk management in middle aged people should also be applied to elderly individuals with a greatest benefit in the subgroup with the lowest HDL cholesterol.     

Effect of early statin therapy after acute coronary syndromes: a concise review of the recent data

HMG Co-A reductase inhibitors(statins) have been shown, in three large randomized trials, to decrease adverse cardiac events in patients with clinically evident coronary artery disease. All of these trials have excluded patients with an acute coronary syndrome within the three months prior to enrollment. Statin therapy is thought to stabilize coronary plaque and decrease the risk of plaque rupture. Statins have been shown to quickly reduce levels of LDL-C in addition to altering systemic inflammatory responses, improving endothelial function, and reducing platelet aggregation and activation. These mechanisms are potentially beneficial in the setting of acute coronary syndromes, a time of profound plaque instability. There is a growing body of evidence supporting the early initiation of statin therapy in the setting of acute coronary syndromes. This paper reviews the available data from randomized-controlled trials and observational studies evaluating the effect of early statin initiation during, or soon following, an acute coronary syndrome.     

Early initiation of statin therapy in acute coronary syndromes: a review of the evidence

Acute coronary syndromes (ACS), such as myocardial infarction and unstable angina, are leading causes of death in developed countries. The risk of recurrent adverse events, rehospitalization, and death remain high in the weeks to months following ACS. Large secondary prevention trials have shown that the initiation of statin therapy within 3-6 months after hospitalization for ACS decreases the risk of recurrent cardiovascular events and death. Although the precise mechanisms behind these clinical benefits are unknown, data from human and animal studies have implicated statins in inflammatory response modulation, plaque stability, thrombus formation, and endothelial function. Several observational studies have demonstrated cardiovascular mortality and morbidity benefits in patients with ACS who were placed on statins within hours to days of their event. Three recent prospective controlled trials confirmed these benefits and demonstrated that moderate doses of statins are safe when used in patients with ACS. We recommend the initiation of statin therapy in all ACS patients prior to hospital discharge.     

Statins in acute coronary syndromes

Statins are the main resource available to reduce LDL-cholesterol levels. Their continuous use decreases cardiovascular morbidity and mortality due to atherosclerosis. The administration of these medications demonstrated to be effective in primary and secondary prevention clinical trials in low and high risk patients. Specialists believe that a possible benefit of hypolipidemic therapy in preventing complications of atherosclerotic diseases is in the reduction of deposition of atherogenic lipoproteins in vulnerable areas of the vasculature. Experimental studies with statins have shown an enormous variety of other effects that could extend the clinical benefit beyond the lipid profile modification itself. Statin-based therapies benefit other important components of the atherothrombotic process: inflammation, oxidation, coagulation, fibrinolysis, endothelial function, vasoreactivity and platelet function. The demonstration of the effects that do not depend on cholesterol lowering or the pleiotropic effects of statins provides the theoretical basis for their potential role as adjunctive therapy in acute coronary syndromes. Retrospective analyses of a variety of studies indicate the potential benefit of statins during acute coronary events. Recent clinical studies have addressed this important issue in prospective controlled trials showing strong evidence for the administration of statins as adjunctive therapy in acute coronary syndromes.     

Effects of HMG-CoA reductase inhibitor on hemostasis

Clinical trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy have demonstrated improvement in coronary atherosclerosis progression and reduction in risk of cardiovascular events. However, improvement in cardiovascular end-points is incompletely explained by the baseline or treated LDL cholesterol level. The beneficial effects of statins on clinical events may involve nonlipid mechanisms that modify hemostasis. Local activation of platelets and thrombus formation adjacent to atheromatous plaques, especially where ruptured or eroded, are now recognized to be of pathophysiological importance in the acute and chronic clinical expression of coronary heart disease. Thus, favorable effects of statins on hemostasis may be relevant to decreasing or delaying the progression and clinical manifestations of atherosclerosis.     

Efficacy and safety of intensive statin therapy in the elderly

Numerous epidemiologic and intervention trials, including many studying elderly cohorts, have demonstrated the importance of lipids in primary and secondary preventions of cardiovascular diseases, including coronary heart disease (CHD) and stroke. More recent studies have demonstrated that more intensive statin therapy that reduces low-density lipoprotein cholesterol levels to <70 to 80 mg/dL have resulted in more marked cardiovascular event reduction than less intensive statin treatment. The authors review the efficacy and safety of intensive vs less intensive statin therapy. Specifically, 4 such studies with sufficient data in elderly patients, including 2 trials of patients with stable CHD and 2 with acute coronary syndrome, demonstrating the efficacy and safety of intensive statin therapy with high-dose (80 mg) atorvastatin are reviewed in detail. Although elderly patients may be more susceptible to drug interactions when receiving high doses of statins, the present evidence supports the use of intensive statin therapy in most high-risk elderly patients both with stable CHD and following acute coronary syndrome.     

Declaring war on undertreatment: rationale for an aggressive approach to lowering cholesterol

Few things are better understood within the medical community than the relationship between elevated total and low-density lipoprotein cholesterol (LDL-C) levels, cardiovascular disease and death. There is consensus in the treatment guidelines of numerous national and international bodies that cholesterol levels in at-risk patients should be reduced to target levels that have been shown in population studies to be associated with low rates of coronary heart disease (CHD). However, dyslipidaemia continues to be underdiagnosed and undertreated. The 'landmark' statin trials have demonstrated unequivocally that effective lipid-lowering therapy significantly decreases CHD morbidity and mortality. Furthermore, these benefits of lipid-lowering therapy are not limited to middle-aged men, but extend across a broad range of patient populations. Recent trial data suggest that lowering LDL-C to target levels is possible in a substantial proportion of patients when statins are administered aggressively and results in a greater reduction in the risk of major coronary events. This reduction in events is seen in patients with stable coronary disease as well as those treated immediately after an acute coronary syndrome. Although strong clinical and angiographic evidence shows that intensive treatment prevents morbidity and saves lives, indications are that clinicians are still waiting too long to treat dyslipidaemia and when treatment is initiated it is often at inadequate dosages. Undertreatment of dyslipidaemia is an issue that the healthcare community can no longer ignore.     

If LDL-C is the answer...what was the question? What do the data really show?

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are frequently utilized in the treatment of hypercholesterolemia. With recently completed statin clinical cardiovascular outcomes data available, the purpose of this review is to analyze the relative benefits of each molecule and to determine whether "lower is better" is a correct hypothesis for secondary prevention. Twenty-one clinical studies, each with a duration of statin therapy of 6 months or longer, were reviewed, and the pharmacologic effects of these agents on cardiovascular outcomes was examined. As evaluated by study drug, statistical event reduction was achieved in seven of nine pravastatin studies, one of three simvastatin studies, one of six lovastatin studies, zero of two fluvastatin studies, and zero of one atorvastatin study. Pravastatin was the only statin proven statistically to reduce events in both primary and secondary prevention. Thus, all of the statins do not appear to be the same in terms of their ability to reduce cardiovascular events. Until head-to-head trials have been completed, these clinical outcomes data suggest that in patients with severe hypercholesterolemia who require high-dose statin therapy, simvastatin 80 mg each evening would appear to be the agent of choice. However, pravastatin 40 mg daily at bedtime appears to be a unique molecule, with the strongest evidence for event reduction in the majority of patients with moderate hypercholesterolemia with, or who are at risk for, coronary heart disease.     

Aggressive statin therapy for acute coronary syndromes

Acute coronary syndromes (ACS) account for an enormous disease burden, especially in the Western world. Patients suffering acute coronary events are now understood to carry a very high risk of further coronary events and although improvements in conventional medical therapy over the past two decades have significantly reduced the risk, it remains high. Therapy with HMG CoA reductase inhibitors (statins) have now been well established for the primary and secondary prevention of stable coronary heart disease, but recently a substantial body of evidence has proven their efficacy in the treatment of ACS. This article examines this emerging evidence for the use of statins in ACS.     

Design and rationale of the ARBITER trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol)--a randomized trial comparing the effects of atorvastatin and pravastatin on carotid artery intima-media thickness

BACKGROUND: As a class, statins are remarkably effective in reducing low-density lipoprotein (LDL) cholesterol, and several of these drugs have now been shown to reduce coronary heart disease morbidity and mortality. However, several important controversies in the use of statins remain to be answered by clinical trials. For example, it is controversial whether marked cholesterol reduction to levels below 100 mg/dL would further reduce the incidence of coronary heart disease. Furthermore, concerns about differences among statins for nonlipid effects has raised the concern that the assumption of a class effect is premature until head-to-head clinical trials are completed. METHODS: Arterial Biology for the Investigation for the Treatment Effects of Reducing Cholesterol (ARBITER) is a single-center, randomized, active-controlled study comparing the efficacy of high-dose atorvastatin (80 mg/d) and pravastatin (40 mg/d) in patients being treated for either the primary or secondary prevention of coronary heart disease. This trial will enroll up to 200 patients for the primary end point of the mean change in intima-media thickness of the common carotid artery. This effect will be evaluated over a treatment duration of 12 months. Secondary end points include the effects of statin therapy on inflammatory and hemostatic markers (C-reactive protein and fibrinogen). CONCLUSION: ARBITER will provide important data on the role of marked LDL reduction and the "class effect" theory of statin therapy in cardiovascular medicine.     

Intensive statin therapy in acute coronary syndromes

Acute coronary syndromes (ACS) represent an enormous disease burden, especially in the Western world, where they are one of the largest causes of mortality and morbidity. Patients suffering an acute coronary event are at very high risk of further coronary events, and although improvements in medical therapy over the past two decades have significantly reduced the risk, it remains high. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are now fully established in the primary and secondary prevention of stable coronary heart disease, and recently a substantial body of evidence has proven their efficacy in ACS. This paper examines the evidence for statin use in ACS.     

Effect of statins therapy prior to percutaneous coronary intervention

Background: Many previous studies have demonstrated that statins pre‐treatment before percutaneous coronary intervention (PCI) reduced myocardial infarction (MI) in statin‐naive patients with both stable angina and acute coronary syndrome. However, clinical benefit of statins is controversial as some studies have shown different results. Methods: A search of MEDLINE, EMBASE using the term statins AND PCI, statins AND percutaneous coronary intervention. The review was limited to articles published in English between January 1990 and July 2011. Results: Most trials noted that statins pretreatment before PCI in patients are associated with risk reduction of periprocedural myocardial infarction (PMI) and major adverse cardiovascular events (MACE). The mechanisms underlying this protective action of statins possibly attribute to the pleiotropic effects. However, controversial results were also reported in some trials that early use of statins before PCI did not influence occurrence of PMI or long‐term clinical outcomes. Conclusion: Statins therapy among PCI patients seems to be associated with a significant mortality advantage at early and long‐term follow‐up. However, currently early statins use before intervention still cannot serve as a routine strategy of treatment. Further large‐scale randomized studies are critically required to demonstrate the importance of early treatment with statins in pre‐PCI. (J Interven Cardiol 2012;25:156–162)     

Lipid management: Considerations in acute coronary syndrome

Managing dyslipidemia is an important part of the primary and secondary prevention of coronary heart disease. Low-density lipoprotein cholesterol reduction remains the primary lipid goal. Patients who have experienced an acute coronary syndrome (ACS) are at very high risk of recurrent adverse cardiovascular events. A growing body of literature supports the concept that early and intensive treatment with statins after an ACS event decreases recurrent adverse cardiovascular events. We review available evidence pertaining to lipid alterations in ACS.