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.     

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.     

Acute statin treatment in reducing risk after acute coronary syndrome: the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) Trial.

Three-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) reduce coronary events and death in both primary and secondary prevention trials. In these trials benefit did not appear for years after randomization. It is noteworthy that these trials did not include patients with recent myocardial infarctions or unstable angina. It is well known that mortality and recurrent ischemic events rates are the highest in the early period after acute coronary syndromes. Favorable physiologic effects of statins have been described within a few weeks of exposure to the statin in a number of experimental studies. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study was designed to bridge the gap between primary and secondary prevention trials and specifically included patients with unstable angina or non-ST elevation myocardial infarction.     

The evolving role of statins in the management of atherosclerosis

Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.     

Role of statins in acute coronary syndromes

Statins reduce major coronary events and all-cause mortality in patients with coronary artery disease. Statin therapy has a proven track record for the secondary prevention of coronary artery disease. The extension of the benefit to patients with acute coronary syndromes can be expected. Apart from their lipid-lowering effects, statins significantly and favourably alter the natural history of acute coronary syndromes. Promotion of plaque stability, improvement of endothelial dysfunction and reversal of coagulation and platelet abnormalities are only some of the effects which are beneficial in the management of these patients. Early potential clinical benefits further strengthen the rationale for starting statin treatment as soon as possible after acute coronary events particularly in patients in whom invasive intervention is planned. This review examines their role in acute coronary syndromes and emphasizes the benefits of early statin therapy.     

New and emerging data from clinical trials of statins

Recent clinical trials of statins have clearly demonstrated the benefit of statin therapy in preventing both coronary and cerebral vascular events. These benefits have been demonstrated to be present without reference to older age, sex, or comorbid conditions, including hypertension and diabetes. Future trials will test the value of more aggressive low-density lipoprotein cholesterol lowering, the value of immediate statin intervention during acute coronary syndromes, the role of cholesterol lowering with or without angioplasty, and the role of cholesterol lowering in stroke prevention.     

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.     

Current questions regarding the use of statins in patients with coronary heart disease

The discovery of statins caused a revolution in the field of lipid intervention. Statins are drugs with a good safety profile. Their clinical benefit has been extensively documented in primary and secondary prevention of coronary heart disease. There is substantial evidence that the clinical outcome can be improved with aggressive statin treatment both in patients with unstable as well as with stable coronary heart disease. Also, early administration of statins in acute coronary syndromes is accompanied by rapid clinical benefits, mainly through their "pleiotropic" action (anti-inflammatory, anti-thrombotic, improvement of endothelial function, etc) which is probably a lipid-independent effect. Moreover, emerging data indicate that statins can achieve additional benefit when low density lipoprotein (LDL) cholesterol reduction is coupled with C-reactive protein reduction (<2 mg/L). The prevailing message from the recent statin trials is that intensive LDL cholesterol lowering treatment with statins achieves further clinical benefit beyond that achieved with standard statin therapy. This should encourage the medical community to consider prescribing statins in every coronary patient, aiming at LDL cholesterol levels <100 mg/dL, preferably in the range of 70-80 mg/dL in stable coronary patients, while in coronary patients at very high risk, the optional target for LDL cholesterol levels should be in the range of 50-70 mg/dL.     

Statin loading before percutaneous coronary intervention: proposed mechanisms and applications

Statin therapy reduces the risk of cardiovascular events in patients with coronary artery disease. Recent in vitro and in vivo studies demonstrated a LDL-independent action of these class of drugs, which appears in modulating endothelial function, inflammation and thrombosis. Periprocedural myocardial infarction and contrast-induced nephropathy after percutaneous coronary intervention (PCI), associated with worse outcome on long-term follow-up, are both complications related to inflammatory pathogenetic mechanisms. Randomized studies demonstrated a beneficial effect of short-term statin pretreatment in reducing periprocedural cardiac marker release in patients undergoing PCI. Statin therapy before elective PCI reduces periprocedural myocardial infarction in patients with stable angina. Furthermore, an acute loading with a high dose of atorvastatin prevents myocardial damage in patients with acute coronary syndromes undergoing early PCI (<48 h). In patients already on chronic statin therapy, a reload with high-dose statins was associated with a significant improvement on 30-day major adverse cardiac event rates. Furthermore, statin therapy at the time of PCI significantly decreased the incidence of contrast-induced nephropathy. This evidence suggests an 'upstream administration' of short-term, high-dose statins in all patients undergoing PCI.     

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-lowering therapies in the management of acute coronary syndromes

Despite the significant advances made in the treatment of acute coronary syndromes (ACS) with antiplatelet and antithrombotic therapy, the risk of serious complications remains high, especially in the first few months following an acute coronary event. Although lipid-lowering therapy in patients with significant risk factors (primary prevention) or stable coronary disease (secondary prevention) is known to improve long-term survival, patients with a recent ACS were specifically excluded from the early statin trials. However, the use of lipid-lowering agents (principally statins) during hospitalization or in the period immediately following an acute coronary event has recently been studied. Statin therapy in this setting has been shown to reduce angina, rehospitalization, and mortality. Improved outcomes associated with lipid-lowering therapy in ACS may be mediated through beneficial effects on plaque stabilization, endothelial function, inflammation, and thrombus formation. This paper reviews the evidence supporting the potential benefits and mechanisms of statin therapy in the management of ACS. Clinical guidelines to achieve optimal lipid management are also discussed.     

Pathological Changes in Acute Coronary Syndromes: The Role of Statin Therapy in the Modulation of Inflammation,Endothelial Function and Coagulation

Considerable progress has been made in our understanding of the pathophysiology of coronary artery disease (CAD), their acute presentations as acute coronary syndromes (ACS) and the role of LDL cholesterol. In particular there is clear evidence that atherosclerosis is far from being a process that leads to an amorphous flow limiting lesion on an angiogram, but rather involves a complex interplay between the endothelium, inflammatory cells and the coagulation cascade occurring throughout the coronary vascular bed. While a culprit flow limiting lesion may be effectively treated by a drug eluting stent or coronary bypass surgery, this will have little impact on the global molecular processes that determine recurrent plaque instability at non-culprit sites. The search for systemic long term therapy, which is safe and effective and reduces the changes in inflammation, endothelial function and thrombosis that are the hallmark of ACS, has pushed statins to the forefront. A number of recent clinical trials have shown the benefits of early statin therapy in the treatment of ACS. In addition to their effects on LDL cholesterol, statins have a number of properties collectively referred to as pleiotropic effects, which enable them to modulate the adverse biological changes that are associated with ACS. The purpose of this review is to acquaint the reader with the biological changes that accompany ACS, highlight how these pathways may be modulated for clinical benefit by statins and identify potential novel targets for future therapy.Abbreviated abstract. Acute coronary syndromes are associated with pathological changes in inflammation, endothelial function, and coagulation, and many of these are attenuate by statins in a lipid independent manner. In light of recent clinical trials showing the early benefit of statin therapy in ACS, this review discusses how the pleiotropic effects of statins may result in early clinical benefit.     

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.     

The role of statins in preventing stroke

Epidemiological studies have not demonstrated a clear relationship between stroke risk and hypercholesterolemia. Clinical trials using statins have demonstrated a reduction in stroke, in particular, in patients with established coronary artery disease. The disparity between epidemiological and clinical studies suggests hypercholesterolemia is a true risk factor for stroke that evaded detection in epidemiological studies, or that statins possess other properties that render them useful in stroke prevention. These effects have been loosely termed "pleiotropic" in the lipid literature and revolve around putative effects of statins on endothelial function, inflammation, thrombosis, plaque stability, and immune regulation. Questions remain as to the mechanisms of benefit of statin therapy in stroke prevention, the role of statins in the primary prevention of stroke, and the role of statins in modulating the immune system in the brain.     

Pleiotropic effects of statins

The advent of statin therapy has revolutionized the ability of the clinician to manage patients at risk for the development of an ischemic event due to dyslipidemia. Large-scale clinical trials involving thousands of patients in both primary and secondary prevention have clearly demonstrated that statin therapy will reduce cardiovascular mortality across a broad spectrum of patient subgroups. Additionally, in adequately powered trials, total mortality has been successfully decreased by the use of statin therapy. However, the precise mechanism underlying the benefit of statin therapy has been controversial due to the multiplicity of potential benefits that statins have demonstrated in addition to pure lipid lowering. The causal theory of pharmacologic benefit reiterates the lipid hypothesis, which states that dyslipidemia is central to the process of atherosclerosis and the clinical benefit which accrues from statin therapy is a function of the degree of lipid lowering. The noncausal theory supports the premise that clinical benefits are related primarily to pleiotropic effects of statins (endothelial function, inflammation, coagulation and plaque vulnerability) as being the major modulators of clinical benefit. This review will focus on the potential beneficial effects of statin therapy on a number of the pleiotropic effects of statins and the potential role that these activities play in the reduction of risk for ischemic events.     

Clinical relevance of statins: instituting treatment early in acute coronary syndrome patients

The efficacy of statins in lowering the total and low-density lipoprotein cholesterol and reducing the risk of cardiac events is now well established. The secondary prevention studies started treatment several months after the acute event. However, the greatest risk of recurrence is shortly after the index event. Recent evidence from small-scale clinical trials shows that standard doses of statins can be both safe and effective when given early after an acute coronary event, including early after thrombolytic therapy for myocardial infarction. Angiographic studies have shown beneficial effects of pravastatin on coronary stenosis when initiated after a coronary event. While none of these studies have been powered to demonstrate an effect on outcome, each has shown a reduction in major cardiovascular events. Two large observational studies have shown a reduction in 6- and 12-month risk-adjusted mortality among post-MI patients treated early with statins. Large-scale trials of all statins are now in progress to evaluate further the efficacy of early initiation of statin therapy in acute coronary syndromes. The largest of these is the Australian Pravastatin Acute Coronary Treatment (PACT) study, which will compare early outcomes in patients treated with pravastatin versus placebo prescribed within the first 24 h of an acute coronary event.     

Lipid abnormalities in women: data for risk, data for management

In multiple randomized, controlled clinical trials, statin treatment of elevated low-density lipoprotein cholesterol in women at increased risk of or with coronary heart disease decreased the risk of coronary events: coronary death, nonfatal myocardial infarction, and myocardial revascularization procedures. Total mortality was unchanged, potentially reflecting the underrepresentation of women in these trials and consequent small number of fatal events. Statin therapy provided comparable benefit for women and men with acute coronary syndromes. Application of lipid-lowering therapy with statin drugs is currently underutilized in women, and represents an opportunity to improve clinical cardiovascular outcomes for women.     

Statins and Contrast-induced Acute Kidney Injury with Coronary Angiography

BackgroundContrast-induced acute kidney injury is an adverse outcome resulting from radiocontrast medium exposure during coronary angiography and percutaneous coronary intervention.MethodsA systematic search was conducted to retrieve studies that investigated the impact of statin exposure before coronary angiography or percutaneous coronary intervention on the development of contrast-induced acute kidney injury. The primary outcome was the development of contrast-induced acute kidney injury. We separately analyzed statin/placebo comparisons and high-/low-dose statin comparisons.ResultsFifteen randomized controlled trials met inclusion criteria: 11 studies with statin-naïve subjects, 2 studies with chronic statin users, and 2 studies with unspecified prior statin exposure. Statin exposure reduced the risk of contrast-induced acute kidney injury relative to placebo (relative risk [RR] 0.63, P = .01) with a nonsignificant reduction in the need for hemodialysis (RR 0.25, P = .08). This benefit was also observed in high-dose versus low-dose statin trials (RR 0.46, P = .004), in statin-naïve patients (RR 0.53, P <.0001), and with all studied statins. Higher statin exposure reduced contrast-induced acute kidney injury in patients with acute coronary syndromes compared with placebo or low-dose statins (RR 0.49, P <.00001), with no significant benefit among patients undergoing elective procedures (RR 0.86, P = .50). Subgroup analyses confirmed the benefit of statins in patients with diabetes, chronic kidney disease, congestive heart failure, and those receiving >140 mL of contrast dye.ConclusionStatin therapy is effective at reducing the risk of contrast-induced acute kidney injury. It should thus be considered, at least on a short-term basis, for patients at increased risk of this complication.     

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.     

Are statins indicated for the primary prevention of CAD in octogenarians? antagonist viewpoint

Statin therapy (3-hydroxy-3methylglutaryl coenzyme A reductase inhibitor) is beneficial for primary prevention of cardiovascular events in patients younger than age 65 years with hyperlipidemia, yet there is uncertainty about using these agents for primary prevention in octogenarians. We present the case that can be made for not treating octogenarians with statins for the primary prevention of cardiovascular disease. This case is built on three points: 1) cholesterol levels are not associated with cardiovascular disease events in octogenarians without overt coronary artery disease; 2) no randomized, controlled trials have assessed the role of statins in reducing events in octogenarians without coronary artery disease; and 3) statins may increase risks of myositis, rhabdomyolysis, and cancer in the elderly. In view of gaps in the current evidence and the resulting clinical uncertainty, it is unclear whether the balance of risk and benefit favors treatment for the primary prevention of coronary artery disease in octogenarians. The use of statins in this age group should be based on patient preference.