Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering Research Articles

Abstract 11456: Elevated Lipoprotein(a) is Associated with Statin Resistance

Introduction: LDL-C reduction by statins is the mainstay pharmacologic strategy for ASCVD risk reduction. Despite adherence, some patients fail to achieve LDL-C goals, a phenomenon known as statin resistance. Current LDL-C assays include cholesterol content on both lipoprotein(a) [Lp(a)] and LDL particles. Because statins do not lower Lp(a), Lp(a)-cholesterol may represent a statin insensitive pool within LDL-C. Hypothesis: Elevated Lp(a) contributes to statin resistance in patients treated with high-intensity statin therapy. Methods: A secondary analysis was performed on 2338 patients from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, randomized to receive atorvastatin 80mg or placebo; baseline and week 16 lipid parameters were analyzed. Results: In the atorvastatin group (n = 1092), mean (SD) baseline LDL-C, absolute LDL-C reduction, median percent LDL-C change from baseline (IQR), and Lp(a) were 123.8 (33.5) mg/dL, 52.2 (36.7) mg/dL, -47.6% (-59.1- -29.9%), and 10.6 (5.1-29.1) mg/dL, respectively. Median (IQR) baseline Lp(a) was higher [12.1 (5.9-38.1) vs 9.2 (4.4-22.4) mg/dL, p < 0.001] in patients with attenuated percent LDL-C reduction compared to group median. The median percent LDL-C reduction on atorvastatin was 42.3% (24.3-52.5%) in patients with baseline Lp(a) between 50 - 99 mg/dL, and 32.6% (11.5-43.7%) with Lp(a) > 100 mg/dL prevalent in ~10% of the population, both significantly attenuated compared to patients with Lp(a) <30 mg/dL (50.4% [33.3-61.1%]), p < 0.001. An LDL-C target of 70 mg/dL or less was achieved in 62.3% of patients with baseline Lp(a) <30 mg/dL, compared to 55.2%, 43.3%, and 24.1% of those with Lp(a) 30 - 49 mg/dL, 50 - 99 mg/dL, and > 100 mg/dL (p < 0.001), respectively [Figure 1]. Conclusions: Elevated Lp(a) is associated with statin resistance and may identify patients who require additional or more potent lipid lowering therapies to achieve LDL-C goals.

Early, intensive statin treatment reduces 'hard' cardiovascular outcomes after acute coronary syndrome.

Background Early, intensive statin treatment is the standard of care after acute coronary syndrome (ACS). However, the benefit of this approach to prevent major adverse cardiovascular events has been demonstrated in only one randomised, placebo controlled trial. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial demonstrated that atorvastatin 80 mg daily, compared with placebo, reduced time to first occurrence of death, non-fatal myocardial infarction, resuscitated cardiac arrest, or hospitalisation for unstable angina (stroke not included) during the 16 week period following ACS. However, there were no significant effects on individual components of the composite endpoint except unstable angina. This led some to question whether early, intensive statin treatment reduces 'hard' events after ACS. Aim The burden of coronary heart disease after ACS, and therefore the efficacy of its treatment, depends not only on the occurrence of one ischaemic event, but rather on cumulative events experienced by patients. Accordingly, we conducted a post-hoc analysis of the MIRACL trial to examine the effect of atorvastatin on first as well as recurrent (i.e. total) hard cardiovascular events after ACS (death, myocardial infarction, stroke, and resuscitated cardiac arrest). Methods and Results In the 3086 patients who comprised the MIRACL trial, atorvastatin 80 mg did not reduce time to first hard event compared with placebo (hazard ratio 0.89, 95% confidence interval 0.72-1.10, P = 0.27). However, atorvastatin significantly reduced total hard events (hazard ratio 0.80, 95% confidence interval 0.66-0.97, P = 0.03). To prevent one hard event during the 16 weeks following ACS, only 11 patient-years of treatment with atorvastatin were required. Conclusion Early, intensive treatment with atorvastatin is an efficient intervention to reduce hard cardiovascular events after ACS.

Abstract 11806: Early, Intensive Atorvastatin Treatment Reduces First and Recurrent Hard Cardiovascular Events After Acute Coronary Syndrome

Background: Early, intensive statin treatment is standard of care after acute coronary syndrome (ACS), but only one placebo (PBO)-controlled trial has demonstrated an early benefit of such treatment. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, the primary outcome of time to first occurrence of death, MI, resuscitated cardiac arrest, or hospitalization for unstable angina (UA) was reduced with atorvastatin (ATV) 80 mg/day, compared with PBO. However, this result was borderline significant (HR 0.84, 95% CI 0.70-1.00, p=0.048) and driven largely by reduced UA, leading some to argue that early intensive statin treatment does not modify early “hard” events after ACS. On the other hand, the efficacy of an intervention after ACS is only partially accounted for by time to first event because patients may experience multiple events of similar importance, especially when competing risk for death is relatively low. Objective: In a post-hoc analysis of MIRACL, we evaluated the efficacy of ATV to reduce total (first and recurrent) hard cardiovascular events after ACS. Hard events were defined as death, MI, stroke, and resuscitated cardiac arrest. Methods: 3086 patients were randomly assigned to treatment with ATV or PBO, beginning 1-4 days after ACS and continuing for 16 weeks. Time to first event was assessed by Cox regression. Total events were analyzed by Cox regression with model-based variance estimation to determine correlation between events within a subject. Results: ATV did not significantly reduce time to first hard event (HR 0.89, 95% CI 0.72-1.11, P=0.27), but did significantly reduce total hard events ( Table ). To prevent 1 hard event, only 10.6 patient-years of treatment with ATV were required. The HR for total events was minimally affected by inclusion or exclusion of UA. Conclusion: Intensive treatment with ATV reduces total hard events over 16 weeks following ACS, and is an efficient secondary prevention intervention.

Circulation Editors' Picks

<i>Circulation</i> Editors' Picks

Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia

We measured oxidized phospholipids (OxPL), lipoprotein (a) [Lp(a)], and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) pre- and postapheresis in 18 patients with familial hypercholesterolemia (FH) and with low(∼10 mg/dl; range 10-11 mg/dl), intermediate (∼50 mg/dl; range 30-61 mg/dl), or high (>100 mg/dl; range 78-128 mg/dl) Lp(a) levels. By using enzymatic and immunoassays, the content of OxPL and Lp-PLA(2) mass and activity were quantitated in lipoprotein density fractions plated in microtiter wells, as well as directly on apoB-100, Lp(a), and apoA-I immunocaptured within each fraction (i.e., OxPL/apoB and Lp-PLA(2)/apoB). In whole fractions, OxPL was primarily detected in the Lp(a)-containing fractions, whereas Lp-PLA(2) was primarily detected in the small, dense LDL and light Lp(a) range. In lipoprotein capture assays, OxPL/apoB and OxPL/apo(a) increased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apoB and Lp-PLA(2)/apoA-I levels were highest in the low Lp(a) group but decreased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apo(a) was lowest in patients with low Lp(a) levels and increased proportionally with increasing Lp(a) levels. Apheresis significantly reduced levels of OxPL and Lp-PLA(2) on apoB and Lp(a) (50-75%), particularly in patients with intermediate and high Lp(a) levels. In contrast, apheresis increased Lp-PLA(2)-specific activity (activity/mass ratio) in buoyant LDL fractions. The impact of apheresis on Lp(a), OxPL, and Lp-PLA(2) provides insights into its therapeutic benefits beyond lowering apoB-containing lipoproteins.

Circulation: Clinical Summaries

Circulation: Clinical Summaries

Relationship of Oxidized Phospholipids and Biomarkers of Oxidized Low-Density Lipoprotein With Cardiovascular Risk Factors, Inflammatory Biomarkers, and Effect of Statin Therapy in Patients With Acute Coronary Syndromes: Results From the MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) Trial

This study sought to define the relationship between oxidative biomarkers, cardiovascular disease (CVD) risk factors, and inflammatory and thrombosis biomarkers. Elevated levels of oxidized phospholipids (OxPL) on apolipoprotein B particles (apoB) represent a novel biomarker of CVD. Previous studies suggest that an increase in OxPL/apoB reflects a positive response to statins and a low-fat diet. This study measured OxPL/apoB, lipoprotein (a) [Lp(a)], and oxidized low-density lipoprotein (OxLDL) biomarkers, consisting of immunoglobulin (Ig)G and IgM autoantibodies to malondialdehyde (MDA)-low-density lipoprotein (LDL) and IgG and IgM apoB-100 immune complexes (IC/apoB), at baseline and after 16 weeks of treatment with atorvastatin 80 mg/day or placebo in 2,342 patients with acute coronary syndromes (ACS) enrolled in the MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) trial. At baseline, potentially atheroprotective IgM autoantibodies and IgM IC/apoB were lower in male patients, diabetic patients, and patients >65 years of age. Patients with an LDL level greater than the median (122 mg/dl) had higher levels of OxPL/apoB, Lp(a), and OxLDL biomarkers compared with those who had an LDL level less than the median. Atorvastatin resulted in significantly larger changes in all biomarkers in female patients, patients age <65 years, patients with LDL cholesterol <122 mg/dl, nonsmokers, and nondiabetic patients (p < 0.0001 for all). In particular, a significant increase in OxPL/apoB in response to atorvastatin was noted in all 20 subgroups evaluated. Weak or no significant correlations were noted between all OxLDL biomarkers and C-reactive protein, serum amyloid A, tissue plasminogen activator, interleukin-6, intercellular adhesion molecule, vascular cell adhesion molecule, P-selectin, and E-selectin at randomization and 16 weeks. In patients with ACS, baseline levels of oxidative biomarkers varied according to specific CVD risk factors and were largely independent of inflammatory biomarkers. Atorvastatin uniformly increased OxPL/apoB levels in all subgroups studied. Future studies are warranted to assess whether the increase in OxPL/apoB levels reflects the benefit of effective therapeutic interventions and prediction of new CVD events.

Adjunctive interventions in myocardial infarction: The role of statin therapy

Statin therapy has reduced cardiovascular morbidity and mortality across the spectrum of atherosclerosis. The administration of statins has been demonstrated to be effective in primary and secondary prevention clinical trials evaluating patients with high and low risk-factor profiles. The presumed mechanism of benefit of hypolipidemic therapy in the prevention of atherosclerotic disease was a reduction in the deposition of atherogenic lipoproteins in vulnerable areas of the coronary vasculature. Subsequent experimental studies with statins demonstrated a variety of potentially beneficial effects that would extend clinical benefit beyond lipid-lowering per se. Statin therapy beneficially alters inflammation, coagulation and fibrinolytic parameters, endothelial function, vasoreactivity, and platelet function. The demonstration of the non-lipid or pleiotropic effects provided the theoretical basis for a possible role as an adjunctive therapy in acute coronary syndromes. Retrospective analysis of a variety of early trials indicated a potential benefit of statins during acute ischemic syndromes. Recent clinical trials have addressed this important clinical question in a prospective controlled manner. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) and the Thrombolysis In Myocardial Infarction (TIMI)-22 studies present strong clinical evidence in favor of the administration of statins as adjunctive therapy in acute ischemic syndromes.

Atorvastatin

An association between hypercholesterolaemia and ischaemic stroke has not yet been clearly defined by observational studies. In clinical trials, however, cholesterol-lowering treatments appear to consistently reduce stroke risk. Data are now available from various primary prevention studies - ALLHAT-LLT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack, Lipid-Lowering Therapy), ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial, Lipid-Lowering Arm), CARDS (Collaborative Atorvastatin Diabetes Study, WOSCOPS (West of Scotland COronary Prevention Study) - and secondary prevention studies - 4S (Scandinavian Simvastatin Survival Study), CARE (Cholesterol and Recurrent Events), GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation), HPS (Heart Protection Study), LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease), MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), TNT (Treating to New Targets) - confirming the ability of statins to reduce stroke risk. Regarding primary prevention, post hoc analyses showed pravastatin reduced the relative risk of stroke by 9-11% (not statistically significant) in the ALLHAT-LLT and WOSCOPS trials, whereas atorvastatin reduced this risk by 27-48% in the ASCOT-LLA (p = 0.024) and CARDS trials. It remains to be established in prospective studies whether cholesterol-lowering is effective in the primary prevention of stroke. Regarding secondary prevention, in five placebo-controlled studies (4S, CARE, HPS, LIPID, MIRACL) involving a total of >40 000 patients with coronary heart disease (CHD), statin therapy reduced the relative risk of fatal or nonfatal stroke by 19-50% (p < or = 0.048); the largest decrease was produced by atorvastatin in the MIRACL study (-50%, p = 0.045). In addition, high-dosage atorvastatin reduced stroke risk by 25% (p = 0.02) relative to lower-dosage therapy in the TNT trial, and by 47% (p = 0.034) relative to 'usual' care in the GREACE study. A post hoc analysis of data for 3280 HPS study participants who had had a previous stroke revealed that simvastatin reduced major vascular events by 20% (p = 0.001).The SPARCL study assessed the secondary preventive efficacy of atorvastatin versus placebo in 4731 patients with a history of stroke or transient ischaemic attack (TIA), but without CHD. Atorvastatin reduced the adjusted relative risk of fatal or nonfatal stroke by 16% (p = 0.03), and that of fatal stroke alone by 43% (p = 0.03). Among secondary study endpoints, atorvastatin reduced the relative risks of stroke and TIA (-23%; p < 0.001), TIA alone (-26%; p = 0.004), and ischaemic stroke (-22%; p = 0.01). Overall, SPARCL study findings suggest that intensive atorvastatin therapy should be started immediately after a stroke or TIA. In summary, atorvastatin has developed a well defined role in the primary and secondary prevention of cerebrovascular disease, and appears to have a particularly prominent place in preventing such disease in CHD patients, and in the post-stroke and post-TIA setting in patients without CHD.

Atorvastatin Efficacy in the Primary and Secondary Prevention of Cardiovascular Events

Atorvastatin has been extensively studied in the primary and secondary prevention of cardiovascular events, and may have some clinical advantages over various other statins in these respects. The principal primary prevention study of atorvastatin, ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm), revealed that atorvastatin reduced the relative risk of primary coronary heart disease (CHD) events by 36% (p = 0.0005) compared with placebo in patients with hypertension. Much published data confirm the secondary preventive benefits of atorvastatin in various clinical settings. The IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) and TNT (Treating to New Targets) trials demonstrate the preventive efficacy of atorvastatin in patients with stable CHD. Relative to simvastatin (in the IDEAL trial) and low-dosage atorvastatin (in the TNT trial), intensive atorvastatin therapy (80 mg/day) reduced the risk of nonfatal myocardial infarction (MI) by 17-22% (p < or = 0.02). Furthermore, the ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events) and GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation) trials highlight the benefits of atorvastatin in the 'real world' setting in patients with stable CHD. Compared with 'usual' care, atorvastatin reduced the risk of nonfatal MI by 47-59% (p < or = 0.0002).Moreover, the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering), PROVE-IT (PRavastatin Or atorVastatin Evaluation and Infection Therapy) and IDEAL-ACS (Acute Coronary Syndromes) studies outline the benefits of high-dosage atorvastatin therapy started within 24-96 hours, 10 days or 2 months, respectively, of an acute coronary syndrome. Relative to placebo, pravastatin and simvastatin, atorvastatin reduced the risk of death or major cardiovascular events by 16-18% (p < or = 0.048). In patients undergoing revascularisation procedures, the AVERT (Atorvastatin VErsus Revascularisation Treatment) study revealed that 18 months' administration of atorvastatin 80 mg/day was at least as effective as angioplasty plus usual care in reducing the risk of ischaemic events in low-risk patients with stable coronary artery disease. Furthermore, the ARMYDA (Atorvastatin for Reduction in MYocardial DAmage during angioplasty) and ARMYDA-3 trials showed that 7 days' administration of atorvastatin 40 mg/day before coronary intervention significantly reduced the risks of periprocedural myocardial damage (ARMYDA), postprocedural MI (p = 0.025; ARMYDA) and atrial fibrillation (p = 0.003; ARMYDA-3) versus placebo. In addition, it has been reported that C-reactive protein levels and the combined incidence of cardiovascular events (death, MI and target segment revascularisation during the 6-month follow-up) were significantly higher in coronaropathic patients undergoing non-surgical revascularisation procedures (stent implantation) not receiving statin therapy compared with those treated with atorvastatin (80mg). Overall, therefore, the marked efficacy of atorvastatin in the primary and secondary prevention of cardiovascular events underscores the pivotal place that this statin has in general cardiovascular disease management, and suggests even greater potential clinical utility for the drug in some clinical settings.

Myocardial 15-Epi-lipoxin A 4 Generation Provides a New Mechanism for the Immunomodulatory Effects of Statins and Thiazolidinediones

“In matters of observation, chance favors only the prepared mind.” This famous maxim of Louis Pasteur, spoken in 1854 during his inaugural lecture as Professor and Dean at the University of Lille, can be applied today to the fortuitous observation that hydroxymethylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors, in addition to their designed lipid-lowering effects, display a fascinating array of antiinflammatory properties. Post hoc analyses of the West of Scotland Coronary Prevention Study (WOSCOPS) population, and more recently the Cholesterol and Recurrent Events (CARE), Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL), Long-term Intervention With Pravastatin in Ischemic Disease (LIPID), and Heart Protection Study (HPS) trials, have all found benefits conferred by statins that are independent of low-density lipoprotein cholesterol–lowering alone.1 Only through careful analyses of early clinical trials of statins administered for lowering cholesterol and cardiovascular events did scientists uncover additional benefit for these agents in cardiac protection beyond their ability to reduce cholesterol synthesis. Inflammation and immune responses are now appreciated to play pivotal roles in the pathobiology of atherosclerosis,2 and recent clinical and basic investigations have uncovered important immunomodulatory roles for statins.3 Of interest, the peroxisome proliferator-activated receptor family of transcription factors is activated by and cooperates with statins in their antiinflammatory actions. In this issue of Circulation , Birnbaum and colleagues4 present evidence for increased myocardial production of 15-epi-lipoxin (LX)A4 by atorvastatin and the peroxisome proliferator-activated receptor-γ ligand pioglitazone. The generation of 15-epi-LXA4 would provide a novel mechanism for immune regulation by statins because this arachidonic acid–derived chalone displays potent antiinflammatory and proresolving properties,5 including many that have also been observed with statins (Table). View this table: Shared Antiinflammatory Actions of Statins and 15-Epi-lipoxin A4 Article p 929 Cell activation initiates the rapid generation of eicosanoids …

Comparative Safety of Atorvastatin 80 mg Versus 10 mg Derived from Analysis of 49 Completed Trials in 14,236 Patients

Atorvastatin has been shown to reduce coronary events and revascularization procedures in patients with multiple risk factors for coronary heart disease. Recent studies with atorvastatin 80 mg support the overall safety of this dose during long-term treatment. However, physicians appear reluctant to use high doses of statins. A retrospective analysis of pooled data from 49 clinical trials of atorvastatin in 14,236 patients treated for an average period of 2 weeks to 52 months was conducted. The study compared the safety of atorvastatin 10 mg (n = 7,258), atorvastatin 80 mg (n = 4,798), and placebo (n = 2,180) and included analyses on treatment-associated adverse events; nonserious and serious adverse events related to the musculoskeletal, hepatic, and renal systems; the incidence of elevations of creatine kinase >10 times the upper limit of normal (ULN); and hepatic transaminases >3 times ULN. Percentages of patients experiencing > or =1 adverse event were similar across all 3 groups. Withdrawals due to treatment-related adverse events were observed in 2.4%, 1.8%, and 1.2% of patients in the atorvastatin 10 mg, atorvastatin 80 mg, and placebo groups, respectively. Serious adverse events were rare and seldom led to treatment withdrawal with any dose. Treatment-associated myalgia was observed in 1.4%, 1.5%, and 0.7% of patients in the atorvastatin 10 mg, atorvastatin 80 mg, and placebo groups, respectively. No cases of rhabdomyolysis were reported in any group. Persistent elevations in hepatic transaminases >3 times ULN were observed in 0.1%, 0.6%, and 0.2% of patients in the atorvastatin 10 mg, atorvastatin 80 mg, and placebo groups, respectively. The incidence of treatment-associated adverse events for atorvastatin 80 mg was similar to that of atorvastatin 10 mg and placebo. In conclusion, the results of this analysis support the positive safety profile of atorvastatin at the highest dose.

Relation of Characteristics of Metabolic Syndrome to Short-Term Prognosis and Effects of Intensive Statin Therapy After Acute Coronary Syndrome

We examined relations between characteristics of the metabolic syndrome, early cardiovascular risk, and effect of early, intensive statin therapy after acute coronary syndrome. A total of 3,038 patients in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial were characterized by the presence or absence of a history of diabetes, a history of hypertension and/or blood pressure > or = 130/> or = 85, BMI >30 kg/m2, HDL cholesterol <40 mg/dl (men) or <50 mg/dl (women), and triglycerides > or = 150 mg/dl. Patients with three or more of these characteristics were categorized as having metabolic syndrome. A total of 38% of patients (n = 1,161) met criteria for metabolic syndrome as defined in this study and had a 19% incidence of a primary end point event (death, nonfatal myocardial infarction, cardiac arrest, or recurrent unstable myocardial ischemia) during the 16-week trial. Patients with two or fewer characteristics (n = 1,877) were classified as not having metabolic syndrome and had a 14% incidence of a primary end point event. In univariate analysis, the individual characteristics that bore a significant relation to risk were diabetes and low HDL cholesterol. In a multivariable model including age, sex, and randomized treatment assignment, presence of metabolic syndrome was associated with a hazard ratio of 1.49 (95% CI 1.24-1.79, P < 0.0001). Relative risk reduction with 80 mg atorvastatin daily compared with placebo was similar in patients with and without metabolic syndrome. Metabolic syndrome, as defined in the context of this clinical trial, is a strong predictor of early recurrent ischemic events after acute coronary syndrome.

Effect of atorvastatin on risk of recurrent cardiovascular events after an acute coronary syndrome associated with high soluble CD40 ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study

Study Question: Patients with acute coronary syndrome (ACS) have elevated plasma levels of the proinflammatory, prothrombotic cytokine CD40 ligand (sCD40L). The present analysis examined the relationship between sCD40L and the risk of recurrent cardiovascular events soon after an ACS in the MIRACL study and tested whether the clinical benefit from statin therapy was related to a reduction in proinflammatory and prothrombotic stimuli associated with sCD40L. Methods: The investigators measured sCD40L in subjects with an ACS enrolled in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study. Subjects were randomized in this double-blind trial either to atorvastatin 80 mg/d or placebo for 16 weeks. Results: Plasma CD40L was measured from 2908 (94%) of 3086 subjects at baseline and 2352 (76%) subjects at 16 weeks. Odds ratios (ORs) and 95% CIs from logistic regression models assessed the risk of recurrent cardiovascular events over 16 weeks (death, nonfatal myocardial infarction, cardiac arrest, and worsening angina requiring rehospitalization) in the placebo group from baseline sCD40L and the effect of atorvastatin on the risk associated with CD40L in all subjects. The effects of atorvastatin on plasma concentrations of CD40L were assessed by Wilcoxon tests. There was a threshold effect, with only high sCD40L (>90th centile) being a risk factor for a recurrent cardiovascular event (OR 1.86, 95% CI 1.25–2.77). This risk was abolished by atorvastatin (OR 1.09, 95% CI 0.69–1.76), which reduced the risk by 48%. Atorvastatin had only a modest effect on sCD40L (p=0.08). Conclusions: The investigators state that, in patients with ACS, atorvastatin abrogated the risk of recurrent cardiovascular events associated with high sCD40L. Perspective: Patients presenting with ACS with highly elevated sCD40L have a higher risk of recurrent coronary events. In this setting, intensive statin therapy may reduce the risk of recurrent events associated with high sCD40L levels without affecting plasma concentrations of this cytokine. The present study points to anti-inflammatory and antithrombotic actions of statins as an additional mechanism of benefit after ACSs. DM

Stopping Statins

Stopping Statins

Management of the acute coronary syndrome patient

Clinical trials have shown that the lowering of total cholesterol or low-density lipoprotein cholesterol levels substantially reduces the risk of morbidity and mortality due to coronary heart disease. However, the benefits of lipid lowering in patients with acute coronary syndromes have been less well studied. The majority of statin trials excluded patients who had experienced recent unstable angina or acute myocardial infarction and, therefore, were not able to evaluate the potential beneficial effects that may result from early statin therapy. However, new evidence is emerging that statins may be effective immediately after an acute coronary event. Recent observational studies indicate that patients who are treated with a statin early after a coronary event have a more favourable outcome than those who are not, and retrospective analyses of clinical trial databases of patients with acute coronary syndromes have also shown this pattern. Statin therapy favourably impacts interrelated pathophysiologic mechanisms that are intimately involved in the pathogenesis of acute coronary syndromes, most notably endothelial function, platelet thrombus deposition and inflammation. The first clinical trial to study early statin intervention in acute coronary syndromes is the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, which has demonstrated that lipid-lowering therapy initiated during hospitalization results in an early reduction in the incidence of recurrent ischaemic events.

Early Intervention With Atorvastatin Modulates Th1/Th2 Imbalance in Patients With Acute Coronary Syndrome: From Bedside to Bench

To the Editor: We read with great interest the recent article by Kinlay et al.1 In that article, they emphasized the antiinflammatory effect of high-dose atorvastatin in subjects enrolled in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, as reflected by lower levels of C-reactive protein (CRP) at 16 weeks. Recent studies showed that helper-T (Th) lymphocytes, which play an important role in the pathogenesis of acute coronary syndrome (ACS), can be divided into Th1 and Th2 cells on the basis of their cytokine profile. Indeed, we recently reported that a Th1 bias in Th1/Th2 immune response may play an important role in ACS patients as measured by the levels of Th1 and Th2 cytokines, such as interleukin (IL)-10, IL-12, and IL-18.2 Moreover, recent basic studies, so-called “bench” findings, demonstrated that statins …

A pharmacoeconomic evaluation of aggressive cholesterol lowering in Sweden

Objective: To estimate the short-term healthcare costs and incremental cost per event avoided, associated with aggressive atorvastatin treatment in patients with acute coronary syndrome in Sweden. Methods: The total expected 16-week healthcare costs per patient on atorvastatin 80 mg per day and placebo were compared using clinical outcomes data from The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study and Swedish cost data sources. The incremental cost per event avoided was also assessed for. The clinical outcomes measured in this pharmacoeconomic analysis included: death, cardiac arrest, non-fatal myocardial infarction, fatal myocardial infarction, angina pectoris, non-fatal stroke, congestive heart failure, and surgical or percutaneous coronary revascularizations. All direct medical costs were taken into account. Results: The probability of the occurrence of an event was 40.4% per patient in the placebo cohort and 36.6% per patient in the atorvastatin cohort. The total expected cost per patient was SEK 17,887 (1950.21€ 1 1 1 EUR=9.17231 SEK. ) in the placebo group and SEK 18,465 (2013.06€) in the atorvastatin group, resulting in an incremental cost of SEK 578 (63.0137€) per patient. The cost per event avoided was SEK 15,076 (1643.64€). Sixty six percent of the cost of atorvastatin treatment was offset by the cost savings obtained through the reduction in the number of events in the atorvastatin group compared to the placebo group. Conclusions: In Sweden, the clinical benefits of aggressive short-term atorvastatin treatment administered within a few days after acute coronary syndrome is associated with a substantial hospitalization cost offset secondary to the clinical benefits of atorvastatin.

Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial.

Completed randomized trials of statin therapy demonstrate that 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors reduce the risk of myocardial infarction, stroke, and other cardiovascular events among individuals with established coronary disease and overt hyperlipidemia.1–6 In aggregate, use of statin therapy in these trials has been associated with an approximate 30% reduction in cardiovascular event rates. Largely on the basis of these cholesterol reduction trials, current treatment algorithms from the National Cholesterol Education Program (NCEP) Adult Treatment Panel III endorse the use of statins in secondary prevention and encourage increased use of statins in primary prevention among those with hyperlipidemia and diabetes.7 Unfortunately, despite evidence provided by the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS2) and the West of Scotland Coronary Prevention Study (WOSCOPS3), use of statins for the primary prevention of cardiovascular disease has not been widely adopted in a cost-effective manner. From a clinical perspective, there are several reasons for this slow adoption. First, almost half of all cardiovascular events occur among apparently healthy men and women who have normal or even low levels of LDL cholesterol (LDL-C). Thus, better screening methods are needed in primary prevention to detect high-risk individuals for whom the number needed to treat (NNT) is small enough to make prophylactic statin therapy cost effective. Second, there has been controversy within the completed clinical trials suggesting that the benefits of statins may extend beyond LDL-C reduction alone. In both the Heart Protection Study of stable high-risk patients6 and the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) study of patients with acute coronary syndromes,8 the risk reduction associated with statin therapy was almost identical among those with low as well those with as high levels of LDL-C. Further, statin therapy reduces the risk of stroke, yet LDL-C is not an …

Place des statines dans les accidents coronaires aigus

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 16weeks with a high dose of once daily atorvastatin 80mg.