Michael Szarek

High-Dose Atorvastatin Enhances the Decline in Inflammatory Markers in Patients With Acute Coronary Syndromes in the MIRACL Study

Background—Inflammation promotes acute coronary syndromes and ensuing clinical complications. Although statins reduce inflammatory markers in asymptomatic adults or in patients with stable angina, the effect of statins on the markedly heightened inflammation in patients with acute coronary syndromes is unknown. Methods and Results—We measured C-reactive protein (CRP), serum amyloid A (SAA), and interleukin 6 (IL-6) in 2402 subjects enrolled the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study. Subjects with unstable angina or non–Q-wave myocardial infarction were randomized to atorvastatin 80 mg/d or placebo within 24 to 96 hours of hospital admission and treated for 16 weeks. The effect of treatment on inflammatory markers was assessed by ANCOVA after adjustment for presenting syndrome, country, and initial level of marker. All 3 markers were markedly elevated at randomization and declined over the 16 weeks in both treatment groups. Compared with placebo, atorvastatin significantly reduced CRP, −83% (95% CI, −84%, −81%) versus −74% (95% CI, −75%, −71%) (P <0.0001) and SAA, −80% (95% CI, −82%, −78%) versus −77% (−79%, −75%) (P =0.0006) but not IL-6, −55% (95% CI, −57%, −53%) versus −53% (95% CI, −55%, −51%) (P =0.3). Reductions in CRP and SAA were observed in patients with unstable angina and non–Q-wave myocardial infarction, with initial LDL cholesterol <3.2 or ≥3.2 mmol/L (125 mg/dL), age ≥65 or <65 years, and in men and women. By 16 weeks, CRP was 34% lower with atorvastatin than with placebo. Conclusions—High-dose atorvastatin potentiated the decline in inflammation in patients with acute coronary syndromes. This supports the value of early statin therapy in these patients.

Lipids, Apolipoproteins, and Their Ratios in Relation to Cardiovascular Events With Statin Treatment

Background— Low-density lipoprotein (LDL) cholesterol is the principal target of lipid-lowering therapy, but recent evidence has suggested more appropriate targets. We compared the relationships of on-treatment levels of LDL cholesterol, non–high-density lipoprotein (HDL) cholesterol, and apolipoprotein B, as well as ratios of total/HDL cholesterol, LDL/HDL cholesterol, and apolipoprotein B/A-I, with the occurrence of cardiovascular events in patients receiving statin therapy. Methods and Results— A post hoc analysis was performed that combined data from 2 prospective, randomized clinical trials in which 10 001 (“Treating to New Targets”) and 8888 (“Incremental Decrease in End Points through Aggressive Lipid Lowering”) patients with established coronary heart disease were assigned to usual-dose or high-dose statin treatment. In models with LDL cholesterol, non-HDL cholesterol and apolipoprotein B were positively associated with cardiovascular outcome, whereas a positive relationship with LDL cholesterol was lost. In a model that contained non-HDL cholesterol and apolipoprotein B, neither was significant owing to collinearity. Total/HDL cholesterol ratio and the apolipoprotein B/A-I ratio in particular were each more closely associated with outcome than any of the individual proatherogenic lipoprotein parameters. Conclusions— In patients receiving statin therapy, on-treatment levels of non-HDL cholesterol and apolipoprotein B were more closely associated with cardiovascular outcome than levels of LDL cholesterol. Inclusion of measurements of the antiatherogenic lipoprotein fraction further strengthened the relationships. These data support the use of non-HDL cholesterol or apolipoprotein B as novel treatment targets for statin therapy. Given the absence of interventions that have been proven to consistently reduce cardiovascular disease risk through raising plasma levels of HDL cholesterol or apolipoprotein A-I, it seems premature to consider the ratio variables as clinically useful.

Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial

BACKGROUND Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS. DESIGN This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred. SUMMARY ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.

Effects of Intense Low-Density Lipoprotein Cholesterol Reduction in Patients With Stroke or Transient Ischemic Attack The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial

Background and Purpose— The intention-to-treat analysis of data from the placebo-controlled Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial found 80 mg atorvastatin per day reduced the risk of stroke and major coronary events in patients with recent stroke or transient ischemic attack. This benefit was present despite only a 78% net difference in adherence to randomized treatment over the course of the trial. In this exploratory analysis, our aim was to evaluate the benefit and risks associated with achieving a ≥50% low-density lipoprotein cholesterol (LDL-C) reduction from baseline. Methods— This post hoc analysis was based on 55 045 LDL-C measurements among the 4731 patients enrolled in SPARCL (average, 11.6 measurements per patient) during a mean follow-up of 4.9 years. At each postrandomization LDL-C assessment, percent change in LDL-C from baseline for each patient was classified as no change or increase from baseline (32.7% of measurements), <50% LDL-C reduction (39.4%), or ≥50% reduction (27.9%). Results— Compared with no change or an increase in LDL-C, analysis of time-varying LDL-C change showed that patients with ≥50% LDL-C reduction had a 31% reduction in stroke risk (hazard ratio, 0.69, 95% CI, 0.55 to 0.87, P=0.0016), a 33% reduction in ischemic stroke (P=0.0018), no statistically significant increase in hemorrhagic stroke (P=0.8864), and a 37% reduction in major coronary events (P=0.0323). There was no increase in the incidence of myalgia or rhabdomyolysis. Persistent liver enzyme elevations were more frequent in the group with ≥50% LDL-C reduction. Conclusions— As compared with having no change or an increase in LDL-C, achieving a ≥50% lowering was associated with a greater reduction in the risk of stroke and major coronary events with no increase in brain hemorrhages.

High-Dose Atorvastatin Reduces Total Plasma Levels of Oxidized Phospholipids and Immune Complexes Present on Apolipoprotein B-100 in Patients With Acute Coronary Syndromes in the MIRACL Trial

Background—Oxidized phospholipids (OxPL) are present within atherosclerotic plaques and bound by lipoprotein (a) [Lp(a)] in plasma. This study evaluated the impact of atorvastatin on oxidized LDL (OxLDL) in patients with acute coronary syndromes (ACS). Methods and Results—OxLDL-E06 (OxPL content on apolipoprotein B-100 [apoB] detected by antibody E06), apoB-100 immune complexes (apoB-IC), OxLDL autoantibodies, and Lp(a) levels were measured in 2341 patients at baseline and after 16 weeks of treatment with atorvastatin 80 mg/d or placebo. The OxLDL-E06 and apoB-IC data are reported per apoB-100 particle (OxPL/apoB, IC/apoB) and as total levels on all apoB-100 particles (total apoB-OxPL and total apoB-IC [eg, OxPL/apoB or IC/apoB×apoB-100 levels]). Compared with baseline values, atorvastatin reduced apoB-100 (−33%), total apoB-OxPL (−29.7%), total apoB-IC IgG (−29.5%), and IgM (−25.7%) (P<0.0001 for all), whereas no change or an increase was observed with placebo. When normalized per apoB-100, compared with placebo, atorvastatin increased OxPL/apoB (9.5% versus −3.9%, P<0.0001) and Lp(a) (8.8% versus −0.7%, (P<0.0001). A strong correlation was noted between OxPL/apoB and Lp(a) (R=0.85, P<0.0001), consistent with previous data that Lp(a) binds OxPL. Conclusions—After atorvastatin treatment, total OxPL on all apoB-100 particles was decreased. However, there was enrichment of OxPL on a smaller pool of apoB-100 particles, in parallel with similar increases in Lp(a), suggesting binding by Lp(a). These data support the hypothesis that atorvastatin promotes mobilization and clearance of proinflammatory OxPL, which may contribute to a reduction in ischemic events after ACS.

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

Background—Patients with acute coronary syndromes have elevated plasma levels of the proinflammatory, prothrombotic cytokine CD40 ligand (sCD40L). Statins inhibit CD40L signaling in vitro, but there are no prospective studies of statins and sCD40L in acute coronary syndromes. Methods and Results—We measured sCD40L in subjects with an acute coronary syndrome enrolled in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study. Subjects were randomized in this double-blind trial to atorvastatin 80 mg/d or placebo for 16 weeks. Plasma CD40L was measured from 2908 (94%) of 3086 subjects at baseline and 2352 (76%) 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 to 2.77). This risk was abolished by atorvastatin (OR 1.09, 95% CI 0.69 to 1.76), which reduced the risk by 48%. Atorvastatin had only a modest effect on sCD40L (P=0.08). Conclusions—In patients with acute coronary syndromes, atorvastatin abrogated the risk of recurrent cardiovascular events associated with high sCD40L. Early statin therapy after acute coronary syndromes counters the risk associated with elevated sCD40L.

Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients.

This analysis assessed the safety of atorvastatin in the 10- to 80-mg dose range using pooled data from 44 completed trials comprising 16,495 dyslipidemic patients treated with atorvastatin (n = 9,416), placebo (n = 1,789), and other statins (n = 5,290). A retrospective analysis was conducted and included treatment-associated adverse events, serious adverse events, and musculoskeletal and hepatic adverse events. Only 3% (n = 241) of atorvastatin-treated patients withdrew from studies due to treatment-associated adverse events, compared with 1% of those (n = 16) on placebo and 4% of those (n = 188) receiving other statins; the most frequently reported treatment-associated adverse events were related to the digestive system. Serious adverse events were rare and seldom led to withdrawal. Persistent elevations in hepatic transaminases to >3 times the upper limit of normal (ULN) were experienced by 0.5% (n = 47) of atorvastatin-treated patients. A persistent elevation in creatine phosphokinase (CPK) (>10 x ULN) was observed in only 1 atorvastatin-treated patient and was not associated with myopathy. The incidence of treatment-associated myalgia was low in the atorvastatin (1.9% [n = 181]), placebo (0.8% [n = 14]), and other statin (2.0% [n = 105]) groups, and was not related to the atorvastatin dose. No cases of rhabdomyolysis or myopathy were reported. Thus, the overall incidence of treatment-associated adverse events observed with atorvastatin did not increase in the 10- to 80-mg dose range, and was similar to that observed with placebo and in patients treated with other statins. Specific analysis of musculoskeletal and hepatic adverse events showed that these occurred infrequently and rarely resulted in treatment discontinuation.

Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients

This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 μg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579.

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

OBJECTIVES This study sought to define the relationship between oxidative biomarkers, cardiovascular disease (CVD) risk factors, and inflammatory and thrombosis biomarkers. BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Targets of Statin Therapy : LDL Cholesterol, Non-HDL Cholesterol, and Apolipoprotein B in Type 2 Diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS)

BACKGROUND LDL can vary considerably in its cholesterol content; thus, lowering LDL cholesterol (LDLC) as a goal of statin treatment implies the existence of considerable variation in the extent to which statin treatment removes circulating LDL particles. This consideration is particularly applicable in diabetes mellitus, in which LDL is frequently depleted of cholesterol. METHODS Type 2 diabetes patients randomly allocated to 10 mg/day atorvastatin (n = 1154) or to placebo (n = 1196) for 1 year were studied to compare spontaneous and statin-induced apolipoprotein B (apo B) concentrations (a measure of LDL particle concentration) at LDLC and non-HDL cholesterol (non-HDLC) concentrations proposed as statin targets in type 2 diabetes. RESULTS Patients treated with atorvastatin produced lower serum apo B concentrations at any given LDLC concentration than patients on placebo. An LDLC concentration of 1.8 mmol/L (70 mg/dL) during atorvastatin treatment was equivalent to a non-HDLC concentration of 2.59 mmol/L (100 mg/dL) or an apo B concentration of 0.8 g/L. At the more conservative LDLC targets of 2.59 mmol/L (100 mg/dL) and 3.37 mmol/L (130 mg/dL) for non-HDLC, however, the apo B concentration exceeded the 0.9-g/L value anticipated in the recent Consensus Statement from the American Diabetes Association and the American College of Cardiology. CONCLUSIONS The apo B concentration provides a more consistent goal for statin treatment than the LDLC or non-HDLC concentration.