Jeffrey S. Riesmeyer

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high‐density lipoprotein (HDL) cholesterol level, reduces the low‐density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high‐risk vascular disease. METHODS In a multicenter, randomized, double‐blind, placebo‐controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end‐point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end‐point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high‐risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998.)

Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: Rationale and design of the ACCELERATE trial

BACKGROUND Potent pharmacologic inhibition of cholesteryl ester transferase protein by the investigational agent evacetrapib increases high-density lipoprotein cholesterol by 54% to 129%, reduces low-density lipoprotein cholesterol by 14% to 36%, and enhances cellular cholesterol efflux capacity. The ACCELERATE trial examines whether the addition of evacetrapib to standard medical therapy reduces the risk of cardiovascular (CV) morbidity and mortality in patients with high-risk vascular disease. STUDY DESIGN ACCELERATE is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients qualified for enrollment if they have experienced an acute coronary syndrome within the prior 30 to 365 days, cerebrovascular accident, or transient ischemic attack; if they have peripheral vascular disease; or they have diabetes with coronary artery disease. A total of 12,092 patients were randomized to evacetrapib 130 mg or placebo daily in addition to standard medical therapy. The primary efficacy end point is time to first event of CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. Treatment will continue until 1,670 patients reached the primary end point; at least 700 patients reach the key secondary efficacy end point of CV death, myocardial infarction, and stroke, and the last patient randomized has been followed up for at least 1.5 years. CONCLUSIONS ACCELERATE will establish whether the cholesteryl ester transfer protein inhibition by evacetrapib improves CV outcomes in patients with high-risk vascular disease.

A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease

BackgroundPlatelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study.MethodsThe primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients.ResultsThere were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events.ConclusionsDespite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.

Relationship Between Exposure to Prasugrel Active Metabolite and Clinical Outcomes in the TRITON-TIMI 38 Substudy

In TRITON‐TIMI 38, levels of the prasugrel active metabolite (pras‐AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pras‐AM was observed in low‐weight or very elderly patients. The authors hypothesized that this higher exposure might explain the higher risk of non—coronary artery bypass graft (CABG)–related TIMI‐related bleeding observed in these 2 patient populations. The relationship between estimated exposure to the pras‐AM and clinical outcomes was assessed in 1159 prasugrel‐treated patients enrolled in the substudy using multivariable logistic regression analysis. There was no relationship between pras‐AM exposure and efficacy through 3 days or after 3 days. Higher estimated pras‐AM exposure was associated with a higher incidence of non‐CABG‐related TIMI major or minor bleeding after 3 days (P < .05) but not through 3 days from start of study drug. Factors associated with increased risk for non‐CABG‐related TIMI bleeding (≥75 years and <60 kg) also identified subgroups with higher exposure to the pras‐AM. Within low body weight and very elderly subgroups, bleeding was largely confined to patients having the highest exposure to the pras‐AM, indicating that a prasugrel lower dose in these subgroups may reduce the risk of bleeding while maintaining efficacy.

TRITON and Beyond: New Insights into the Profile of Prasugrel

Prasugrel, a third-generation thienopyridine antiplatelet agent, demonstrated superior efficacy to clopidogrel but with an increased risk of bleeding in the phase III pivotal registration Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). This article reviews and discusses select components of a large literature of prasugrel data that has emerged since the TRITON-TIMI 38 (TRITON) study primary disclosure.

ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease: A Nested Case-Control Study

Importance A pharmacogenetic analysis of dalcetrapib, a cholesteryl ester transfer protein inhibitor, reported an association between a single-nucleotide polymorphism (SNP) in the ADCY9 gene (rs1967309) and reduction in major adverse cardiovascular events despite a neutral result for the overall trial. Objective To determine whether the association between the SNP in the ADCY9 gene and a reduction in major adverse cardiovascular events could be replicated for another cholesteryl ester transfer protein inhibitor, evacetrapib, in patients with high-risk vascular disease. Design, Setting, and Participants A nested case-control study examining the rs1967309 SNP in 1427 cases and 1532 matched controls selected from the 12 092–patient Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial, a randomized, double-blind, placebo-controlled phase 3 trial conducted in patients with high-risk vascular disease randomized from October 2012 through December 2013. The genotyping was conducted from January 2017 to March 2017, and the data analyses were conducted from July 2017 to November 2017. Exposures Evacetrapib, 130 mg, or matching placebo. Main Outcomes and Measures The primary analyses used a conditional logistic regression model to assess the odds ratio (OR) for major adverse cardiovascular events for evacetrapib compared with placebo for each genotype. The basic model included adjustment for age, sex, and the top 5 principal components. An additional model included cardiovascular risk factors to adjust for potential bias in selecting control patients. The primary major adverse cardiovascular event end point was the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. Results For patients with the AA genotype reported to demonstrate a beneficial effect from dalcetrapib, the OR for evacetrapib compared with placebo was 0.88 (95% CI, 0.69-1.12). For patients with the AG genotype, the OR was 1.04 (95% CI, 0.90-1.21). For patients with the GG genotype reported to show evidence for a harmful effect from dalcetrapib, the OR for evacetrapib was 1.18 (95% CI, 0.98-1.41). The interaction P value among the 3 genotypes was P = .17 and the trend P value was P = .06. When adjusted for cardiovascular risk factors, the OR for evacetrapib was 0.93 (95% CI, 0.73-1.19) for the AA genotype, 1.05 (95% CI, 0.91-1.22) for the AG genotype, and 1.02 (95% CI 0.85-1.24) for the GG genotype; interaction P = .71 and trend P = .59. Conclusions and Relevance Pharmacogenetic analysis did not show a significant association between the ADCY9 SNP (rs1967309) and cardiovascular benefit or harm for the cholesteryl ester transfer protein inhibitor evacetrapib.

Safety of abciximab administration during PCI of patients with previous stroke.

Objectives: To examine the frequency of cerebrovascular complications among patients receiving abciximab (AB) undergoing PCI with prior intracranial hemorrhage (ICH) or recent (< 2 years) ischemic strokes.Background: AB improves clinical outcomes in high-risk patients undergoing percutaneous coronary intervention (PCI); however, the safety of AB in patients with prior stroke has not been adequately studied.Methods: A database review of 7,244 consecutive PCIs, from 7/97 to 10/01, identified 6,190 PCIs performed with AB among which 515 interventions were performed in patients with prior stroke history [ICH or recent ischemic stroke, (n = 101) and remote (> 2 years) ischemic stroke, (n = 414)].Results: The post-PCI stroke rate was significantly higher in patients with prior stroke (2.06% vs. 0.35%, p < 0.001 for all stroke; 0.38% vs. 0.03%, p = 0.023 for ICH). The incidence of ICH among the AB-treated group was 0.065%; a history of prior stroke did not increase the incidence of ICH in the AB-treated group (0.39% vs. 0.0%, p = ns). Moreover, the post-PCI stroke rate was similar between the prior ICH or recent ischemic stroke–group and remote ischemic stroke-group (2 vs. 1.9%; OR: 1.03; 95% CI: 0.21–4.90; p = ns for all strokes; 2% vs. 1.5%; OR: 1.4; 95% CI: 0.27–6.91; p = ns for ischemic stroke). Importantly, no ICH occurred in patients with recent ischemic or any prior ICH stroke.Conclusions: Abciximab, in addition to aspirin, heparin and ADP-inhibitors does not increase the risk of stroke in patients with prior stroke undergoing PCI.

GENDER SPECIFIC FACTORS ASSOCIATED WITH MAJOR ADVERSE CARDIOVASCULAR EVENTS: INSIGHTS FROM ACCELERATE

It remains unknown whether the factors associated with major adverse cardiovascular events (MACE) in the contemporary setting of statin therapy for high vascular risk patients differ, according to gender. The ACCELERATE trial compared the effects of evacetrapib and placebo on MACE (cardiovascular

Efficacy and Safety of the Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib in Combination With Atorvastatin in Japanese Patients With Primary Hypercholesterolemia

BACKGROUND Inhibition of cholesteryl ester transfer protein by evacetrapib when added to atorvastatin may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal.Methods and Results:This multicenter, randomized, 12-week, double-blind, parallel-group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib with atorvastatin in reducing LDL-C in 149 Japanese patients (evacetrapib/atorvastatin, n=53; ezetimibe/atorvastatin, n=50; placebo/atorvastatin, n=46) with primary hypercholesterolemia. The primary efficacy measure was percent change from baseline to week 12 in LDL-C (β quantification). Treatment with evacetrapib 130 mg daily for 12 weeks resulted in a statistically significant treatment difference of -25.70% compared with placebo in percentage decrease in LDL-C (95% CI: -34.73 to -16.68; P<0.001). Treatment with evacetrapib 130 mg also resulted in a statistically significant difference of 126.39% in the change in high-density lipoprotein cholesterol (HDL-C) compared with placebo (95% CI: 113.54-139.24; P<0.001). No deaths or serious adverse events were reported. Four patients (3 in the evacetrapib group and 1 in the ezetimibe group) discontinued due to adverse events. CONCLUSIONS Evacetrapib daily in combination with atorvastatin was superior to placebo in lowering LDL-C after 12 weeks, and resulted in a statistically significant increase of HDL-C compared with placebo. Also, no new safety risks were identified.

Efficacy and Safety of Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib Administered as Monotherapy in Japanese Patients With Primary Hypercholesterolemia

BACKGROUND Inhibition of cholesteryl ester transfer protein with evacetrapib may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal with statins or patients who cannot tolerate statins.Methods and Results:This multicenter, randomized, 12-week, double-blind, parallel group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib in reducing LDL-C in 54 Japanese patients (27 evacetrapib, 27 placebo) with primary hypercholesterolemia. Primary efficacy measure was the percent change from baseline to week 12 in LDL-C (β quantification). Treatment with evacetrapib 130 mg once daily for 12 weeks resulted in statistically significant (P<0.001) change in LDL-C (β quantification) compared with placebo. Least-squares mean percentage changes from baseline were -34.3% in the evacetrapib group vs. 0.0% in the placebo group. Treatment with evacetrapib 130 mg also resulted in a statistically significant (P<0.001) increase in high-density lipoprotein cholesterol compared with placebo in mean percent change from baseline, with a least-squares mean difference of 124.0% (95% confidence interval: 104.6-143.5). No deaths, serious adverse events, or discontinuations because of adverse events were reported; 5 patients (18.5%) in the evacetrapib group and 7 patients (26.9%) in the placebo group experienced treatment-emergent adverse events. CONCLUSIONS Once-daily evacetrapib 130 mg monotherapy was superior to placebo in lowering LDL-C after 12 weeks. No new safety risks were identified.