Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes - ACCELERATE

Contribution To Literature:

The ACCELERATE study suggests that evacetrapib is not superior to placebo in reducing cardiovascular outcomes in patients at high risk for vascular risk despite favorable effects on both high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).

Description:

The goal of the trial was to compare the safety and efficacy of evacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, in patients at high vascular risk.

Study Design

Patients at high vascular risk were randomized in a 1:1 fashion to either evacetrapib 130 mg daily (n = 6,038) or placebo (n = 6,054).

  • Total number of enrollees: 12,092
  • Duration of follow-up: 30 months
  • Mean patient age: 65 years
  • Percentage female: 23%
  • Percentage diabetics: 68%

Other salient features/characteristics:

  • Prior myocardial infarction (MI): 67%
  • Peripheral arterial disease: 14%
  • High-intensity statin use: 46%
  • Mean LDL-C: 81 mg/dl
  • Mean HDL-C: 45 mg/dl

Inclusion criteria:

  • Acute coronary syndrome (ACS) within 30-365 days          
  • Diabetes with coronary disease
  • Peripheral arterial disease
  • Cerebrovascular disease
  • Must be treated with a statin for at least 30 days prior to screening; or, if not treated with a statin, must have documented statin intolerance or contraindication to statin
  • HDL-C <80 mg/dl
  • Triglycerides ≤400 mg/dl

Exclusion criteria:

  • History of transient ischemic attack (TIA) or ischemic stroke <30 days and ACS <30 days
  • Blood pressure ≥180/110 mm Hg
  • History of hemorrhagic stroke or intracranial hemorrhage
  • New York Heart Association class III or IV congestive heart failure
  • Serum creatinine >2.2 mg/dl
  • Clinically active liver disease
  • History of malignancy within the preceding 3 years prior to screening

Principal Findings:

The trial was terminated early due to futility.

The primary outcome, cardiovascular death/MI/stroke/coronary revascularization/unstable angina for evacetrapib vs. placebo: 12.8% vs. 12.7%, p = 0.85

Components of the primary outcome (for evacetrapib vs. placebo):

  • CV death: 7.2% vs.7.3%, p = 0.73
  • MI: 4.2% vs. 4.2%, p = 0.97
  • Stroke: 1.5% vs. 1.6%, p = 0.82

Secondary outcomes:

  • Mean HDL-C for evacetrapib vs. placebo at 30 months: 104 mg/dl vs. 46 mg/dl, p < 0.001
  • Mean LDL-C at 30 months: 55 mg/dl vs. 84 mg/dl, p < 0.001
  • All-cause mortality: 3.8% vs. 4.1%, p = 0.06
  • Drug discontinuation due to adverse events: 8.6% vs. 8.7%, p = 0.86
  • Change in high-sensitivity C-reactive protein: 4.6% vs. -8%
  • New hypertension: 11.4% vs. 10.1%, p < 0.05. mean difference in systolic blood pressure = 0.9 mm Hg during the trial

Effect of genotyping: This was performed for a single-nucleotide polymorphism (SNP) in the ADCY9 gene (rs1967309) among 1,427 cases and 1,532 matched controls. For patients with AA genotype, major adverse cardiac events for evacetrapib vs. placebo: odds ratio 0.88 (95% CI, 0.69-1.12); AG: 1.04 (95% CI, 0.90-1.21); GG 1.18 (95% CI, 0.98-1.41), p for interaction = 0.17.

Interpretation:

The results of this trial indicate that evacetrapib is not superior to placebo in reducing cardiovascular outcomes in patients at high risk for vascular risk despite a 130% increase in HDL-C and a 37% decrease in LDL-C. Reasons for this are unclear, but may be related to a blood pressure increasing effect of these drugs (although it only increased by 1 mm Hg during the trial). Inflammatory markers such as high-sensitivity C-reactive protein were also elevated with evacetrapib. This trial, coupled with negative results for torcetrapib and dalcetrapib, suggests that CETP inhibition may not be a good strategy to mitigate residual cardiovascular risk. Unlike what was observed for dalcetrapib, no interaction was noted between the ADCY9 SNP (rs1967309) and cardiovascular benefit.

References:

Nissen SE, Pillai SG, Nicholls SJ, et al. ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease: A Nested Case-Control Study. JAMA Cardiol 2018;Mar 11:[Epub ahead of print].

Editor’s Note: Sabatine MS. Pharmacogenetics and the Promise of Personalized Medicine. JAMA Cardiol 2018;Mar 11:[Epub ahead of print].

Presented by Dr. Steven E. Nissen at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 11, 2018.

Presented by Dr. A. Michael Lincoff at the European Society of Cardiology Congress, Rome, Italy, August 28, 2016.

Presented by Dr. Stephen J. Nicholls at at the American College of Cardiology Annual Scientific Session, Chicago, IL, April 3, 2016.

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Hypertension

Keywords: ACC18, ACC Annual Scientific Session, Acute Coronary Syndrome, Angina, Unstable, Benzodiazepines, Cerebrovascular Disorders, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Lipoproteins, HDL, Metabolic Syndrome X, Myocardial Infarction, Peripheral Arterial Disease, Risk Factors, Secondary Prevention, Stroke, Vascular Diseases, ESC Congress


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