REVEAL: Anacetrapib in ASCVD

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The HPS3/TIMI55-REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017;377:1217-27.

Bottom line: In patients with ASCVD & a risk of coronary events ~3%/year, anacetrapib reduced the risk of major coronary events (NNT 100 over 4.1 years, or NNT 410/year).

Anacetrapib's CV benefit is proportional to its LDL-C reduction, & may be unrelated to its effect on HDL-C.

Context

  • Lower HDL-C concentrations are associated with greater risk of CV disease; however, no trial has yet to show benefit of increasing HDL-C with pharmacological therapy;
  • Mechanism: Cholesteryl ester transfer protein (CETP) transfer triglycerides & cholesteryl esters between LDL or VLDL to HDL. Inhibiting CETP results in greater HDL-C serum concentrations & lower LDL-C & non-HDL-C serum concentrations;
  • Previous trials of CETP inhibitors have all failed to demonstrate clinical benefit, & some even caused harm:
    • ILLUMINATE: RCT of 15,067 patients at high risk of ASCVD. Torcetrapib increased the risk of CV events versus placebo over 550 days (6.2% vs 5.0% [NNH 84); hazard ratio [HR] 1.25, 1.09-1.44), as well as death (1.2% vs 0.8% [NNH 250], HR 1.58, 1.14-2.19);
    • dal-OUTCOMES: RCT of 15,871 patients with recent ACS. Dalcetrapib did not reduce the risk of CV events versus placebo over 31 months (8.3% vs 8.0%; HR 1.04, 0.93-1.16);
    • ACCELERATE: RCT of 12,092 patients with ASCVD stopped early for futility. Evacetrapib did not reduce CV events versus placebo over 26 months (12.9% vs 12.8%; HR 1.01, 0.91-1.11).
  • In October 2017, the maker of anacetrapib announced that it would not seek market approval, essentially ensuring that no CETP inhibitor would reach clinical use.

Patients (n=30,449)

  • Inclusion
    • Age >50 years
    • Hx of ASCVD (MI, cerebrovascular aatherosclerotic disease, PAD, or diabetes with symptomatic CAD)
  • Exclusion
    • ACS or stroke <3 months ago
    • Planned CABG/PCI
    • "Clinically significant liver, kidney, inflammatory muscle, or other disease"
    • Current tx with a fibrate, niacin, "or any drug contraindicated with anacetrapib or atorvastatin"
    • Previous statin-related adverse reaction
    • Known poor adherence to clinic visits or medications
  • Baseline characteristics
    • Age 67 y
    • Male 88%
    • PMHx
      • ASCVD: CAD 88%, cerebrovascular disease 22%, PAD 8%
      • Diabetes 37%
      • HF 6%
    • BP 131/78 mm Hg
    • HDL-C 1.0 mmol/L
    • LDL-C 1.6 mmol/L
    • Non-HDL-C 2.4 mmol/L

Interventions

  • Intervention: Anacetrapib 100 mg once daily
  • Control: Matching placebo
  • Co-intervention for all: Atorvastatin to reduce LDL-C <2.0 mmol/L

Results @ median 4.1 years

  • Effect on lipids (difference vs placebo) @ year 2:
    • HDL-C: +104% (+1.1 mmol/L)
    • LDL-C, non-HDL-C, ApoB: -18% (LDL-C -0.3 mmol/L)
    • Lp(a) -25%
  • Effect on BP: +0.7/0.3 mm Hg with anacetrapib vs placebo
  • Note 1: The reduction in major coronary events only became apparent after day 3; additionally, the relative risk reduction (RRR) increased over time (e.g. from 2% at year 1 up to 17% after year 4)
  • Note 2: Annualized NNT for major coronary events: ~410/year

Safety

  • Serious adverse events: Anacetrapib 58.4%, placebo 58.5%
  • Non-serious adverse events: Anacetrapib 5.4%, placebo 5.4%
  • eGFR <60 mL/min: Anacetrapib 11.5%, placebo 10.6%, p=0.04 (NNH 112)

Generalizability & other considerations

  • Key characteristics of included patients
    • Moderate risk for a population with existing ASCVD (risk of major vascular event ~3.5%/year & major coronary event ~3%/year) in control group)
    • Excellent LDL-C control (mean ~1.6 mmol/L), & low baseline HDL-C (mean ~1.0 mmol/L)
  • It's unclear if the coronary event reduction with anacetrapib resulted from the HDL-C increase or LDL-C reduction. However, the benefits in REVEAL are consistent with what would be expected based on the LDL-C reduction:

Internal validity: Low risk of bias

  • Allocation: Randomization by minimization, allocation concealed
  • Performance & detection: Patients, clinicians blinded, matching placebo
  • Attrition: Loss-to-follow-up 0.1%, intention-to-treat analysis
  • Selective outcome reporting: Reporting of all clinical outcomes of interest for both efficacy & safety