ODYSSEY ESCAPE - PCSK9 inhibitor alirocumab for heterozygous familial hypercholesterolemia requiring lipid apheresis (short)

Moriarty PM, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial.


In HeFH patients previously requiring lipoprotein apheresis for LDL-lowering, a PCSK9 inhibitor further lowered LDL by ~55%. LDL-lowering with a PCSK9 inhibitor allowed for a 75% reduction in the rate of apheresis sessions (e.g. from once-weekly to once-monthly), and allowed up to two-thirds of patients to completely stop apheresis during a 3-month period (NNT <2). Although apheresis is an intermediate outcome, the high cost and burden to quality of life associated with this procedure make it an important clinical outcome to reduce.

This 62-patient trial was too small to accurately assess safety and tolerability of alirocumab, so clinicians should monitor for neurocognitive decline, ophthalmologic events, myalgias and injection-site reactions as previously reported to occur more commonly with PCSK9 inhibitors.


Context (from our review of FH)

  • Heterozygous familial hypercholesterolemia (HeFH) is genetic dyslipidemia that affects ~1/500 Canadians
  • HeFH presents clinically with an LDL 5-13 mmol/L +/- physical stigmata of elevated cholesterol, and increased risk of atherosclerotic cardiovascular disease (ASCVD)
    • Patients with untreated HeFH experience a coronary event 20+ years earlier than the general population
    • The cumulative risk of coronary events by age 50 is 44% in men and 20% in women
  • The treatment goal in patients with HeFH is to reduce LDL by >50% from baseline, generally with a max-tolerated statin dose and other lipid-lowering therapies
    • ipoprotein apheresis is an expensive last-line therapeutic procedure involving extracorporeal filtering of apoB-containing lipoproteins (i.e. LDL) from the blood
  • PCSK9 inhibitors, including alirocumab and evolocumab, lower LDL by ~60% in addition to diet, exercise and other lipid-lowering therapies
    • Mega-trials evaluating clinically-important outcomes are underway


    • Multicenter (14 centers in Germany & USA, enrollment March-September 2015)
    • Inclusion criteria:
      • HeFH diagnosed by clinical criteria (Simon Broome or Dutch Lipid Network criteria) or genotyping
      • Consistently received lipoprotein apheresis q1week x4+ weeks or q2weeks x8+ weeks
      • Stable background lipid-lowering therapy, diet, exercise x8+ weeks
    • Exclusion criteria: Homozygous FH
    • Screened 76 patients -> randomized 62 (41 to alirocumab, 21 to placebo)
    • "Average" patient @ baseline
      • 58 y
      • Male 58%
      • LDL: Alirocumab 4.5 mmol/L, placebo 5.0 mmol/L
      • Median apheresis duration before study: 4.9 y (range: 0.5-32.9 y)
      • Lipid-lowering therapies:
        • Statin ~55% (~half on max dose)
        • Others unknown (only reported "ever taken")
      • Apheresis regimen: q1w (43.5%), q2w (56.5%)

    Interventions & Co-Interventions

    • I: Alirocumab 150 mg (as 1 mL volume) subcutaneously q2weeks x18 weeks, administered at study site
      • # of injections: Mean 8.6 (SD 1.3)
    • C: Placebo as per above regimen
      • # of injections: Mean 8.4 (SD 1.7)
    • Co-i: Apheresis continued unless LDL measured as reduced by >30% from baseline


    • LDL
      • Baseline: 4.5 vs 5.0 mmol/L
      • @ week 6 (when pre-study apheresis regimen was maintained): 2.3 vs 4.8 mmol/L (55% greater reduction from baseline with alirocumab vs placebo)
      • @ week 18 (when apheresis sessions were omitted if LDL >30% lower than baseline): 2.9 vs 4.9 mmol/L
    • Apheresis
      • Difference in apheresis rate in weeks 7-18: 75% fewer apheresis sessions with alirocumab vs placebo
        • % of apheresis sessions required, median (range): 0% (0-100) vs 83% (42-100)
      • % of patients requiring no apheresis in weeks 7-18: 63.4% vs 0% (NNT 2)
    • Safety
      • Serious adverse events: 9.8% vs 9.5% 
      • Adverse event leading to study drug discontinuation: 4.9% vs 4.8%
      • Any adverse event: 75.6% vs 76.2%
        • Fatigue: 14.6% vs 9.5%
        • Myalgia: 9.8% vs 4.8%
        • CK >3x ULN: 7.3% vs 0%

    Issues with internal validity?

    • No: 2:1 randomization, allocation-concealed, double-blind (patients & apheresis site personnel blinded to LDL values) RCT with intention-to-treat analysis that accounted for drop-outs (8%)
    • Design involved 2 intervals:
      • Weeks 0-6: Apheresis contined as per established pre-study regimen
      • Weeks 7-18: Apheresis frequency adjusted based on LDL response to treatment; not performed if LDL decreased 30% or more from baseline LDL