Sabatine MS, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.
Bottom line: In patients previously enrolled in a phase 2/3 trial of evolocumab due to elevated LDL in the context of HeFH, statin intolerance, or maximum-tolerated statin therapy, addition of evolocumab lowered LDL by ~60% versus standard therapy alone. This LDL reduction resulted in a reduction in CV events (NNT 82 at 11 months), which may be an inaccurate estimate due to high risk of performance and detection bias.
Patients (n=4465)
- Inclusion
- Patients who completed one of the 12 phase 2 & 3 RCTs of evolocumab without discontinuation due to an adverse event
- No unstable medical condition
- Basic patient populations enrolled in phase 2 & 3 trials:
- MENDEL-1 & 2: LDL 2.6-4.9 mmol/L without background lipid lowering
- GAUSE-1: LDL >2.6 mmol/L, statin intolerant
- GAUSE-2: LDL 2.6-4.9 mmol/L, statin intolerant
- DESCARTES, THOMAS1&2: LDL >1.9 mmol/L with statin (DESCARTES: +/- ezetimibe)
- LAPLACE-TIMI 57: LDL >2.1 mmol/L with statin +/- ezetimibe
- LAPLACE-2: LDL >2.0 mmol/L with "intensive" statin, >2.6 mmol/L on "non-intensive" statin, or >3.9 mmol/L without statin at baseline, added to statin +/- ezetimibe
- RUTHERFORD-1 & 2: HeFH with LDL >2.6 mmol/L with statin +/- ezetimibe
- YUKAWA-1: "High-risk" Japanese patients with LDL 3.0 mmol/L or greater while receiving statin
- 4465 randomized (74.1% of eligible from phase 2 & 3 trials)
- "Average" patients (baseline of phase 2 & 3 trials)
- 58 y
- Male 51%
- White 85%
- North American 47%
- CV risk factors
- Smoker 15%
- Known CAD 20%, MI 9%, PCI 11%, CABG 7%
- Cerebrovascular or peripheral-artery disease 9%
- Family hx of premature CAD 24%
- HTN 52%
- Diabetes 13%
- Known FH 10%
- Lipids: Total cholesterol 5.1, LDL 3.1, HDL 1.3, trig 1.35 mmol/L
- Meds
- Statin 70%, high-intensity 27%
- Ezetimibe 14%
Issues with generalizability (external validity)?
- Yes: The patients in OSLER 1 & 2 represent a highly-selected patient population enrolled into early phase 2/3 mechanistic efficacy trials who were adherent and tolerant to their allocated therapy in the phase 2/3 trial
- In care of real-world patients with greater likelihood of comorbid conditions and frailty, we'd expect lower eficacy, adherence, tolerability and safety than estimated from these trials.
Interventions
- I: Evolocumab x56 weeks + standard of care lipid-lowering therapy per local guidelines
- OSLER-1: 420 mg q1 month
- OSLER-2: Patient's choice of 140 mg q2weeks or 420 mg q1month
- In-person clinic visit q3 months
- C: No evolocumab x48 weeks + standard of care lipid-lowering therapy per local guidelines
- After trial: Open-label evolocumab for all patients completing OSLER-1&2
Results @ median ~11 months
- LDL reduction
- Change from baseline to week 12 of OSLER for evolocumab+standard therapy vs standard therapy alone = 61%
- @ baseline: Median 3.1 mmol/L in both groups
- @ week 12 of OSLER trial (variable time from baseline): Median 1.2 vs 3.1 mmol/L
- <1.8 mmol/L target: 73.6% vs 3.8%
- Statistically significant reduction in composite CV outcome (death, MI, unstable angina requiring hospitalization, coronary revascularization, stroke/TIA, or HF requiring hospitalization): Hazard ratio 0.47 (0.28-0.78)
- 0.95% vs 2.18% (NNT 82)
- Not clearly driven by any single component of the composite outcome (e.g. MI or stroke)
- No patients developed neutralizing antibodies against evolocumab
Issues with internal validity?
- Yes: Randomized, allocation-concealed, open-label (participants, clinicians and investigators aware of allocated treatment) non-placebo controlled trial with ? lost-to-follow-up analyzed using intention-to-treat population
- High risk of performance and detection bias, particularly relating to "soft" CV outcomes such as hospitalizations and decision to revascularize
- Notably, this is actually a pooled report of 2 RCTs: OSLER-1 is an extension of 5 phase-2 trials, and OSLER-2 is an extension of 7 phase-3 trials
