Robinson JG, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
Bottom line: In patients at high risk of ASCVD, alirocumab lowered LDL by 62% more than placebo when added to maximum-tolerated statin therapy. This trial provides weak and mixed statistical evidence that additional LDL reduction with alirocumab may reduce CV events, primarily from reduction in non-fatal MI (NNT 72 over 78 weeks). This underpowered trial also suggests that alirocumab increases the risk of myalgia (NNH 40), and cannot rule out an increased risk of neurocognitive and ophthalmic events.
The ongoing ODYSSEY OUTCOMES trial should provide definitive CV and safety outcome data.
Patients
- Multicenter (320 sites in 27 countries in Africa, Europe, & North/South America)
- Inclusion
- Adults at high risk of ASCVD, defined as
- HeFH (diagnosed based on clinical criteria or genotyping)
- Established coronary artery disease (CAD), defined as history of
- MI, silent MI or unstable angina
- PCI or CABG
- CAD diagnosed by invasive (coronary angiography) or non-invasive testing (treadmill stress test, stress echo, nuclear imaging)
- "Coronary heart disease equivalent"
- Peripheral artery disease (PAD; current intermittent claudication with ABI <0.9 in either leg, history of intermitent claudication treated with endovascular or surgical procedure, or history of critical limb ischemia treated with thrombolysis or procedure)
- Ischemic stroke
- eGFR <60 for at least 3 months
- Type 2 diabetes + 1 more risk factor (HTN, ABI <0.90, albuminuria, retinopathy, family hx of premature CAD)
- LDL 1.8 mmol/L or more at screening (on maximum-tolerated statin dose)
- Exclusion
- Recent cardiovascular event leading to hospitalization or intervention
- Planned revascularization (carotid, coronary or peripheral) during study
- HF NYHA III-IV in past year
- SBP/DBP >180/110 mm Hg at screening/randomization visit
- PMHx
- Hemorrhagic stroke
- Optic nerve disease
- Hep B or C, or ALT/AST >3x ULN
- CKD with eGFR <30 mL/min
- Homozygous FH
- Trigs >4.5 mmol/L on 2 tests
- HbA1c >10%
- Known loss-of-function of PCSK9
- CK >3x ULN
- HIV
- Other major systemic disease that may preclude ability to complete study
- Meds
- Taking statin other than atorvastatin, rosuvastatin or simvastatin
- Not taking statin daily
- Use of systemic steroids (unless for pituitary/adrenal replacement stable for at least 6 weeks)
- Use of HRT (unless stable x6 weeks & no plan to change regimen during study)
- Involved in any previous PCSK9 inhibitor trial
- 5142 screened -> 2341 randomized
- "Average" patient
- 60.5 y
- Male 62%
- White 93%
- CV risk factors
- HeFH 18%
- CAD ~70%
- CAD-risk equivalent 41%
- Smoker 20%
- T2 diabetes 34%
- Meds
- Statin ~100%, high-dose 47%
- Other lipid-lowering therapy 28%
- Lipid panel: LDL 3.2, HDL 1.29, fasting trig 1.52 mmol/L
Interventions
- I: Alirocumab 150 mg subcutaneously (1 mL) q2 weeks administered at home
- Mean exposure 70 weeks (max 78)
- Mean adherence 98% of doses
- C: Matching placebo
- Co-intervention: Maximum-tolerated statin, diet per NCEP ATP III guidelines
Issues with generalizability (external validity)?
- High-risk CV population: Doesn't apply to "primary prevention" population without HeFH
- Excluded patients with any significant comorbidity who would be expected to have competing risks for death and hospitalization, as well as a greater absolute risk of adverse effects and intolerability with these drugs
- We'd expect overestimation of benefit and underestimation of harm in frail patients and in those with significant comorbid conditions (including those with heart failure)
Results
- LDL reduction
- Change from baseline to 24 weeks for alirocumab vs placebo = 62% difference
- @ baseline: 3.2 mmol/L in both groups
- @ 24 weeks: 1.2 vs 3.1 mmol/L
- Achieved goal <1.8 mmol/L @ week 24: 79.3% vs 8%
- Highlights:
- Differences in LDL remained consistent between groups through to week 78 among patients continuing study treatment
- Similar % reduction in LDL in patients with & without HeFH
- Uncertain effect on CV outcomes
- No statistically significant difference in composite CV outcome (death due to CAD or from unknown cause, non-fatal MI, ischemic stroke, unstable angina requiring hospitalization, HF hospitalization, ischemia-driven coronary revascularization)
- Statistically significant reduction in post-hoc analysis of components of above non-significant outcome
- "Major adverse CV event" (coronary death, non-fatal MI, ischemic stroke, unstable angina requiring hospitalization): 1.7% vs 3.3% (NNT 63, p=0.02)
- Driven by difference in non-fatal MI: 0.9% vs 2.3% (NNT 72, p=0.01)
- Safety
- Serious adverse event: 18.7% vs 19.5% (p=0.40)
- Discontinued study drug: 28.2% vs 24.5% (NNH 27)
- Discontinued due to adverse event: 7.2% vs 5.8% (p=0.26)
- Select adverse events
- Neurocognitive disorder: 1.2% vs 0.5% (p=0.17)
- Ophthalmic event: 2.9% vs 1.9% (p=0.65)
- Myalgia: 5.4% vs 2.9% (NNH 40, p=0.006)
- No statistically significant difference in new diabetes (1.8% vs 2.0%) or worsening of existing diabetes (12.9% vs 13.6%)
- No statistically significant difference in AST/ALT or CK elevations
Issues with internal validity?
- Randomized, allocation-concealed, triple-blind (patients, clinicians & investigators) trial with ~27% drop-out rate analyzed using the intention-to-treat population
- The high drop-out rate does not necessarily introduce between-group bias, but may have led to underestimation of CV and safety outcome events
- Stratified based on (1) HeFH status, (2) hx of MI or stroke, (3) background statin of atorva 40-80/rosuva 20-40 vs simvastatin at any dose or atorva <40/rosuva <20, (4) geography.
