Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease
Marc S Sabatine, Robert P Giugliano, Anthony C Keech, Terje R Pedersen, FOURIER Steering Committee and Investigators - New England Journal of Medicine, 2017
Evolocumab, a PCSK9 inhibitor, lowered LDL by 59% (to a median of 30 mg/dL) on top of statins and reduced the primary cardiovascular composite (HR 0.85). It is strong evidence that even very low LDL is safe and beneficial - but it is also a key skeptic exhibit: the absolute benefit was modest, and the short median follow-up (2.2 years) was too brief to test whether halving LDL extends life.
Key findings
- Primary composite: 9.8% vs 11.3%; HR 0.85 (95% CI 0.79-0.92, p<0.001).
- Key secondary (CV death, MI, stroke): 5.9% vs 7.4%; HR 0.80 (95% CI 0.73-0.88).
- LDL lowered 59%, from a median 92 to 30 mg/dL; follow-up too short (2.2 years) to test a mortality effect.
Effect measures
- Hazard Ratio: 0.85 (primary composite)95% CI 0.79-0.92
- Absolute Risk Reduction: 1.5 percentage points (9.8% vs 11.3%)
Why this evidence tier (High)
- Risk of bias:
- Very large double-blind randomized placebo-controlled trial.
- Precision:
- Large event count; precise estimate.
- Directness:
- Hard clinical composite; tests a third LDL-lowering mechanism (PCSK9 inhibition).
- Consistency:
- Event reduction concordant with statin/ezetimibe evidence; the short follow-up leaves the mortality question open.
- Funding / COI:
- Manufacturer-funded (Amgen); several authors were Amgen employees.
High certainty that PCSK9-driven LDL lowering reduces events safely at very low LDL; the short follow-up means the trial could not test a mortality effect, a genuine limitation skeptics rightly emphasise.
- Population:
- 27,564 patients with established atherosclerotic cardiovascular disease and LDL >=70 mg/dL already on statins, randomized to the PCSK9 inhibitor evolocumab vs placebo; median follow-up 2.2 years.
- Conflicts of interest:
- Industry-funded by Amgen, which manufactures evolocumab. Several co-authors were Amgen employees.
- Funding:
- Amgen (manufacturer of evolocumab); NCT01764633.
Limitations
- Short median follow-up (2.2 years), too brief to test a mortality effect; absolute benefit modest.
- Manufacturer-funded.