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Reference - FOURIER trial (N Engl J Med 2017 Mar 17 early online) (level 1 [likely reliable] evidence)
- Evolocumab, a fully-human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers low-density lipoprotein (LDL) cholesterol.
- To evaluate whether adjunctive therapy with evolocumab also reduces the risk of adverse cardiovascular events, 27,564 patients with atherosclerotic cardiovascular disease treated with statins and other cardiovascular protective therapies were randomized to evolocumab subcutaneous injections vs. placebo.
- After a median of 26 months, the addition of evolocumab to statin therapy decreased the risk of the composite outcome of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization (occurring in 9.8% with evolocumab vs. 11.3% with placebo, p < 0.001). Longer term follow-up is necessary to evaluate potential adverse effects.
Some patients with established atherosclerotic disease taking cardiovascular protective therapies continue to have adverse cardiovascular outcomes, indicating the need for other treatment options. Evolocumab and alirocumab are two medications approved by the FDA in 2015 to lower low-density lipoprotein (LDL) cholesterol in adult patients with familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease as an adjunct to a modified diet and maximally-tolerated statin therapy (FDA Press Release 2015 Aug 27) (FDA Press Release 2015 Jul 24). Both are fully-human monoclonal antibodies that reduce LDL levels by interfering with proprotein convertase subtilisin-kexin type 9 (PCSK9)-mediated degradation of the LDL receptor. Their efficacy to reduce LDL cholesterol has been established (N Engl J Med 2014 May 8;370(19):1809, JAMA 2014 May 14;311(18):1870, N Engl J Med 2015 Apr 16;372(16):1489), but trials primarily investigating clinical outcomes have been lacking. With this aim, 27,564 adults (mean age 63 years, 75% male) with fasting LDL cholesterol ≥ 70 mg/dL (≥ 1.8 mmol/L) or non-high-density lipoprotein (non-HDL) cholesterol level ≥ 100 mg/dL (≥ 2.6 mmol/L) while taking high- to moderate-intensity statin therapy were randomized to evolocumab vs. placebo subcutaneous injections. Patients could choose to receive evolocumab 140 mg injections every 2 weeks or evolocumab 420 mg injections every month. Patients in the trial had established atherosclerotic disease with 81% having had a prior myocardial infarction, 19% having had nonhemorrhagic stroke, and 13% having had symptomatic peripheral artery disease. They were also taking other cardiovascular protective treatments including antiplatelet therapy in 92% and antihypertensives in about 75%. The primary outcome was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.
Comparing evolocumab vs. placebo at a median follow-up of 26 months, the primary outcome occurred in 9.8% vs. 11.3% (p < 0.001, NNT 67) (hazard ratio [HR] 0.85, 95% CI 0.79-0.92), myocardial infarction in 3.4% vs. 4.6% (p < 0.001, NNT 84), stroke in 1.5% vs. 1.9% (p = 0.01, NNT 250), and coronary revascularization in 5.5% vs. 7% (p < 0.001, NNT 67). There were however no significant differences in cardiovascular death (in 1.8% vs. 1.7%) or hospitalization for unstable angina (in 1.7% vs. 1.7%). Comparing evolocumab vs. placebo at 12 months, LDL cholesterol was ≤ 70 mg/dL (≤ 1.8 mmol/L) in 87% vs. 18% (NNT 2), ≤ 40 mg/dL (≤ 1 mmol/L) in 67% vs. 0.5% (NNT 2), and ≤ 25 mg/dL (≤ 0.65 mmol/L) in 42% vs. 0.1% (NNT 3) (p < 0.001 for each). There was no significant difference in serious adverse events, but injection site reactions were more common in the evolocumab group (2.1% vs. 1.6%, p < 0.001, NNH 200). Ninety percent of patients chose the 2-week interval as the initial dosing regimen. The rate of treatment discontinuation was 12% (1,682 patients) in the evolocumab group and 13% (1,746 patients) in the placebo group with an adverse event given as the reason in 37.3% with evolocumab and 33.3% with placebo (statistical comparisons not reported).
The FOURIER trial found that addition of evolocumab to statin therapy reduced the risk of a composite of adverse cardiovascular outcomes at 26 months in patients with atherosclerotic cardiovascular disease. The 1.5% absolute reduction in risk associated with evolocumab is relatively modest, but this should be interpreted in light of the short follow-up period in this trial. Longer term follow-up will reveal if there is a greater reduction in risk over time. Other pending results include evaluation of potential negative effects of PCSK9 inhibition on neurocognitive function. This is being investigated in the EBBINGHAUS trial in a subset of patients in the present trial. Overall, the FOURIER trial suggests that further reductions in LDL cholesterol achieved by addition of evolocumab to statin therapy is beneficial for clinical outcomes in patients with established atherosclerotic cardiovascular disease. This is similar to the IMPROVE-IT trial (N Engl J Med 2015 Jun 18;372(25):2387) where adding ezetimibe to simvastatin was associated with a modest benefit in patients with acute coronary syndrome. Patients who may benefit most from PCSK9 inhibition include those with coronary artery disease who are statin intolerant, those with familial hypercholesterolemia who do not achieve sufficiently reduced LDL cholesterol levels despite aggressive LDL cholesterol lowering therapy, or those with coronary artery disease who tolerate statins but for whom lower LDL may be associated with some (modest) additional benefit.
See the Hypercholesterolemia, Familial Hypercholesterolemia, and Secondary prevention of coronary artery disease topics in DynaMed Plus for more information. DynaMed users click here.