The Clinical Times
The Front Page of Medicine

Cardiology · 2017

FOURIER (Evolocumab / PCSK9 inhibition) and the PCSK9 era

Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk

Crystal structure of the PCSK9 protein, the target of evolocumab and other PCSK9 inhibitors
Emw / CC BY-SA 3.0 (Wikimedia Commons)

The discovery that loss-of-function mutations in PCSK9 conferred lifelong low LDL levels and markedly reduced coronary disease risk established the target before the drug existed. Carriers of inactivating PCSK9 mutations identified in Dallas cohorts had LDL levels around 100 mg/dL lower than unaffected relatives and a 90% reduction in cardiovascular events over decades. Statins remained the primary tool for LDL lowering, but even maximally dosed statins typically reduced LDL by 50 to 60%, leaving many high-risk patients well above guideline targets. The human genetics data suggested that deeper, sustained reductions would be safe and beneficial.

FOURIER enrolled 27,564 patients with established atherosclerotic cardiovascular disease who were already on statin therapy and had LDL at or above 70 mg/dL. Marc Sabatine of Harvard Medical School and Brigham and Women's Hospital served as principal investigator; Robert Giugliano was co-investigator and led the primary analysis. Participants were randomized to subcutaneous evolocumab every two or four weeks, or matching placebo. Over a median follow-up of 2.2 years, evolocumab reduced median LDL from 92 mg/dL at baseline to 30 mg/dL, a level previously unreached in a large outcome trial. The primary composite endpoint fell by 15%.

The most contested finding was that cardiovascular death did not differ significantly between groups. Critics argued that 2.2 years of follow-up may have been insufficient to see a mortality signal, given that atherosclerosis regression and plaque stabilization require years. The companion ODYSSEY OUTCOMES trial, reported at the 2018 ACC meeting, randomized 18,924 post-acute coronary syndrome patients to alirocumab and did show a reduction in all-cause mortality, partially resolving the concern. In FOURIER, secondary endpoint analyses showed that the relative risk reduction for MI and stroke grew over time, consistent with a delayed but accumulating atherosclerotic benefit.

Separately, the data reinforced that no floor existed in the LDL-cardiovascular risk relationship at levels tested in clinical trials. Participants in FOURIER who achieved LDL below 20 mg/dL had lower event rates than those in the 20 to 30 mg/dL range, with no apparent increase in adverse effects including neurocognitive dysfunction, hemorrhagic stroke, or new-onset diabetes. That finding directly challenged the notion of a lower threshold for safe LDL reduction, a question that had been prominent since earlier observational analyses suggested possible harm at very low levels.

PCSK9 inhibitors entered ACC/AHA and European Society of Cardiology guidelines as add-on therapy for very high-risk patients who remain above LDL targets despite maximally tolerated statin and ezetimibe. Uptake was initially limited by cost, with annual prices exceeding $14,000 in the United States, though manufacturer rebates and insurer negotiations brought effective costs down substantially by 2020. A small-interfering RNA agent, inclisiran, subsequently entered trials and practice as a twice-yearly subcutaneous alternative targeting the same pathway, demonstrating that PCSK9 inhibition could be achieved through multiple molecular mechanisms.

Key People

Read the original — PubMed

N Engl J Med, 2017

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