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Long-term therapy with evolocumab associated with lower CV mortality

Presented by
Prof. Michelle O'Donoghue, Brigham and Women's Hospital, MA, USA
ESC 2022
The long-term open extension of the FOURIER trial revealed that therapy with evolocumab is safe and effective: during a median time of 5 years, low LDL concentrations were maintained. In addition, in contrast to the pivotal study, longer exposure to evolocumab was associated with lower mortality.

In the FOURIER trial, including 6,635 patients with stable atherosclerotic cardiovascular disease, the PCSK9 inhibitor evolocumab reduced the risk of major cardiovascular events, but there was no observed effect on cardiovascular mortality.

The median follow-up was only 2.2 years, so potentially too short to show an effect on mortality. To further evaluate safety and efficacy of evolocumab, the open label extension FOURIER-OLE was conducted [1]. Twelve months after randomisation, placebo patients were switched to evolocumab and all study participants were treated with evolocumab until week 240.

Once patients received evolocumab, their LDL concentration dropped quickly to comparable values of patients treated with evolocumab from the beginning. “Notably, during the median 5-year extension period, participants maintained low LDL concentrations,” said Prof. Michelle O'Donoghue (Brigham and Women's Hospital, MA, USA), principal investigator of the FOURIER trial. Median LDL concentration at week 260 was 0.75 mmol/L. In addition, the incidence rate of side effects did not exceed that of placebo. Some of the patients were treated for more than 8 years but there were no unexpected safety signals.

After 5 years, the composite primary endpoint of cardiovascular death, myocardial infarction (MI), stroke, unstable angina, or coronary revascularisation was reduced by 15%; 17.5% of patients treated originally with placebo and then evolocumab achieved this endpoint compared with 15.4% of patients that were treated with evolocumab from the beginning. “There was a reduction of 23% in the cardiovascular mortality although there was not such a difference in the mother study,” Prof. O'Donoghue explained. As she pointed out, in the FOURIER trial the curves were essentially superimposed, it was not until the open-label extension that the benefit in terms of CV mortality reduction became apparent.

Overall, earlier initiation of evolocumab was associated with continued accrual of cardiovascular benefit, including cardiovascular mortality, over the next several years. These findings argue for early initiation of a marked and sustained LDL-C reduction to maximise clinical benefit.

  1. O'Donoghue ML. Long-term evolocumab in patients with established atherosclerotic cardiovascular disease: primary results of the FOURIER-OLE (open-label extension) studies. ESC Congress 2022, Barcelona, Spain, 26–29 August.


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