American College of Cardiology
American College of Cardiology
March 17, 2017
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FOURIER: Reducing LDL to very low levels with evolocumab confers reduced risk for CV events

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WASHINGTON — Reduction of LDL to a median of 30 mg/dL with the PCSK9 inhibitor evolocumab in patients with atherosclerotic CVD was associated with lowered risk for CV events, according to data presented at the American College of Cardiology Scientific Session and published in The New England Journal of Medicine.

Previous research had shown evolocumab (Repatha, Amgen), a fully human monoclonal antibody, dramatically lowers LDL, but its effect on clinical outcomes was unknown. The drug is currently approved by the FDA for lowering of LDL in patients with atherosclerotic CVD or familial hypercholesterolemia.

Marc S. Sabatine, MD, MPH
Marc S. Sabatine

Marc S. Sabatine, MD, MPH, chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group and the Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine at Brigham and Women’s Hospital, and colleagues randomly assigned 27,564 patients with atherosclerotic CVD and LDL 70 mg/dL to subcutaneous injections of evolocumab 140 mg every 2 weeks or 420 mg monthly or matching placebo.

Most patients were also assigned statin therapy, and some were also assigned ezetimibe (Zetia, Merck), Sabatine said during a press conference.

The primary outcome was a composite of CV death, MI, stroke, hospitalization for unstable angina or coronary revascularization. The key secondary outcome was a composite of CV death, MI or stroke. Median follow-up was 2.2 years.

Compared with placebo, evolocumab at 48 weeks was associated with a least-squares mean percentage reduction in LDL of 59% from a median of 92 mg/dL at baseline to a median of 30 mg/dL, and 87% of those in the evolocumab group had LDL reduced to 70 mg/dL, whereas 67% had it reduced to 40 mg/dL and 42% had it reduced to 25 mg/dL (P < .001 vs. placebo for all), Sabatine and colleagues found.

“One-quarter of the patients had an achieved LDL level of less than 20 [mg/dL],” Sabatine said at the press conference. “This LDL reduction was rock steady over the duration of the trial.”

The primary endpoint occurred in 9.8% of those assigned evolocumab vs. 11.3% of those assigned placebo (HR = 0.85; 95% CI, 0.79-0.92), according to the researchers.

Sabatine and colleagues also found that the key secondary endpoint was lower in the evolocumab group vs. the placebo group (5.9% vs. 7.4%; HR = 0.8; 95% CI, 0.73-0.88).

Magnitude of risk reduction for the primary endpoint associated with evolocumab increased over time, from 12% (95% CI, 3-20) in the first year to 19% (95% CI, 11-25) beyond the first year, according to the researchers. Evolocumab reduced the key secondary endpoint by 16% in the first year (HR = 0.84; 95% CI, 0.74-0.96) and 25% beyond the first year (HR = 0.75; 95% CI, 0.66-0.85), and fatal or nonfatal MI or stroke by 19% in the first year and 33% beyond the first year, Sabatine said.

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“The curves separate sometime during the first year and the continue to separate over time,” Sabatine said. “An important point ... is that it takes time for LDL lowering to translate into healthier arteries.”

There was no significant difference between the groups in CV death (HR = 1.05; 95% CI, 0.88-1.25), so the other individual endpoints must be considered exploratory, Sabatine and colleagues wrote in NEJM. Compared with placebo, evolocumab was linked to reduced risk for MI (HR = 0.73; 95% CI, 0.68-0.82), stroke (HR = 0.79; 95% CI, 0.66-0.95) and coronary revascularization (HR = 0.78; 95% CI, 0.71-0.86), but not for hospitalization for unstable angina (HR = 0.99; 95% CI, 0.82-1.18), CV death or hospitalization for worsening HF (HR = 0.98; 95% CI, 0.86-1.13) or all-cause mortality (HR = 1.04; 95% CI, 0.91-1.19).

Results were consistent regardless of age, sex, type of atherosclerotic vascular disease and quartiles of baseline LDL, according to the researchers.

“Even lower LDL ... appears to be even better,” Sabatine said during the press conference. “There is a very nice linear relationship now down to unprecedented levels of LDL, as low as 22 mg/dL.”

Adverse events, serious adverse events, adverse events leading to study drug discontinuation, muscle-related events, onset of cataracts, neurocognitive adverse events and hemorrhagic stroke did not differ between the groups, but injection-site reactions were more common with evolocumab (2.1% vs. 1.6%), according to Sabatine and colleagues.

There was no difference between the groups in new-onset diabetes (HR = 1.05; 95% CI, 0.94-1.17).

Valentin Fuster
Valentin Fuster

Among those assigned evolocumab, new binding antibodies developed in 0.3% of patients, but neutralizing antibodies did not develop in any patient.

Valentin Fuster, MD, PhD, physician-in-chief at The Mount Sinai Hospital, director of Mount Sinai Heart Institute, editor-in-chief of the Journal of the American College of Cardiology and past president of the American Heart Association and the World Heart Federation, said in a discussant presentation that the results are encouraging, but some caution is required.

“When you look at the absolute improvement in mortality [and other outcomes], it was just 2%,” he said. “The curves did diverge, so I assume that this 2% would be 4% in 2 or 3 more years. I feel very positive about that. The caution is cost-effectiveness. We live in a society where we have to be very, very careful about [a drug that is] very expensive. We cannot say that everyone will take PCSK9 inhibitors and it will be no problem. We have to be sure to identify the right people in which this type of approach should be meaningful.” – by Erik Swain

References:

Sabatine MS, et al. Joint ACC/JACC Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 17-19, 2017; Washington, D.C.

Sabatine MS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615664.

Disclosure : The study was funded by Amgen. Sabatine reports receiving grants from Abbott Laboratories, Critical Diagnostics, Daiichi Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Janssen Research Development, Novartis, Poxel, Roche Diagnostics and Takeda; grants and personal fees from Amgen, AstraZeneca, Intarcia, MedImmune and Merck; and personal fees from Alnylam, Cubist, CVS Caremark, Esperion, Ionis, MyoKardia, The Medicines Company and Zeus Scientific.