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ORLANDO -- Alirocumab (Praluent) reduced major cardiovascular event risks in patients with a recent acute coronary syndrome and elevated cholesterol in the ODYSSEY Outcomes trial, including a win in perhaps the most important outcome: mortality.

The PCSK9 inhibitor reduced the composite of coronary heart disease death, nonfatal myocardial infarction (MI), fatal or nonfatal ischemic stroke, and unstable angina requiring hospitalization by a relative 15% compared with placebo (9.5% vs 11.1%, P=0.0003), P. Gabriel Steg, MD, of Université Paris Diderot, reported here at the American College of Cardiology meeting.

Notable among secondary endpoints was a relative 15% reduction in all-cause mortality, with a nominal P-value of 0.026 due to hierarchical analysis (3.5% vs 4.1%). Death from cardiovascular causes or from coronary heart disease slightly favored the PCSK9 inhibitor but without statistical significance. Steg suggested that statistical power may have played a role.

Still, that was a win compared with the first large cardiovascular outcomes trial with a PCSK9 inhibitor -- FOURIER for evolocumab (Repatha) -- in which cardiovascular and all-cause mortality both went slightly in the wrong direction.

Overall, the primary composite in FOURIER (which added revascularization) came out with a 15% relative risk reduction identical to that in ODYSSEY, despite the different population (stable atherosclerotic cardiovascular disease). But while that 15% was viewed with disappointment when presented last year at the same meeting, Christopher Cannon, MD, of Brigham and Women’s Hospital in Boston, suggested it was now welcomed because expectations had changed.

“This is not a minimal improvement. It is in range of what aspirin achieves,” Steg said at a press conference for the late-breaking clinical trial.

The trial hit key hopes: Along with the mortality benefit, it helped define a somewhat narrower group that benefits most and helped the argument for broader reimbursement.

"The biggest issue [with PCSK9 inhibitors] is the cost and insurance coverage. I think the importance of these data is that it is mortality data, so it may shift the needle when payors are considering coverage of a subgroup of patients -- the subgroup of patients on a high intensity statin and still have [high LDL]," commented ACC president Mary Norine Walsh, MD.

High Baseline LDL

Patients with higher cholesterol drove the composite primary outcome, with the relative risk cut by about a quarter among those entering the trial with an LDL of at least 100 mg/dL (HR 0.75) but no significant impact for those with lower baseline LDL. A post hoc analysis by that prespecified subgroup showed again the biggest impact on all-cause mortality with baseline LDL of at least 100 mg/dL (HR 0.71), although the interaction term was not significant.

Indeed, that needle may have already begun to shift in response to the trial, as alirocumab-makers Sanofi and Regeneron have announced a plan to cut the price of the drug as long as insurers remove hurdles for high-risk patients with high baseline LDL.

ODYSSEY Outcomes randomized 18,924 patients with an acute coronary syndrome in the prior 1 to 12 months who met lipid entry criteria (primarily LDL 70 mg/dL or higher) after a run-in on high-intensity or maximally-tolerated statin randomized to subcutaneous injections of alirocumab or placebo every 2 weeks.

The subgroup with LDL of at least 100 mg/dL at baseline accounted for 5,629. That group is likely to include many familial hypercholesterolemia (FH) patients, Katherine Wilemon, CEO of the FH Foundation, noted in a statement sent to press, although there were no FH-specific analyses. “In the pre-PCKS9i era, data show that only 30% of FH patients achieve an LDL <100 mg/dL.”

Other secondary endpoint benefits in ODYSSEY for alirocumab compared with placebo included significant 12% to 14% relative reductions in the following:

• Coronary heart disease events
• Major coronary heart disease events
• Cardiovascular events
• Composite of death, MI, and ischemic stroke

Ischemia-driven coronary revascularization, which had been included in FOURIER's primary endpoint, again showed a 12% relative reduction (P=0.009).

The alirocumab dose was targeted to reach LDL of 25 to 50 mg/dL, although down to 15 mg/dL was considered acceptable. The average baseline LDL was 87 mg/dL in both groups. During the trial, 7.7% of the alirocumab group had to be blindly switched to placebo for two consecutive readings below 15 mg/dL.

But this strategy may have hampered alirocumab from reaching its full potential, commented Steven Nissen, MD, of the Cleveland Clinic. “Many patients were given a very low dose…. As a result the trial did not perform as well as it might have performed had they given full doses as they did in FOURIER.”

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