Alirocumab Lp(a) Effects Claimed Share of Credit for Benefit in ODYSSEY-Outcomes

April 02, 2019

NEW ORLEANS – A substantial part of the cardiac-event risk decline seen in patients taking alirocumab (Praluent, Sanofi/Regeneron) in the ODYSSEY Outcomes trial can be attributed to reductions in lipoprotein(a), or Lp(a), suggests a post hoc analysis of the trial.

Also, among patients with the highest Lp(a) levels going into the randomized trial, reductions in those levels accounted for about one-fourth of the primary-endpoint risk reduction seen in the group assigned to the PCSK9 inhibitor.

Although the contribution of reduced Lp(a) to alirocumab's treatment effect was much less than that from reduced LDL-cholesterol (LDL-C), it was also independent of the LDL-C benefit, the analysis further suggested.

Indeed, baseline Lp(a) levels emerged as a significant outcomes predictor in the trial, which compared more than 18,000 patients with recent acute coronary syndrome (ACS) on maximal statins and other standard meds with and without the addition of alirocumab.

As previously reported for ODYSSEY Outcomes as a whole, patients who received the PCSK9 inhibitor showed a 15% decline in the primary end point of death from coronary heart disease (CHD), nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, and hospitalization for unstable angina (P < .001) over a median of 2.8 years.

Lp(a) as Risk Predictor

"We had a cohort of well-treated people with ACS and despite that, Lp(a) still predicted risk," Vera Bittner, MD, University of Alabama at Birmingham, told| Medscape Cardiology.

"Right now, clinicians don't measure Lp(a) very much, and maybe we should so we can identify the highest-risk individuals."

Moreover, she said, the analysis suggested that "Lp(a) lowering matters." Although LDL-C reductions were by far the "dominant driver" of the alirocumab clinical benefit, Lp(a) effects "made a very clinically significant impact" among patients in the highest baseline Lp(a) quartile.

Bittner presented the post hoc ODYSSEY Outcomes analysis here at the American College of Cardiology 68th Annual Scientific Session (ACC.19).

Importantly, the findings also support an independent role for Lp(a) as a treatment target for some patients with recent ACS, she said, and could conceivably influence their choice of therapy.

In a patient with high LDL-C despite statin therapy, she said, "and let's say money is no object, if that person had high Lp(a), it might sway me toward using the PCSK9 inhibitor, whereas in somebody who has a very low Lp(a), I would probably just put on ezetimibe."

But such treatment implications based on the current study are just speculation. "It was an analysis based on a trial that wasn't specifically designed to answer that question," she cautioned. "What you'd want is an Lp(a)-specific drug, and you want to test it the correct way, with a randomized trial."

The current analysis indeed suggests that alirocumab has "potential for being able to directly affect Lp(a)," said Pamela Ouyang, MBBS, MD, Johns Hopkins University, Baltimore, as a panelist after Bittner's presentation.

She pointed out, however, that the analysis of Lp(a) effects on outcomes included a limited number of covariates. As presented, it controlled only for baseline Lp(a), baseline corrected LDL-C, and early change in corrected LDL-C.

Perhaps not all of the clinical benefit is conferred by Lp(a) and LDL-C reductions, Ouyang proposed. Lp(a) appears to be a culprit in vascular disease by a number of mechanisms, one of which is inflammation. So the analysis might have turned out differently had it controlled for other potential mediators of inflammation that PCSK9 inhibition may have influenced.

Bittner acknowledged that the analysis did not control for other markers of inflammation.

At a different point in the presentation, Bittner noted that Lp(a) also has prothrombotic effects, which — more than its atherogenic effects — might account for its clinical benefit more in ACS patients than in patients without ACS.

Benefit Proportional to Baseline Levels

In the trial's placebo group, Bittner reported, there was a continuous rise in primary end-point and CHD death rates with increasing quartiles of baseline Lp(a) level (< .0001 for trend); quartile 1 included baseline levels below 6.7 mg/dL and quartile 4 levels were at least 59.6 mg/dL. No such significant correlation was seen for ischemic stroke, cardiovascular (CV) death, or death from any cause.

On the other hand, no significant correlation emerged between baseline Lp(a) and changes in LDL-C levels over the course of the study.

Absolute Primary Endpoint Risk Reduction by Baseline Lp(a) Quartile in ODYSSEY Outcomes (Interaction P = .0011)
Quartile Range n Risk Reduction 95% CI
<6.7 mg/dL 4730 0.4 –1.2 to 2.1
6.7 to <21.2 mg/dL 4731 1.4 –0.3 to 3.1
21.2 to <59.6 mg/dL 4729 2.3 0.6 to 4.1
≥59.6mg/dL 4734 2.1 0.2 to 3.9
Overall 18,924 1.6 0.7 to 2.4

Primary end-point reductions in the alirocumab group compared with those who did not receive the PCSK9 inhibitor were more pronounced, with increasing baseline Lp(a) levels (P = .0011 for trend) and the benefit reaching significance beginning at quartile 3.

Although reductions in LDL-C were determined to account for most of the alirocumab treatment effect in ODYSSEY Outcomes, the proportion of clinical benefit coming from Lp(a) reductions rose significantly with increasing baseline Lp(a) levels. That was observed for the primary end point and for the composite of any CV event or death from any cause.

Proportions* of Clinical Benefit Attributable to Change in Lp(a) Levels and to Change in Levels of Corrected LDL-C, by Baseline Lp(a) Percentile
End Point 25th Percentile, 6.7 mg/dL 50th Percentile, 21.2 mg/dL 75th Percentile, 59.6 mg/dL
Primary 4, 96 11, 89 27, 73
CV event or any-cause death 3, 97 9, 91 21, 79
*Lp(a)%, corrected LDL-C%
Adjusted for baseline Lp(a), baseline corrected LDL-C, and change from baseline to month 4 in corrected LDL-C

Bittner pointed to evidence that the PCSK9 inhibitor evolocumab (Repatha, Amgen) had similar effects on Lp(a) in FOURIER, which randomized more than 27,000 patients with clinical atherosclerotic cardiovascular disease already on statin therapy.

In that trial, a recent post hoc analysis suggested, high baseline Lp(a) levels predicted outcomes independently from high LDL-C, and higher baseline Lp(a) levels were associated with greater clinical benefit from evolocumab.

But that analysis, Bittner said, differed from the current one in not defining relative contributions of Lp(a) and LDL-C reductions to outcomes.

ODYSSEY Outcomes was funded by Sanofi and Regeneron Pharmaceuticals. Bittner discloses receiving consultant fees or honoraria from Sanofi Aventis; receiving and research grants from Amgen, AstraZeneca, and Bayer Healthcare; and having unspecified relationships with AstraZeneca, DalCor, Esperion. Ouyang discloses receiving research grants from Cordex.

American College of Cardiology (ACC) 68th Annual Scientific Session: Abstract 413-12. Presented March 18, 2019.

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