Highest Risk, Biggest Benefit in ACS Patients Treated With Alirocumab: ODYSSEY OUTCOMES

Two new analyses of the ODYSSEY OUTCOMES trial testing the addition of alirocumab (Praluent; Sanofi/Regeneron) to maximally tolerated statin therapy in ACS patients show that the PCSK9 inhibitor is particularly effective in higher-risk populations, such as those with extensive vascular disease or patients who previously underwent CABG surgery.

In the first analysis, investigators led by J. Wouter Jukema, MD, PhD (Leiden University Medical Center, the Netherlands), reported that alirocumab reduced the absolute risk of coronary heart disease (CHD) death, nonfatal MI, nonfatal ischemic stroke, or unstable angina by 1.4% in patients with CAD alone. In contrast, treatment with alirocumab reduced the absolute risk of MACE by 13.0% in patients with vascular disease in three arterial beds (coronary, peripheral, and cerebrovascular).  

In the second analysis, this time focusing on ACS patients who had previously undergone CABG surgery, treatment with alirocumab led to an absolute 6.4% reduction in the MACE rate and an absolute 3.6% reduction in the risk of all-cause mortality when compared with statin therapy alone. In contrast, for those without prior CABG surgery, the absolute reductions in MACE and all-cause mortality were 1.3% and 0.4%, respectively.

“We anticipated that patients with a prior CABG would be at a higher risk for recurrent events,” Shaun Goodman, MD (St. Michael’s Hospital/University of Toronto, Canada), who led the analysis of patients with prior surgery, told TCTMD. “Some of that is mediated by persistent elevations in atherogenic lipoproteins like LDL cholesterol, and so more aggressive LDL-lowering in this case, and other favorable changes with PCSK9 inhibition with alirocumab compared with placebo, would be expected to have as good as relative benefit regardless of how they were managed.”

And because patients with prior CABG are at such higher risk—they qualified for ODYSSEY OUTCOMES because they had a recent ACS—Goodman said they expected to see a “bigger bang for the buck” with alirocumab in this population. Although the investigators did not perform a cost-effectiveness analysis, treatment with alirocumab in patients with a prior CABG was associated with a lower number needed-to-treat (NNT) to prevent one clinical event. The NNT for 2.8 years to prevent one MACE was 16 in those with a prior CABG and 77 for those without prior surgery.

Both prespecified secondary analyses of ODYSSEY OUTCOMES were published online August 23, 2019, in the Journal of the American College of Cardiology.

CABG and Recurrent Events

It’s well known that benefits across a range of primary and secondary prevention medications are proportional to patient risk. For example, multiple studies have shown that the effect of adding ezetimibe to statin therapy is greater among patients with prior CABG surgery, while outcomes among ACS patients who’ve previously undergone CABG tend to have worse clinical outcomes than those without a past surgery. Analyses from FOURIER with evolocumab (Repatha; Amgen) showed significantly larger reductions in the risk of major clinical events among patients with PAD, prior MI, and extensive and/or severe CAD.

In ODYSSEY OUTCOMES, 18,924 stabilized ACS patients with LDL cholesterol levels ≥ 70 mg/dL were randomized to treatment with alirocumab or placebo on top of maximally tolerated statin therapy. Patients were categorized by CABG status: no prior CABG (n = 16,896), prior CABG before the qualifying ACS (n = 1,003), or CABG during the index hospitalization for ACS (n = 1,025), a group that included patients who underwent surgery after the qualifying ACS but before randomization to treatment. The ODYSSEY OUTCOMES study enrolled patients randomized to treatment anywhere from 1 to 12 months after ACS.

In the Goodman et al paper, the MACE rate was significantly higher among patients with prior CABG (27.7%) compared with those without prior surgery (9.5%) and those treated with CABG following the index ACS hospitalization (7.1%). The findings were consistent across CABG subgroups. Alirocumab reduced the relative risk of the composite endpoint of CHD death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization by 14%, 15%, and 23%, respectively in patients with no prior CABG, CABG after the qualifying ACS, and prior CABG. In the same CABG subgroups, the absolute reduction in the risk of MACE was 1.3%, 0.9%, and 6.4%, while the absolute risk of death was reduced 0.4%, 0.5%, and 3.6%.

“We can assume that no matter how these patients present, no matter their CABG status, they are going to derive a similar [relative] reduction in risk with alirocumab compared with placebo,” said Goodman. “Of course, because the prior CABG patients have such a higher event rate over the next two-and-a-half to 3 years, they derive a much greater absolute risk reduction.”

In the Jukema et al analysis, investigators stratified patients based on the extent of vascular disease. Of 18,924 patients, 17,320 had CAD alone, 1,404 had vascular disease in two beds (coronary and peripheral artery or cerebrovascular disease), and 149 had vascular disease in all three arterial beds.

In the placebo arm, the MACE rate was 10.0%, 22.2%, and 39.7% for patients with CAD, CAD and one additional vascular bed, and CAD plus PAD and cerebrovascular disease, respectively. In these three groups, adding alirocumab reduced the absolute risk of MACE by 1.4%, 1.9%, and 13.0%, respectively, when compared with the placebo arm. Similarly, alirocumab also reduced the absolute risk of death by 0.4%, 1.3%, and 16.2%.

The researchers suggest that patients with polyvascular disease comprise an easily-identifiable subgroup of ACS patients with a high absolute risk of MACE and death who would benefit from more intensive lipid-lowering with alirocumab.

Risk and Cost Going Hand in Hand

Erin Michos, MD (Johns Hopkins School of Medicine, Baltimore, MD), who was not involved in the studies, said both line up with other published reports, including FOURIER with evolocumab, showing that individuals at the highest risk for recurrent ischemic events derive the largest absolute benefit from intensified LDL cholesterol-lowering therapy.

“This is particularly important when you have a class of drugs like PCSK9 inhibitors that still carry a steep price tag, even with recent 60% cost reductions in the past year,” said Michos, adding that alirocumab and evolocumab still cost approximately $6,000 per year. “But even if you were to ignore the hefty price tag of PCSK9 inhibitors for the moment, for any pharmacologic therapy you would want to match the intensity of therapy to those who are most likely to derive the greatest absolute benefit. We see the same thing with statin therapy, too—high-intensity statins have the greatest benefit among those at highest [atherosclerotic cardiovascular disease (ASCVD)] risk.”

Given the lower NNT, Goodman said the cost-effectiveness of alirocumab would be favorable in these higher-risk prior-CABG patients.

“One of the unfortunate realities is that new therapies, even when proven to be beneficial, we just can’t right now afford to give everybody with ASCVD evolocumab like in FOURIER,” said Goodman. “We can’t afford to give everybody alirocumab post-ACS even though the trial suggests that everybody would benefit. That’s because of access/cost issues. As the cost is coming down, and that’s what we see with all therapies over the course of time, I’m confident that in the future the cost and access won’t be an issue and we can treat a very broad spectrum of post-ACS patients who meet the eligibility criteria for ODYSSEY OUTCOMES.”

Recognizing that not all patients can afford or have access to the PCSK9 inhibitors, focusing on high-risk patients using easily-identifiable clinical characteristics, such as a prior CABG surgery, is one way forward for using the agents in high-risk ACS patients with still elevated LDL cholesterol levels.

To TCTMD, Michos noted that the 2018 American College of Cardiology/American Heart Association cholesterol guidelines for secondary prevention differentiate treatment based on patient risk. “Among patients with coronary heart disease, there is a difference between a patient who might have gotten a stent 10 years ago for stable angina but otherwise has been doing well on medical therapy versus the patient who is in your CCU with acute coronary syndrome, the latter being at much higher risk for recurrent ischemia,” she said.

The guidelines recommended (class IIa) the addition of a PCSK9 inhibitor in very-high-risk ASCVD patients treated with maximally tolerated statin therapy and ezetimibe if LDL cholesterol levels exceed 70 mg/dL. Following this latest ODYSSEY OUTCOMES analysis, as well as prior data from FOURIER, Michos said she discusses PCSK9 inhibition (on top of maximally tolerated statins and ezetimibe) in her highest-risk ASCVD patients, such as those with extensive and severe coronary disease and concomitant vascular disease. Polyvascular disease is often undiagnosed given the lack of routine screening, she added, and yet these patients having such a tremendously high risk of recurrent events.

In an editorial accompanying the paper, Jacques Genest, MD, Alexandre Bélanger, MD (both McGill University Health Centre, Montreal, Canada), and Mandeep Sidhu, MD (Albany Medical College, Albany, NY), state that a “reasonable first step in the approach to patient care is for physicians to apply, with enthusiasm, secondary prevention guidelines in post-CABG and polyvascular disease patients.” In addition, intensive lifestyle modification, such as smoking cessation and physical activity, is also recommended.