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ODYSSEY Outcomes: Alirocumab lowers CV events in ACS population
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ORLANDO, Fla. — Reducing LDL to very low levels with the PCSK9 inhibitor alirocumab lowered risk for major adverse CV events and all-cause mortality in patients with ACS on statin therapy, according to anticipated results of the ODYSSEY Outcomes trial presented as a late-breaking clinical trial at the American College of Cardiology Scientific Session.
For the primary outcome of major adverse CV events, defined as CHD death, nonfatal MI, ischemic stroke or unstable angina requiring hospitalization, alirocumab (Praluent, Sanofi/Regeneron) conferred a 15% risk reduction compared with placebo (HR = 0.85; 95% CI, 0.78-0.93; absolute risk reduction = 1.6%). All 18,924 patients (mean age, 58 years; 25% women) were followed for at least 2 years, with 44% followed for at least 3 years (median, 2.8 years).
Patients assigned alirocumab also had reduced risk for all-cause mortality (HR = 0.85; 95% CI, 0.73-0.98; absolute risk reduction = 0.6%) compared with those assigned placebo, Philippe Gabriel Steg, MD, FESC, FACC, director of the coronary care unit in the cardiology department at Hôpital Bichat, Paris, professor of cardiology at the Université Paris – Diderot, and Cardiology Today’s Intervention Editorial Board Member, said during a presentation.
Aside from injection-site reactions, alirocumab was not linked to excess adverse events compared with placebo, Steg said.
Trial inclusion criteria included age older than 40 years, presence of ACS within 1 to 12 months before randomization, use of a maximally tolerated dose of atorvastatin or rosuvastatin for 2 to 16 weeks before randomization, LDL of at least 70 mg/dL, non-HDL of at least 100 mg/dL and apolipoprotein B of at least 80 mg/dL.
The ODYSSEY Outcomes patient population was different than patients enrolled in the FOURIER outcomes trial of evolocumab (Repatha, Amgen), which included high-risk patients with stable CHD, Steg said.
“Residual risk after acute coronary syndromes remains high,” Steg said. “A big factor is high levels of LDL, even on high-intensity statin therapy.”
For patients assigned alirocumab, the target LDL range was 25 to 50 mg/dL, but levels as low as 15 mg/dL were acceptable, Steg said. To minimize the number of patients below the target range, some were blindly down-titrated or switched to placebo.
Patients were enrolled at 1,315 centers in 57 countries (2,511 patients from United States).
Premature treatment discontinuation occurred in 14.2% of the alirocumab group vs. 15.8% of the placebo group. Nearly 8% of patients in the alirocumab group had a blinded switch to placebo because of two consecutive LDL measurements of less than 15 mg/dL.
Topline results presented
Among the components of the primary endpoint, compared with placebo, the alirocumab group had reduced risk for nonfatal MI (HR = 0.86; 95% CI, 0.77-0.96), ischemic stroke (HR = 0.73; 95% CI, 0.57-0.93) and unstable angina (HR = 0.61; 95% CI, 0.41-0.92). The same trend was not observed for CHD death (HR = 0.92; 95% CI, 0.76-1.11).
The alirocumab group also had lower risk for ischemia-driven coronary revascularization (HR = 0.88; 95% CI, 0.79-0.97), but not hospitalization for congestive HF (HR = 0.98; 95% CI, 0.79-1.2), compared with placebo.
In a post hoc analysis, the treatment effect of alirocumab for prevention of all-cause death was stronger in patients with baseline LDL of at least 100 mg/dL (HR = 0.71; 95% CI, 0.56-0.9; absolute risk reduction = 1.7%) vs. those with lower baseline LDL. Steg noted that assignment to alirocumab in these patients with LDL > 100 mg/dL also conferred a 24% reduced risk for major adverse CV events (HR = 0.76; 95% CI, 0.65-0.47; absolute risk reduction = 3.4%), 28% reduced risk for CHD death (HR = 0.72; 95% CI, 0.53-0.98; absolute risk reduction = 1%) and 31% reduced risk for CV death (HR = 0.69; 95% CI, 0.52-0.92; absolute risk reduction = 1.3%).
“These are the patients who may benefit most from treatment” with alirocumab, Steg said.
‘The results were not trivial’
Valentin Fuster, MD, PhD, director of Mount Sinai Heart and physician-in-chief of The Mount Sinai Hospital, provided his take on the ODYSSEY Outcomes findings during a press conference.
“I believe this study is going to change practice because of the hypothesis that has been fulfilled. The results were not trivial. There was a decrease in the primary endpoint by 15%. If LDL was more than 100 mg/dL, the decrease was 24%. It was interesting that the achieved LDL levels were very low. The message is that maybe what we consider a normal LDL level today is too high.” – by Erik Swain
Reference:
Steg PG, et al. Joint ACC/JACC Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.
Disclosures: The study was funded by Sanofi and Regeneron. Steg reports he has received research grants from Bayer, Merck, Sanofi and Servier and speaker/consultant fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi and Servier. Fuster reports no relevant financial disclosures.
Perspective
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Steven E. Nissen, MD, MACC
In ODYSSEY Outcomes, we saw the same 15% reduction in the primary outcome as was seen in the FOURIER outcomes trial of evolocumab. The investigators could have done a better strategy for dosing, which really hurt them. For patients who achieved LDL less than 15 mg/dL, the investigators took them off alirocumab or down-titrated them, and I’m not sure why. The benefit in FOURIER was seen to a greater degree the lower the achieved LDL.
Fortunately, an all-cause mortality benefit was seen with alirocumab, and that will provide a lot of help with payers, showing that patients clearly derive a significant benefit from this therapy. There was not a statistically significant reduction in CHD death, but the trend was encouraging.
Perspective
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B. Hadley Wilson, MD, FACC
The biggest takeaway from ODYSSEY Outcomes was that patients treated with alirocumab had significant reductions in major adverse CV events over a 3- to 5-year period, particularly in all-cause death, MI and stroke. Of interest, the group with most benefit were those with the highest LDL, greater than 100 mg/dL, and that may be a target population we would consider for this therapy, considering the costs of this medication over time.
Despite some differences from the FOURIER trial, I think these benefits still have to be considered a class effect of PCSK9 inhibitors. The question will be which groups will receive the most benefit, whether in ACS as in ODYSSEY Outcomes or in more stable patients as in the FOURIER outcomes trial. The bottom line will be that we need to identify high-risk groups in both populations, perhaps related to their LDL levels. We need to think about creative programs to target the appropriate audience and reduce the cost for them, showing a cost benefit over time.
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