PCSK9 inhibitor reduces CV risk irrespective of age
Effect of alirocumab on cardiovascular outcomes after acute coronary syndromes according to age: an ODYSSEY OUTCOMES trial analysis
Literature - Sinnaeve PR, Schwartz GG, Wojdyla DM et al., - Eur Heart J. 2020. doi: 10.1093/eurheartj/ehz809.Introduction and methods
Lowering LDL-c with statins reduces CV risk irrespective of age, but evidence is less strong in older patients >75 years. In fact, because older patients are underrepresented in such trials [1], it remains uncertain whether benefits outweigh risks with intensive LDL-c lowering in older patients, particularly after an acute coronary syndrome (ACS). Older patients are less likely to be prescribed lipid-lowering therapies and statin doses are often lower [2]. In addition, older patients in secondary prevention have lower adherence to statins, associated with increased risk of death [3]. For these reasons, additional non-statin therapies might be appealing for older patients with established CAD [4].
The Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) trial showed a reduction in primary composite endpoint of death from CAD, non-fatal MI, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization in patients (n=18924) after treatment with PCSK9 inhibitor alirocumab added to high-intensity or maximum-tolerated statin treatment as compared with placebo [5]. Included patients had been hospitalized with ACS (MI or unstable angina) 1-12 months before randomization, and were randomized to receive 75 mg alirocumab or matching placebo every 2 weeks.
This prespecified analysis of the ODYSSEY OUTCOMES trial assessed the impact of age on occurrence of primary endpoint and on efficacy of alirocumab to lower LDL-c and primary endpoint as compared to placebo. Treatment effects were assessed by analyzing age as categorical variables (prespecified<65 vs. ≥65 years and non-prespecified <75 vs. ≥75 years) and continuous variable.
Main results
- Mean age of patients was 59 (SD 9 years), with 5084 patients (26.9%) ≥65 years, 1007 patients (5.3%) ≥75 years, and 42 patients (0.2%) ≥85 years.
- In patients <65 vs. ≥65 years, LDL-c levels were similar 1 month after randomization (both 1.11 mmol/L), 4 months after randomization (<65 years: 1.02 mmol/L, ≥65 years: 1.05 mmol/L), and 8 months after randomization (both 1.17mmol/L). Subsequent LDL-c levels increased irrespective of age, but with a less pronounced effect in patients ≥65 years vs. in patients <65 years.
- At 3 years, alirocumab reduced primary endpoint risk compared to placebo in patients ≥65 years (12.9% vs. 16.8%, HR 0.78, 95%CI 0.68-0.91) and in patients <65 years (8.8% vs. 9.7%, HR 0.89, 95%CI 0.80-1.00) with a P-interaction=0.19 and a greater absolute reduction in the older patients (P=0.015).
- At 3 years, alirocumab reduced all-cause death compared to placebo in patients ≥65 years (HR 0.77, 95%CI 0.62-0.95). In patients <65 years the HR for all-cause death was 0.94 (95%CI 0.77-1.15) after alirocumab (P-interaction=0.46). Absolute reduction was greater in the older patients (P=0.024).
- Secondary combined endpoint of all-cause death, MI, or ischemic stroke did not differ between age groups after alirocumab as compared to placebo (≥65 years HR 0.78, 95%CI 0.68-0.90 vs. <65 years HR 0.91, 95%CI 0.82-1.02; P-interaction=0.19).
- At 3 years, using the non-prespecified 75-year cut-off, alirocumab reduced primary endpoint risk in patients ≥75 years (18.8% vs. 21.4%; HR 0.85, 95%CI 0.64–1.13) and in patients <75 years (9.4% vs. 11.1%; HR 0.85, 95%CI 0.78–0.93; P-interaction=0.19). There was no significant difference by age category set at 75 in the relative effect of alirocumab on all-cause death.
- Analyzing age as continuous variable, relative benefit of alirocumab over placebo on primary endpoint was consistent across the whole age range (45-85 years).
- Absolute benefits of alirocumab increased with advancing age due to higher absolute risk at older age. NNT for 3 years to prevent one primary endpoint decreased with increasing age: 43 (25–186) at age 45, 26 (15–97) at age 75, and 12 (6–81) at age 85 years.
- For major CHD events, NNT decreased from 49 (27–259) at age 45, to 34 (18–297) at age 75, and to 14 (7–269) at age 85.
- Adverse events (AEs) were more frequent in patients ≥65 years, but there were no differences in AEs between treatment groups in both age groups. Similarly, serious AEs or AEs that led to discontinuation of the trial regimen were more frequent in older patients, but there were no differences between treatment groups.
Conclusion
In the ODYSSEY OUTCOMES trial, alirocumab added to maximally tolerated high-intensity statins significantly reduced CV risk in patients after ACS irrespective of age. More AEs occurred in older patients as compared to younger patients, but not between treatment groups. In addition, absolute benefit of alirocumab increased with advancing age, suggesting that additional PCSK9i therapy may be an important secondary preventive intervention after ACS in older patients.
References
1. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet 2019;393:407–415.
2. Ofori-Asenso R, Ilomaki J, Tacey M, Zomer E, Curtis AJ, Si S, Zullo AR, Korhonen MJ, Bell JS, Zoungas S, Liew D. Switching, discontinuation, and reinitiation of statins among older adults. J Am Coll Cardiol 2018;72:2675–2677.
3. Rodriguez F, Maron DJ, Knowles JW, Virani SS, Lin S, Heidenreich PA. Association of statin adherence with mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol 2019;4:206–213.
4. Bach RG, Cannon CP, Giugliano RP, White JA, Lokhnygina Y, Bohula EA, Califf RM, Braunwald E, Blazing MA. Effect of simvastatin-ezetimibe compared with simvastatin monotherapy after acute coronary syndrome among patients 75 years or older: a secondary analysis of a randomized clinical trial. JAMA Cardiol 2019;doi: 10.1001/jamacardio.2019.2306 [Epub ahead of print].
5. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Lecorps G, Mahaffey KW, Moryusef A, Pordy R, Quintero K, Roe MT, Sasiela WJ, Tamby JF, Tricoci P, White HD, Zeiher AM. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–2107.
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