Peripheral Artery Disease and Venous Thromboembolic Events After Acute Coronary Syndrome: Role of Lipoprotein(a) and Modification by Alirocumab: Prespecified Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial

Gregory G Schwartz, Philippe Gabriel Steg, Michael Szarek, Vera A Bittner, Rafael Diaz, Shaun G Goodman, Yong-Un Kim, J Wouter Jukema, Robert Pordy, Matthew T Roe, Harvey D White, Deepak L Bhatt, ODYSSEY OUTCOMES Committees and Investigators*, Gregory G Schwartz, Philippe Gabriel Steg, Michael Szarek, Vera A Bittner, Rafael Diaz, Shaun G Goodman, Yong-Un Kim, J Wouter Jukema, Robert Pordy, Matthew T Roe, Harvey D White, Deepak L Bhatt, ODYSSEY OUTCOMES Committees and Investigators*

Abstract

Background: Patients with acute coronary syndrome are at risk for peripheral artery disease (PAD) events and venous thromboembolism (VTE). PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C) levels. Our objective was to ascertain whether PCSK9 inhibition reduces the risk of PAD events or VTE after acute coronary syndrome, and if such effects are related to levels of lipoprotein(a) or LDL-C.

Methods: This was a prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome), which was conducted in 18 924 patients with recent acute coronary syndrome on intensive or maximum-tolerated statin treatment who were randomized to the PCSK9 inhibitor alirocumab or placebo. In a prespecified analysis, PAD events (critical limb ischemia, limb revascularization, or amputation for ischemia) and VTE (deep vein thrombosis or pulmonary embolism) were assessed. LDL-C was corrected (LDL-Ccorrected) for cholesterol content in lipoprotein(a).

Results: At baseline, median lipoprotein(a) and LDL-Ccorrected were 21 and 75 mg/dL, respectively; with alirocumab, median relative reductions were 23.5% and 70.6%, respectively. PAD events and VTE occurred in 246 and 92 patients, respectively. In the placebo group, risk of PAD events was related to baseline quartile of lipoprotein(a) (Ptrend=0.0021), and tended to associate with baseline quartile of LDL-Ccorrected (Ptrend=0.06); VTE tended to associate with baseline quartile of lipoprotein(a) (Ptrend=0.06), but not LDL-Ccorrected (Ptrend=0.85). Alirocumab reduced risk of PAD events (hazard ratio [HR], 0.69 [95% CI, 0.54-0.89]; P=0.004), with nonsignificantly fewer VTE events (HR, 0.67 [95% CI, 0.44-1.01]; P=0.06). Reduction in PAD events with alirocumab was associated with baseline quartile of lipoprotein(a) (Ptrend=0.03), but not LDL-Ccorrected (Ptrend=0.50). With alirocumab, the change from baseline to Month 4 in lipoprotein(a), but not LDL-Ccorrected, was associated with the risk of VTE and the composite of VTE and PAD events.

Conclusions: In statin-treated patients with recent acute coronary syndrome, risk of PAD events is related to lipoprotein(a) level and is reduced by alirocumab, particularly among those with high lipoprotein(a). Further study is required to confirm whether risk of VTE is related to lipoprotein(a) level and its reduction with alirocumab. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Keywords: acute coronary syndrome; lipoprotein(a); low-density lipoproteins; peripheral artery disease; proprotein convertase subtilisin/kexin type 9; venous thromboembolism.

Figures

Figure 1.
Figure 1.
Risk of peripheral artery disease and venous thromboembolism events in the placebo group by baseline lipoprotein(a) or LDL-Ccorrected quartiles. Peripheral artery disease (PAD) events (top) and venous thromboembolism (VTE) events (bottom) in the placebo group are shown according to baseline quartile of lipoprotein(a) (Lp(a); left) or baseline quartile of corrected low-density lipoprotein cholesterol (LDL-Ccorrected; right). The hazard ratios (HRs [95% CIs]) for quartile 2, quartile 3, and quartile 4, relative to quartile 1, are 1.40 (0.83–2.35), 1.35 (0.81–2.28), and 2.22 (1.38–3.57) for lipoprotein(a) and PAD events; 1.06 (0.48–2.37), 1.03 (0.46–2.30), and 1.64 (0.80–3.38) for lipoprotein(a) and VTE events; 1.03 (0.62–1.70), 1.34 (0.84–2.15), and 1.46 (0.91–2.32) for LDL-Ccorrected and PAD events; and 0.72 (0.33–1.58), 0.90 (0.43–1.86), and 1.00 (0.49–2.05) for LDL-Ccorrected and VTE events. P values reflect linear trend across quartiles in an unadjusted Cox regression model.
Figure 2.
Figure 2.
Effects of alirocumab or placebo on peripheral artery disease and venous thromboembolism events. Kaplan-Meier curves depict the cumulative rate of peripheral artery disease (PAD) events (blue), venous thromboembolism (VTE) events (red), and the combination of PAD or VTE events (green). HR indicates hazard ratio.
Figure 3.
Figure 3.
Treatment effect of alirocumab on peripheral artery disease and venous thromboembolism events according to baseline quartile of LDL-Ccorrected or lipoprotein(a). Hazard ratios (HRs; alirocumab:placebo) for peripheral artery disease (PAD) events (top) and venous thromboembolism (VTE) events (bottom) according to baseline quartile of lipoprotein(a) (left) or baseline quartile of corrected low-density lipoprotein cholesterol (LDL-Ccorrected; right). Overall treatment effect is shown in red. P values indicate test of linear trend across baseline quartiles.

References

    1. Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, Norman PE, Sampson UK, Williams LJ, Mensah GA, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382:1329–1340. doi: 10.1016/S0140-6736(13)61249-0.
    1. Nehler MR, Duval S, Diao L, Annex BH, Hiatt WR, Rogers K, Zakharyan A, Hirsch AT. Epidemiology of peripheral arterial disease and critical limb ischemia in an insured national population. J Vasc Surg. 2014;60:686–95.e2. doi: 10.1016/j.jvs.2014.03.290.
    1. Steg PG, Bhatt DL, Wilson PW, D’Agostino R, Sr, Ohman EM, Röther J, Liau CS, Hirsch AT, Mas JL, Ikeda Y, et al. REACH Registry Investigators. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA. 2007;297:1197–1206. doi: 10.1001/jama.297.11.1197.
    1. Hirsch AT, Hartman L, Town RJ, Virnig BA. National health care costs of peripheral arterial disease in the Medicare population. Vasc Med. 2008;13:209–215. doi: 10.1177/1358863X08089277.
    1. Wu A, Coresh J, Selvin E, Tanaka H, Heiss G, Hirsch AT, Jaar BG, Matsushita K. Lower extremity peripheral artery disease and quality of life among older individuals in the community. J Am Heart Assoc. 2017;6:e004519. doi: 10.1161/JAHA.116.004519.
    1. Aday AW, Lawler PR, Cook NR, Ridker PM, Mora S, Pradhan AD. Lipoprotein particle profiles, standard lipids, and peripheral artery disease incidence. Circulation. 2018;138:2330–2341. doi: 10.1161/CIRCULATIONAHA.118.035432.
    1. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001;285:2481–2485. doi: 10.1001/jama.285.19.2481.
    1. Vidula H, Liu K, Criqui MH, Szklo M, Allison M, Sibley C, Ouyang P, Tracy RP, Chan C, McDermott MM. Metabolic syndrome and incident peripheral artery disease - the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. 2015;243:198–203. doi: 10.1016/j.atherosclerosis.2015.08.044.
    1. Wattanakit K, Folsom AR, Selvin E, Weatherley BD, Pankow JS, Brancati FL, Hirsch AT. Risk factors for peripheral arterial disease incidence in persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis. 2005;180:389–397. doi: 10.1016/j.atherosclerosis.2004.11.024.
    1. Emanuelsson F, Nordestgaard BG, Tybjærg-Hansen A, Benn M. Impact of LDL cholesterol on microvascular versus macrovascular disease: a mendelian randomization study. J Am Coll Cardiol. 2019;74:1465–1476. doi: 10.1016/j.jacc.2019.07.037.
    1. Kennedy M, Solomon C, Manolio TA, Criqui MH, Newman AB, Polak JF, Burke GL, Enright P, Cushman M. Risk factors for declining ankle-brachial index in men and women 65 years or older: the Cardiovascular Health Study. Arch Intern Med. 2005;165:1896–1902. doi: 10.1001/archinte.165.16.1896.
    1. Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017;69:692–711. doi: 10.1016/j.jacc.2016.11.042.
    1. Gurdasani D, Sjouke B, Tsimikas S, Hovingh GK, Luben RN, Wainwright NW, Pomilla C, Wareham NJ, Khaw KT, Boekholdt SM, et al. Lipoprotein(a) and risk of coronary, cerebrovascular, and peripheral artery disease: the EPIC-Norfolk prospective population study. Arterioscler Thromb Vasc Biol. 2012;32:3058–3065. doi: 10.1161/ATVBAHA.112.255521.
    1. Kosmas CE, Silverio D, Sourlas A, Peralta R, Montan PD, Guzman E, Garcia MJ. Role of lipoprotein (a) in peripheral arterial disease. Ann Transl Med. 2019;7(Suppl 6):S242. doi: 10.21037/atm.2019.08.77.
    1. Laschkolnig A, Kollerits B, Lamina C, Meisinger C, Rantner B, Stadler M, Peters A, Koenig W, Stöckl A, Dähnhardt D, et al. Lipoprotein (a) concentrations, apolipoprotein (a) phenotypes, and peripheral arterial disease in three independent cohorts. Cardiovasc Res. 2014;103:28–36. doi: 10.1093/cvr/cvu107.
    1. Pradhan AD, Shrivastava S, Cook NR, Rifai N, Creager MA, Ridker PM. Symptomatic peripheral arterial disease in women: nontraditional biomarkers of elevated risk. Circulation. 2008;117:823–831. doi: 10.1161/CIRCULATIONAHA.107.719369.
    1. Sartori M, Favaretto E, Legnani C, Cini M, Conti E, Amato A, Palareti G. Thrombophilic risk factors and peripheral arterial disease severity. Thromb Haemost. 2010;104:71–77. doi: 10.1160/TH09-11-0772.
    1. Cheng SW, Ting AC. Lipoprotein (a) level and mortality in patients with critical lower limb ischaemia. Eur J Vasc Endovasc Surg. 2001;22:124–129. doi: 10.1053/ejvs.2001.1431.
    1. Weiss N, Julius U. Lipoprotein(a) apheresis in patients with peripheral arterial disease: rationale and clinical results. Clin Res Cardiol Suppl. 2019;14(Suppl 1):39–44. doi: 10.1007/s11789-019-00097-1.
    1. Folsom AR, Lutsey PL, Astor BC, Cushman M. C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort. Thromb Haemost. 2009;102:615–619. doi: 10.1160/TH09-04-0274.
    1. Franchini M, Mannucci PM. Association between venous and arterial thrombosis: clinical implications. Eur J Intern Med. 2012;23:333–337. doi: 10.1016/j.ejim.2012.02.008.
    1. Prandoni P, Bilora F, Marchiori A, Bernardi E, Petrobelli F, Lensing AW, Prins MH, Girolami A. An association between atherosclerosis and venous thrombosis. N Engl J Med. 2003;348:1435–1441. doi: 10.1056/NEJMoa022157.
    1. Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360:1851–1861. doi: 10.1056/NEJMoa0900241.
    1. Danik JS, Buring JE, Chasman DI, Zee RY, Ridker PM, Glynn RJ. Lipoprotein(a), polymorphisms in the LPA gene, and incident venous thromboembolism among 21483 women. J Thromb Haemost. 2013;11:205–208. doi: 10.1111/jth.12056.
    1. Dentali F, Gessi V, Marcucci R, Gianni M, Grandi AM, Franchini M. Lipoprotein(a) as a risk factor for venous thromboembolism: a systematic review and meta-analysis of the literature. Semin Thromb Hemost. 2017;43:614–620. doi: 10.1055/s-0036-1598002.
    1. Sticchi E, Magi A, Kamstrup PR, Marcucci R, Prisco D, Martinelli I, Mannucci PM, Abbate R, Giusti B. Apolipoprotein(a) kringle-IV type 2 copy number variation is associated with venous thromboembolism. PLoS One. 2016;11:e0149427. doi: 10.1371/journal.pone.0149427.
    1. Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med. 2002;162:1182–1189. doi: 10.1001/archinte.162.10.1182.
    1. Bonaca MP, Creager MA. Pharmacological treatment and current management of peripheral artery disease. Circ Res. 2015;116:1579–1598. doi: 10.1161/CIRCRESAHA.114.303505.
    1. Kumbhani DJ, Steg PG, Cannon CP, Eagle KA, Smith SC, Jr, Goto S, Ohman EM, Elbez Y, Sritara P, Baumgartner I, et al. REACH Registry Investigators. Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. Eur Heart J. 2014;35:2864–2872. doi: 10.1093/eurheartj/ehu080.
    1. Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, Kuder J, Murphy SA, Jukema JW, Lewis BS, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation. 2018;137:338–350. doi: 10.1161/CIRCULATIONAHA.117.032235.
    1. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, et al. ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–2107. doi: 10.1056/NEJMoa1801174.
    1. Bittner VA, Szarek M, Aylward PE, Bhatt DL, Diaz R, Edelberg JM, Fras Z, Goodman SG, Halvorsen S, Hanotin C, et al. ODYSSEY OUTCOMES Committees and Investigators. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol. 2020;75:133–144. doi: 10.1016/j.jacc.2019.10.057.
    1. Jukema JW, Szarek M, Zijlstra LE, de Silva HA, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, et al. ODYSSEY OUTCOMES Committees and Investigators. Alirocumab in patients with polyvascular disease and recent acute coronary syndrome: ODYSSEY OUTCOMES trial. J Am Coll Cardiol. 2019;74:1167–1176. doi: 10.1016/j.jacc.2019.03.013.
    1. Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R, Goodman SG, Hanotin C, Harrington RA, Jukema JW, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY OUTCOMES trial. Am Heart J. 2014;168:682–689. doi: 10.1016/j.ahj.2014.07.028.
    1. Dahlen GH. Incidence of Lp(a) Among Populations. In: Scanu AM, editor. In: Lipoprotein(a) San Diego: Academic Press; 1990. pp. 151–173.
    1. Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Pedersen TR, Schwartz GG, Olsson AG, Colhoun HM, Kronenberg F, et al. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet. 2018;392:1311–1320. doi: 10.1016/S0140-6736(18)31652-0.
    1. Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J, Ridker PM, Mora S. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation. 2014;129:635–642. doi: 10.1161/CIRCULATIONAHA.113.004406.
    1. Tsimikas S, Fazio S, Ferdinand KC, Ginsberg HN, Koschinsky ML, Marcovina SM, Moriarty PM, Rader DJ, Remaley AT, Reyes-Soffer G, et al. NHLBI working group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J Am Coll Cardiol. 2018;71:177–192. doi: 10.1016/j.jacc.2017.11.014.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe