Joint statement from the European Atherosclerosis Society and European Society of Vascular Medicine focuses on patients with peripheral arterial disease

Abstract

Peripheral arterial disease (PAD) is one of the three leading cardiovascular diseases globally, together with coronary heart disease and cerebrovascular disease. Recent estimates show that PAD affects over 235 million people worldwide [[1]Song P. Rudan D. Zhu Y. et al.Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis.Lancet. Glob. Health. 2019; 7: e1020-e1030Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar], with almost three quarters asymptomatic [[2]GBD 2017 Disease and Injury Prevalence Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2018; 392: 1789-1858Abstract Full Text Full Text PDF PubMed Scopus (4373) Google Scholar]. Prevalence increases with age, with more than one in five people older than 60 years affected [[3]Fowkes F.G.R. Aboyans V. Fowkes F.J.I. Peripheral artery disease: epidemiology and global perspectives.Nat. Rev. Cardiol. 2016; 14: 156-170Crossref PubMed Scopus (274) Google Scholar]. As populations age, PAD will become more common, posing an increasing burden of disease. Increasingly this burden will be in lower and middle-income countries, aligned with smoking and diabetes trends [[1]Song P. Rudan D. Zhu Y. et al.Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis.Lancet. Glob. Health. 2019; 7: e1020-e1030Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar]. Given a common atherosclerotic pathway, coronary artery disease (CAD) and PAD are often grouped together. There is, however, evidence that factors associated with PAD enhance susceptibility to the clinical manifestations of atherosclerosis [[4]Rein P. Saely C.H. Silbernagel G. et al.Systemic inflammation is higher in peripheral artery disease than in stable coronary artery disease.Atherosclerosis. 2015; 239: 299-303Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar,[5]Tunstall-Pedoe H. Peters S.A.E. Woodward M. et al.Twenty-year predictors of peripheral arterial disease compared with coronary heart disease in the Scottish Heart Health Extended Cohort (SHHEC).J. Am. Heart. Assoc. 2017; 6e005967Crossref PubMed Scopus (43) Google Scholar]. Mortality among PAD patients is substantially higher than among those with CAD and even higher than many common cancers [[6]Droz-Perroteau C. Blin P. Dureau-Pournin C. et al.Six-year survival study after myocardial infarction: the EOLE prospective cohort study. Long-term survival after MI.Therapie. 2019; 74: 459-468Crossref PubMed Scopus (4) Google Scholar,[7]American Cancer Society Cancer-facts-and-figures.https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2019.htmlDate: 2019Date accessed: November 3, 2021Google Scholar]. Despite this pessimistic prognosis, PAD has not received the same priority as CAD in research, or clinical and public health strategies, with little change in mortality rates over the past 25 years [[8]Sartipy F. Sigvant B. Lundin F. Wahlberg E. Ten year mortality in different peripheral arterial disease stages: a population based observational study on outcome.Eur. J. Vasc. Endovasc. Surg. 2018; 55: 529-536Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,[9]Criqui M.H. Fronek A. Barrett-Connor E. et al.The prevalence of peripheral arterial disease in a defined population.Circulation. 1985; 71: 510-515Crossref PubMed Scopus (934) Google Scholar]. Thus, PAD is the cardiovascular iceberg: underdiagnosed and undertreated. Urgent action to counteract this situation is needed. This new joint statement from the European Atherosclerosis Society (EAS) and European Society of Vascular Medicine (ESVM) is timely [[10]Belch J.J.F. Brodmann M. Baumgartner R. et al.European atherosclerosis society/European society of vascular medicine joint statement: lipid-lowering and anti-thrombotic therapy in patients with peripheral arterial disease.Eur. J. Vasc. Med. 8 November 2021; (Published simultaneously in Atherosclerosis and Vasa)https://www.atherosclerosis-journal.com/article/S0021-9150(21)01362-9/fulltextGoogle Scholar]. The mission is two-fold; to update the evidence for two of the major modifiable cardiovascular risk factors - dyslipidaemia and thrombotic factors - and by doing so, improve awareness and management for this debilitating and deadly condition. Despite previous controversy, there is now irrefutable evidence that elevated lipids are associated with increased cardiovascular risk in PAD. As for other phenotypes of atherosclerosis, apolipoprotein (apo)B-containing lipoproteins are important drivers of the clinical manifestations of this disease [[11]Boren J. Chapman M.J. Krauss R.M. et al.Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.Eur. Heart J. 2020; 41: 2313-2330Crossref PubMed Scopus (295) Google Scholar,[12]Nordestgaard B.G. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology.Circ. Res. 2016; 118: 547-563Crossref PubMed Scopus (429) Google Scholar]. The strongest evidence comes from genetics. For example, the Million Veteran Program (MVP), a genome-wide association study, showed that variants in genes encoding the low-density lipoprotein receptor (LDLR), lipoprotein lipase (LPL), and lipoprotein(a) (LPA), in addition to variants linked with either hypercholesterolaemia or hypertriglyceridaemia, associated with PAD [[13]Klarin D. Lynch J. Aragam K. et al.Genome-wide association study of peripheral artery disease in the Million Veteran Program.Nat. Med. 2019; 25: 1274-1279Crossref PubMed Scopus (62) Google Scholar]. Epidemiological studies are less conclusive in defining which of these apoB lipoproteins are key drivers of symptomatic PAD [[5]Tunstall-Pedoe H. Peters S.A.E. Woodward M. et al.Twenty-year predictors of peripheral arterial disease compared with coronary heart disease in the Scottish Heart Health Extended Cohort (SHHEC).J. Am. Heart. Assoc. 2017; 6e005967Crossref PubMed Scopus (43) Google Scholar]. Despite this, it should be emphasised that as low-density lipoprotein cholesterol (LDL-C) is causal for atherosclerotic cardiovascular disease [[11]Boren J. Chapman M.J. Krauss R.M. et al.Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.Eur. Heart J. 2020; 41: 2313-2330Crossref PubMed Scopus (295) Google Scholar,[14]Ference B.A. Ginsberg H.N. Graham I. et al.Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.Eur. Heart J. 2017; 38: 2459-2472Crossref PubMed Scopus (1215) Google Scholar], it should be the primary target when treating dyslipidaemia in patients with PAD. According to the 2019 European Society of Cardiology/EAS) dyslipidaemia guidelines, PAD is categorised as very high risk (≥10% risk of a fatal cardiovascular event over 10 years). Thus, the LDL-C goal is < 1.4 mmol/L (<55 mg/dL) and ≥50% reduction in LDL-C from baseline if pre-treatment values are 1.8–3.5 mmol/L (70–135 mg/dL) [[15]Mach F. Baigent C. Catapano A.L. et al.2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2020; 41: 111-188Crossref PubMed Scopus (2229) Google Scholar]. Lowering LDL-C is associated with ∼25% reduction in total cardiovascular events, ∼30% reduction in major adverse limb events such as amputation and graft occlusion/revascularization, as well as reduction in clinical endpoints that impact walking performance and contribute to the morbidity of PAD [[16]Aung P.P. Maxwell H.G. Jepson R.G. et al.Lipid-lowering for peripheral arterial disease of the lower limb.Cochrane Database Syst. Rev. 2007; https://doi.org/10.1002/14651858.CD000123.pub2:CD000123Crossref PubMed Google Scholar,[17]Pastori D. Farcomeni A. Milanese A. et al.Statins and major adverse limb events in patients with peripheral artery disease: a systematic review and meta-analysis.Thromb. Haemostasis. 2020; 120: 866-875Crossref PubMed Scopus (28) Google Scholar]. In clinical practice, however, most PAD patients do not attain these goals, and management is typically inferior to that for CAD patients [[18]Dopheide J.F. Papac L. Schindewolf M. et al.Poor attainment of lipid targets in patients with symptomatic peripheral artery disease.J. Clin. Lipidol. 2018; 12: 711-717Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. Urgent action is needed to improve the implementation of guideline-recommended LDL-C goals for PAD. This EAS/ESVM statement recommends statins as the primary lipid lowering therapy, with the combination of non-statin therapy, firstly ezetimibe, to attain LDL-C goal. A PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor may be added if LDL-C levels remain above goal (Table 1). These recommendations are supported by data from IMPROVE-IT (statin plus ezetimibe), and FOURIER and ODYSSEY OUTCOMES (statin plus a PCSK9 inhibitor) [19Bonaca M.P. Gutierrez J.A. Cannon C. et al.Polyvascular disease, type 2 diabetes, and long-term vascular risk: a secondary analysis of the IMPROVE-IT trial.Lance. Diabetes. Endocrinol. 2018; 6: 934-943Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 20Bonaca M.P. Nault P. Giugliano R.P. 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: 338-350Crossref PubMed Scopus (365) Google Scholar, 21Jukema J.W. Szarek M. Zijlstra L.E. et al.Alirocumab in patients with polyvascular disease and recent acute coronary syndrome: ODYSSEY OUTCOMES Trial.J. Am. Coll. Cardiol. 2019; 74: 1167-1176Crossref PubMed Scopus (91) Google Scholar]. Given their higher absolute risk, PAD patients gain greater absolute clinical benefit from intensification of LDL-C lowering with combination therapy versus statin monotherapy, both in terms of reductions in cardiovascular events and major adverse limb events [19Bonaca M.P. Gutierrez J.A. Cannon C. et al.Polyvascular disease, type 2 diabetes, and long-term vascular risk: a secondary analysis of the IMPROVE-IT trial.Lance. Diabetes. Endocrinol. 2018; 6: 934-943Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 20Bonaca M.P. Nault P. Giugliano R.P. 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: 338-350Crossref PubMed Scopus (365) Google Scholar, 21Jukema J.W. Szarek M. Zijlstra L.E. et al.Alirocumab in patients with polyvascular disease and recent acute coronary syndrome: ODYSSEY OUTCOMES Trial.J. Am. Coll. Cardiol. 2019; 74: 1167-1176Crossref PubMed Scopus (91) Google Scholar]. Indeed, FOURIER was the first randomized trial to show that the combination of a PCSK9 inhibitor and statin reduced major adverse limb events, including amputation, by 42% [[20]Bonaca M.P. Nault P. Giugliano R.P. 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: 338-350Crossref PubMed Scopus (365) Google Scholar].Table 1Key recommendations for managing peripheral arterial disease (PAD): the European Atherosclerosis Society/European Society of Vascular Medicine Task Force.Recommendation 1. Statins, at the highest tolerated dose, are indicated in patients with PAD for the prevention of cardiovascular events.Recommendation 2. Low-density lipoprotein cholesterol (LDL-C) should be lowered to <1.4 mmol/L (<55 mg/dL) and by ≥50% if pre-treatment values are 1.8–3.5 mmol/L (70–135 mg/dL).Recommendation 3. Combination treatment with a statin and ezetimibe may be considered to improve LDL-C goal attainment. This approach could allow better tolerance of a lower dose of statin in patients with statin side effects.Recommendation 4. A PCSK9 inhibitor should be added if LDL-C levels remain 50% higher than goal despite statin treatment, with or without ezetimibe.Recommendation 5. Antiplatelet therapy is indicated to prevent further cardiovascular events. This should be either clopidogrel 75 mg/day, or the combination of aspirin 100 mg/day and rivaroxaban (2 × 2.5 mg/day).Recommendation 6. Dual antiplatelet therapy (DAPT) should be given for at least one month after drug coated balloon angioplasty, and for 3 months after either drug eluting or covered stent implantation.Recommendation 7. Based on results from the VOYAGER study, combination therapy with aspirin (100 mg/day) and rivaroxaban (2 × 2.5 mg/day) should be considered for DAPT post-intervention. Open table in a new tab This statement also addresses the issue of statin associated muscle symptoms (often referred to as SAMS), which may be a particular clinical concern for PAD patients, impacting treatment adherence and discontinuation. The Task Force emphasises strategies to overcome SAMS, notably the use of a lower statin dose combined with a non-statin lipid-lowering therapy, to ensure that PAD patients remain on treatment and attain LDL-C goal (Table 1). With this approach, the risk of these adverse effects is outweighed by the significant clinical benefit from reduction in cardiovascular and limb adverse events. While much of the focus of this statement is on management of dyslipidaemia, recommendations for antithrombotic therapy are also discussed. These largely derive from major prospective studies which support the benefit of dual antiplatelet therapy to prevent cardiovascular events, as well as adverse limb events following lower-extremity revascularization (Table 1). Notably, the COMPASS trial in patients with stable CAD or PAD showed that dual therapy with rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily reduced major adverse limb events including amputation by 46% [[23]Anand S.S. Caron F. Eikelboom J.W. et al.Major adverse limb events and mortality in patients with peripheral artery disease: the COMPASS Trial.J. Am. Coll. Cardiol. 2018; 71: 2306-2315Crossref PubMed Scopus (193) Google Scholar]. The Task Force did acknowledge a small increased bleeding risk from thrombotic therapy, as shown in both the COMPASS and the VOYAGER PAD trials in patients undergoing lower-extremity revascularization [22Eikelboom J.W. Connolly S.J. Bosch J. et al.Rivaroxaban with or without aspirin in stable cardiovascular disease.N. Engl. J. Med. 2017; 377: 1319-1330Crossref PubMed Scopus (1209) Google Scholar, 23Anand S.S. Caron F. Eikelboom J.W. et al.Major adverse limb events and mortality in patients with peripheral artery disease: the COMPASS Trial.J. Am. Coll. Cardiol. 2018; 71: 2306-2315Crossref PubMed Scopus (193) Google Scholar, 24Bonaca M.P. Bauersachs R.M. Anand S.S. et al.Rivaroxaban in peripheral artery disease after revascularization.N. Engl. J. Med. 2020; 382: 1994-2004Crossref PubMed Scopus (238) Google Scholar]. In their recommendations, they advocate weighing the clinical benefit from reduction in major adverse cardiovascular and limb events, including acute limb ischaemia and amputation, versus any potential bleeding risk for individual patients. This joint statement from the EAS and the ESVM provides clinical guidance for the management of dyslipidaemia and thrombotic factors in patients with PAD. Importantly, both PCSK9 inhibitors and rivaroxaban were shown to reduce major adverse limb events, including amputation. Finally, this new guidance is another example of how collaboration between academic societies can help in achieving the United Nations Sustainable Development 2030 Agenda [[25]Parini P. Frikke-Schmidt R. Tselepis A.D. et al.Taking action: European atherosclerosis society targets the united Nations sustainable development goals 2030 agenda to fight atherosclerotic cardiovascular disease in europe.Atherosclerosis. 2021; 322: 77-81Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. Education and the use of SMART health tools are essential to translate these recommendations to clinical practice, and ultimately, improve the appalling prognosis of PAD patients.