A continuous publication, open access, peer-reviewed journal ACCESS ONLINE REVIEW Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial José Luis Hernández MD, PhD1, Francisco S Lozano MD, PhD2 , Vincent Riambau MD, PhD3, Manuel Almendro-Delia MD, PhD4, Juan Cosín-Sales MD, PhD5, Sergi Bellmunt-Montoya MD, PhD6, Javier Garcia-Alegria MD, PhD7, Xavier Garcia-Moll MD, FESC, FACC8, Juan José Gomez-Doblas MD, PhD9, José R Gonzalez-Juanatey MD, PhD10, Carmen Suarez Fernández MD11 1Internal Medicine Department, Hospital Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Santander, Spain; 2Department of Vascular Surgery, Hospital Clínico de Salamanca, Salamanca, Spain; 3Vascular Surgery Division, CardioVascular Institute Hospital Clinic University of Barcelona, Barcelona, Spain; 4Intensive Cardiovascular Care Unit, Cardiovascular Clinical Trials & Translational Research Unit, Cardiology and Cardiovascular Surgery Division, Virgen Macarena University Hospital, Seville, Spain; 5Cardiology Department, Hospital Arnau de Vilanova. Facultad de Medicina, Universidad CEU-Cardenal Herrena, Valencia, Spain; 6Vascular Surgery Department, Universitari Hospital Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; 7Department of Medicine, Hospital Costa del Sol, Marbella, Spain; 8Cardiology Department, Hospital Sant Pau, Barcelona, Spain; 9Cardiology Department, Hospital Universitario Virgen de la Victoria, CIBERCV, Malaga, Spain; 10Cardiology and Intensive Cardiac Care Department, University Hospital Santiago de Compostela, CIBERCV, Santiago de Compostela, Spain; 11Internal Medicine Department, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain Abstract and limb outcomes, and related complications, with a good Patients with peripheral artery disease (PAD) are at a high risk safety profile. In fact, the net clinical benefit outcome composed not only for the classical cardiovascular (CV) outcomes (major of MACE; MALE, including major amputation, and fatal or critical adverse cardiovascular events; MACE) but also for vascular organ bleeding was significantly reduced by 28% with the limb events (major adverse limb events; MALE). Therefore, a COMPASS strategy, (hazard ratio: 0.72; 95% confidence interval: comprehensive approach for these patients should include both 0.59–0.87). Therefore, the rivaroxaban plus aspirin approach goals. However, the traditional antithrombotic approach with provides comprehensive protection and should be considered only antiplatelet agents (single or dual antiplatelet therapy) for most patients with PAD at high risk of such events. does not sufficiently reduce the risk of recurrent thrombotic Keywords: COMPASS, peripheral artery disease, residual risk, events. Importantly, the underlying cause of atherosclerosis rivaroxaban. in patients with PAD implies both platelet activation and the initiation and promotion of coagulation cascade, in which Citation Factor Xa plays a key role. Therefore, to reduce residual Hernández JL, Lozano FS, Riambau V, Almendro-Delia M, Cosín- vascular risk, it is necessary to address both targets. In the Sales J, Bellmunt-Montoya S, Garcia-Alegria J, Garcia-Moll X, Cardiovascular Outcomes for People Using Anticoagulation Gomez-Doblas JJ, Gonzalez-Juanatey JR, Suarez Fernández C. Strategies (COMPASS) trial that included patients with stable Reducing residual thrombotic risk in patients with peripheral atherosclerotic vascular disease, the rivaroxaban plus aspirin artery disease: impact of the COMPASS trial. Drugs in Context strategy (versus aspirin) markedly reduced the risk of both CV 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 Introduction cross-sectional analysis of 1568 subjects, aged 45–74 years, the prevalence of PAD was 3.8%.5 In the MERITO study, the Peripheral artery disease (PAD) is very common in clinical prevalence of PAD evaluated by the ankle–brachial index in practice, although underdiagnosed.1,2 It has been estimated patients with metabolic syndrome was 28% and in patients that more than 200 million people worldwide are affected with a previous coronary event, cerebrovascular disease, or by lower extremity PAD.3 The prevalence of PAD markedly both, it was 34, 32, and 54%, respectively.6,7 increases with age, from approximately 5% in patients aged 45–49 years to around 10% in patients aged 65–74 In addition, it is expected that these numbers will increase in years and nearly 20% by the age of 80 years.3,4 In Spain, in a the following years due to the aging of the population and Hernández JL, Lozano FS, Riambau V, et al. Drugs in Context 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 1 of 15 ISSN: 1740-4398 REVIEW – Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial drugsincontext.com the increased rates of diabetes, hypertension, and smoking.3 with PAD than in patients with CAD.12 On the other hand, in Importantly, the majority of patients with PAD do not refer patients with asymptomatic carotid stenosis, approximately specific symptoms. Thus, according to different studies, up to two-thirds of late deaths are related to cardiac events, with an one-third of patients with an ankle–brachial index <0.90 have annual mortality rate of 2.9%.18 typical intermittent claudication.4,8,9 Patients with PAD are not only at high risk of MACE, but also Atherosclerotic disease is the underlying cause of PAD.1,2 As of major adverse limb events (MALE), including severe limb atherosclerosis is often generalized, patients with PAD have ischemia and amputation.19 Thus, it has been calculated that usually more vascular beds affected. Thus, in the Reduction of the annual incidence of major amputation ranges between 120 Atherothrombosis for Continued Health (REACH) registry, 61.5% and 500 per million, and in Western Europe, the PAD-related of patients with PAD had concomitant disease in other vascular mortality reached 3.5 per 100,000 individuals (excluding beds (versus 24.7% of patients with coronary artery disease stroke and myocardial infarction) in 2010, and the years of [CAD]).10 Patients with polyvascular disease have an increased life lost due to PAD were estimated at 31.7 years per 100,000 risk of morbidity and mortality, being greater as a higher inhabitants.1,20,21 Therefore, in patients with PAD, it is not only number of vascular beds are affected.11–14 mandatory to reduce MACE, but also MALE. Patients with symptomatic or asymptomatic PAD have In a specific substudy of the Cardiovascular Outcomes for an increased risk of cardiovascular (CV) death, myocardial People Using Anticoagulation Strategies (COMPASS) trial, which infarction, and stroke (major adverse cardiovascular events; analyzed the impact of MALE on the prognosis of patients with MACE).15 Compared with patients without PAD, the risk of CV lower extremity PAD, showed that after MALE, death is increased among patients with asymptomatic and the 1-year cumulative risk of subsequent hospitalization, symptomatic PAD, by 5 and 11%, respectively.16 In addition, vascular amputations, death, and MACE were 61.5; 20.5; 8.3; approximately one-fifth of patients with symptomatic PAD and 3.7%, respectively. Importantly, experiencing MALE have myocardial infarction, and around 10–15% die after a dramatically increased the risk of subsequent amputations 5-year period of follow-up.17 Of the one hand, the risk of CV (hazard ratio [HR]: 197.5; p<0.0001), and death (HR: 3.23; death, myocardial infarction, or stroke is even higher in patients p<0.001) (Figure 1).22 Figure 1. Outcomes in patients before and after MALE in the COMPASS study.22 HR 7.56; 95% CI 5.14–11.12; P <0.0001 26.0 HR 197.5; 95% CI 97.33–400.8; P <0.0001 22.0 Incidence Rate per 100 Person-years HR 3.23; 95% CI 1.87–5.56; P <0.0001 10.5 HR 1.52; 95% CI 0.72–3.24; P=0.27 5.4 3.4 3.6 3.1 0.1 MACE Total vascular MACE + total vascular All-cause mortality amputation amputation Before MALE After MALE MACE: cardiovascular death, myocardial infarction, stroke. Hernández JL, Lozano FS, Riambau V, et al. Drugs in Context 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 2 of 15 ISSN: 1740-4398 REVIEW – Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial drugsincontext.com As a result, PAD is a very common condition in routine insufficient to effectively reduce not only MACE but also MALE practice, with very high rates of MACE and MALE. Reducing in PAD patients.31,32 In addition, the 2017 European guidelines both and the related complications with the appropriate recognize that the results of the COMPASS trial were not prophylaxis is mandatory. In this narrative review, data about included at the time of publication but should be updated after how to reduce residual risk through the best antithrombotic a critical analysis.1 approach among patients with PAD, with a particular focus Thus, the evidence supporting the use of aspirin or clopidogrel on the COMPASS trial, are updated in order to provide some to prevent MACE in PAD patients remains insufficient. In a practical recommendations about its use in this population. For meta-analysis of 18 clinical trials involving 5269 individuals this purpose, a search was performed (up to March 2020) on with PAD, treatment with aspirin alone resulted in a statistically PubMed (MEDLINE), using the MeSH terms [peripheral artery nonsignificant reduction in MACE, and only a significant disease] + [COMPASS] + [rivaroxaban] + [treatment]. Original decrease in nonfatal stroke (Table 1).33 In another meta- data from clinical trials, prospective and retrospective studies, analysis of 287 studies, aspirin reduced the risk of MACE among and more useful reviews were selected. patients with atherosclerotic vascular disease, including those with PAD.34 In patients with symptomatic PAD and no history Antithrombotic treatment in of stroke/transient ischemic attack included in the REACH registry, despite 61% of patients treated with aspirin and 83% patients with PAD with at least one antiplatelet agent, MACE rates reached 4.7% during the first year and increased continuously by 4–5% per Progressive atherosclerosis is the underlying cause of PAD and year; the limb ischemic event rate was 5.7% at 2 years.35 In the results in a spectrum of symptoms that, in the case of lower Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events extremity PAD, ranges from asymptomatic to intermittent (CAPRIE) trial, among 19,185 patients with atherosclerotic claudication, ischemic rest pain, and major and minor trophic vascular disease, including recent ischemic stroke, recent changes. On the other hand, acute limb ischemia (ALI) is caused myocardial infarction, or symptomatic PAD, after a mean by native atherosclerotic plaque disruption and thrombus follow-up of 1.91 years, compared with aspirin, clopidogrel formation, and in the case of patients previously revascularized, significantly reduced the risk of MACE, including the subgroup thrombosis of the stent or graft.1,2,20,23 After atherosclerotic of patients with PAD (Table 1).36 In the Clopidogrel for High plaque disruption, the thrombogenic subendothelial matrix Atherothrombotic Risk and Ischemic Stabilization, Management is exposed to circulating blood, leading to activation of and Avoidance (CHARISMA) study, in the subgroup of circulating platelets and the coagulation cascade and lastly to patients with prior myocardial infarction, ischemic stroke, or thrombus formation.24–28 As a result, to reduce CV outcomes symptomatic PAD, while the combination of clopidogrel plus and the risk of PAD-related complications, it is necessary not aspirin (versus aspirin alone) significantly reduced the risk of only to control CV risk factors, but also follow a comprehensive MACE by 17%, there was a nonsignificant reduction of 13% antithrombotic approach that includes not only acting on in the PAD subpopulation. No reduction of mortality was platelets but also on coagulation inhibition.29 observed. Moderate bleeding, but not severe bleeding, was With regard to antithrombotic therapy, in patients with lower more common with the combination (Table 1).37 extremity PAD, the European guidelines recommend the use of This limited efficacy of antiplatelet agents in patients with PAD long-term single antiplatelet therapy in symptomatic patients has not only been limited to the traditional antiplatelet agents, (recommendation I A) and in all patients who have undergone such as aspirin or clopidogrel, but also with the newer ones. revascularization (recommendation I C). Furthermore, The Trial to Assess the Effects of Vorapaxar in Preventing Heart clopidogrel may be preferred over aspirin (recommendation Attack and Stroke in Patients with Atherosclerosis–Thrombolysis IIb B). In addition, dual antiplatelet therapy with aspirin and in Myocardial Infarction 50 (TRA 2P–TIMI 50) study compared clopidogrel for at least 1 month should be considered after vorapaxar plus aspirin versus aspirin in patients with chronic infra-inguinal stent implantation (recommendation IIa C) and atherosclerotic vascular disease. In the subgroup of 3787 may be considered in below-the-knee bypass with a prosthetic patients with chronic symptomatic PAD, vorapaxar did not graft (recommendation IIb B). Importantly, antiplatelet therapy reduce the risk of MACE, but significantly reduced the rates of is not routinely indicated in patients with asymptomatic PAD hospitalization for ALI and peripheral artery revascularization (recommendation III A).1 On the other hand, long-term single by 42 and 16%, respectively. Major bleeding was more common antiplatelet therapy is also recommended in patients with with the combination (Table 1).38 Ticagrelor, 90 mg, twice daily symptomatic carotid stenosis (recommendation I A), and dual was compared with clopidogrel, 75 mg, once daily in 13,885 antiplatelet therapy with aspirin and clopidogrel for at least patients with symptomatic PAD in the Effects of Ticagrelor and 1 month after carotid artery stenting (recommendation I B).1 Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) Despite these indications, patients with PAD treated with trial. After a median follow-up of 30 months, rates of MACE, current evidence-based recommended care have an ALI, CV death, and major bleeding were similar between both unacceptably high residual CV risk.29,30 This is not surprising as groups (Table 1).39 In the Prevention of Cardiovascular Events in the current only antiplatelet-based antithrombotic approach is Patients with Prior Heart Attack Using Ticagrelor Compared to Hernández JL, Lozano FS, Riambau V, et al. Drugs in Context 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 3 of 15 ISSN: 1740-4398 Table 1. Efficacy and safety of antithrombotic treatment in patients with peripheral artery disease.33,36–41 Study Treatment Study population Results ISSN: 1740-4398 Berger, et al33 Aspirin versus Meta-analysis of randomized • CV death: RR: 0.94; 95% CI: 0.74–1.19; p=0.59 • CV death: No control trials (5269 patients with PAD) • Nonfatal myocardial infarction: RR: 1.04; 95% CI: 0.78–1.39; • Myocardial infarction: No p=0.81 • Stroke: Yes • Non-fatal stroke: RR: 0.66; 95% CI: 0.47–0.94; p=0.02 • MACE: No • MACE: RR: 0.88; 95% CI: 0.76–1.04; p=0.13 CAPRIE36 Clopidogrel 19,185 patients with • MACE: • MACE: Yes versus aspirin atherosclerotic vascular Overall population: RR:R 8.7%; 95% CI: 0.3–16.5%; p=0.043 disease (ischemic stroke, PAD population: RR: 23.8%; 95% CI: 8.9–36.2%; =0.0028 recent myocardial infarction, or symptomatic PAD) CHARISMA37 Clopidogrel + 9478 patients with documented • MACE: • MACE: No aspirin versus prior MI, ischemic stroke, or Overall population with CV atherosclerotic disease: HR: • Mortality: No aspirin symptomatic PAD 0.83; 95% CI: 0.72–0.96; p=0.01 PAD population: HR: 0.87; 95% CI: 0.67–1.13; p=0.29 • All-cause mortality: HR: 0.91; 95% CI: 0.77–1.09; p=0.32 • CV mortality: HR: 0.87; 95% CI: 0.70–1.09; p=0.22 • Severe bleeding: HR: 1.12; 95% CI: 0.81–1.53; p=0.51 • Moderate bleeding: HR: 1.60; 95% CI: 1.16–2.20, p=0.004 TRA 2P–TIMI 5038 Vorapaxar 3787 patients with a history • MACE: HR: 0.94; 95% CI: 0.78–1.14; p=0.53 • MACE: No +aspirin versus of claudication and an ankle– • Hospitalization for ALI: HR: 0.58; 95% CI: 0.39–0.86; p=0.006 • Hospitalization for ALI: Yes Hernández JL, Lozano FS, Riambau V, et al. Drugs in Context 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 aspirin brachial index of <0.85 or • Hospitalization for artery revascularization: HR: 0.84; 95% prior revascularization for limb CI: 0.73–0.97; p=0.017 ischemia • Major bleeding: HR: 1.62; 95% CI: 1.21–2.18; p=0.001 REVIEW – Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial EUCLID39 Ticagrelor (90 13,885 patients with symptomatic • MACE: HR: 1.02; 95% CI: 0.92–1.13; p=0.65 • MACE: No mg) versus PAD • ALI: HR: 1.03; 95% CI: 0.79–1.33; p=0.85 • ALI: No clopidogrel • CV death: HR: 1.07; 95% CI: 0.92–1.23; p=0.40 • CV death: No • Major bleeding: HR: 1.10; 95% CI: 0.84–1.43; p=0.49 4 of 15 drugsincontext.com (Continued) Table 1. (Continued) Study Treatment Study population Results ISSN: 1740-4398 PEGASUS–TIMI Ticagrelor, 60/90 1143 patients with PAD and prior • MACE: Ticagrelor 90 mg: 5440 mg, + aspirin myocardial infarction (1–3 years) Ticagrelor, 90 mg: HR: 0.81; 95% CI: 0.57–1.15; p=0.24 • MACE: No versus aspirin Ticagrelor, 60 mg: HR: 0.69; 95% CI: 0.47–0.99; p=0.045 • MALE: Yes • MALE: • Ischemic stroke: No Ticagrelor, 90 mg: HR: 0.49; 95% CI: 0.30–0.81; p=0.005 • CV death: No Ticagrelor, 60 mg: HR: 0.81; 95% CI: 0.53–1.24; p=0.33 • Ischemic stroke: Ticagrelor, 60 mg: Ticagrelor, 90 mg: HR: 0.47; 95% CI: 0.19–1.14; p=0.095 • MACE: Yes Ticagrelor, 60 mg: HR: 0.52; 95% CI: 0.22–1.22; p=0.13 • MALE: No • CV death: Ticagrelor, 90 mg: HR: 0.83; 95% CI: 0.50–1.38; p=0.46 • Ischemic stroke: No Ticagrelor, 60 mg: HR: 0.47; 95% CI: 0.25–0.86; p=0.014 • CV death: Yes • Major bleeding: Ticagrelor, 90 mg: HR: 1.46; 95% CI: 0.39–5.43; p=0.57 Ticagrelor, 60 mg: HR: 1.18; 95% CI: 0.29–4.70; p=0.82 COMPASS41 Rivaroxaban, 2.5 7470 patients with chronic PAD • MACE: HR: 0.72; 95% CI: 0.57–0.90; p=0.0047 • MACE: Yes mg, + aspirin • Stroke: HR: 0.54; 95% CI: 0.33–0.87 • Stroke: Yes versus aspirin • CV death: HR: 0.82; 95% CI: 0.59–1.14 • CV death: No • MALE: HR:: 0.54; 95% CI: 0.35–0.84; p=0.0054 • MALE: Yes • All vascular amputations: HR: 0.40; 95% CI: 0.20–0.79; • All vascular amputations: p=0.0069 Yes Hernández JL, Lozano FS, Riambau V, et al. Drugs in Context 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 • Major amputation: HR: 0.30; 95% CI: 0.11–0.80; p=0.011 • Major amputation: Yes • Major bleeding: HR: 1.61; 95% CI: 1.12–2.31; p=0.0089 • Fatal bleeding or symptomatic bleeding into a critical organ: HR: 1.10; 95% CI: 0.59–2.05 REVIEW – Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial • Fatal or symptomatic bleeding into a critical organ or surgical site bleeding leading to re-operation: HR: 1.13; 95% CI: 0.64–2.01 • Net clinical benefit: HR: 0.72; 95% CI: 0.59–0.87; p=0.0008 ALI, acute limb ischemia; CV, cardiovascular;, PAD, peripheral artery disease; MACE: CV death, myocardial infarction, or stroke; MALE, major adverse limb event. 5 of 15 drugsincontext.com REVIEW – Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial drugsincontext.com Placebo on a Background of Aspirin–Thrombolysis in Myocardial CI: 0.66–0.86; p<0.001). This beneficial effect was independent Infarction 54 (PEGASUS–TIMI 54) trial, 21,162 patients with prior of the presence of PAD (p for interaction was 0.61). The risk of myocardial infarction (1–3 years) were randomized to receive ischemic stroke, myocardial infarction, ALI, or death from CAD ticagrelor, 90 mg, twice daily plus aspirin and ticagrelor, 60 was also reduced by 28% with the combination (HR: 0.72; 95% mg, twice daily plus aspirin or placebo plus aspirin. Compared CI: 0.63–0.83; p<0.001), and also the risk of MACE or ALI by 26% with aspirin in monotherapy, the combination of ticagrelor, 90 (HR: 0.74; 95% CI: 0.65–0.85; p<0.001). The risk of stroke and mg, and aspirin did not significantly reduce the risk of MACE, hospitalization for CV causes was also significantly reduced by ischemic stroke, or CV death, but significantly reduced the risk the rivaroxaban plus aspirin approach. But more importantly, of MALE by 51%. By contrast, ticagrelor, 60 mg, plus aspirin there was a trend toward a lower risk of both CV death and significantly reduced the risk of MACE and CV deaths by 31 and death from any cause with the combination of rivaroxaban 53%, respectively, but not the risk of MALE or ischemic stroke plus aspirin compared with aspirin. Although the risk of major (Table 1).40 All these data clearly indicate that treating PAD bleeding was increased with the combination (HR: 1.70; 95% patients with antiplatelets (single or dual antiplatelet therapy) CI: 1.40–2.05; p<0.001), the risk of fatal bleeding or intracranial does not provide a comprehensive approach with the double bleeding did not significantly differ between the groups.54 target of reducing MACE and MALE.41 Importantly, while there was an absolute risk reduction of 0.5% On the other hand, full anticoagulation with vitamin K in CV death between aspirin alone and the rivaroxaban plus antagonists has not been shown to provide further protection aspirin approach (from 2.2 to 1.7%; p=0.02) and an absolute risk compared with single antiplatelet therapy in patients with reduction of 0.7% in death from any cause (from 4.1 to 3.4%; PAD.42,43 p=0.01), there was a nonsignificant absolute increase of 0.1% in fatal bleeding (from 0.1 to 0.2%; p=0.32), without any difference Finding an antithrombotic regimen that targets both platelet in the risk of nonfatal symptomatic intracranial hemorrhage and anticoagulation cascade activation may be more effective (0.2% in both groups; p=0.77).54 In summary, in patients with in preventing MACE and MALE in patients with PAD.25,26,44–47 chronic atherosclerotic vascular disease, the beneficial effect of In addition, experimental data have shown that the inhibition the combination of rivaroxaban plus aspirin on MACE is much of Factor Xa decreases inflammation and platelet-dependent higher than the possible increase in bleeding risk. thrombin generation; attenuates neointima formation after vascular injury; has protective, repairing, and fibrinolytic effects on vascular endothelium; and stabilizes atherosclerotic plaque and reduces its progression. Of note, most of these positive Efficacy and safety of the vascular data on experimental models have been obtained specifically dose of rivaroxaban in patients with rivaroxaban.48–52 All these data strongly suggest that an inhibition of Factor Xa, as rivaroxaban, could exert a positive with established PAD impact on patients with PAD. This hypothesis has been tested The COMPASS substudy included a total of 7470 patients with in the COMPASS study. PAD. The definitions of PAD, according to the COMPASS criteria, are summarized in Table 2. Briefly, to be included, patients The COMPASS study was a double-blind superiority trial that should have a history of PAD of the lower extremities (previous included a total of 27,395 subjects with chronic atherosclerotic revascularization, amputation, or intermittent claudication), of vascular disease (CAD or PAD). Patients were randomly allocated the carotid arteries (previous revascularization or asymptomatic to receive rivaroxaban, 2.5 mg, twice daily combined with ≥50% carotid artery stenosis), or patients with ischemic heart aspirin, 100 mg, once daily, rivaroxaban, 5 mg, twice daily or disease and an ankle–brachial index <0.90. Although all these aspirin, 100 mg, once daily. At baseline, mean age was 68 years, patients were included according to PAD criteria, there were 91% of patients had CAD (62% previous myocardial infarction; relevant differences in the clinical profile of these subgroups 73% only CAD; 18% CAD and PAD), and 27% had PAD (9% only of patients. With regard to the exclusion criteria, patients who PAD). The study was prematurely stopped due to the beneficial required dual antiplatelet therapy for any clinical condition effects found with rivaroxaban, 2.5 mg, twice daily (vascular or with a high risk of bleeding were excluded from the study dose of rivaroxaban) plus aspirin over aspirin after a mean (Table 2).41,53 follow-up of only 23 months.53,54 This is very relevant as the Kaplan–Meier survival curves between rivaroxaban plus aspirin Mean age of patients with PAD was 68 years, 81% had and aspirin alone separated over time, mainly after the first symptomatic PAD, 55% symptomatic PAD of lower extremities, year of treatment, but the excess of bleeding risk dramatically 26% previous carotid revascularization or ≥50% carotid stenosis, fell after 1 year of therapy.53,54 As a result, compared with the 20% CAD and an ankle–brachial index <0.90, and 4.5% prior traditional approach of aspirin alone in patients with chronic limb or foot amputation. In addition, 66% of patients with PAD atherosclerotic vascular disease, the net clinical benefit of the had concomitant CAD and 28% renal insufficiency (Table 3).41 rivaroxaban plus aspirin approach increases over time. Among PAD patients, compared with aspirin, the rivaroxaban Overall, compared with aspirin, the rivaroxaban plus aspirin plus aspirin approach significantly reduced the risk of MACE combination reduced the risk of MACE by 24% (HR: 0.76; 95% by 28%; the risk of ischemic heart disease death, myocardial Hernández JL, Lozano FS, Riambau V, et al. Drugs in Context 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 6 of 15 ISSN: 1740-4398 REVIEW – Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial drugsincontext.com Table 2. Definition of peripheral artery disease and main exclusion criteria in the COMPASS trial.41,53 • Definition of PAD (any of the following): • Main exclusion criteria: Previous aortofemoral or limb bypass surgery, or high risk of bleeding percutaneous transluminal angioplasty revascularization stroke ≤30 days or any history of hemorrhagic or of the iliac/infrainguinal arteries, or lacunar stroke Previous limb/foot amputation due to arterial vascular severe heart failure (LVEF< 30% or NYHA class III or IV) disease, or eGFR < 15 mL/min History of intermittent claudication and ≥1 of the need for dual antiplatelet therapy, or anticoagulation. following: • an ankle/arm blood pressure ratio <0.90 • significant peripheral artery stenosis (≥50%) (detected by angiography or duplex ultrasound) • previous carotid revascularization or asymptomatic carotid artery stenosis ≥50% (detected by duplex ultrasound or angiography). eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PAD, peripheral artery disease. Table 3. Baseline clinical characteristics of patients with peripheral artery disease (lower extremities or carotid) included in the COMPASS trial.41 Total population Patients with PAD (n) 7470 Symptomatic PAD of the lower extremities (n) 4129 Previous carotid revascularization or carotid stenosis ≥50% (n) 1919 CAD who had an ABI <0.90 (n) 1422 Biodemographic data Mean age, years 68 Men (%) 71 Cardiovascular risk factors Hypertension (%) 80 Diabetes (%) 44 Smoking status (%) Current 27 Former 46 Never 27 Vascular disease CAD (%) 66 Renal insufficiency (%) 28 Previous stroke (%) 7 Concomitant medications Antiplatelets (%) 87 Lipid-lowering drugs (%) 83 Renin–angiotensin system inhibitors (%) 70 ABI, ankle–brachial index; CAD, coronary artery disease; PAD, peripheral artery disease. Hernández JL, Lozano FS, Riambau V, et al. Drugs in Context 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 7 of 15 ISSN: 1740-4398 REVIEW – Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial drugsincontext.com infarction, ischemic stroke, and ALI by 32%; the risk of CV death, Major bleeding occurred more frequently with the combined myocardial infarction, ischemic stroke, and ALI by 29%; and the therapy than with aspirin alone (3 versus 2%; HR: 1.61; 95% risk of MACE plus MALE by 31% (HR: 0.69; 95% CI: 0.56–0.85; CI: 1.12–2.31; p=0.0089), mainly gastrointestinal. Importantly, p=0.0004). In addition, the risk of stroke was significantly fatal bleeding and non-fatal symptomatic intracranial reduced by the combination of rivaroxaban plus aspirin (HR: hemorrhage occurred in less than 1% of patients, regardless of 0.54; 95% CI: 0.33–0.87), and there was a trend toward a lower the assigned group (Figure 2).41 risk of CV death (HR: 0.82; 95% CI: 0.59–1.14) and death for any As a result, while the proportion of patients with MACE plus cause (HR: 0.91; 95% CI: 0.72–1.16) (Figure 2).41 Of note, the MALE decreased from 9 to 6% and the risk of death from 6 effects of low-dose rivaroxaban plus aspirin versus aspirin alone to 5% with the combined therapy, the risk of fatal bleeding on the combined outcome of MACE and MALE including major was <1% in both groups (Figure 2). In addition, the net clinical amputation were consistent regardless the presence of CAD (p benefit outcome composed of MACE, MALE, including major for interaction was 0.33).41 amputation, and fatal or critical organ bleeding was reduced Compared with the traditional approach of aspirin alone, the by 28% with the rivaroxaban plus aspirin strategy compared to combination of rivaroxaban plus aspirin markedly reduced the aspirin alone (HR: 0.72; 95% CI: 0.59–0.87; p=0.0008). As a result, prespecified limb outcomes. Thus, the rivaroxaban plus aspirin during a 21-month period, for every 1000 patients treated with approach significantly reduced the risk of ALI by 44%, the risk of the COMPASS strategy, 27 events of MACE or MALE, including MALE by 46%, the risk of all vascular amputations by 60%, and major amputation, would be prevented, but 1 fatal and 1 the risk of major amputations by 70% (Figure 3).41 critical organ hemorrhage would occur.41 Figure 2. Effects of treatment on MACE, MACE or MALE including major amputation, MACE plus acute limb ischemia, death and fatal bleeding in patients with chronic peripheral artery disease from the COMPASS study.41 HR 0.69; 95% CI 0.56–0.85; HR 0.72; 95% CI 0.59–0.87; P=0.0004 P=0.0008 9% 9% HR 0.71; 95% CI 0.57–0.88; P=0.0019 8% HR 0.72; 95% CI 0.57–0.90; P=0.0047 7% 7% HR 0.91; 95% CI 0.72–1,16 6% 6% 6% 5% 5% <1% <1% MACE MACE or MALE MACE1 + ALI Death Fatal bleeding Net clinical benefit including major amputation Low-dose rivaroxaban + aspirin Aspirin alone MACE: Cardiovascular death, myocardial infarction, MACE1: Cardiovascular death, myocardial infarction, ischemic stroke; MALE: major adverse limb event; ALI: acute limb ischemia. Hernández JL, Lozano FS, Riambau V, et al. Drugs in Context 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 8 of 15 ISSN: 1740-4398 REVIEW – Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial drugsincontext.com Figure 3. Effects of treatment on prespecified limb outcomes in patients with chronic peripheral artery disease from the COMPASS study.41 ALI Chronic limb ischemia MALE All vascular amputations Major amputation –33% HR 0.67; 95% CI 0.35–1.26; P=0.21 –44% HR 0.56; 95% CI 0.32–0.99; –46% P=0.042 HR 0.54; 95% CI 0.35–0.84; P=0.0054 –60% HR 0.40; 95% CI 0.20–0.79; P=0.0069 –70% HR 0.30; 95% CI 0.11–0.80; P=0.0011 ALI: acute limb ischemia; MALE: Major adverse limb event Beneficial effects of the vascular Approximately one-third of patients with symptomatic PAD have heart failure (HF).59 In fact, the risk of HF is doubled in dose of rivaroxaban in patients patients with PAD60 or even more in elderly patients.61 In with established PAD and other the COMPASS trial, although patients with severe HF were excluded from the study, 22% of patients had a history of clinical conditions mild-to-moderate HF. In the COMPASS trial, in patients with Many patients with PAD have other vascular beds affected, chronic ischemic heart disease or PAD and a history of mild thus increasing the risk of CV morbidity and mortality.10–14 or moderate HF, the rivaroxaban plus aspirin approach (versus In the COMPASS trial, two-thirds of patients with PAD had aspirin) resulted in a similar relative but higher absolute risk concomitant CAD,41 and among patients with CAD, 20% of reduction in MACE and mortality compared to those patients patients had also PAD, defined according to COMPASS inclusion without HF, with a similar excess hazard for major bleeding, criteria.55 In those patients with ischemic heart disease, the independently of the presence of HF.62 presence of PAD did not modify the effects of the rivaroxaban plus aspirin approach on the primary outcome (p for interaction Discussion was 0.37), major bleeding (p for interaction was 0.46), and net Patients with PAD are at a very high risk of both MACE and clinical benefit (p for interaction 0.24).55 MALE, and treatment should be necessarily focused on both Chronic kidney disease increases both the risk of bleeding and targets.19,63,64 Thus, although CV death is the main cause of MACE.56,57 In the COMPASS study, rates of MACE and major mortality in this population,15–17 it should not be forgotten that bleeding were more common in those patients with renal in patients with PAD who experience MALE, the risk of death insufficiency than in those individuals with normal function. increases by 3 and the risk of subsequent vascular amputation Importantly, while the beneficial effect of the rivaroxaban plus by 200.22 The traditional approach with antiplatelet treatment aspirin approach over aspirin on MACE was independent of with a single or dual antiplatelet therapy has failed in providing renal function, there was no excess hazard of major bleeding.58 complete protection of patients with PAD. For example, in the Hernández JL, Lozano FS, Riambau V, et al. Drugs in Context 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 9 of 15 ISSN: 1740-4398 REVIEW – Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial drugsincontext.com PEGASUS–TIMI 54 study, while ticagrelor, 60 mg, reduced the risk intracranial bleeding (<1%), the reduction in the risk of these of MACE, no beneficial effect was obtained on limb outcomes.40 outcomes by the combination of rivaroxaban plus aspirin was In the CHARISMA trial, the combination of clopidogrel plus greater than the possible risk of fatal or intracranial bleeding. aspirin did not reduce the risk of MACE compared with In addition, most of the major bleedings had a gastrointestinal aspirin in monotherapy.36 Full anticoagulation with vitamin K origin and rarely are fatal or leave permanent sequelae.41 In antagonists has not been shown to provide further protection addition, compared with aspirin alone, the risk of major bleeding over antiplatelet therapy in PAD patients.42,43 By contrast, was increased with the rivaroxaban plus aspirin approach only the COMPASS trial demonstrated in the PAD population that during the first year of treatment, but not during the following compared with aspirin, 100 mg, once daily in monotherapy, years.55 Therefore, the concern about the risk of bleeding should the rivaroxaban, 2.5 mg, twice daily plus aspirin, 100 mg, once not be to avoid the use of the combination of the vascular dose daily approach significantly reduced the risk of MACE by 28% of rivaroxaban plus aspirin in patients with PAD at high risk and the risk of MALE by 46%. Even more, the combination of of MACE or MALE. However, it should be emphasized that as vascular doses of rivaroxaban (2.5 mg twice daily) plus aspirin these data are provided from post-hoc subgroup analysis, the reduced by 60% the risk of all vascular amputations and by 70% generalization of the results may be limited. the risk of major amputations (Table 1).41 The development of Rivaroxaban, 2.5 mg, twice daily, coadministered with atherosclerosis in patients with PAD includes both platelet and 75–100 mg aspirin, once daily is currently indicated for the coagulation cascade activation, with Factor Xa playing a key prevention of atherothrombotic events in adult patients with role. The good results of the COMPASS trial are in line with the CAD or symptomatic PAD at high risk of ischemic events.71 underlying cause of atherosclerosis.24–28,48–52 Importantly, a However, it is important to ascertain which patients with great proportion of patients with PAD in clinical practice meet chronic atherosclerotic vascular may benefit more from the the inclusion criteria of the COMPASS trial, indicating that the COMPASS strategy.24,31,44,64,72,73 In patients with PAD, not only results of this study can be extended to this population.65–67 those patients at high risk of MACE but also at high risk of As a result, all these data strongly suggest that the rivaroxaban MALE should be taken into account.22,74–76 A recent analysis plus aspirin approach should be considered as the first choice for of the COMPASS trial showed that patients with ≥2 vascular the treatment of patients with PAD to achieve the double target beds affected, HF, renal insufficiency, diabetes, or having a of MACE and MALE. In fact, current guidelines recommend the high REACH score had the highest risk of recurrent vascular use of the combination of aspirin plus rivaroxaban, 2.5 mg, twice events.74 Other recent analysis of the COMPASS trial showed daily in different clinical settings. Thus, the 2019 ESC Guidelines that those patients with PAD and Fontaine classification III of chronic coronary syndromes recommend the use of the or IV ischemia, history of peripheral revascularization, prior rivaroxaban plus aspirin approach in those patients at high or amputation, or patients with MALE, treated with aspirin moderate risk of ischemic events, but without a high bleeding alone as antithrombotic therapy, had the highest risk of risk (recommendation IIb).68 However, despite the COMPASS recurrent limb events.22 Considering these studies and other trial showing a trend toward a reduction of mortality rates in recommendations, excepting for those patients with any of this population, but not other antithrombotic approaches (i.e. the main exclusion criteria of the COMPASS trial (high risk clopidogrel, ticagrelor, or prasugrel), these guidelines performed of bleeding, recent stroke, severe HF or renal insufficiency, the same recommendation for all these drugs. Nonetheless, and need for dual antiplatelet therapy or anticoagulation), in the light of the results of clinical trials, net clinical benefit those patients with PAD who meet any of the criteria for high clearly favors rivaroxaban over other antithrombotic strategies, risk of MACE or MALE may be considered for the treatment and the recommendations of use should not have been the with the rivaroxaban plus aspirin approach (Table 4). On the same. On the other hand, the 2019 ESC Guidelines on diabetes, other hand, the Vascular Outcomes studY of ASA along with prediabetes, and CV diseases indicate that the low-dose rivaroxaban in Endovascular or surgical limb Revascularization rivaroxaban, 2.5 mg, twice daily plus aspirin, 100 mg, daily for PAD (VOYAGER PAD) study has shown in patients with PAD may be considered in patients with diabetes and symptomatic who have undergone lower-extremity revascularization that lower extremity artery disease (recommendation IIa).69 The rivaroxaban, 2.5 mg, twice daily plus aspirin was associated global vascular guidelines on the management of chronic with a significantly lower incidence of the composite outcome limb-threatening ischemia state that low-dose aspirin and of ALI, major amputation for vascular causes, or MACE rivaroxaban, 2.5 mg, twice daily should be considered to reduce compared with aspirin alone. In addition, the incidence of adverse CV events and lower extremity ischemic events in TIMI major bleeding was similar between both groups, but patients with chronic limb-threatening ischemia (grade 2; level the incidence of International Society on Thrombosis and of evidence B).70 Haemostasis (ISTH) major bleeding was significantly higher The COMPASS trial showed that the rivaroxaban plus aspirin with the combination.77 approach had a higher risk of major bleeding than aspirin alone. A number of studies have analyzed whether the combination However, there was no excess in fatal or intracranial bleeds. of the vascular dose of rivaroxaban plus aspirin is a cost- Of note, as the risk of MACE or MALE (7 and 2%, in the aspirin effective approach according to different National Healthcare group, respectively) was much higher than the risk of fatal or Systems. All of them have shown that in those patients with Hernández JL, Lozano FS, Riambau V, et al. Drugs in Context 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 10 of 15 ISSN: 1740-4398 REVIEW – Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial drugsincontext.com Table 4. Patients with peripheral artery disease who may benefit more from a COMPASS strategy. 22,31,74–76 To reduce MACE To reduce MALE • ≥2 vascular beds • Fontaine classification III or IV ischemia • Previous stroke/transient ischemic attack • History of peripheral revascularization • Coronary artery disease (surgery or angioplasty) • Heart failure • Previous ischemic limb events • Renal insufficiency • Previous amputation or high risk of amputation • Diabetes • Patients with MALE, treated with aspirin alone as antithrombotic therapy • High REACH score MACE, major adverse cardiovascular events (cardiovascular death, stroke, myocardial infarction); MALE, major adverse limb events: acute or chronic limb ischemia, including all major vascular amputations. lower extremity PAD or carotid artery disease, rivaroxaban plus more cost-effective studies are mandatory in order to facilitate aspirin therapy is effective and cost effective in the prevention a potential reimbursement by the authorities. of recurrent CV disease compared to the traditional approach of aspirin therapy alone.78–80 These data emphasize its use in clinical practice for the majority of patients with PAD at high Conclusions risk of vascular or limb events. Patients with PAD have a high risk of both adverse vascular In light of all these data, more efforts are required to implement and limb outcomes. The underlying cause of atherosclerosis the COMPASS strategy in patients with PAD in routine practice. in PAD patients implies not only platelet activation but also Thus, guidelines should be updated including the information the initiation and promotion of coagulation cascade, in which of the COMPASS trial and its substudies, indicating those Factor Xa plays a key role. The traditional antithrombotic patients who may benefit more from this approach. In addition, approach with only antiplatelet agents (single or dual specific educational activities for general practitioners, vascular antiplatelet therapy) has failed to provide complete protection specialists, cardiologists, and internists would be very helpful in PAD patients. By contrast, the rivaroxaban plus aspirin to better understand the benefits and risks of the rivaroxaban strategy markedly reduces the risk of both MACE and MALE, plus aspirin approach for PAD patients. Importantly, screening and related complications, with a low risk of bleeding. of PAD should be emphasized not only by general practitioners Therefore, the rivaroxaban plus aspirin approach provides a but also by other specialists who manage patients with vascular comprehensive protection and should be considered for many disease, regardless of the vascular bed affected. Moreover, patients with PAD at high risk of such events. Contributions: All authors contributed equally to the preparation of this review. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Disclosure and potential conflicts of interest: JLH reports consulting fees and/or lectures honoraria from Bayer, Daiichi Sankyo, Sanofi, Abbie, and AMGEN. FSL received compensation for advisory-board membership from Boehringer-Ingelheim, Bayer Health Care, Daiichi Sankyo, Rovi, and Sanofi-Aventis; and lectures fees from Bayer Health Care, Daiichi Sankyo, Glaxo Smith Kline, Leo Pharma, Menarini, Rovi, and Sanofi-Aventis. VR reports consulting fees from Bayer, Sanofi, and AstraZeneca. MAD reports consulting fees and/or lectures honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Eli Lilly, GlaxoSmithKline, Daiichi-Sankyo, Rovi Pharmaceuticals, and Sanofi Aventis, and grants support from AstraZeneca. JCS reports consulting fees and/or lectures honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer-BMS. SBM reports consulting fees from Bayer. JGA reports consulting fees and/or lectures honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Daiichi Sankyo. XGM reports consulting fees and/or lectures honoraria and/or advisory-board membership with Astra-Zeneca, Bayer, Boehringer-Ingelheim, Daiichi Sankyo, and Bristol-Myers Squibb/Pfizer. JJGD reports consulting fees and/or lectures honoraria from Bayer, Boehringer Ingelheim, AstraZeneca, and Daiichi Sankyo. JRGJ reports honoraria for lectures and advisory board from Bayer. CSF reports consulting fees and/or lectures honoraria from Bayer, Daiichi Sankyo, Pfizer-BMS and SBM. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2020/06/dic.2020-5-5-COI.pdf Acknowledgements: Writing and editorial assistance was provided by Content Ed Net, Madrid, Spain. Funding declaration: Writing and editorial assistance was funded by Bayer Hispania. Hernández JL, Lozano FS, Riambau V, et al. Drugs in Context 2020; 9: 2020-5-5. DOI: 10.7573/dic.2020-5-5 11 of 15 ISSN: 1740-4398 REVIEW – Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial drugsincontext.com Copyright: Copyright © 2020 Hernández JL, Lozano FS, Riambau V, Almendro-Delia M, Cosín-Sales J, Bellmunt-Montoya S, Garcia-Alegria J, Garcia-Moll X, Gomez-Doblas JJ, Gonzalez-Juanatey JR, Suarez Fernández C. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission. Correct attribution: Copyright © 2020 Hernández JL, Lozano FS, Riambau V, Almendro-Delia M, Cosín-Sales J, Bellmunt-Montoya S, Garcia- Alegria J, Garcia-Moll X, Gomez-Doblas JJ, Gonzalez-Juanatey JR, Suarez Fernández C. https://doi.org/10.7573/dic.2020-5-5. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0. Article URL: https://www.drugsincontext.com/reducing-residual-thrombotic-risk-in-patients-with-peripheral-artery-disease:-impact-of-the- compass-trial Correspondence: José Luis Hernández, Hospital Universitario de Marqués de Valdecillas, Av. Valdecilla, 25, 39008 Santander, Cantabria, Spain. hernandezjluis@gmail.com Provenance: submitted; externally peer reviewed. Submitted: 12 May 2020; Peer review comments to author: 20 May 2020; Revised manuscript received: 26 May 2020; Accepted: 28 May 2020; Publication date: 6 July 2020. Drugs in Context is published by BioExcel Publishing Ltd. Registered office: Plaza Building, Lee High Road, London, England, SE13 5PT. BioExcel Publishing Limited is registered in England Number 10038393. VAT GB 252 7720 07. For all manuscript and submissions enquiries, contact the Editorial office editorial@drugsincontext.com For all permissions, rights and reprints, contact David Hughes david.hughes@bioexcelpublishing.com References 1. Aboyans V, Ricco JB, Bartelink MEL, et al. 2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries endorsed by: the European Stroke Organization (ESO) the task force for the diagnosis and treatment of peripheral arterial diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). 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