Atherosclerotic cardiovascular disease (CVD) affects an

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1 Atherothrombosis Drugs Compendium Synergy of Dual Pathway Inhibition in Chronic Cardiovascular Disease Lessons From the COMPASS Trial Michiel Coppens, Jeffrey I. Weitz, John W.A. Eikelboom Abstract: Although acetylsalicylic acid is of proven benefit for secondary prevention in patients with cardiovascular disease, the risk of recurrent ischemic events remains high. Intensification of antithrombotic therapy with more potent antiplatelet drugs, dual antiplatelet therapy, or vitamin K antagonists further reduces the risk of major adverse cardiovascular events compared with acetylsalicylic acid alone but increases the risk of bleeding without reducing mortality. In patients with prior coronary artery disease or peripheral arterial disease the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial revealed that compared with acetylsalicylic acid alone, dual pathway inhibition with low-dose rivaroxaban (2.5 mg twice-daily), an oral factor Xa inhibitor, plus acetylsalicylic acid reduced major adverse cardiovascular event by 24%, major adverse limb events by 47%, and mortality by 18%. Major bleeding was increased by 70%, but there was no increase in fatal or intracranial bleeding. This article (1) reviews the results of the COMPASS trial, (2) explains why dual pathway inhibition is superior to antiplatelet or anticoagulant therapy alone, (3) compares the results with rivaroxaban plus aspirin with those with other antithrombotic regimens, and (4) provides insight into how best to apply the COMPASS results into practice. (Circ Res. 2019;124: DOI: /CIRCRESAHA ) Key Words: cardiovascular disease coronary artery disease peripheral arterial disease rivaroxaban secondary prevention Atherosclerotic cardiovascular disease (CVD) affects an estimated 300 million persons worldwide and accounts for >17 million deaths each year. 1 The most severe complications of atherosclerotic CVD are stroke, myocardial infarction (MI), and critical limb ischemia, which can lead to death, permanent disability, and limb loss. Lifestyle changes, treatments that lower blood lipids, blood pressure and blood glucose, angiotensin-converting enzyme inhibitors, and antiplatelet therapy are effective and widely used for long-term secondary prevention. Despite their benefits, however, the risk of serious complications remains high. When used for long-term secondary prevention, acetylsalicylic acid (ASA) reduces the risk of major adverse cardiovascular events (MACE), a composite of cardiovascular death, stroke, or MI, by 19% and mortality by 10%, at the cost of increased bleeding. 2 Compared with ASA, the use of more potent antiplatelet drugs, such as clopidogrel, prasugrel, or ticagrelor, alone or in combinations with ASA, so-called dual antiplatelet therapy (DAPT), or the use of vitamin K antagonists (VKAs) alone or in combination with antiplatelet drugs further reduces the risk of MACE, but increases the risk of bleeding and does not reduce mortality (Figures 1, 2, and 3). 3 8 The COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) examined whether longterm treatment with a low dose of rivaroxaban, an oral factor Xa inhibitor, given alone or in combination with ASA further reduces MACE with an acceptable risk of bleeding in patients with chronic coronary artery disease (CAD) or peripheral arterial disease (PAD). The main finding was that compared with ASA alone, the combination of rivaroxaban (2.5 mg twice-daily [bid]) plus ASA reduced the primary outcome of MACE by 24% at the cost of a 70% increase in major bleeding. Combination therapy also reduced mortality by 18%, improved net clinical benefit by 20%, and reduced the risk of major adverse limb events (MALE) by 47%. 9 Rivaroxaban 5 mg bid alone did not significantly reduce MACE compared with ASA but did increase major bleeding by 51%. The purpose of this article is to (1) review the design and results of the COMPASS trial, (2) provide mechanistic insights into why adding rivaroxaban on top of ASA, so-called dual pathway inhibition, is superior to antiplatelet therapy or anticoagulant therapy alone for secondary CVD prevention, (3) show how the combination of rivaroxaban plus ASA compares with other antithrombotic therapies for secondary prevention From the Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centres, location AMC, the Netherlands (M.C.); McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada (J.I.W., J.W.A.E.); and Population Health Research Institute, and Hamilton Health Sciences, Hamilton, Ontario, Canada (J.W.A.E.). Correspondence to Michiel Coppens, MD, PhD, Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centres, Amsterdam UMC, location AMC, F4-152, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. m.coppens@amc.nl 2019 American Heart Association, Inc. Circulation Research is available at DOI: /CIRCRESAHA

2 Coppens et al Synergy of Dual Pathway Inhibition in CVD 417 Nonstandard Abbreviations and Acronyms ACS APPRAISE-2 ASA acute coronary syndrome Apixaban for Prevention of Acute Ischemic Events 2 acetylsalicylic acid ATLAS ACS 2-TIMI 51 Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46 bid twice-daily CAD coronary artery disease CHARISMA Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance COMPASS Cardiovascular Outcomes for People Using Anticoagulation Strategies CYP cytochrome P450 CVD cardiovascular disease DAPT dual antiplatelet therapy GUSTO Global Utilization Of Streptokinase And Tpa For Occluded Arteries HR Hazard ratio INR International normalized ratio MACE major adverse cardiovascular events MALE major adverse limb events PAD Peripheral arterial disease PAR protease-activated receptor PCSK9 proprotein convertase subtilisin/kexin type 9 PEGASUS-TIMI 54 Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin Thrombolysis in Myocardial Infarction 54 qd once-daily SGLT2 sodium/glucose cotransporter 2 TIMI Thrombolysis in Myocardial Infarction TRA2 P-TIMI 50 VKA VOYAGER-PAD Trial to assess the effects of vorapaxar in preventing heart attack and stroke in patients with atherosclerosis-thrombolysis in myocardial infarction 50 Vitamin K antagonists Vascular Outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease of CVD, and (4) provide insights on how best to apply the COMPASS trial results in patients with CAD, PAD, or both. Design and Results of the COMPASS Trial This section focuses on (1) the design of the COMPASS trial with an emphasis on why the 2.5 and 5 mg bid doses of rivaroxaban were selected, (2) the unmet medical need in the CAD and PAD population, and (3) the results of the COMPASS trial. Rationale for the Rivaroxaban Dose The therapeutic dose of rivaroxaban for stroke prevention in patients with atrial fibrillation or treatment of venous thromboembolism is 20 mg once-daily (qd) with a dose reduction to 15 mg qd for patients with renal impairment in patients with atrial fibrillation. In COMPASS, the rivaroxaban dose was 2.5 mg bid in combination with ASA, or 5 mg bid alone, which represent 25% and 50% of the full daily dose used for atrial fibrillation and venous thromboembolism patients. The rationale for evaluation of these low doses came from the ATLAS ACS 2-TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome 2 Thrombolysis in Myocardial Infarction 51). 10 In that trial, patients with the acute coronary syndrome (ACS) were randomized within 1 week of an acute e- vent to receive rivaroxaban 2.5 mg bid, rivaroxaban 5 mg bid, or placebo and were then followed for a median of 13.1 months. The majority of patients (93%) also received DAPT with ASA and clopidogrel, while the remainder received ASA alone. Compared with placebo, both doses of rivaroxaban reduced MACE (2.5 mg bid versus placebo: 9.1% versus 10.7%; hazard ratio [HR] 0.84; 95% CI, and 5 mg bid versus placebo: 8.8% versus 10.7%; HR, 0.85; 95% CI, ) at the cost of increased TIMI major bleeding (2.5 mg bid versus placebo: 1.8% versus 0.6%; HR, 3.46; 95% CI, and 5 mg bid versus placebo: 2.4% versus 0.6%; HR, 4.47; 95% CI, ), including intracranial bleeding (2.5 mg bid versus placebo: 0.4% versus 0.2%; HR, 2.83; 95% CI, and 5 mg bid versus placebo: 0.7% versus 0.2%; HR, 3.74; 95% CI, ). Rivaroxaban 2.5 mg bid reduced mortality compared with placebo (2.9% versus 4.5%; HR, 0.68; 95% CI, ), whereas rivaroxaban 5 mg bid did not (4.4% versus 4.5%; HR, 0.95; 95% CI, ). Based on these results, the European Medicines Agency approved the low-dose rivaroxaban regimen (2.5 mg bid) in high-risk ACS patients as an adjunct to DAPT with ASA and clopidogrel or to ASA alone. In contrast to the results with rivaroxaban in ACS patients, apixaban given at the dose of 5 mg bid, the same dose used for stroke prevention in atrial fibrillation, increased bleeding but did not reduce MACE. Thus, in the APPRAISE-2 trial (Apixaban for Prevention of Acute Ischemic Events 2), patients with ACS and additional risk factors were randomized within 1 week of the acute event to receive apixaban (5 mg bid) or placebo. 11 Most patients (81%) also received a combination of ASA and a P2Y12 receptor antagonist, predominantly clopidogrel. Apixaban did not significantly reduce MACE compared with placebo (13.2% versus 14.0%; HR, 0.95; 95% CI, ) or influence mortality (4.2% versus 3.9%; HR, 1.08; 95% CI, ), but increased the risk of TIMI major bleeding (2.4% versus 0.9%; HR, 2.59; 95% CI, ). Because of the lack of benefit and the increased bleeding, the trial was stopped early after a median follow-up of 7.9 months. Therefore, when used in conjunction with antiplatelet therapy, low doses of rivaroxaban appear to be better than full doses. Patient Eligibility, Trial Design, and Outcomes COMPASS was a phase 3 trial that evaluated the use of rivaroxaban alone or in combination with ASA in patients with chronic CAD or PAD. Patients with CAD were eligible if they had a history of MI or angina pectoris with evidence of multivessel disease, or if they had previously undergone multivessel revascularization. Patients with PAD were eligible if they had a history of intermittent claudication with objective evidence of arterial disease, amputation, or revascularization. Patients with carotid artery disease were eligible if they had

3 418 Circulation Research February 1, 2019 Figure 1. Sites of action of antiplatelet drugs (in red) and anticoagulants (in blue) discussed in the present review. Aspirin inhibits the synthesis of thromboxane A 2 (TXA 2 ) by irreversibly acetylating cyclo-oxygenase 1 (COX-1). The reduced release of TXA 2 attenuates platelet activation and recruitment to the site of vascular injury. Clopidogrel, and prasugrel irreversibly block P2Y 12, a key ADP receptor on the platelet surface; ticagrelor is a reversible inhibitor of P2Y 12. Vorapaxar inhibits thrombinmediated platelet activation by targeting PAR-1 (protease-activated receptor-1), the major thrombin receptor on platelets. Rivaroxaban blocks activated coagulation factor X (Xa). VKA (Vitamin K antagonists) attenuates thrombin formation by inhibition of the synthesis of coagulation factors II (prothrombin), VII, IX, and X. GpIIb/IIIa indicates glycoprotein IIb/IIIb receptor on platelets; and VWF, Von Willebrand Factor. previously undergone carotid revascularization, or if they had asymptomatic carotid disease with at least 50% stenosis (Table 1). 12 Patients with a stroke within the last month or with a history of hemorrhagic or lacunar stroke were ineligible. Full inclusion and exclusion criteria are presented in Table 2. Eligible patients were randomized to treatment with rivaroxaban 2.5 mg bid in combination with ASA 100 mg qd, rivaroxaban 5 mg bid (and placebo ASA), or ASA 100 mg qd (and placebo rivaroxaban; Figure 4). Using a 3 2 partial factorial design, patients not already taking a proton pump inhibitor at baseline were randomized to receive pantoprazole 40 mg qd or placebo. Aside from those enrolled within 4 to 14 days after coronary artery bypass graft surgery, potentially eligible patients were first entered into a 30-day run-in period during which they received rivaroxaban placebo bid and ASA. Those who were at least 80% adherent to run-in therapy and were willing to continue were then randomized. The primary efficacy outcome was MACE. Secondary efficacy outcomes were the composites of (1) ischemic stroke, MI, acute limb events, or death from coronary heart disease, (2) ischemic stroke, MI, acute limb events, or cardiovascular death, and (3) all-cause mortality. The primary safety outcome was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding, which included fatal bleeding, symptomatic bleeding in a critical organ, bleeding into the surgical site requiring reoperation, or bleeding leading to hospitalization (including presentation to an a- cute care facility without overnight stay). MALE was defined as acute or chronic limb ischemia. 13 Acute limb ischemia had to be objectively confirmed, limb-threatening, and leading to an acute intervention (pharmacological, surgical, angioplasty, or amputation) within 30 days. Chronic limb ischemia had to lead to hospitalization and intervention and included participants with Fontaine classification III-IV at baseline who had a Figure 2. Relative effects of intensified antithrombotic regimens compared with acetylsalicylic acid alone with respect to major adverse cardiovascular events (MACE) and mortality. Clop indicates clopidogrel; INR, international normalized ratio; Riva, rivaroxaban; Tica, ticagrelor; and VKA, vitamin K antagonist. Numbers are derived from references 3 9.

4 Coppens et al Synergy of Dual Pathway Inhibition in CVD 419 Table 1. COMPASS Trial Eligibility Criteria Figure 3. Relative effects of intensified antithrombotic regimens compared with acetylsalicylic acid (ASA) alone with respect to major/severe bleeding (definitions as used in the respective trials). Clop indicates clopidogrel; INR, international normalized ratio; Riva, rivaroxaban; Tica, ticagrelor; and VKA, vitamin K antagonist. Numbers are derived from references 3 9. peripheral vascular intervention during the trial. The prespecified net clinical benefit outcome was a composite of cardiovascular death, stroke, MI, fatal bleeding, and symptomatic bleeding into a critical organ. Baseline Characteristics Of a total of patients who entered the run-in phase, were randomized and 2320 were excluded because they did not successfully complete the run-in. 9 An additional 1448 patients were randomized 4 to 14 days after CABG surgery without entering the run-in. Therefore, a total of patients were randomized of whom 91% had CAD and 27% had PAD. The mean age was 68 years, 78% were male and at baseline 90% were receiving lipid-lowering drugs and 71% were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist. Stroke was not an eligibility criterion, but 4% of patients had a clinical history of nonlacunar stroke. Additionally, 75% of patients had hypertension, 21% were smokers, 22% had heart failure, 38% had diabetes mellitus, and 23% had chronic kidney disease (estimated glomerular filtration rate <60 ml/min). Efficacy and Safety According to Randomized Treatment Table 3 details efficacy and safety outcomes according to randomized treatment. 9 Compared with ASA, rivaroxaban alone did not significantly reduce MACE (4.9% versus 5.4%; HR, 0.90; 95% CI, ) or mortality (4.0% versus 4.1%; HR, 0.97; 95% CI, ) but increased major bleeding (2.8% versus 1.9%; HR, 1.51; 95% CI, ) as well as intracranial bleeding (0.5% versus 0.3%; HR, 1.80; 95% CI, ). In contrast, compared with ASA monotherapy, the combination of rivaroxaban and ASA reduced MACE by 24% (4.1% versus 5.4%; HR, 0.76; 95% CI, ) and mortality by 18% (3.4% versus 4.1%; HR, 0.82; 95% CI, ), but increased major bleeding by 70% (3.1% versus 1.9%; HR, 1.70; 95% CI, ) without a significant increase in fatal or intracranial bleeding. Rivaroxaban plus ASA resulted in Coronary Artery Disease, Defined as: Myocardial infarction within the past 20 y, or Multi-vessel coronary disease* with symptoms or with history of stable or unstable angina, or Multi-vessel percutaneous coronary intervention, or Multi-vessel CABG surgery. Peripheral arterial disease, defined as: Previous aortofemoral bypass surgery, limb bypass surgery, or percutaneous transluminal angioplasty revascularization of the iliac, or infra-inguinal arteries, or Previous limb or foot amputation for arterial vascular disease, or History of intermittent claudication and 1 or more of the following: an ankle/arm blood pressure ratio <0.90, or significant peripheral artery stenosis ( 50%) documented using angiography, or duplex ultrasound, or Previous carotid revascularization or asymptomatic carotid artery stenosis 50% as diagnosed using duplex ultrasound or angiography. COMPASS indicates Cardiovascular Outcomes for People Using Anticoagulation Strategies. *Refers to stenosis of 50% in 2 or more coronary arteries, confirmed using invasive coronary angiography, or noninvasive imaging or stress studies (eg, exercise or pharmacological) suggestive of significant ischemia in 2 coronary territories; or in 1 coronary territory if at least 1 other territory has been revascularized. a net clinical benefit over ASA alone (4.7% versus 5.9%; HR, 0.80; 95% CI, ) whereas rivaroxaban 5 mg bid did not (5.5% versus 5.9%; HR, 0.94; 95% CI, ). The results in patients with CAD and PAD were similar (Table 4). 9,14 CAD Patients Of the patients with CAD, 62% had multi-vessel CAD and 69% had a history of prior MI. Of the patients with prior MI, 7% were enrolled within 1 year of the event, 14% within 1 to 2 years, 29% within 2 to 5 years, and 50% >5 years after MI. 14 Treatment effects were consistent, regardless of the time since MI (Table 4). In a landmark analysis that examined the effects of treatment over time, the combination of rivaroxaban plus ASA increased bleeding compared with ASA during the first year after randomization (2.0% versus 0.8%; HR, 2.32; 95% CI, ) but not in the second year (1.0% versus 0.8%; HR, 1.19; 95% CI, ) or thereafter (0.8% versus 0.8%; HR, 1.05; 95% CI, ), whereas MACE was consistently reduced (Table 4). 14 PAD Patients Of the 7470 patients with PAD, 55% had symptomatic PAD of the lower extremities, 4% had prior limb or foot amputation, 27% had prior lower limb bypass surgery or percutaneous angioplasty, 19% had asymptomatic PAD with an ankle-brachial index (ABI) <0.90 (these patients all had CAD), and 26% had carotid artery disease. 15 Treatment effects were consistent regardless of whether patients had symptomatic or asymptomatic PAD or disease involving the lower limbs or carotids. Compared with ASA alone, rivaroxaban plus ASA reduced the risk of MALE by 46% (1.2% versus 2.2%; HR, 0.54; 95% CI,

5 420 Circulation Research February 1, 2019 Table 2. Inclusion and Exclusion Criteria for the COMPASS Trial Inclusion Criteria Willing and able to provide written informed consent Meet criteria for CAD and PAD (see Table 1) Subjects with CAD must also meet at least 1 of the following criteria: Age 65 y or older, or Age younger than 65 y and documented atherosclerosis or revascularization involving at least 2 vascular beds* or at least 2 additional risk factors: Current smoker (within 1 y of randomization) Diabetes mellitus Renal insufficiency with estimated glomerular filtration rate < 60 ml/ min Heart failure Nonlacunar ischemic stroke 1 mo ago Exclusion criteria High risk of bleeding Stroke within 1 mo or any history of hemorrhagic or lacunar stroke Severe heart failure with known ejection fraction < 30% or New York Heart Association class III or IV symptoms Estimated glomerular filtration rate < 15 ml/min Need for dual antiplatelet therapy, other nonaspirin antiplatelet therapy, or oral anticoagulant therapy. Known noncardiovascular disease that is associated with poor prognosis (eg, metastatic cancer) or that increases the risk of an adverse reaction to study interventions. History of hypersensitivity or known contraindication for rivaroxaban, aspirin, pantoprazole, or excipients, if applicable. Systemic treatment with strong inhibitors of CYP 3A4 as well as p-glycoprotein (eg, systemic azole antimycotics, such as ketoconazole, and HIV-protease inhibitors, such as ritonavir), or strong inducers of CYP 3A4 (eg, rifampicin, rifabutin, phenobarbital, phenytoin, and carbamazepine). Any known hepatic disease associated with coagulopathy. Subjects who are pregnant, breastfeeding, or are of childbearing potential, and sexually active and not practicing an effective method of birth control (eg, surgically sterile, prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, and male partner sterilization). Previous assignment to treatment during this study Concomitant participation in another study with investigational drug Known contraindication to any study-related procedures CAD indicates coronary artery disease; COMPASS, Cardiovascular Outcomes for People Using Anticoagulation Strategies; CYP, Cytochrome P450; and PAD, peripheral artery disease. *Because CAD involves disease in the coronary vasculature, only 1 additional vascular bed is required (eg, the aorta, arterial supply to the brain, gastrointestinal tract, lower limbs, upper limbs, and kidneys) ) and amputation by 60% (0.4% versus 1.1%; HR, 0.40; 95% CI, ; Table 4), whereas rivaroxaban a- lone reduced MALE (1.4% versus 2.2%; HR, 0.63; 95% CI, ) but did not reduce amputation (0.7% versus 1.1%; HR, 0.61; 95% CI, ). 15 The significance of MALE Figure 4. Randomization of patients enrolled in the COMPASS trial. is highlighted by the poor prognosis after such events. 13 After MALE, the 1-year incidences of hospitalization, amputation, MACE, or death were 62%, 21%, 4%, and 8%, respectively. The risk of death after an episode of MALE was increased compared with the period before MALE in patients randomized to ASA monotherapy (HR, 5.97; 95% CI, ) but not in patients randomized to rivaroxaban 2.5 mg bid plus ASA. Likewise, the composite of MACE or vascular amputation after MALE was increased 10-fold compared with before MALE in patients randomized to ASA alone (HR, 10.24; 95% CI, ) but not in patients randomized to combination therapy. 13 Therefore, combination therapy not only prevented MALE but also reduced the risk of death or amputation after MALE. Dual Pathway Inhibition: Mechanisms of Benefit ASA attenuates platelet activation by thromboxane A2, whereas by inhibiting factor Xa, rivaroxaban attenuates thrombin generation. Therefore, this combination inhibits thrombus formation via dual pathways: platelet activation and thrombin generation. Attenuation of both pathways is important because disruption of atherosclerotic plaques not only triggers platelet activation and aggregation but also exposes tissue factor, which induces thrombin generation. In support of this concept, patients with a history of MI have evidence of persistent coagulation activation, despite antiplatelet therapy and thrombin is a potent platelet agonist. 16,17 Therefore, inhibition of thrombin generation can be expected to reduce both platelet activation and fibrin formation, thereby reducing the risk of thrombus formation at sites of atherosclerotic plaque disruption. Some of the benefits of the combination of rivaroxaban and aspirin compared with aspirin alone may also be explained by anti-inflammatory and anti-atherogenic effects. By inhibiting factor Xa and reducing thrombin generation, rivaroxaban inhibits factor Xa-induced activation of PAR (protease-activated receptor)-2 and thrombin-induced activation of PAR-1 and PAR-4, thereby suppressing inflammation that is important in the development and progression of atherosclerosis. Supporting these concepts, rivaroxaban has been shown to reduce atherosclerotic plaque progression in mouse models and to enhance plaque stability by thickening the protective fibrous cap Whether rivaroxaban affects atherosclerotic plaque growth and composition in humans remain to be demonstrated. Dual Pathway Inhibition With Rivaroxaban Plus ASA Versus Other Intensified Antithrombotic Regimens Previous randomized trials have demonstrated that intensification of antithrombotic therapy using more potent antiplatelet drug regimens reduces the risk of recurrent ischemic events in patients with a recent ACS or cerebrovascular event

6 Coppens et al Synergy of Dual Pathway Inhibition in CVD 421 Table 3. Effects of Rivaroxaban Plus ASA and Rivaroxaban Alone Versus ASA Alone in the COMPASS Trial Rivaroxaban 2.5 mg bid+asa 100 mg qd (%) However, the benefits of these regimens were less evident after the first year, presumably because the extent of platelet activation subsides over time. The potential for long-term anticoagulant therapy to further reduce risk in patients with chronic CVD was first suggested by trials with VKAs, such as warfarin, but their use was associated with an unacceptable increase in bleeding, and no mortality benefit (Figures 2 and 3). 5 The COMPASS trial evaluated the same doses of rivaroxaban that were shown to be effective in ATLAS, and demonstrated a clear benefit with long-term combination treatment, with a reduction in MACE, MALE, and mortality. 9 The reduced rivaroxaban dose of 2.5 mg bid in combination with ASA increased major bleeding but did not increase fatal or critical organ bleeding (Figure 3), which explains the improved net benefit, particularly after the first year of treatment. In patients with a history of CAD, low-intensity VKA therapy (target international normalized ratio below 2) plus ASA did not increase major bleeding but did not reduce MACE (Figures 2 and 3). 5 A similar lack of efficacy was reported when reduced intensity VKA was evaluated for secondary prevention of venous thromboembolism. Thus, Rivaroxaban 5 mg bid (%) ASA 100 mg qd (%) n=9152 n=9117 n=9126 Rivaroxaban Plus ASA vs ASA Alone (HR [95% CI]) Rivaroxaban Alone vs ASA Alone (HR [95% CI]) Primary efficacy outcome: CV death, stroke, or MI ( ) 0.90 ( ) Secondary efficacy outcomes: Ischemic stroke, MI, ALI, CHD death ( ) 0.88 ( ) Ischemic stroke, MI, ALI, CV death ( ) 0.88 ( ) Death from any cause ( ) 0.97 ( ) Other efficacy outcomes: MI ( ) 0.89 ( ) Stroke ( ) 0.82 ( ) Ischemic or undetermined stroke ( ) 0.69 ( ) Hemorrhagic ( ) 2.70 ( ) CV death ( ) 0.96 ( ) Primary safety outcome: Major bleeding ( ) 1.51 ( ) Other safety outcomes: ISTH major bleeding ( ) 1.52 ( ) Fatal bleeding ( ) 1.40 ( ) Minor bleeding ( ) 1.50 ( ) Intracranial bleeding ( ) 1.80 ( ) Gastrointestinal bleeding ( ) 1.40 ( ) Net clinical benefit: CV death, stroke, MI, fatal bleeding, symptomatic bleeding into critical organ ( ) 0.94 ( ) ALI indicates acute limb ischemia; ASA, acetylsalicylic acid; CHD, coronary heart disease; CV, cardiovascular; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; and MI, myocardial infarction. low-intensity warfarin therapy (targeting international normalized ratio of ) was inferior to usual intensity therapy (target international normalized ratio of ) and was not associated with a reduction in bleeding. 25 In contrast, reduced doses of rivaroxaban (10 mg qd) or apixaban (2.5 mg bid) were as effective as full doses for secondary venous thromboembolism prevention and were associated with a trend for less bleeding. 26,27 Therefore, reduced intensity treatment with rivaroxaban is effective for secondary prevention in patients with arterial or venous thrombosis, whereas reduced intensity treatment with VKAs is not. The combination of rivaroxaban and aspirin produced less bleeding in COMPASS than in ATLAS because patients receiving DAPT were ineligible for COMPASS, whereas the majority of patients enrolled in ATLAS received concomitant DAPT. In the CHARISMA trial (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance), long-term DAPT consisting of ASA and clopidogrel reduced the risk of cardiovascular death, stroke, or MI by 17% in the subgroup of patients with prior MI, stroke or symptomatic PAD without increasing GUSTO

7 422 Circulation Research February 1, 2019 Table 4. Rivaroxaban Plus ASA Versus ASA Alone in Key Subgroups of the COMPASS Trial Rivaroxaban 2.5 mg bid+asa 100 mg qd (%) ASA 100 mg qd (%) Overall trial population, N Rivaroxaban+ASA vs ASA Alone (HR [95% CI]) CV death, stroke, or MI ( ) Major bleeding ( ) Net clinical benefit ( ) CAD patients, N CV death, stroke, or MI ( ) < 1 y of therapy ( ) 1 2 of therapy ( ) >2 y of therapy ( ) <2 y since MI ( ) 2 5 y since MI ( ) >5 y since MI ( ) Heart failure ( ) Diabetes mellitus ( ) Renal impairment* ( ) Major bleeding ( ) <1 y of therapy ( ) 1 2 y of therapy ( ) >2 y of therapy ( ) <2 y since MI ( ) 2 5 y since MI ( ) >5 y since MI ( ) Heart failure ( ) Diabetes mellitus ( ) Renal impairment* ( ) Net clinical benefit ( ) <1 y of therapy ( ) 1 2 y of therapy ( ) >2 y of therapy ( ) <2 y because MI ( ) 2 5 y because MI ( ) >5 y because MI ( ) Heart failure ( ) Diabetes mellitus ( ) Renal impairment* ( ) PAD patients CV death, stroke or MI ( ) Major bleeding ( ) Net clinical benefit ( ) (Continued ) Table 4. Continued Rivaroxaban 2.5 mg bid+asa 100 mg qd (%) ASA 100 mg qd (%) MALE ( ) Amputation ( ) Patients with CAD and PAD Rivaroxaban+ASA vs ASA Alone (HR [95% CI]) CV death, stroke or MI ( ) Major bleeding ( ) Net clinical benefit ( ) ASA indicates acetylsalicylic acid; bid, twice-daily; CAD, coronary artery disease; CKD, chronic kidney disease; CV, cardiovascular; egfr, estimated glomerular filtration rate; HR, hazard ratio; MALE, major adverse limb event; MI, myocardial infarction; PAD, peripheral arterial disease; and qd, once-daily. *Renal impairment was defined as CKD stage 3 or higher (egfr <60 ml/min). (Global Utilization Of Streptokinase And Tpa For Occluded Arteries) severe bleeding and without a mortality benefit. 6 Similarly, the PEGASUS (Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin) TIMI 54 trial revealed that compared with ASA a- lone, DAPT consisting of ASA plus ticagrelor (90 or 60 mg bid) reduced the risk of MACE in patients enrolled 1 to 3 years after an MI. 7 These benefits came at the cost of a 2.7-fold and 2.3-fold increase in TIMI major bleeding with the 90 and 60 mg ticagrelor regimen, respectively, and no reduction in mortality. Therefore, dual pathway inhibition with rivaroxaban plus ASA appears to be better than more intensive antiplatelet therapy for long-term management of patients after MI. Application of the COMPASS Results to Practice Although the benefit of the combination of rivaroxaban 2.5 mg bid and ASA was consistent in most subgroups, it makes sense that the initial target population for combination therapy would be those at highest risk of CVD who would derive the greatest absolute benefit. Additionally, formal cost-effectives analyses are awaited but it seems likely that the treatment is going to be cost-effective in the majority of countries around the world. In the next section, we discuss the potential role of combination therapy in different subgroups of CVD patients. CAD Patients With Recent ACS In patients with ACS, DAPT consisting of clopidogrel and ASA reduces MACE compared with ASA monotherapy. 24,28 Compared with ASA plus clopidogrel, ASA plus prasugrel, a more potent P2Y12 inhibitor, reduced MACE and stent thrombosis in ACS patients undergoing revascularisation but not in those who were medically managed. 23,29 Stent implantation damages the vessel wall and promotes platelet activation. Therefore, it is not surprising that more potent platelet inhibition with prasugrel reduces MACE and stent thrombosis more effectively than clopidogrel. Although long-term DAPT reduces MACE compared with ASA monotherapy, the benefit is less than that after coronary intervention and there is no

8 Coppens et al Synergy of Dual Pathway Inhibition in CVD 423 mortality benefit, likely due to the reduced platelet activation that occurs once the target vessel undergoes re-endothelisation. This suggests that patients at highest risk of stent-related events, such as those with multiple stents, long lesion length (eg, >60 mm total stent length), complex lesions (eg, bifurcation treated with 2 stents), left main or proximal LAD stenting, or patients with prior stent thrombosis may benefit most from prolonged DAPT. Although patients with an indication for DAPT could not be enrolled in the COMPASS trial, the combination of low-dose rivaroxaban and ASA reduced MACE and mortality compared with ASA alone in CAD patients irrespective of the time since MI. This raises the question of when ACS patients should be switched from DAPT to dual pathway treatment. Because the benefit of DAPT decreases over time, it would be reasonable to consider transitioning patients who are not at high risk of stent-related events to dual pathway therapy after 12 months. Chronic CAD Whereas the benefit of DAPT over ASA monotherapy after ACS seems to decrease over time, the benefit of combination therapy with rivaroxaban 2.5 mg bid and ASA over ASA alone does not. Interestingly, compared with ASA, the increased risk of major bleeding with rivaroxaban plus ASA was only evident during the first year of therapy; thereafter the risk of major bleeding with combination therapy was similar to that with ASA alone. Consequently, the net benefit of combination therapy over ASA increases over time. Therefore, combination therapy is an appealing alternative to ASA monotherapy for most patients with chronic CAD. Peripheral Arterial Disease Patients with PAD are at particularly high risk of MACE. Most guidelines recommend monotherapy with either ASA or clopidogrel for patients with symptomatic PAD. MALE is the most feared complication of PAD, but the incidence of MALE is substantially lower than that of MACE (2.2% versus 6.9% in patients treated with ASA alone in COMPASS). Even patients with asymptomatic PAD (ie, CAD combined with an ABI <0.90) had a substantially higher risk of MACE than patients without PAD in COMPASS (7.3% versus 4.3%). Because of the consistency of the benefit of rivaroxaban plus ASA over ASA alone, PAD patients are among those who benefited most from combination therapy with respect to MACE. Furthermore, combination therapy reduced the risk of MALE and improved the prognosis after MALE compared with ASA (Figure 5). Addition of vorapaxar or ticagrelor to ASA also reduces ALI in PAD patients. 30,31 Vorapaxar inhibits PAR-1, the major thrombin receptor on platelets. The TRA2 P (Trial to assess the effects of vorapaxar in preventing heart attack and stroke in patients with atherosclerosis)-timi 50 trial enrolled patients with symptomatic PAD or patients with MI or ischemic stroke and randomized them to vorapaxar (2.5 mg qd) or placebo on top of standard care. 8 In patients with symptomatic PAD at baseline, vorapaxar reduced ALI (2.3% versus 3.9%; HR, 0.58; 95% CI, ; Figure 5) at the cost of an increase in non-cabg related TIMI major bleeding, including intracranial bleeding, and no reduction in mortality (Figures 1, 2, and 5). 8,31 The high incidence of intracranial bleeding in patients with prior stroke observed during the course of the TRA2 P-TIMI 50 trial prompted the exclusion of patients with prior stroke. In the United States, vorapaxar is licensed for patients with prior MI or PAD and is contraindicated in patients with prior stroke or TIA; vorapaxar was recently withdrawn from the European market for commercial reasons. In the PEGASUS-TIMI 54 trial, the combination of ticagrelor (90 mg bid) and ASA also reduced the risk of MALE by 51% (HR, 0.49; 95% CI, ; Figure 5) at the cost of a substantial increase in TIMI major bleeding without a mortality benefit. 30 Thus, when used on top of ASA both vorapaxar and ticagrelor reduce MALE in PAD patients. However, only the combination of rivaroxaban (2.5 mg bid) plus ASA also reduces mortality, which renders it a more attractive option. In COMPASS, only about 10% of PAD patients had an ABI of 0.70 or lower. In the currently ongoing VOYAGER (Vascular Outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization)-pad trial (URL: Unique identifier: NCT ) patients with symptomatic PAD are randomized to rivaroxaban (2.5 mg bid) or placebo within 10 days of revascularization. This trial will determine whether the benefits of combination therapy over ASA alone in PAD patients observed in COMPASS with respect to MACE and MALE also apply to patients in the immediate postrevascularization period. Stroke The COMPASS trial excluded patients with a stroke within the previous year and patients with a history of any hemorrhagic or lacunar stroke. Nonetheless, a total of 1032 patients in COMPASS had a history of nonlacunar ischemic stroke. 9 Moreover, a COMPASS-Magnetic Resonance Figure 5. Relative effects of intensified antithrombotic regimens compared with acetylsalicylic acid (ASA) alone with respect to MALE. * ALI was reported instead of MALE. Severe lower extremity ischemia was reported in stead of MALE. INR indicates international normalized ratio; MALE, major adverse limb events; Riva, rivaroxaban; Tica, ticagrelor; and VKA, vitamin K antagonist. Numbers are derived from references 13, 15, 30, 31,

9 424 Circulation Research February 1, 2019 Imaging substudy among 1760 patients revealed that 35% of patients had brain infarct at randomization. 32 The relative risk reduction with rivaroxaban 2.5 mg bid plus ASA compared with ASA alone was greatest for the outcome of ischemic or unspecified stroke, most of which were lacunar strokes (0.7% versus 1.4%; HR, 0.51; 95% CI, ). 9 Although the current standard of care for long-term management of patients with ischemic strokes is either ASA or clopidogrel monotherapy, or ASA combined with dipyridamole, these data suggest that dual pathway inhibition with a COMPASS-like regimen may further reduce subsequent stroke with an acceptable increase in bleeding. Polyvascular Disease Polyvascular CVD refers to patients with CVD involving >1 vascular bed (CAD, PAD, or cerebrovascular disease). The current standard of care is ASA or clopidogrel monotherapy with DAPT for selected high-risk patients with CAD. In COMPASS, the vast majority of patients with polyvascular disease had a combination of CAD and PAD, although 4% of patients had a history of stroke and CAD or PAD. The risk of MACE was higher in patients with polyvascular disease than in those with CAD alone (8.4% versus 4.9% in patients treated with ASA alone) and in this subgroup, rivaroxaban plus ASA compared with ASA alone produced a consistent reduction in MACE (5.7% versus 8.4%; relative risk, 0.67; 95% CI, ). Because of the high risk of MACE, patients with polyvascular bed involvement are likely to be among those who will benefit most from combination therapy. Other Comorbidities Associated With High Risk of MACE Patients at particularly high risk of MACE are those with chronic CAD and diabetes mellitus (in patients treated with ASA alone: 7.0% versus 4.8% in CAD patients without diabetes mellitus), chronic kidney disease stage 3 (8.5% versus 4.5% in patients with preserved renal function), or heart failure (7.9% versus 4.7% in patients without heart failure). Compared with ASA alone, the combination of rivaroxaban plus ASA produced consistent effects on MACE in these patients, indicating that they are likely to achieve the largest absolute benefits from combination therapy (Table 4). Conclusions and Future Directions In the COMPASS trial, combination therapy with low-dose rivaroxaban plus ASA was superior to ASA alone in patients with chronic CVD. The 18% mortality reduction with combination therapy is a unique finding that has not been previously demonstrated with other intensified antithrombotic regimens when used long-term. Therefore, dual pathway inhibition with rivaroxaban plus ASA represents a paradigm shift for secondary CVD prevention. Patients who will benefit the most from dual pathway inhibition are those with polyvascular disease, symptomatic PAD and those with CAD and diabetes mellitus, heart failure or renal impairment. Additionally, clinicians also will have to decide the use of the COMPASS regimen in the context of other emerging therapies including drugs that target cholesterol (eg, PCSK9 inhibitors 33,34 ), inflammation (eg, canakinumab 35 ), and glucose (eg, SGLT [sodium/glucose cotransporter]-2 inhibitors 36 ), each of which have been shown to be reduce cardiovascular events. Although rivaroxaban plus ASA increases the risk of bleeding, there is no increase in fatal or intracranial bleeding. The results of the second randomization to pantoprazole or placebo will help to determine whether concomitant proton pump inhibitor use mitigates the risk of gastrointestinal bleeding with rivaroxaban plus ASA, whereas the VOYAGER trial will determine whether this combination also is of benefit in PAD patients in the immediate postrevascularization period. Although there is more to be learned, the results of the COMPASS trial will change the standard of care for secondary CVD prevention. Disclosures Dr Coppens has received financial support for research and health innovation, as well as lecturing and consultancy fees from Bayer, Boehringer Ingelheim, Bristol Myers-Squibb, Daiichi Sankyo, Pfizer, Portola, and Sanquin Blood Supply. J.I. Weitz has received consulting fees and honoraria from Bayer, Boehringer Ingelheim, Bristol Myers- Squibb, Pfizer, Janssen, Daiichi Sankyo, Servier, Portola, Ionis, and Novartis and research support from Boehringer Ingelheim and Bayer. J.W. 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