A 63-year-old woman with a history of ischemic stroke 3 years prior, coronary artery disease (CAD) with a remote drug eluting stent placement to the right coronary artery and peripheral artery disease (PAD) with typical claudication after walking 3 blocks presents to your outpatient clinic. She denies resting foot pain, non-healing ulcers or loss of motor or sensory functions involving the limbs. Her additional risk factors include type II diabetes mellitus, hypertension, dyslipidemia and 25 pack-years of tobacco use. She denies alcohol or illicit drug use. Family history is notable for premature CAD in multiple members.
Current medications include aspirin 81 mg daily, metoprolol 50 mg daily, lisinopril 40 mg daily, atorvastatin 80 mg daily, cilostazol 100 mg twice daily and metformin 1000 mg twice daily.
Cardiac exam is within normal limits. Vascular exam is notable for bilateral carotid bruits, symmetrically decreased 1+ dorsalis pedis and posterior tibial artery pulses and otherwise intact peripheral pulses throughout. Feet are warm with rapid capillary refill and preserved motor and sensory functions. There are no ulcerations and no tissue or hair loss.
Ankle-brachial indices are 0.80 on the right and 0.78 on the left.
The addition of which of the following antiplatelet/anticoagulant agents is most appropriate to reduce both cardiovascular and limb-related events in this patient?
Show Answer
The correct answer is: C. Rivaroxaban 2.5 mg twice daily.
A randomized controlled trial (RCT) involving 27,395 patients with stable atherosclerotic vascular disease (the COMPASS [Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Pheripheral Artery Disease] trial) demonstrated reduction in the composite endpoint of cardiovascular (CV) death, stroke or myocardial infarction (MI) with the addition of low dose rivaroxaban (2.5 mg twice daily) to aspirin compared to aspirin alone (event rate 4.1% vs. 5.4%; hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.66, 0.86; p < 0.001).1 A subsequent analysis within COMPASS of 7470 patients with PAD of the lower extremities or carotid arteries similarly demonstrated reduction in the composite endpoint with low dose rivaroxaban plus aspirin over aspirin alone (5% vs. 7%; HR 0.72; 95% CI 0.57-0.90; p = 0.0047) and in major adverse limb events including major amputation (1% vs. 2%; HR 0.54; 95% CI 0.35-0.82; p = 0.0037) at 21 months mean follow-up. There was associated increased major bleeding in the rivaroxaban group (3% vs. 2%; HR 1.61; 95% CI 1.12-2.38; p = 0.0089) without fatal or critical organ bleeding complications.2 Although currently available in other countries, Food and Drug Administration approval of low dose rivaroxaban for this indication is currently under review.
The current American Heart Association (AHA)/American College of Cardiology (ACC) 2016 guidelines recommend monotherapy with aspirin or clopidogrel alone to reduce MI, stroke and vascular death in patients with symptomatic PAD (Class IA).3-7 A subgroup analysis involving 6452 symptomatic PAD patients in the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) trial, which randomized patients with atherosclerotic diseases to either aspirin 325 mg daily or clopidogrel 75 mg daily, showed a relative risk reduction of 23.8% for the composite endpoint of ischemic stroke, MI or CV death with clopidogrel therapy.7 It is possible clopidogrel may be superior to aspirin among patients with PAD, but data are limited to this single RCT. Nonetheless, the European Society of Cardiology guidelines currently recommend clopidogrel monotherapy for patients with symptomatic PAD.8
As noted in the current ACC/AHA PAD guidelines, the effectiveness of dual-antiplatelet therapy (answer option A) is not well established (Class IIb).3 A post hoc analysis of patients with symptomatic (N = 2838) or asymptomatic (N = 258) PAD from an RCT comparing the efficacy of aspirin (75-165 mg daily) plus clopidogrel (75 mg daily) versus aspirin and placebo (CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance]) showed no differences in the primary outcome of MI, stroke or CV death while a reduction in MI (HR 0.63; 95% CI 0.42-0.96; p = 0.028) with increased minor bleeding (odds ratio 1.99; 95% CI 1.69-2.34; p < 0.001) was noted in those treated with dual antiplatelet therapy over 18 months of follow-up.10 Thus, option A is incorrect.
The overall benefit of vorapaxar (answer option B) in addition to existing antiplatelet therapy remains uncertain (Class IIb in the current ACC/AHA guidelines).3 Vorapaxar is an antagonist of protease-activated receptor-1, a primary receptor for thrombin on human platelets also present on vascular smooth muscle and endothelium. In a study with stable atherosclerotic vascular disease including 3787 symptomatic PAD patients randomized to vorapaxar in addition to baseline antiplatelet therapy versus placebo, there were significant reductions in hospitalization for acute limb ischemia (2.3% vs. 3.9%; HR 0.58' 95% CI 0.39-0.86; p = 0.006) and peripheral artery revascularization (18.4% vs. 22.2%; HR 0.85; 95% CI 0.73-0.97; p = 0.017) in those randomized to vorapaxar with higher bleeding rates (7.4 vs. 4.5%; HR 1.62; 95% CI 1.21-2.18; p = 0.001) at 2-year median follow-up. There was no difference in the primary endpoint of stroke, MI or CV death.11 A subsequent 3-year follow-up analysis demonstrated significant reductions in acute limb ischemic events in these patients.12 However, the addition of vorapaxar did not reduced CV endpoints, and the study involving patients with prior stroke was stopped early due to increased bleeding complications. Given this patient's history of stroke and our interest in reducing both CV and limb-related events, option B is incorrect.
There is no evidence supporting therapeutic anticoagulation monotherapy or combination therapy with an antiplatelet therapy (answer option D) for reducing the risk of cardiovascular ischemic events in PAD patients. Current guidelines recommend against its use for this purpose (Class III: Harm).3,13-15 For instance, in a study involving 2161 patients with PAD randomized to an antiplatelet agent plus therapeutic warfarin versus antiplatelet therapy alone, there were no differences in the primary endpoint of MI, stroke or CV death at 35 months [12.4 vs. 13.3%; risk ratio (RR) 0.92; 95% CI 0.73, 1.16; p = 0.48] while a significant increase in life-threatening bleeding was observed in those receiving combination therapy with warfarin (4% vs. 1.2%; RR 3.41; 95% CI 1.84, 6.35; p < 0.001).15
While dipyridamole (answer option E) is often used for the secondary prevention of stroke in combination with aspirin (Aggrenox (R)), the data involving patients with PAD is limited, and it is not recommended in the current guidelines.3,16-17
References
Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319-30.
Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2017. [Epub ahead of print]
Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;69:1465-1508.
Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
Critical Leg Ischaemia Prevention Study (CLIPS) Gropu, Catalano M, Born G, Peto R. Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial. J Intern Med 2007;261:276-84.
Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA 2009;301:1909-19.
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39.
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). Eur Heart J 2018;39:763-816.
Hiatt WR, Fowkes FG, Heizer G, et al. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med 2017;376:32-40.
Cacoub PP, Bhatt DL, Steg PG, Topol EJ, Creager MA, CHARISMA Investigators. Patients with peripheral arterial disease in the CHARISMA trial. Eur Heart J 2009;30:192-201.
Bonaca MP, Scirica BM, Creager MA, et al. Vorapaxar in patients with peripheral artery disease: results from TRA2oP-TIMI 50. Circulation 2013;127:1522-9.
Bonaca MP, Gutierrez JA, Creager MA, et al. Acute limb ischemia and outcomes with vorapaxar in patients with peripheral artery disease: results from the trial to assess the effects of vorapaxar in preventing heart attack and stroke in patients with atherosclerosis-thrombolysis in myocardial infarction 50 (TRA2oP-TIMI 50). Circulation 2016;133:997-1005.
Alonso-Coello P, Bellmunt S, McGorrian C, et al. Antithrombotic therapy in peripheral artery disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e669S-90S.
Johnson WC, Williford WO, Department of Veterans Affairs Cooporative Study #362. Benefits, morbidity, and mortality associated with long-term administration of oral anticoagulant therapy to patients with peripheral arterial bypass procedures: a prospective randomized study. J Vasc Surg 2002;35:413-21.
Warfarin Antiplatelet Vascular Evaluation Trial Investigators, Anand S, Yusuf S, , et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007;357:217-27.
Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy--II: maintenance of vascular graft or arterial patency by antiplatelet therapy. BMJ 1994;308:159-68.
Kohler TR, Kaufman JL, Kacoyanis G, et al. Effect of aspirin and dipyridamole on the patency of lower extremity bypass grafts. Surgery 1984;96:462-6.
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