Abstract
Abstract. This review treats antithrombotic use for peripheral arterial disease (PAD). In asymptomatic patients, there are no scientific data to support single antiplatelet therapy (SAPT) for primary prophylaxis. In symptomatic PAD, SAPT with aspirin or clopidogrel is indicated. The efficacy of aspirin is controversial. Clopidogrel may be preferred over aspirin. Ticagrelor is not superior to clopidogrel in reducing major adverse cardiovascular events and major adverse limb events, but lowers the risk of ischaemic stroke. In symptomatic PAD, dual antiplatelet therapy (DAPT) with clopidogrel and aspirin does not provide benefit over SAPT with aspirin alone and is associated with increased risk of major bleeding. DAPT with ticagrelor 60 mg b. i. d. and aspirin provides a significant major adverse cardiovascular events reduction in symptomatic PAD patients and may be considered in PAD patients with prior myocardial infarction. The use of a new thrombin receptor antagonist, vorapaxar, on top of SAPT or DAPT with aspirin and/or clopidogrel, reduces the risk of acute limb ischaemia and peripheral artery revascularization in patients with symptomatic PAD, at the cost of an increased risk for bleeding. Rivaroxaban (2.5 mg b. i. d.) plus aspirin (100 mg daily) is the first antithrombotic association that proved significant benefit for PAD patients, in terms of strong endpoints – total mortality and cardiovascular mortality. Therefore, this association shows the strongest evidence for secondary prevention of symptomatic PAD patients. In PAD patients undergoing percutaneous peripheral interventions, at least four weeks of DAPT with aspirin and clopidogrel is recommended after infrainguinal stent implantation. Stenting below-the-knee arteries is often followed by a longer period of DAPT, but no specific evidence is available. Anticoagulation is mandatory to prevent arterial occlusion during radial or brachial invasive procedures. The strategy includes use of unfractioned heparin, bivalirudin or enoxaparin. Vitamin K antagonists may be considered after autologous vein infrainguinal bypass.
Literature
. Noninvasively diagnosed peripheral arterial disease as a predictor of mortality: results from a prospective study. Circulation. 1985;72:768–73.
Perioperative use of aspirin for patients undergoing carotid endarterectomy. Vasa. 2012;41:282–7.
Secondary medical prevention in patients with peripheral arterial disease – prescriptions of vascular surgeons and medical doctors (angiologists) in a multidisciplinary vascular centre. Vasa. 2010;39:145–52.
Platelet activation is increased in peripheral arterial Disease. J Vasc Surg. 2003;38(1):99–103.
Dual antiplatelet therapy responsiveness in patients undergoing percutaneous revascularization for peripheral arterial occlusive disease. J Am Coll Cardiol. 2012;59(13):E2049.
Coagulation, fibrinolysis and platelet P-selectin expression in peripheral vascular disease. Eur J Vasc Endovasc Surg. 2001;21:147–54.
Increased platelet aggregation and activation in peripheral arterial disease. Eur J Vasc Endovasc Surg. 2003;25:16–22.
A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization. Circulation. 2017;135(25):2534–55.
. Is aspirin still the drug of choice for management of patients with peripheral arterial disease? Vasa. 2013;42:88–95.
. An aspirin a day: Are we barking up the wrong willow tree? Pharmacotherapy. 2010;30:115–8.
. Antiplatelet therapy for peripheral arterial disease and critical limb ischemia: Guidelines abound, but where are the data? J Cardiovasc Pharmacol Ther. 2015;20:144–56.
Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: A randomized controlled trial. JAMA. 2010;303:841–8.
The prevention of progression of arterial disease and diabetes (POPADAD) trial: Factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ. 2008;337:a1840.
. Antithrombotic therapy in peripheral artery disease. Vasc Med. 2016;21(2):156–69.
ASCEND . A Study of Cardiovascular Events in Diabetes. http://www.ctsu.ox.ac.uk/ascend.Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D): design of a randomized study of the efficacy of low-dose aspirin in the prevention of cardiovascular events in subjects with diabetes mellitus treated with statins. Trials. 2007;8:21.
Feasibility of conducting a primary prevention trial of low-dose aspirin for major adverse cardiovascular events in older people in Australia: results from the ASPirin in Reducing Events in the Elderly (ASPREE) pilot study. Med J Aust. 2008;189:105–9.
Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) Trial. http://www.arrive- study.com.
2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2016;37:2315–81.
2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases. Eur Heart J. 2017;00:1–60.
. “Aspirin–resistance”? A few critical considerations on definition, terminology, diagnosis, clinical value, natural course of atherosclerotic disease, and therapeutic consequences. Vasa. 2011;40:429–38.
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.
Aspirin for the Prevention of Cardiovascular Events in Patients With Peripheral Artery Disease A Meta-analysis of Randomized Trials. JAMA. 2009;301(18):1909–19.
Critical Leg Ischaemia Prevention Study Group . Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: Randomized, double-blind trial. J Intern Med. 2007;261:276–84.Contemporary cardiovascular risk and secondary preventive drug treatment patterns in peripheral artery disease patients undergoing revascularization. J Vasc Surg. 2016;64(4):1009–17.
CAPRIE Steering Committee . A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329–39.Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–57.
Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med. 2017;376:32–40.
Ticagrelor compared with clopidogrel in patients with prior lower extremity revascularization for peripheral artery disease. Circulation. 2017;135:241–50.
Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. J Intern Med. 1990;227:301–8.
German guideline on the diagnosis and treatment of peripheral artery disease – a comprehensive update 2016. Vasa. 2017;46:79–86.
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502.
Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA. 2002;288:2411–20.
Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706–17.
Patients with peripheral arterial disease in the CHARISMA trial. Eur Heart J. 2009;30:192–201.
Long-Term Use of Dual Antiplatelet Therapy For The Secondary Prevention of Atherothrombotic Events: Meta-analysis of Randomized Controlled Trials. Cardiovasc Revasc Med. 2017;18(1):10–5.
Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. N Engl J Med. 2015;372(19):1791–800.
Efficacy and Safety of Ticagrelor as Long-Term Secondary Prevention in Patients with Peripheral Artery Disease and Prior Myocardial Infarction. J Am Coll of Cardiol. 2016;67(23):2719–28.
Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366:1404–13.
Vorapaxar in patients with peripheral artery disease: Results from TRA2P-TIMI 50. Circulation. 2013;127:1522–9.
Peripheral Revascularization in Patients With Peripheral Artery Disease With Vorapaxar: Insights From the TRA2P-TIMI 50 Trial. JACC Cardiovasc Interv. 2016;9(20):2157–64.
WAVE Trial Investigators . Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 2007;357:217–27.Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017 Oct 5;377(14):1319–1330.
. An important step for thrombocardiology. N Engl J Med. 2017 Oct 5;377(14):1387–1388.
Efficacy and safety of rivaroxaban in reducing the risk of major thrombotic vascular events in subjects with symptomatic peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities (VOYAGER PAD). ClinicalTrials.gov Identifier: NCT02504216. Available at: https://clinicaltrials.gov/ct2/show/NCT02504216.
A review of antithrombotic therapy and the rationale and design of the randomized edoxaban in patients with peripheral artery disease (ePAD) trial adding edoxaban or clopidogrel to aspirin after femoropopliteal endovascular intervention. J Endovasc Ther. 2015;22:261–8.
Response to antiplatelet therapy and platelet reactivity to thrombin receptor activating peptide-6 in cardiovascular interventions: Differences between peripheral and coronary angioplasty. Atherosclerosis. 2014;232(1):119–24.
Platelet-reactivity tests identify patients at risk of secondary cardiovascular events: a systematic review and meta-analysis. J Thromb Haemost. 2014;12(5):736e47.
. Long-Term Prognosis of Patients With Peripheral Arterial Disease. A Comparison in Patients With Coronary Artery Disease. J Am Coll Cardiol. 2008;51(16):1588–96.
. Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following peripheral endovascular treatment (Review). Cochrane Database Syst Rev. 2012 Aug 15;(8):CD002071.
Management of peripheral arterial interventions with mono or dual antiplatelet therapy – The MIRROR study: A randomised and double-blinded clinical trial. Eur Radiol. 2012;22:1998–2006.
Cilostazol reduces restenosis after endovascular therapy in patients with femoropopliteal lesions. J Vasc Surg. 2008;48:144–9.
. Anticoagulation in coronary intervention. Eur Heart J. 2016;37:3376–85.
. Low-dose aspirin combined with dipyridamole versus anticoagulants after femoropopliteal percutaneous transluminal angioplasty. Radiology. 1994;193:567–71.
Nd:YAG laser with sapphire tip combined with balloon angioplasty in peripheral arterial occlusions. Long-term results. Circulation. 1991;83:141–7.
Zur Rezidivprophylaxe nach perkutaner transluminaler Angioplastie (PTA): Antikoagulation versus Ticlopidin. Vasa. 1987;16(Suppl. 20):355–6.
Low-molecular-weight heparin for prevention of restenosis after femoropopliteal percutaneous transluminal angioplasty: a randomized controlled trial. J Vasc Surg. 2006;44:1247–53.
. Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial. J Vasc Surg. 2010;52:825–33.
WAVE Trial Investigators . The effects of oral anticoagulants in patients with peripheral arterial disease: Rationale, design and baseline characteristics of the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, including a meta-analysis of trials. Am Heart J. 2006;151:1–9.. 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.
Dutch Bypass Oral Anticoagulants or Aspirin (BOA) Study Group . Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (the Dutch Bypass Oral Anticoagulants or Aspirin Study): A randomised trial. Lancet. 2000;355:346–51.. Do we have to change therapeutic considerations in peripheral arterial disease? Vasa. 2018;47:5–6.
Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017 Nov 10. doi: 10.1016/S0140-6736(17)32409-1.
