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Medical therapy and follow-up in patients with lower extremity arterial disease

Written by Maarit Venermo2020
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 Introduction

Although its exact prevalence is unknown, lower extremity arterial disease (LEAD) is estimated to affect 200 million people worldwide. In 2008, almost 100,000 endovascular procedures and over 86,000 surgical revascularizations were performed for lower limb arterial disease in Germany alone, illustrating the burden of peripheral revascularization interventions in Europe1Eickmeyer F, Moysidis T, Nowak T, Fifer B, Santosa F, Luther B, et al. Trends in lower extremity surgical and endovascular revascularization in Germany. Vasa. 2011;40(5):398-403.. The majority of the patients with LEAD are asymptomatic. Yet, asymptomatic LEAD is also a marker of significant systemic atherosclerosis, with associated cardiovascular (CV) mortality rates at 1, 5, and 10 years as high as 12%, 42% and 65%, respectively2Laivuori M, Hakovirta H, Kauhanen P, Sinisalo J, Sund R, Alback A, et al. Toe pressure should be part of a vascular surgeon’s first-line investigation in the assessment of lower extremity artery disease and cardiovascular risk of a patient. J Vasc Surg. 2020.. Thus, all patients with LEAD require risk factor modification and medical management to slow down the progression of the atherosclerosis. As it is usually a progressive disease, regular follow-up of patients with LEAD is recomended to check compliance with risk factor modification, and provide motivation, where needed. In more severe disease, lower limb revascularization is indicated to preserve functional ability and quality of life, as well as to prevent amputation (and death). Follow-up after revascularization aims to ensure implementation of preventive strategies to avoid other cardiovascular events and disease progression, as well as the recurrence of symptoms and the need for redo revascularization.

Medical therapy and follow-up of asymptomatic patients and conservatively treated symptomatic patients

An ankle brachial pressure index (ABPI) of less than 0.90 is 95% sensitive in identifying angiographically confirmed LEAD. Interestingly, more than 50% of people with an abnormal ABPI do not have typical symptoms of claudication or chronic limb-threatening ischaemia (CLTI). However, even in the absence of symptoms, all patients presenting with LEAD (ABPI < 0.9) are at increased risk of cardiovascular events, including myocardial infarction (MI), stroke and cardiovascular death2Laivuori M, Hakovirta H, Kauhanen P, Sinisalo J, Sund R, Alback A, et al. Toe pressure should be part of a vascular surgeon’s first-line investigation in the assessment of lower extremity artery disease and cardiovascular risk of a patient. J Vasc Surg. 2020., 3Wickstrom JE, Laivuori M, Aro E, Sund RT, Hautero O, Venermo M, et al. Toe Pressure and Toe Brachial Index are Predictive of Cardiovascular Mortality, Overall Mortality, and Amputation Free Survival in Patients with Peripheral Artery Disease. Eur J Vasc Endovasc Surg. 2017;53(5):696-703., 4Diehm C, Allenberg JR, Pittrow D, Mahn M, Tepohl G, Haberl RL, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation. 2009;120(21):2053-61.. Based on population studies, the estimated ratio of asymptomatic to symptomatic LEAD  is as high as 3:15Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg. 2007;33 Suppl 1:S1-75.. There is wide agreement that risk factor modification is indicated for any patient with lower extremity LEAD, regardless of the presence or severity of symptoms.

Antithrombotic therapy

According to best current evidence, asymptomatic LEAD alone is not an indication for antithrombotic medication, and, at present, it is not indicated routinely6Fowkes FG, Price JF, Stewart MC, Butcher I, Leng GC, Pell AC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA. 2010;303(9):841-8.,7Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T, 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 arteriesEndorsed 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(9):763-816.. In patients with symptomatic LEAD, numerous studies have demonstrated that aspirin (ASA) therapy significantly lowers the risk of combined non-fatal MI, stroke, and CV death8Berger 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(18):1909-19.,9Collaborative overview of randomised trials of antiplatelet therapy–I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ. 1994;308(6921):81-106.. Clopidogrel may be used instead of ASA for risk reduction in symptomatic LEAD. In a post hoc analysis of clopidogrel versus ASA in the Patients at Risk of Ischaemic Events (CAPRIE) trial, clopidogrel was significantly better than ASA in the subgroup of symptomatic patients with LEAD, with significant reductions in CV mortality (hazard ratio [HR] 0.76 [95% CI 0.64–0.91]) and major adverse cardiovascular events (MACE) (HR 0.78 [95% CI 0.65–0.93])10Committee CS. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348(9038):1329-39.. Furthermore, gastrointestinal bleeding was significantly less common in patients who took clopidogrel, 1.99%, compared to those on ASA (2.66%, p < .05). Severe gastrointestinal bleeding rate occurred in 0.49% of patients on clopidogrel and 0,71% on ASA (p < .05). Thus, clopidogrel is recommended over ASA, especially in patients with history of gastrointestinal bleeding.

The COMPASS trial, which was a multi-centre, double-blind, randomised placebo-controlled trial, enrolled 7,470 patients with peripheral arterial disease (PAD) and compared the combination of low-dose rivaroxaban (2.5 mg x 2) plus ASA (100 mg x 1) with ASA (100 mg x 1) alone in the reduction of CV death, MI or stroke. The primary PAD outcome was major adverse limb events, including major amputation11Anand SS, Eikelboom JW, Dyal L, Bosch J, Neumann C, Widimsky P, et al. Rivaroxaban Plus Aspirin Versus Aspirin in Relation to Vascular Risk in the COMPASS Trial. J Am Coll Cardiol. 2019;73(25):3271-80.. The PAD patient group included:  those with previous peripheral bypass surgery or angioplasty, limb or foot amputation, or intermittent claudication with objective evidence of PAD; a carotid group which included:  previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%; and a group with coronary artery disease and an ABPI < 0.90. The combination of rivaroxaban plus ASA (dual pathway inhibition), compared with ASA alone, reduced the composite end point of CV death, MI or stroke (5% vs 7%; HR 0.72, 95% CI 0.57–0.90, p= .047), as well as major adverse limb events, including major amputation (1% vs 2%; HR 0.54 95% CI 0.35–0.82, p = 0.0037). The third arm in the COMPASS trial received rivaroxaban alone 5 mg twice a day. Compared with patients receiving ASA alone, these patients did not have significantly fewer composite end points (HR 0·86, 95% CI 0.69–1.08, p=.19), but they did have fewer major adverse limb events, including major amputation (HR 0.67, 95% CI 0.45–1.00, p = .05). The median duration of treatment was 21 months. The use of the rivaroxaban plus ASA combination increased major bleeding events when compared with ASA alone (3% vs 2%; HR 1.61, 95% CI 1.12–2.31, p = 0.0089); bleeding that was observed was mainly gastrointestinal. Although major bleeding was increased, fatal or critical organ bleeding was not. These results suggest that low-dose rivaroxaban taken twice a day plus ASA once a day is beneficial and should be considered for high-risk patients, especially patients with PAD and stable coronary artery disease. However, the risk of bleeding must be evaluated individually, and dual pathway inhibition is not recommended if the risk is significant.

A combination of ASA and clopidogrel (dual antiplatelet therapy, DAPT) may also be beneficial in very-high-risk patients who are not considered to be at an increased risk of bleeding. A statistically significant benefit, documented as a reduction in MI, stroke or death, was noted in patients with symptomatic lower extremity ischaemia treated with ASA and clopidogrel, when compared with those who received ASA and placebo12Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007;49(19):1982-8.. However, vessel patency rates were not better, and MACE were not reduced.

Ticagrelor and clopidogrel have been compared in symptomatic patients with LEAD in a large randomized trial (EUCLID), but no significant difference between the drugs was seen in the incidence of MACE or major bleeding13Baumgartner I, Norgren L, Fowkes FGR, Mulder H, Patel MR, Berger JS, et al. Cardiovascular Outcomes After Lower Extremity Endovascular or Surgical Revascularization: The EUCLID Trial. J Am Coll Cardiol. 2018;72(14):1563-72.

Cholesterol-lowering therapy

Cholesterol-lowering therapy is recommended for all patients with LEAD regardless of symptoms, to reduce the risk of myocardial cardiovascular events and mortality. The target level for serum low-density lipoprotein cholesterol (LDL-C) is < 1.8 mmol/L (< 70 mg/dL), or a decrease of ≥ 50% if the initial LDL-C level is between 1.8 and 3.5 mmol/L (70 and 135 mg/dL)7Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T, 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 arteriesEndorsed 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(9):763-816.. In the Reduction of Atherothrombosis for Continued Health (REACH) registry, statin use was associated with a 17% decrease in major CV events14Kumbhani DJ, Steg PG, Cannon CP, Eagle KA, Smith SC, Jr., Goto S, et al. Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. Eur Heart J. 2014;35(41):2864-72.. Combination treatment with ezetimibe or evolocumab is an acceptable alternative15Murphy SA, Cannon CP, Blazing MA, Giugliano RP, White JA, Lokhnygina Y, et al. Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial. J Am Coll Cardiol. 2016;67(4):353-61.,16Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-22..  In the FOURIER trial, use of additional evolocumab in patients who did not reach LDL targets with statin alone reduced CV events in patients with LEAD and a history of stroke and/or MI, as well as those with LEAD alone. The mean LDL level in the study group was 0.78 mmol/l, and the benefit increased linearly with the lowering of the LDL level16Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-22..

Smoking cessation

Smoking is a strong risk factor for the development of LEAD, and also the progression of atherosclerosis. It is a known contributor to the development of coronary atherosclerosis, but an even more powerful risk factor in the development of LEAD. The highest relative risk associated with LEAD is current smoking of 25 or more cigarettes daily (OR = 7.3, 95% CI 4.2–12.8)17Fowler B, Jamrozik K, Norman P, Allen Y. Prevalence of peripheral arterial disease: persistence of excess risk in former smokers. Aust N Z J Public Health. 2002;26(3):219-24.. The multivariate adjusted hazard ratio according to pack-years of smoking is 2.52 (1.49–4.25) for fewer than 10, 6.75 (4.33–10.52) for 10–30, and 11.09 (6.94–17.72) for over 30 pack-years18Tracy RP, Psaty BM, Macy E, Bovill EG, Cushman M, Cornell ES, et al. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol. 1997;17(10):2167-76..

Diabetes combined with smoking has a high positive predictive value for asymptomatic LEAD (15%); when neither is present, the risk of asymptomatic LEAD is only 1%19Eason SL, Petersen NJ, Suarez-Almazor M, Davis B, Collins TC. Diabetes mellitus, smoking, and the risk for asymptomatic peripheral arterial disease: whom should we screen? J Am Board Fam Pract. 2005;18(5):355-61.. In the Framingham study, among the patients who did not have claudication at baseline, smokers developed claudication twice as often as non-smokers during 16 years’ follow-up, and the relationship was dose-dependent. In large epidemiological studies, smoking increases the risk of developing PAD from two- to six-fold, with heavy smokers being at highest risk20Bowlin SJ, Medalie JH, Flocke SA, Zyzanski SJ, Goldbourt U. Epidemiology of intermittent claudication in middle-aged men. Am J Epidemiol. 1994;140(5):418-30., 21Smith GD, Shipley MJ, Rose G. Intermittent claudication, heart disease risk factors, and mortality. The Whitehall Study. Circulation. 1990;82(6):1925-31., 22Fowkes FG, Housley E, Riemersma RA, Macintyre CC, Cawood EH, Prescott RJ, et al. Smoking, lipids, glucose intolerance, and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study. Am J Epidemiol. 1992;135(4):331-40.. Thus, smoking cessation is crucial in the management of all people with LEAD. Smoking cessation reduces deaths from CHD, as well as the rates of lower extremity interventions and amputations in both men and women. Smoking cessation equally important in asymptomatic and symptomatic LEAD. Furthermore, smoking is associated with accelerated graft failure after lower extremity revascularization23Willigendael EM, Teijink JA, Bartelink ML, Peters RJ, Buller HR, Prins MH. Smoking and the patency of lower extremity bypass grafts: a meta-analysis. J Vasc Surg. 2005;42(1):67-74.,24Faulkner KW, House AK, Castleden WM. The effect of cessation of smoking on the accumulative survival rates of patients with symptomatic peripheral vascular disease. Med J Aust. 1983;1(5):217-9..

Medical therapy and follow-up after revascularization

Antithrombotic therapy

Single antiplatelet therapy with ASA or clopidogrel is indicated for all patients with symptomatic LEAD, and the patient should be on the medication preoperatively. Antiplatelet therapy decreases the risk of cardiovascular events and, after revascularisation, may also improve early graft patency9Collaborative overview of randomised trials of antiplatelet therapy–I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ. 1994;308(6921):81-106., 25Girolami B, Bernardi E, Prins MH, ten Cate JW, Prandoni P, Simioni P, et al. Antiplatelet therapy and other interventions after revascularisation procedures in patients with peripheral arterial disease: a meta-analysis. Eur J Vasc Endovasc Surg. 2000;19(4):370-80., 26Watson HR, Belcher G, Horrocks M. Adjuvant medical therapy in peripheral bypass surgery. Br J Surg. 1999;86(8):981-91., 27Collins TC, Souchek J, Beyth RJ. Benefits of antithrombotic therapy after infrainguinal bypass grafting: a meta-analysis. Am J Med. 2004;117(2):93-9., 28Collaborative overview of randomised trials of antiplatelet therapy–II: Maintenance of vascular graft or arterial patency by antiplatelet therapy. Antiplatelet Trialists’ Collaboration. BMJ. 1994;308(6922):159-68.. Dual antiplatelet therapy is currently recommended for at least one month after endovascular revascularization. Rivaroxaban 2.5 mg twice daily combined with ASA is beneficial after revascularization in patients who do not have increased risk of bleeding.

In a Cochrane database systematic review on the effects of antiplatelet agents in the prevention of thrombosis in individuals with lower limb atherosclerosis who underwent femoro-popliteal or femoro-distal bypass grafting, 16 studies with 5,683 participants were included. The treatments compared in six studies, which allowed robust conclusions, were ASA alone or ASA with dipyridamole (ASA/DIP) versus placebo or nothing. Significantly better graft patency was seen in the ASA or ASA/DIP treatment group compared to placebo (OR 0.42; 95% CI 0.22–0.83; p =  .01; 952 participants). This effect was seen for both venous grafts and prosthetic grafts at any of the time points up to 12 months (OR 0.19, 95% CI 0.10–0.36; p<  .00001; 222 participants). No difference was seen in any of the side effects, including general and gastrointestinal side effects, bleeding and wound/graft infection. Furthermore, the rates of amputation, CV events and deaths were similar between the treatment groups29Bedenis R, Lethaby A, Maxwell H, Acosta S, Prins MH. Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery. Cochrane Database Syst Rev. 2015(2):CD000535..

The CASPAR study compared clopidogrel and ASA versus ASA alone in 851 patients after a bypass operation, and there was no difference in primary patency at 24 months for any graft type. However, the total bleeding rate was higher in those who had clopidogrel and ASA (OR 2.65, 95% CI 1.69–4.15), although no difference in major or fatal bleeding (2.1 vs 1.2%). There was no difference between the treatment groups in limb amputations or mortality. In patients with a prosthetic graft, the primary efficacy end point was reduced in patients receiving DAPT (HR 0.65, 95% CI 0.45–0.95). For vein bypasses, there was no significant difference in the incidence of primary events30Belch JJ, Dormandy J, Committee CW, Biasi GM, Cairols M, Diehm C, et al. Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial. J Vasc Surg. 2010;52(4):825-33, 33 e1-2..

Two studies have compared ASA or ASA/DIP with vitamin K antagonists , but no differences were seen between the groups in primary graft patency at 3, 6, 12 or 24 months, or in the rate of major amputations, cardiovascular events or deaths. In the Dutch Bypass Oral Anticoagulants or Aspirin Study, graft patency was similar with ASA (or ASA/dipyridamole) and a vitamin K antagonists after 2 years of follow-up (HR 0.64, 95% CI 0.25–1.63), and the mortality and amputation rates were similar31Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral Anticoagulants or Aspirin Study): a randomised trial. Lancet. 2000;355(9201):346-51.. The risk of major bleeding, however, was doubled with vitamin K antagonists. There were significantly fewer veins bypass occlusions with a vitamin K antagonist (HR 0.69, 95% CI 0.51–0.94). Similarly, in a second study, no significant difference was seen in graft patency, but the risk of bleeding was doubled with vitamin K antagonists and ASA, compared to ASA alone32Johnson WC, Williford WO, Department of Veterans Affairs Cooperative S. 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(3):413-21.. A study that compared dual antiplatelet therapies with vitamin K antagonists and clopidogrel in 341 femoro-popliteal bypasses showed a slightly lower graft failure rate with clopidogrel, but a higher bleeding rate, and no effect on MACE32Johnson WC, Williford WO, Department of Veterans Affairs Cooperative S. 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(3):413-21..

The results of the VOYAGER PAD were published in 2020 [33]. Some 6364 patients who underwent lower extremity revascularization due to LEAD were randomized to receive rivaroxaban (2.5 mg twice daily) plus ASA or placebo plus ASA. The primary efficacy outcome was a composite of endpoints acute limb ischaemia, major amputation for vascular causes, myocardial infarction, ischaemic stroke, or death from CV cause after lower-extremity revascularization. The principal safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) ; the secondary safety outcome was major bleeding as defined by the International Society on Thrombosis and Haemostasis . A total of 3286 patients were assigned to a rivaroxaban group, and 3278 were assigned to placebo. The primary efficacy outcome occurred in 508 and 584 patients in the groups respectively; the Kaplan-Maier estimates of the incidence at 3 years were 17.3% in the rivaroxaban and ASA group and 19.9% in the ASA alone group (HR 0.85, 95% CI 0.76 – 0.96; P = .009). TIMI major bleeding rates were 2.65% and 1.87% respectively (HR 1.43; 95% CI 0.97 – 2.10; P = .07). ISTH major bleeding occurred in 5.94% and 4.06% respectively (HR 1.42; 95% CI, 1.10 – 1.84; P = .007)33Capell WH, Bonaca MP, Nehler MR, Chen E, Kittelson JM, Anand SS, et al. Rationale and design for the Vascular Outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD). Am Heart J. 2018;199:83-91..

Anticoagulation has been tested prospectively after percutaneous infra-inguinal revascularization, with no benefit in terms of patency, but with a significantly increased of bleeding34Dagher NN, Modrall JG. Pharmacotherapy before and after revascularization: anticoagulation, antiplatelet agents, and statins. Semin Vasc Surg. 2007;20(1):10-4..

Antithrombotic therapy after redo revascularization

The evidence on the optimal antiplatelet medication after redo procedures for earlier revascularization is sparse. After bypass, the incidence of vein graft stenosis during the first year is 20%, and the treatment is usually endovascular, 35Wilson YG, Davies AH, Currie IC, Morgan M, McGrath C, Baird RN, et al. Vein graft stenosis: incidence and intervention. Eur J Vasc Endovasc Surg. 1996;11(2):164-9., 36Bandyk DF, Bergamini TM, Towne JB, Schmitt DD, Seabrook GR. Durability of vein graft revision: the outcome of secondary procedures. J Vasc Surg. 1991;13(2):200-8; discussion 9-10..  After redo revascularization, the aim is to increase the anticoagulation effect, whilst mindful of the risk of bleeding. After endovascular treatment for vein graft stenosis, 1–6-month dual antiplatelet treatment with ASA and clopidogrel is usually prescribed unless the patient has an increased bleeding risk7Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T, 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 arteriesEndorsed 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(9):763-816., 37Venermo M, Sprynger M, Desormais I, Bjorck M, Brodmann M, Cohnert T, et al. Editor’s Choice – Follow-up of Patients After Revascularisation for Peripheral Arterial Diseases: A Consensus Document From the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases and the European Society for Vascular Surgery. Eur J Vasc Endovasc Surg. 2019;58(5):641-53.. After revascularization following vein graft occlusion, anticoagulants (usually low-molecular weight heparin [LMWH]; in the longer term vitamin K antagonist) are combined with antiplatelet therapy (ASA or clopidogrel) for at least one month, but after several occlusions this may even entail lifelong treatment. The treatment should be tailored according to the cause of the graft occlusion, to previous thrombotic events (particularly previous graft occlusions) and to the risk of bleeding. Furthermore, possible resistance for antithrombotic agents should be tested. After a prosthetic bypass occlusion, long-term anticoagulation should be considered38Liang NL, Baril DT, Avgerinos ED, Leers SA, Makaroun MS, Chaer RA. Comparative effectiveness of anticoagulation on midterm infrainguinal bypass graft patency. J Vasc Surg. 2017;66(2):499-505 e2.. In a registry-based study on 7,612 bypass operations extracted from the Vascular Quality Initiative, a propensity-weighted analysis showed no significant benefit from anticoagulation on primary patency in the overall cohort (HR 0.98; 95% CI 0.86–1.11; p = .8) but did demonstrate improved secondary patency in those with a prosthetic bypass graft (HR 0.77; 95% CI 0.62–0.96; p = .02) or a prosthetic bypass to an infrapopliteal target (HR 0.72; 95% CI 0.54–0.97; p = .02). Considering the lack of data on direct oral anticoagulants used for this indication, long-term vitamin K antagonists are usually recommended37Venermo M, Sprynger M, Desormais I, Bjorck M, Brodmann M, Cohnert T, et al. Editor’s Choice – Follow-up of Patients After Revascularisation for Peripheral Arterial Diseases: A Consensus Document From the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases and the European Society for Vascular Surgery. Eur J Vasc Endovasc Surg. 2019;58(5):641-53..)

After an endovascular reintervention, treatment with ASA and clopidogrel should be considered for longer than after the first intervention, and at least for 3 months, taking into account the patient’s bleeding risk and the location of the lesion (shorter duration for proximal lesions). These recommendations are based on expert opinion, as no good-quality comparative studies exist37Venermo M, Sprynger M, Desormais I, Bjorck M, Brodmann M, Cohnert T, et al. Editor’s Choice – Follow-up of Patients After Revascularisation for Peripheral Arterial Diseases: A Consensus Document From the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases and the European Society for Vascular Surgery. Eur J Vasc Endovasc Surg. 2019;58(5):641-53..

Follow-up after revascularization

Follow-up after revascularization may vary according to the indication for,  and the type of revascularization, as well as the patient’s general physical condition.

Patients with multisite artery disease more often have progressive atherosclerosis in all vascular beds and have a higher incidence of CV events39Bhatt DL, Steg PG, Ohman EM, Hirsch AT, Ikeda Y, Mas JL, et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA. 2006;295(2):180-9., 40Nicoloff AD, Taylor LM, Jr., Sexton GJ, Schuff RA, Edwards JM, Yeager RA, et al. Relationship between site of initial symptoms and subsequent progression of disease in a prospective study of atherosclerosis progression in patients receiving long-term treatment for symptomatic peripheral arterial disease. J Vasc Surg. 2002;35(1):38-46; discussion -7.. In a meta-analysis, as many as one in five patients who suffered from intermittent claudication developed CLTI, and 4%–27% of them underwent amputation during 5-year follow-up41Sigvant B, Lundin F, Wahlberg E. The Risk of Disease Progression in Peripheral Arterial Disease is Higher than Expected: A Meta-Analysis of Mortality and Disease Progression in Peripheral Arterial Disease. Eur J Vasc Endovasc Surg. 2016;51(3):395-403.. Therefore, it is important to try to limit the progression of atherosclerosis by risk factor modification, as well as exercise and medical therapy. A regular follow-up programme of monitoring should involve the assessment of atherosclerosis in both legs and clinical manifestations of atherosclerosis in other clinical sites, such as coronary and carotid arteries, and the abdominal aorta7Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T, 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 arteriesEndorsed 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(9):763-816.. The follow-up procedures for the revascularized leg are slightly different after bypass and endovascular therapy.

After revascularization for CLTI, follow-up and wound care is recommended until the wounds have healed, and 30-day as well as 3–6 and 12-month surveillance is recommended. After wound healing, annual appointments with vascular physicians/surgeons should be organized to check for symptoms, feet condition, ABPI and CV risk factors, with the option of checking toe pressures and TcPO2 if needed (Table 1)7Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T, 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 arteriesEndorsed 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(9):763-816.).

Bypass surgery

Almost 15% of bypass grafts that fail do so during the first month, a further 80% during the first two years and no more than 5% thereafter42Mills JL. Mechanisms of vein graft failure: the location, distribution, and characteristics of lesions that predispose to graft failure. Semin Vasc Surg. 1993;6(2):78-91., 43Shah DM, Darling RC, 3rd, Chang BB, Fitzgerald KM, Paty PS, Leather RP. Long-term results of in situ saphenous vein bypass. Analysis of 2058 cases. Ann Surg. 1995;222(4):438-46; discussion 46-8.. While bypass failure in the early phase is generally associated with technical errors at the time of surgery, the main cause during the mid-term is intimal hyperplasia. Approximately 80% of the bypass graft stenoses are asymptomatic44Disselhoff B, Buth J, Jakimowicz J. Early detection of stenosis of femoro-distal grafts. A surveillance study using colour-duplex scanning. Eur J Vasc Surg. 1989;3(1):43-8., 45Ihlberg L, Luther M, Alback A, Kantonen I, Lepantalo M. Does a completely accomplished duplex-based surveillance prevent vein-graft failure? Eur J Vasc Endovasc Surg. 1999;18(5):395-400.. The sensitivity of the ABPI to detect imminent graft failure is poor, although a drop of > 0.15 has been suggested to detect failure. Duplex ultrasound (DUS) is effective in detecting anastomotic or graft stenosis, as a three-fold increase in peak systolic velocity suggests significant stenosis. Therefore, ABPI should be used in combination with DUS46Meissner OA, Verrel F, Tato F, Siebert U, Ramirez H, Ruppert V, et al. Magnetic resonance angiography in the follow-up of distal lower-extremity bypass surgery: comparison with duplex ultrasound and digital subtraction angiography. J Vasc Interv Radiol. 2004;15(11):1269-77.. In patients with abnormal DUS and ABPI findings, the reported graft failure rate is 66% within three months47Saarinen E, Kauhanen P, Soderstrom M, Alback A, Venermo M. Long-term Results of Inframalleolar Bypass for Critical Limb Ischaemia. Eur J Vasc Endovasc Surg. 2016;52(6):815-22.. Angiography (CTA, MRA or digital subtraction angiography) is recommended when clinical and/or ultrasound data suggest graft failure or disease progression.

If an autologous vein bypass graft has been in place without problems for one year, the annual risk of late graft failure is only around 1%–2% per year47Saarinen E, Kauhanen P, Soderstrom M, Alback A, Venermo M. Long-term Results of Inframalleolar Bypass for Critical Limb Ischaemia. Eur J Vasc Endovasc Surg. 2016;52(6):815-22., 48Armstrong PA, Bandyk DF, Wilson JS, Shames ML, Johnson BL, Back MR. Optimizing infrainguinal arm vein bypass patency with duplex ultrasound surveillance and endovascular therapy. J Vasc Surg. 2004;40(4):724-30; discussion 30-1.. Late failure rates for prosthetic grafts are significantly higher: within five years, as many as 40% of femoro-popliteal grafts will occlude49Ambler GK, Twine CP. Graft type for femoro-popliteal bypass surgery. Cochrane Database Syst Rev. 2018;2:CD001487.. Typically, stenosis develops in anastomotic regions when the bypass graft is prosthetic.

Progression of atherosclerosis occurs in around one in five patients50McLafferty RB, Moneta GL, Masser PA, Taylor LM, Jr., Porter JM. Progression of atherosclerosis in arteries distal to lower extremity revascularizations. J Vasc Surg. 1995;22(4):450-5; discussion 5-6., usually in either the inflow or outflow vessels, and the patient usually remains asymptomatic. If the progression is severe, typical symptoms (claudication, rest pain, tissue lesion) or graft occlusion may occur. Typically, these patients visit their doctor when symptoms appear. If the progression of atherosclerosis threatens bypass graft patency, intervention should be considered even with mild or no clinical symptoms.

Graft surveillance aims to identify graft failure before occlusion occurs. Not all graft stenoses progress to occlusion: in a study of 63 stenoses with > 50% diameter reduction on DUS, 43% resulted in bypass thrombosis during the following 8 months51Nielsen TG. Natural history of infrainguinal vein bypass stenoses: early lesions increase the risk of thrombosis. Eur J Vasc Endovasc Surg. 1996;12(1):60-4.. Low flow is also reported to be a risk factor of graft failure52Brumberg RS, Back MR, Armstrong PA, Cuthbertson D, Shames ML, Johnson BL, et al. The relative importance of graft surveillance and warfarin therapy in infrainguinal prosthetic bypass failure. J Vasc Surg. 2007;46(6):1160-6..

Complete surveillance includes a clinical examination, ABPI (or toe pressure) measurement and DUS. Optimally, a description of the procedure and previous DUS examinations should be available for the sonographer. In a meta-analysis of 15 RCTs, DUS surveillance after venous bypass surgery did not improve graft patency and or amputation rate (OR 0.7, 95% CI 0.23–2.13)53Abu Dabrh AM, Mohammed K, Farah W, Haydour Q, Zierler RE, Wang Z, et al. Systematic review and meta-analysis of duplex ultrasound surveillance for infrainguinal vein bypass grafts. J Vasc Surg. 2017;66(6):1885-91 e8..  In a retrospective analysis of 1404 bypasses, 200 (14%) occluded. In a multivariate analysis, non-adherence to a DUS surveillance programme was independently associated with vein graft occlusion (HR 1.58, 95%CI 1.10-2.27)54Spijkerboer AM, Nass PC, de Valois JC, van der Graaf Y, Eikelboom BC, Mali WP. Evaluation of femoropopliteal arteries with duplex ultrasound after angioplasty. Can we predict results at one year? Eur J Vasc Endovasc Surg. 1996;12(4):418-23.. In addition to DUS surveillance, treatment adherence and clinical follow-up also improved the outcome, emphasizing the importance of the long-term medical management of these patients beyond imaging.

Despite the lack of evidence, there is a consensus that surveillance is worthwhile after vein bypass, and the first post-discharge test should be done after 4–6 weeks and thereafter at 3, 6, 12 and 24 months after bypass surgery. If a redo intervention is performed for graft stenosis or occlusion, the surveillance programme should be started again from the beginning. Even if DUS surveillance does not continue beyond 24 months, clinical surveillance should be life-long, particularly in patients treated for

Spliced grafts, poor-quality vein (varicose lesions, thick wall, post-thrombotic change, vein diameter < 3 mm), and poor runoff are associated with an increased risk of graft thrombosis and warrant closer surveillance55Mewissen MW, Kinney EV, Bandyk DF, Reifsnyder T, Seabrook GR, Lipchik EO, et al. The role of duplex scanning versus angiography in predicting outcome after balloon angioplasty in the femoropopliteal artery. J Vasc Surg. 1992;15(5):860-5; discussion 5-6., 56McBride OMB, Mofidi R, Griffiths GD, Dawson AR, Chalmers RTA, Stonebridge PA. Development of a Decision Tree to Streamline Infrainguinal Vein Graft Surveillance. Ann Vasc Surg. 2016;36:182-9.. Furthermore, an abnormal DUS scan at 4–8 weeks is predictive for later graft failure. McBride et al. proposed a decision tree to identify high-risk grafts for DUS surveillance. In their surveillance of 249 bypass grafts, the sensitivity and specificity of their model in the prediction of graft stenosis occlusion were 95% and 52%, respectively, the negative predictive value being 97%56McBride OMB, Mofidi R, Griffiths GD, Dawson AR, Chalmers RTA, Stonebridge PA. Development of a Decision Tree to Streamline Infrainguinal Vein Graft Surveillance. Ann Vasc Surg. 2016;36:182-9..

Endovascular therapy

Restenosis after endovascular therapy is mainly related to intimal hyperplasia at the site of balloon dilatation and, if a stent is used, at the proximal or distal ends of the stent. Sometimes it is related to initial suboptimal procedural results, such as residual stenosis or dissection, acute recoil, distal embolization, or inadequate inflow or outflow treatment57Brodmann M, Keirse K, Scheinert D, Spak L, Jaff MR, Schmahl R, et al. Drug-Coated Balloon Treatment for Femoropopliteal Artery Disease: The IN.PACT Global Study De Novo In-Stent Restenosis Imaging Cohort. JACC Cardiovasc Interv. 2017;10(20):2113-23., 58Shishehbor MH, Jaff MR. Percutaneous Therapies for Peripheral Artery Disease. Circulation. 2016;134(24):2008-27.. Restenosis and/occlusion after endovascular revascularization is relatively common, and the risk is related to the anatomical region, being only 5% in the pelvic region and rising up to over 50% in the infra-popliteal arteries. Recurrence of symptoms during follow-up may also be due to disease progression above or below the angioplasty site41Sigvant B, Lundin F, Wahlberg E. The Risk of Disease Progression in Peripheral Arterial Disease is Higher than Expected: A Meta-Analysis of Mortality and Disease Progression in Peripheral Arterial Disease. Eur J Vasc Endovasc Surg. 2016;51(3):395-403..

Restenosis/occlusion or stent failure can be asymptomatic or cause typical symptoms, including claudication and rest pain. Pulse palpation and ABPI in combination with DUS may be used for follow-up (Table 2). Endovascular reintervention is the first-line treatment option in clinically relevant restenosis or occlusion. If EVT is not successful, bypass surgery may be considered. After a second failure of EVT, a multidisciplinary vascular team should evaluate the alternatives7Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T, 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 arteriesEndorsed 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(9):763-816..

After EVT, the incidence of revascularization failure remains relatively constant over at least five years. It is lowest in the iliac arteries and significantly higher in the femoro-popliteal and crural arteries. The five-year reintervention rate after iliac stenting is as low as 2.5% for primary stenotic lesions and 12.5% for primary occlusions; with 6-year primary patency rates of 82.4% and 77.7%, respectively59Pulli R, Dorigo W, Fargion A, Innocenti AA, Pratesi G, Marek J, et al. Early and long-term comparison of endovascular treatment of iliac artery occlusions and stenosis. J Vasc Surg. 2011;53(1):92-8.. In the femoro-popliteal segment, the reported freedom from target lesion revascularization is around 70%–80%60Dake MD, Ansel GM, Jaff MR, Ohki T, Saxon RR, Smouse HB, et al. Durable Clinical Effectiveness With Paclitaxel-Eluting Stents in the Femoropopliteal Artery: 5-Year Results of the Zilver PTX Randomized Trial. Circulation. 2016;133(15):1472-83; discussion 83.. Beyond one year, the reported incidence of late stent thrombosis is 10% at a median follow-up of 19 months in the femoro-popliteal segment61Bui TD, Mills JL, Sr., Ihnat DM, Gruessner AC, Goshima KR, Hughes JD. The natural history of duplex-detected stenosis after femoropopliteal endovascular therapy suggests questionable clinical utility of routine duplex surveillance. J Vasc Surg. 2012;55(2):346-52.. However, most studies reporting long-term data on this segment include only patients with TASC A and B lesions. Very few studies describe long-term results after infra-popliteal EVT; the 5-year primary patency ranges from 38% in one study on balloon angioplasty62Lo RC, Darling J, Bensley RP, Giles KA, Dahlberg SE, Hamdan AD, et al. Outcomes following infrapopliteal angioplasty for critical limb ischemia. J Vasc Surg. 2013;57(6):1455-63; discussion 63-4. to 9% with bare metal stents and 12% with drug-eluting stents in another trial63Spreen MI, Martens JM, Knippenberg B, van Dijk LC, de Vries JPM, Vos JA, et al. Long-Term Follow-up of the PADI Trial: Percutaneous Transluminal Angioplasty Versus Drug-Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia. J Am Heart Assoc. 2017;6(4).. In both trials, the 5-year freedom from major amputation rate (range 66%–81%) was definitely higher than the primary patency in both trials.

Severe restenosis is the indication for the majority of reinterventions; since restenosis is usually symptomatic, DUS surveillance is not helpful in guiding reinterventions61Bui TD, Mills JL, Sr., Ihnat DM, Gruessner AC, Goshima KR, Hughes JD. The natural history of duplex-detected stenosis after femoropopliteal endovascular therapy suggests questionable clinical utility of routine duplex surveillance. J Vasc Surg. 2012;55(2):346-52.. Furthermore, stent occlusion is not always preceded by severe in-stent restenosis, making this complication unpredictable by means of DUS surveillance. If symptoms reoccur, DUS is indicated to detect the restenosis. Restenosis is treated with repeat balloon angioplasty with, or without stenting, or with bypass in the case of repeated failure. Acute thrombosis can be treated by aspiration and/or thrombolysis, but revascularization by EVT is much more difficult if the thrombosis is established. The decision on reintervention should be made individually, preferably by a multidisciplinary team, taking into account the severity of symptoms, the general condition of the patient (renal function, bleeding risk) and the likelihood of success (history of recurrent restenosis).

Surveillance after EVT includes clinical assessment, looking for recurrent symptoms or signs and APBI (or toe pressures); DUS is indicated for symptoms or a significant decrease in ABPI. ABPI measurements are recommended within 1 month of EVT and at 6 and 12 months. Duplex imaging is more sensitive than ABPI or toe pressures in detecting restenosis, however, there is no evidence that routine DUS surveillance improves limb outcome. If an endovascular procedure fails, the arterial segment can usually be reopened with a re-do endovascular procedure, unlike after bypass surgery with autologous vein, when graft failure usually to the loss of bypass graft. An abnormal first DUS (1–30 days after EVT) is associated with higher target lesion revascularization rates at one year54Spijkerboer AM, Nass PC, de Valois JC, van der Graaf Y, Eikelboom BC, Mali WP. Evaluation of femoropopliteal arteries with duplex ultrasound after angioplasty. Can we predict results at one year? Eur J Vasc Endovasc Surg. 1996;12(4):418-23., 55Mewissen MW, Kinney EV, Bandyk DF, Reifsnyder T, Seabrook GR, Lipchik EO, et al. The role of duplex scanning versus angiography in predicting outcome after balloon angioplasty in the femoropopliteal artery. J Vasc Surg. 1992;15(5):860-5; discussion 5-6.. DUS surveillance has been reported to predict severe in-stent restenosis with a specificity of over 90%64Baril DT, Rhee RY, Kim J, Makaroun MS, Chaer RA, Marone LK. Duplex criteria for determination of in-stent stenosis after angioplasty and stenting of the superficial femoral artery. J Vasc Surg. 2009;49(1):133-8; discussion 9.. Roughly half of all severe restenoses present with ischaemic symptoms, regardless of the DUS findings. Whether an asymptomatic severe restenoses should be treated or just followed up is uncertain. If restenosis requiring treatment is suspected on DUS, a digital subtraction angiogram is recommended, with re-EVT if possible during the same session.

In a consensus document, a group of specialists recommended DUS surveillance after EVT, with an initial test performed between discharge and one month of the procedure. If the result is  normal, DUS is only needed if symptoms reappear. However, if the initial DUS is abnormal, reintervention or closer DUS follow-up should be discussed individually. The value of a yearly DUS beyond 12 months in patients who remain asymptomatic has never been proven and cannot be recommended routinely. All these patients benefit from regular CV surveillance focused on risk factor management, exercise and medical therapy37Venermo M, Sprynger M, Desormais I, Bjorck M, Brodmann M, Cohnert T, et al. Editor’s Choice – Follow-up of Patients After Revascularisation for Peripheral Arterial Diseases: A Consensus Document From the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases and the European Society for Vascular Surgery. Eur J Vasc Endovasc Surg. 2019;58(5):641-53. (Table 1).

Summary

ABPI of less than 0.90 is 95% sensitive in identifying angiographically confirmed LEAD, and most of the patients are asymptomatic. Because LEAD is always a marker of significant systemic atherosclerosis and increased CV mortality, all patients, regardless of symptoms, require risk factor modification and often medical management to slow down the progression of the atherosclerotic process. Statin therapy is indicated for all patients and antithrombotic (clopidogrel or ASA) therapy for symptomatic patients. Low-dose rivaroxaban twice a day plus ASA once a day is beneficial, especially in PAD patients with stable CAD, as long as their risk of bleeding is not increased. After revascularization, dual antiplatelet therapy is recommended for at least one 1 month after endovascular revascularization followed by life-long single-agent antiplatelet therapy. Dual pathway inhibition is beneficial after revascularization in patients who do not have increased risk of bleeding.  Smoking is an even more powerful risk factor in the development of LEAD than coronary atherosclerosis. Smoking is also associated with accelerated graft failure after lower extremity revascularization. Smoking cessation reduces deaths from CHD, lower extremity intervention and amputations.

Regular follow-up of patients with LEAD aims to encourage and monitor adherence to conservative treatment (Table 1). Lower limb revascularization is indicated to preserve the quality of life and functional ability, as well as to prevent amputation and death in patients with severe LEAD. In addition to risk factor control, more intensive follow-up may be indicated to those who undergo revascularization.  Follow-up procedures are slightly different after bypass surgery and EVT (Table 2).   

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