The Diagnosis and Treatment of Peripheral Arterial Vascular Disease

Background: In peripheral arterial occlusive disease (PAOD), arterial stenosis or occlusion impairs perfusion in the territory of the distal portion of the aorta and the iliac and leg arteries. In Germany, the prevalence of PAOD rises with age, reaching 20% among persons over age 70.

Methods: This guideline was prepared by a collaboration of 22 medical specialty societies and two patient self-help organizations on the basis of pertinent publications that were retrieved by a systematic search in PubMed for articles that appeared from 2008 to April 2014, with a subsequent update to May 2015.

Results: 294 articles were assessed, including 34 systematic reviews and 98 randomized controlled trials (RCTs). The diagnostic assessment of PAOD is based on physical examination, blood pressure at the ankles, and color-coded duplex ultrasonography (grade A recommendation). Other tomographic imaging methods can be used for suitable indications. The main elements of the treatment of PAOD are the control of cardiovascular risk factors and structured vascular exercise (grade A recommendation). Acetylsalicylic acid and statins are the main drugs for symptomatic PAOD (grade A recommendation). Patients with claudication and correlated structural findings can undergo an endovascular or open surgical procedure. Critical ischemia is an indication for arterial revascularization as soon as possible (grade A recommendation); this may be performed either by open surgery or by an endovascular procedure of one of the types that are now undergoing rapid development, or one of the crural treatment options. There is inadequate evidence concerning the optimal drug regimen after revascularization procedures.

Conclusion: The diagnostic assessment of PAOD is based on physical examination, measurement of the ankle-brachial index (ABI), and duplex ultrasonography. Acetylsalicylic acid and statins are indicated for patients with symptomatic PAOD. Endovascular procedures should be used if indicated. Randomized studies are needed to provide better evidence on many open questions in the treatment of PAOD.

In peripheral arterial occlusive disease (PAOD), perfusion is impaired in the territory of the distal portion of the aorta and/or the pelvic, femoral and crural arteries because of a narrowing (stenosis) or complete blockage (occlusion) of the arterial lumen. By far the most important cause of PAOD is atherosclerosis. More than 200 million persons around the world have PAOD (defined as an ankle-brachial index less than 0.9), and the number is growing (1). In Germany, the prevalence of PAOD rises with age, reaching 20% among persons over age 70 (2). Only 25% of persons with PAOD have symptoms (3).

The first German S3 guideline on the diagnosis and treatment of PAOD appeared in 2009 (4). Its recommendations have now been reassessed by an interdisciplinary group of experts under the leadership of the German Society of Angiology (Deutsche Gesellschaft für Angiologie, DGA). The many changes in the treatment of PAOD since 2009 are mainly due to the widespread introduction of new endovascular techniques.

The goal of this update was not just to provide current, evidence-based recommendations on the diagnosis, treatment, and post-interventional care of PAOD, but also to propose a new approach to the use of arterial revascularization procedures, differing from the exclusively morphological TASC criteria that have been used to date for this purpose (3) in Germany as elsewhere. The TransAtlantic Inter-Society Consensus (TASC) classifies PAOD on the basis of its radiological appearance. Because of the rapid development of endovascular techniques, the TASC criteria for the choice of treatment are now partly out of date.

The current state of the evidence on the treatment of PAOD is poor. Large-scale randomized controlled trials (RCTs) are still lacking that might conclusively answer the important open questions on endovascular and open surgical treatment and on post-interventional care, including the question of the optimal post-interventional drug regimen. Such trials are needed if there is to be better evidential support for the recommendations contained in this guideline.

Methods

The process of creating the guideline

The existing S3 guideline on PAOD was updated in a multistep nominal procedure by 24 collaborating medical specialty societies and patient organizations (eBox 1). The long version of the guideline can be seen online (5).

The guideline-creating procedure was based on the regulatory framework of the Association of Scientific Medical Societies in Germany (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften). Recommendations were formulated under the moderation of an AWMF representative (Prof. I. Kopp, Marburg) and confirmed by a consensus procedure (>75% approval required). Each recommendation was given one of three different grades, whose differing strengths were expressed by the three German verbs “soll,” “sollte,” and “kann” (roughly: “must,” “should,” and “may”). The recommendations presented here were assessed on the basis of a systematic literature review and unanimously approved. For questions of central importance on which no evidence at all was available, a recommendation was given on the basis of expert consensus.

Literature review and evidence assessment

The database of the Guidelines International Network was systematically searched for national and international guidelines published after the closure date of the old S3 guideline (2009) and up to the date of the search, i.e., 30 April 2014.

Potential reference guidelines were selected on the basis of the methodological quality criteria summarized in the German Instrument for the Evaluation of Guidelines (DELBI, Deutsches Leitlinien-Bewertungsinstrument). Moreover, all available new systematic Cochrane Reviews since April 2009 were examined, chapter by chapter, for pertinent information. A systematic literature search was carried out in the Medline, PubMed, and DIMDI databases for the period 2008 to April 2014 (Figure 1). Relevant guidelines, reviews, and RCTs that were published up to 30 May 2015 were analyzed. From this date onward until the date of publication of the guideline, no further major changes were made in the recommendations. Evidence levels were characterized according to the Oxford scheme, described in 2009 (6).

Figure 1

The course and results

Epidemiology

The prevalence of PAOD is 3–10% (2). Among persons aged 70 and above in Germany, its prevalence is 20%. Nearly 75% of persons with PAOD, of whatever age, have no symptoms (7). Most younger patients with PAOD are men, but the sexes are about equally represented among older patients (8).

Symptomatic PAOD is divided into the stage of intermittent claudication (IC), i.e., pain that arises on movement of the affected limb(s), and the stage of critical limb ischemia (CLI), with pain at rest and ulcer formation (Table 1). Patients in the CLI stage are at a significantly higher risk of undergoing a major amputation within 1 year (25% without arterial revascularization vs. 8% with sucessfull arterial revascularization) (3, 9).

Table 1

Classification of PAOD: Fontaine stages and Rutherford categories

The number of hospital admissions for CLI in Germany rose by 32% from 2005 to 2009 (10). A further rise is predicted because of the aging of the population.

Prognosis

Among patients with IC, walking ability worsens in about 25%, while the symptoms remain stable in about 50%. The risk that IC will progress to CLI is very low. Only 2% of patients with IC undergo a major amputation within 10 years (3).

Predictors for PAOD and for major amputation include include advanced age, diabetes mellitus, male sex, and smoking (11). Patients with PAOD have significantly elevated cardiovascular morbidity and mortality. Overt PAOD is associated with a threefold risk elevation for myocardial infarction (odds ratio [OR] 3.3 [2.1; 5.0]) and a fourfold risk elevation for stroke (OR 4.2 [1.8; 9.5]) (12). The 5-year mortality of patients with asymptomatic PAOD is 19%; that of patients with symptomatic PAOD is 24% (11).

Nationwide health care data reveal that patients with PAOD are still undertreated with respect to their risk factors and accompanying illnesses. In one study (13), 37% of 4298 patients who underwent an amputation because of PAOD had not previously undergone either an angiogram or a revascularization procedure.

Diagnostic evaluation

History and physical examination

The relevant history includes cardiovascular risk factors and atherosclerotic comorbidities. Typical symptoms of PAOD are exercise-induced muscle pain in the lower limb(s) (IC) and pain at rest and/or trophic lesions in the foot (CLI). The pulses in the lower limbs should always be examined, but palpable pulses do not rule out PAOD. The trophic state of the skin, the temperature of the limbs, muscle bulk and strength, and the shape of the feet should all be examined and described.

All patients with PAOD should undergo regular clinical examination of the feet (grade A recommendation, level 1 evidence).

The ankle-brachial index (ABI)

Determination of the ABI by non-invasive measurement of the double occlusion pressure is a suitable test for detecting PAOD (3). The ABI value with the lower arterial pressure at the ankle is the one to be taken for diagnostic purposes (14). A value below 0.9 at rest establishes the diagnosis of PAOD (4, 15).

In patients with a proximal occlusion and adequate collateral circulation, the ABI at rest may be normal; a decline by more than 20% on exercise in a patient with intermittent claudication establishes the diagnosis of PAOD (15). If the ABI values are implausible, e.g., in patients with medial calcific sclerosis, the toe brachial index (TBI) should be used instead (16).

Imaging studies

Color-coded duplex ultrasonography is the imaging method of choice for the aorta and the iliac and femoral arteries (17). If the vessels are well seen and the findings are unambiguous, color-coded duplex ultrasonography is the only imaging study needed before either the initiation of conservative treatment or angiography with the option of proceeding to an interventional procedure (e1).

Further imaging studies (contrast-enhanced MR angiography [MRA], CT angiography, and digital subtraction angiography) are indicated if the findings might have additional implications for treatment, or if color-coded duplex ultrasonography is unavailable or has yielded unclear findings. Contrast-enhanced MRA is the study of choice in this situation (Figure 2).

Figure 2

Diagnostic algorithm for peripheral arterial occlusive disease.

The interdisciplinary care of PAOD patients involves angiologists, vascular surgeons, interventional radiologists, and (depending on the accompanying illnesses) diabetologists, cardiologists, and nephrologists.

The indication for any diagnostic angiographic procedure should be agreed upon in an interdisciplinary conference (consensus recommendation).

Treatment goals

The main objectives of treatment are the control of cardiovascular risk factors and accompanying illnesses and the improvement of peripheral blood flow in patients with symptomatic PAOD. Depending on the clinical stage, the focus of treatment may lie on cardiovascular risk reduction, improved walking ability to keep the patient mobile, improved quality of life (IC), or limb retention (CLI).

Vascular surgical and endovascular-interventional arterial reconstruction procedures for patients with PAOD should be decided upon by an interdisciplinary team in consideration of the stage of disease and the degree of difficulty and invasiveness, risks, and expected outcome of the procedure (consensus recommendation).

Fundamentals of treatment

The basic treatment of PAOD consists of structured vascular exercise, smoking cessation, and the control of cardiovascular risk factors.

For patients with symptomatic PAOD, secondary prevention with a platelet aggregation inhibitor is indicated (18).

For diabetic patients, assessment and treatment of diabetes is indicated. Diabetics with PAOD have a high risk of developing diabetic foot syndrome (19) and a high risk of amputation (OR 1.5 [1.4; 1.54]) (13). The target values for glycemic control should be adjusted to the patient’s age, comorbidities, and life expectancy (20). No target value for LDL-cholesterol is given, because intervention trials in patients with PAOD and elevated cholesterol levels are lacking. All PAOD patients should be given a statin unless this is contraindicated (21). Omega-3 fatty acids and nicotinic acid preparations have no effect on morbidity and mortality.

PAOD patients with high blood pressure should be given antihypertensive drugs, with a target blood pressure below 140/90 mmHg (22). ACE inhibitors improve walking performance (23). Beta-blockers are not contraindicated in patients with PAOD. The main therapeutic recommendations are listed in Table 2.

Table 2

Recommendations on conservative treatment, revascularization, and post-interventional care in PAOD*

Vascular exercise and drug treatment

The treatment of choice for patients with PAOD and IC is vascular exercise, which consists of regular exercise training, walking exercises, and gymnastic exercises under professional guidance.

Structured walking exercises are the main non-pharmacological treatment and should be used in combination with the rigorous treatment of cardiovascular risk factors. In prospective studies, the performance of structured walking exercises under professional guidance for at least three months significantly increased the distance that patients were able to walk (by 109 m; 95% confidence interval [CI], 38–180 m) and significantly improved their quality of life (MD 2.15; 95% CI 1.26–3.04) (24). The functional long-term outcome of a vascular intervention as the sole treatment for patients with claudication is no better than that of structured walking exercises (25, 26). Thus, professionally guided structured walking exercises should be offered to all patients with PAOD as part of their basic treatment (grade A recommendation, level 1 evidence).

Pharmacotherapy

Vasoactive drugs should be given in the claudication stage if the patient’s quality of life is markedly impaired and walking exercises can be performed only to a limited extent or not at all.

Randomized drug trials have documented that only two drugs, cilostazol and naftidrofuryl, can significantly increase the distance patients are able to walk (27, 28). There is inadequate evidence for the benefit of pentoxifylline, L-arginine, buflomedil or ginkgo biloba in patients with claudication. The same holds for other alternative treatment methods.

Prostanoids have been considered a treatment option for patients with critical ischemia who cannot undergo a revascularization procedure, but their benefit is unclear (29). There is no current evidence-based alternative to arterial revascularization for these patients. Their treatment should be based on pain therapy, antibiotics in case of infection, and structured wound care.

Arterial revascularization

Endovascular and surgical treatment

Arterial reconstruction, whether by endovascular intervention or by open vascular surgery, is a type of symptomatic treatment and does not solve the underlying problem of progressive arteriosclerosis. Arterial reconstruction is not indicated for asymptomatic patients. It should be performed in patients with intermittent claudication only for strict indications, as the primary treatment outcome is no better over the long term than that of conservative treatment with vascular exercise (25, 26). The main criterion is the impairment of the patient’s quality of life by the lessened mobility due to pain.

Invasive treatments should be decided upon by an interdisciplinary team in consideration of their degree of difficulty and invasiveness, risks, and expected outcomes. The clinical stage, the morphology and complexity of the vascular lesions, the accompanying illnesses, and the patient’s individual wishes about treatment should all be taken into account.

The reality of patient care today presents a somewhat different picture. Liberalization of the strict indications for invasive procedures is supported in current international guidelines (30, 31): specifically, it is stated that low-risk balloon angioplasty of the aorto-iliac and femoro-popliteal arteries or thrombendarterectomy (TEA) of the femoral artery bifurcation to treat occlusion of the common femoral artery can be offered without any prior trial of conservative treatment.

Patients with CLI should undergo revascularization as soon as possible, depending on the extent of tissue loss and inflammatory activity. There is an algorithm for treatment decisions (Figure 3). Revascularization should be attempted by all available means before proceeding to amputation. In planned amputations, the level of amputation should be chosen in consideration of the prospects for wound healing, rehabilitation, and restoration of the patient’s quality of life.

Figure 3

Algorithm for the treatment of patients with critical limb ischemia

Endovascular and open surgical revascularization are complementary techniques. The use of one or the other depends on the site, length, and complexity of the vascular lesion, as well as on the available therapeutic expertise and equipment and the wishes of the patient. Neither technique is clearly preferable to the other; the current state of the evidence on this question is poor (32). Hybrid procedures are feasible and reasonable, in suitable cases, as a means of reducing risks while simultaneously sparing resources (33).

For any occlusive process at any site, an endovascular procedure should always be preferred if its expected technical and clinical outcome is comparable to that of open surgery (9, 34).

Thus, endovascular revascularization is to be preferred whenever the expected short-term and long-term symptomatic improvement is comparable to that of an open vascular surgical procedure (grade A recommendation, level 2 evidence).

For lesions at multiple levels, the elimination of obstacles to inflow has priority over the treatment of more distal lesions. Structured walking exercises should be offered along with invasive treatment (26).

For patients with IC, definite indications for surgery include occlusions or stenoses of the iliac axis or femoral artery bifurcation that cannot be treated by endovascular means and lesions of the profunda femoris artery with simultaneous occlusion of the superficial femoral artery.

Patients with these problems whose individual operative risk is judged to be low or intermediate can be offered a surgical procedure as a prerequisite to regular walking exercises that must be performed thereafter. Long femoro-popliteal lesions should be treated by percutaneous transluminal angioplasty (PTA) with stent implantation (35).

In the treatment of lesions of the superficial femoral artery, drug-coated balloons lower the restenosis rate (e2). The clinical utility of drug-coated stent implants and of drug-coated balloons when used for angioplasty of the infrapopliteal arteries cannot yet be conclusively judged. Although their use has been found to lower the restenosis rate in comparison to simple PTA (36, 37), not enough information is available yet about patient-relevant endpoints (the distance the patient is able to walk, morbidity, mortality, quality of life, limb retention). The implantation of stents in vascular segments that cross a joint is generally not indicated, but it can be considered in CLI when no other treatment options are available.

The TASC classification is based on the morphological complexity of vascular lesions as revealed by angiography. It no longer provides sufficient information for decision-making about invasive treatment. Both morphological and clinical criteria must now be considered (eBox 2).

eBox 2

Angiomorphological and clinical criteria for the choice of an open surgical vs. endovascular procedure

There are some constellations of findings in which an open vascular surgical procedure is to be recommended as the primary treatment, and an endovascular procedure is generally not indicated:

• Subrenal aortic occlusion with bilateral occlusion of the iliac arteries
• Occlusion of the common femoral artery
• Occlusion of the external iliac artery or the superficial femoral artery extending to the common femoral artery
• Long occlusion of the superficial femoral artery, the popliteal artery, and the trifurcation
• Long occlusion of the popliteal artery, the trifurcation, and all tibial arteries with well-preserved distal crural or pedal arterial segments.

Autologous venous material should be used for bypasses if possible (grade A recommendation) (38).

Post-interventional treatment

Anticoagulant drugs or platelet function inhibitors are given to prevent restenosis after bypass procedures involving venous material or prostheses (respectively) (e3). The benefit of platelet function inhibitors is supported by evidence (39). Thus, in line with the recommendations of international guidelines, routine oral anticoagulation after infra-inguinal venous bypass procedures is not recommended (18, 30, 31).

Anticoagulation is indicated to prevent recurrence of cardiac and arterio-arterial embolism, as an accompaniment to clot lysis procedures, and after the recanalization of arterial occlusions with a predominantly thrombotic component (40).

A course of rehabilitation is recommended for PAOD patients so that they can learn the requisite structured walking exercises and so that secondary preventive measures can be optimized with resulting improvement of quality of life.

A structured post-interventional care program for patients with PAOD consists of the following: counseling about and rigorous control of vascular risk factors, regular semiannual check-ups after invasive procedures, and consideration of all potential further options for treatment. Structured vascular exercises should be offered to all patients after invasive treatment.

Overview for routine clinical practice

PAOD is common and becomes more common with age. Its treatment depends on the clinical stage. The basic treatment consists of the administration of platelet function inhibitors and statins along with structured vascular exercise. Vasoactive drugs are given only when the patient’s quality of life is markedly impaired and vascular exercises can be performed only to a limited extent or not at all. In the treatment of critical limb ischemia, rapid arterial revascularization has the highest priority. Endovascular and vascular surgical techniques are complementary; the use of one or the other, or of a hybrid procedure, depends on the indication. Decisions about invasive therapy should be made on an interdisciplinary basis in vascular centers with due consideration of the risk–benefit profile.

Endovascular treatment is preferable to an open surgical bypass procedure whenever the indication is suitable. A platelet function inhibitor must be given after any invasive treatment for PAOD.

Conflict of interest statement

Dr. Lawall is a member of the UCB advisory board. He has received third-party funding for carrying out clinical trials on behalf of Astra Zeneca, Novartis, and UCB. He has been paid for preparing scientific lectures by UCB, BARO, Bayer Vital GmbH, medac GmbH, and Amgen.

Prof. Espinola-Klein is a member of the advisory boards of Merck, Sharp & Dohme GmbH, Amgen, Boehringer Ingelheim, and Daiichi Sankyo. She has received funding from Berlin Chemie for a research project that she initiated, and for carrying out clinical trials. She has received third-party funding for carrying out clinical trials on behalf of Merck, Sharp & Dohme GmbH, Astra Zeneca, Bayer Vital GmbH, and Sanofi Aventis. She has been paid for preparing scientific lectures by Bayer Vital GmbH, Pfizer Pharma GmbH, Amgen, Boehringer Ingelheim, Daiichi Sankyo, and Bristol-Myers Squibb.

Prof. Rümenapf has received reimbursement of meeting participation fees and travel and accommodation expenses from Jotec.

Prof. Huppert states that he has no conflict of interest.

Manuscript submitted on 2 June 2016, revised version accepted on
21 July 2016.

Translated from the original German by Ethan Taub, M.D.

Correesponding author
Dr. med. Holger Lawall
Praxis für Herzkreislauferkrankungen Ettlingen
Max-Grundig-Klinik Bühlerhöhe
Schwarzwaldhochstr. 1
77815 Bühl, Germany

@Supplementary material
For eReferences please refer to::
www.aerzteblatt-international.de/ref4316

eTables, eBoxes:
www.aerzteblatt-international.de/16m0729

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