ESC Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases Developed in Collaboration With the EASD

The Task Force on Diabetes, Pre-Diabetes, and Cardiovascular Diseases of the European Society of Cardiology (ESC) and Developed in Collaboration With the European Association for the Study of Diabetes (EASD)

Lars Rydén (ESC Chairperson) (Sweden); Peter J. Grant (EASD Chairperson) (UK); Stefan D. Anker (Germany); Christian Berne (Sweden); Francesco Cosentino (Italy); Nicolas Danchin (France); Christi Deaton (UK); Javier Escaned (Spain); Hans-Peter Hammes (Germany); Heikki Huikuri (Finland); Michel Marre (France); Nikolaus Marx (Germany); Linda Mellbin (Sweden); Jan Ostergren (Sweden); Carlo Patrono (Italy); Petar Seferovic (Serbia); Miguel Sousa Uva (Portugal); Marja-Riita Taskinen (Finland); Michal Tendera (Poland); Jaakko Tuomilehto (Finland); Paul Valensi (France); Jose Luis Zamorano (Spain); Jose Luis Zamorano (Chairperson) (Spain); Stephan Achenbach (Germany); Helmut Baumgartner (Germany); Jeroen J. Bax (Netherlands); Héctor Bueno (Spain); Veronica Dean (France); Christi Deaton (UK); Çetin Erol (Turkey); Robert Fagard (Belgium); Roberto Ferrari (Italy); David Hasdai (Israel); ArnoW. Hoes (Netherlands); Paulus Kirchhof (Germany UK); Juhani Knuuti (Finland); Philippe Kolh (Belgium); Patrizio Lancellotti (Belgium); Ales Linhart (Czech Republic); Petros Nihoyannopoulos (UK); Massimo F. Piepoli (Italy); Piotr Ponikowski (Poland); Per Anton Sirnes (Norway); Juan Luis Tamargo (Spain); Michal Tendera (Poland); Adam Torbicki (Poland); William Wijns (Belgium); Stephan Windecker (Switzerland); Guy De Backer (Review Coordinator) (Belgium); Per Anton Sirnes (CPG Review Coordinator) (Norway); Eduardo Alegria Ezquerra (Spain); Angelo Avogaro (Italy); Lina Badimon (Spain); Elena Baranova (Russia); Helmut Baumgartner (Germany); John Betteridge (UK); Antonio Ceriello (Spain); Robert Fagard (Belgium); Christian Funck-Brentano (France); Dietrich C. Gulba (Germany); David Hasdai (Israel); Arno W. Hoes (Netherlands); John K. Kjekshus (Norway); Juhani Knuuti (Finland); Philippe Kolh (Belgium); Eli Lev (Israel); Christian Mueller (Switzerland); Ludwig Neyses (Luxembourg); Peter M. Nilsson (Sweden); Joep Perk (Sweden); Piotr Ponikowski (Poland); Zeljko Reiner (Croatia); Naveed Sattar (UK); Volker Schächinger (Germany); André Scheen (Belgium);

Disclosures

Eur Heart J. 2013;34(39):3035-3087. 

In This Article

10. Peripheral- and Cerebrovascular Disease

The definition of PAD used by the current ESC Guidelines includes atherosclerotic lesions in the extracranial carotid and vertebral, upper and lower extremity, mesenteric and renal arteries.[475] The same definition will be used in the present document. Although abdominal aortic aneurysm is frequent in patients with DM, it is not included in the current PAD definition. Moreover, diagnosis and management of abdominal aortic aneurysm are carried out independent of the presence or absence of DM.

10.1 Peripheral Artery Disease

Diabetes mellitus is a risk factor for the development of atherosclerosis at any vascular site, but particularly for lower extremity artery disease (LEAD), for which it increases risk two- to four-fold and for carotid artery disease. In LEAD, cigarette smoking, DM and hypertension are important risk factors. Although the association of DM with LEAD is inconsistent on multivariable analysis, it appears that the duration and severity of DM particularly influence the risk of gangrene and ulceration.[476,477] In population studies, the presence of carotid artery stenosis was associated with DM and other classical risk factors, irrespective of age.[478–480] DM is present in a significant proportion of patients with multi-site atherosclerosis, who have a worse prognosis than those with a single disease location.[481,482] Patients with DM should undergo comprehensive screening for the presence of PAD at different vascular sites. Medical history and physical examination (Table 11 and Table 12) are the cornerstones of diagnostic workup and should include a review of the different vascular beds and their specific symptoms,[475] although many patients remain asymptomatic. Further diagnostic evaluation and treatment should be applied according to the ESC Guidelines on PAD.[475] Briefly, in all DM patients, clinical screening to detect PAD should be performed annually and beneficial lifestyle changes encouraged.[483] All patients with PAD should receive adequate lipid-lowering, antihypertensive and antiplatelet treatment,[125,274,484,485] with optimal glycaemic control.[154,291,486]

10.2 Lower Extremity Artery Disease

Vascular obstructions are often located distally in patients with DM and typical lesions occur in the popliteal artery or in the vessels of the lower leg. In a cohort of 6880 patients over 65 years, one in five patients had LEAD, though only 10% were symptomatic.[487] The incidence and prevalence of LEAD increase with age and duration of DM. The National Health and Nutrition Examination Survey (NHANES II) determined pulse amplitudes in adults and diminished or absent pulsation of the dorsalis pedis artery was found in 16% of adults with DM aged 35–54 years and in 24% of those aged 55–74 years.[488] In many older patients, LEAD is already present at the time of diagnosis of DM. Progression of LEAD may result in foot ulceration, gangrene and ultimate amputation of part of the affected extremity. DM accounts for approximately 50% of all non-traumatic amputations in the United States and a second amputation is common. Mortality is increased in patients with LEAD and three-year survival after an amputation is less than 50%.[485] Early diagnosis of LEAD in patients with DM is important for the prevention of progression of LEAD, as well as for prediction of the overall cardiovascular risk.

Diagnosis: Symptoms suggestive of claudication are walking impairment, e.g. fatigue, aching, cramping, or pain with localization to buttock, thigh, calf, or foot, particularly when symptoms are quickly relieved at rest. Palpation of pulses and visual inspection of the feet are essential. Dependent rubor, pallor when the foot is elevated, delayed hyperaemia when the foot is lowered, absence of hair growth and dystrophic toenails are signs of limb ischaemia. An objective measure of LEAD is the ABI, calculated by dividing the systolic blood pressure at the posterior tibial or dorsalis pedal level with the brachial systolic blood pressure. An index of <0.9 is suggestive of LEAD, particularly in the presence of symptoms or clinical findings such as bruits or absent pulses. An ABI <0.8 indicates PAD, regardless of symptoms. Sensitivity of ABI measurement may be increased after exercise. Post-exercise ABI may identify significant LEAD, even in people with a normal resting ABI.[489] An ABI >1.40 indicates poorly compressible vessels as a result of stiff arterial walls (medial calcinosis) that can impede the correct estimation of pressure in the artery, even in severe ischaemia of the extremities.

Primary and secondary prevention of LEAD in patients with DM consists of lifestyle changes (addressing obesity, smoking and lack of exercise) and control of risk factors, including hyperglycaemia, hyperlipidaemia and hypertension.

Treatment: In a systematic review of RCTs of exercise programmes in symptomatic claudication, supervised exercise therapy was effective in increasing walking time, compared with standard care.[490] Combination therapy including drugs and exercise is often used. Although several drugs such as cilostazol, naftidrofuryl and pentoxifylline increase walking distance in patients with intermittent claudication, their role remains uncertain. In addition, statin therapy has been reported to be of benefit by increasing walking distance in patients with PAD.[475,491] If conservative therapy is unsuccessful, revascularization should be considered. In case of disabling claudication with culprit lesions located at aorta/iliac arteries, revascularization should be the first choice, along with management of risk factors.[475] An algorithm for the treatment of intermittent claudication is shown in Figure 8.

Figure 8.

Algorithm for treatment of intermittent claudication (from Tendera et al. 475 with permission). CV = cardiovascular.

Critical limb ischaemia (CLI) is defined by the presence of ischaemic pain at rest and ischaemic lesions or gangrene attributable to arterial occlusive disease that is chronic and distinguishable from acute limb ischaemia. An algorithm for the management of CLI is provided in Figure 9.

Figure 9.

Algorithm for the management of critical limb ischaemia (from Tendera et al. 475 with permission). CVD = cardiovascular disease.

Importantly, beta-blockers are not contra-indicated in patients with LEAD and DM. A meta-analysis of 11 RCTs found that beta-blockers do not adversely affect walking capacity or symptoms of intermittent claudication in patients with mild-to-moderate PAD.[492] At 32-month follow-up of 490 patients with PAD and prior MI, beta-blockers caused a 53% significant and independent decrease in new coronary events.[493]

Comprehensive management requires multidisciplinary care to control atherosclerotic risk factors, provision of revascularization where possible, optimization of wound care, wearing of appropriate shoes, treatment of infection and rehabilitation.[475] The cornerstone of management is arterial reconstruction and limb salvage, which should be attempted without delay in all patients with critical limb ischaemia (CLI) when technically possible. The screening for—or assessment of—coronary or cerebrovascular diseases should not delay management of patients with CLI if clinically stable. Medical baseline therapy, including platelet inhibitors and statins, should be initiated according to principles outlined elsewhere in this document.[475,494,495]

The choice of revascularization strategy depends primarily on the anatomy of the arterial lesion. Outcomes of endovascular iliac artery repair in DM have been reported as similar to or worse than those without DM, and long-term patency is lower.[496] Long-term patency rates of intravascular interventions in the tibio-peroneal region are low in patients with and without DM, but may be sufficient in the short term to facilitate healing of foot ulcers.[496]

The diabetic foot is a specific clinical entity that may involve neuropathy, trauma, arterial disease, infection and inflammation, often in combination. The serious consequences are ulceration, gangrene and high rates of amputation. Typically, in DM patients, LEAD is diffuse and particularly severe in distal vessels. When arterial disease is suspected, clinical examination of pulses with measurement of ABI is indicated to assess ischaemia. When, due to a heavily calcified arterial wall, the ABI is inconclusive, toe pressure, distal Doppler waveform analyses, or transcutaneous oxygen can assess the arterial status. When ischaemia is present, imaging should be performed to plan revascularization, which should be applied by the same criteria as for CLI. It is important to have direct flow to the foot to improve healing of ulcerations. Sufficient amputation is necessary in order to achieve adequate perfusion which, in combination with revascularization, will contain the ischaemic, inflammatory and infective process.

Follow-up should include patient education, smoking cessation, protective shoes, periodic foot care and reconstructive foot surgery as needed. The management of risk factors including glycaemic control and revascularization surveillance are mandatory.[497]

10.3 Carotid Artery Disease

Cerebrovascular disease is one of the leading causes of morbidity and mortality in Europe. DM is an independent risk factor for ischaemic stroke with an incidence 2.5–3.5 times higher than in people without DM.[498,499] In this document, the discussion of stroke and transient ischaemic attack (TIA) prevention will be limited to the aspects related to carotid artery disease. It should be noted that only about 20% of all ischaemic strokes can be causally related to carotid artery stenosis.[500] Although the presence of DM increases the likelihood of carotid artery disease, its presence does not change the general diagnostic and therapeutic approach.

Diagnosis: Carotid bruits are common in patients with carotid artery stenosis, although many remain asymptomatic regardless of lesion severity. Although the spectrum of symptoms is wide, only those who have suffered a stroke or TIA within the past six months are regarded as symptomatic.[501,502] In this group of patients, the probability of recurrent stroke or TIA is high,[503] therefore urgent imaging of the brain and supra-aortic vessels is mandatory in patients presenting with TIA or stroke. Duplex ultrasonography, computed tomography angiography and magnetic resonance imaging are indicated to evaluate carotid artery stenosis.

Treatment: Management depends on symptoms, severity of the lesion, prognosis for 5-year survival and the outcome of revascularization procedures. A management algorithm is shown in Figure 10.

Figure 10.

Algorithm for the management of extra cranial carotid artery disease (from Tendera et al.,475 with permission).
BMT = best medical therapy; CTA = computed tomography angiography; MRA = magnetic resonance angiography; TIA = transient ischaemic attack.

Whilst carotid endarterectomy seems to offer a clear advantage over conservative treatment in patients with symptomatic carotid artery disease, the role of revascularization in asymptomatic patients remains less clear.[475] It needs to be emphasized that most data in patients with no symptoms were collected before statins and antiplatelet agents became standard therapy. On the other hand, the results of both endarterectomy and carotid stenting have improved over time and the role of revascularization in this cohort needs to be reassessed.

10.4 Gaps in Knowledge

  • In comparison with aspirin and clopidogrel, the efficacy of new antiplatelet drugs in patients with DM and PAD is not well known.

  • There is a need for comparisons of endovascular and surgical interventions in different subsets of patients with DM and concomitant carotid or lower extremity artery disease.

10.5 Recommendations for Management of Peripheral Artery Disease in Diabetes

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