© Borgis - Postępy Nauk Medycznych 8/2012, s. 660-667
*Adam Lewszuk, Walerian Staszkiewicz, Grzegorz Madycki, Bartosz Pacewski
Choroba niedokrwienna kończyn dolnych w świetle najnowszych wytycznych leczenia zachowawczego
Peripheral artery disease – current recommendations and best medical treatment
Department of Vascular Surgery and Angiology of the Medical Centre for Postgraduate Education, The Jerzy Popiełuszko Memorial Bielański Hospital
Head of Department: prof. Walerian Staszkiewicz, MD, PhD
Manifestacje przewlekłego procesu miażdżycowego, takie jak choroba niedokrwienna serca, niedokrwienie OUN oraz przewlekłe niedokrwienie kończyn dolnych (PAD) stanowią prawie połowę przyczyn śmierci w Europie każdego roku. Przewlekłe niedokrwienie kończyn dolnych nie musi mieć ścisłego związku z objawami klinicznymi i bardzo często przebiega bezobjawowo. PAD jest nie tylko chorobą niedokrwienną kończyn, rozwój procesu miażdżycowego jest chorobą uogólnioną i dotyczy również mózgu, serca oraz innych organów wewnętrznych. W związku z tym pacjenci z PAD narażeni są na poważne komplikacje o charakterze naczyniowo-niedokrwiennym, w tym np. na zawał mięśnia sercowego lub niedokrwienie OUN. Liczba osób z PAD drastycznie wzrasta i w chwili obecnej osiąga 16% społeczeństwa w wieku ponad 55 lat, w związku z tym ta grupa pacjentów wymaga całościowego podejścia do tego problemu. Proces diagnostyczno-leczniczy powinien obejmować zarówno modyfikację czynników ryzyka rozwoju miażdżycy, jak również terapię lekami przeciwpłytkowymi mającymi na celu redukcję wystąpienie powikłań zakrzepowo-zatorowych. Najnowsze zalecenia obejmują również stosowanie statyn, celem leczenia hipercholesterolemii, inhibitorów ACE, celem redukcji nadciśnienia tętniczego oraz kwasu acetylosalicylowego lub klopidogrelu jako leków p/płytkowych. W leczeniu chromania przestankowego zaleca się początkowo wprowadzenie nadzorowanego treningu marszowego i/lub włączenie terapii cilostazolem, jako leku o najlepiej udowodnionej skuteczności. U pacjentów kwalifikowanych do operacji naczyniowych zaleca się stosowanie terapii antypłytkowej jako prewencji zakrzepowej. Rekomenduje się również stosowanie B-blokerów, celem redukcji powikłań okołooperacyjnych.
Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis that is associated with a high risk of cardiovascular mortality and significant limitation in function because of limb ischemia. Patients with PAD should be considered to have significant coronary and cerebral arterial disease that requires aggressive risk factor management, including the prescription of antiplatelet drugs in order to lower the subsequent risk of myocardial infarction, stroke, and death. In the population with PAD, evidence supports the use of statin for lipid management, angiotensin-converting enzyme-1 inhibitors for blood pressure control, and aspirin or clopidogrel as antiplatelet agents. Once this is accomplished, the severity of limb symptoms should be assessed, and a structured exercise program or the selected use of drugs such as cilostazol to treat the intermittent claudication should be prescribed. In patients primarily considered for surgical treatment, antiplatelet and anticoagulant drug therapy can be used as a mean of promoting graft patency, and beta-adrenergic blockers can be used as a mean of reducing the perioperative risks associated with vascular surgery.
The peripheral arterial disease (PAD) is one of the most common and the most important manifestation of systemic atherosclerosis. The disease progresses with aging regardless from gender (1, 2). After the age of 40 years, there is two- to three-fold increase in risk of PAD development in each decade. PAD is closely related to coexistence of risk factors for the atherosclerosis development: smoking, diabetes mellitus, hyperlipidemia and hypertension (2-4).
While PAD develops, risk of vascular and ischemic complications associated with myocardium, and CNS increases, as well as risk of other vascular death (5). It is estimated that in patients with PAD, comparing to the remaining population of the patients, there is three-fold increase in risk of any vascular death, and six-fold increase in risk of cardiac death (6). In this case, gender does not matter, and risk is still high despite absence of the ischemic heart disease in the past (7, 8). It has been proven that together with increasing intensity of the peripheral arterial disease measured by the ankle-brachial index, risk of myocardial ischemia, ischemic stroke, and other vascular death, proportionally increases as well (9, 10). The main purpose of pharmacological treatment is an aggressive modification of risk factors, which is extremely important in inhibiting development of the peripheral arterial disease, as well as in lowering risk of other vascular complications. Introduction of antiplatelet therapy together with ACE inhibitors provides significant benefits in reducing occurrence of undesirable cardiovascular events.
The most common manifestation of the peripheral arterial disease is the intermittent claudication. Conservative treatment includes smoking cessation at the beginning, and then supervised exercises and pharmacological therapy in order to stop progress of the disease as well as reduce risk of occurrence of the vascular events. The patients with critical peripheral arterial disease require surgical treatment in order to supply the limb with blood, which provides optimum conditions for treatment of the ischemic lesions. In such cases, pharmacological therapy is an adjunctive therapy for the first-line surgical treatment.
Very important in the group of patients undergoing surgical treatment is to prevent myocardial ischemia during perioperative course and to provide long-term protection from coagulation in the vascular graft. In order to achieve these goals, beta-blockers and acetylsalicylic acid should be administered in the perioperative course.
This article presents review of current recommendations regarding conservative therapy of the peripheral arterial disease, which purpose is to modify risk factors for cardiovascular complications and to increase walking distance. Conservative treatment should also include prevention of the disease progress, treatment of coexisting diseases, improvement in the limb blood supply, prevention of necrotic lesions, and treatment of skin lesions.
As it was mentioned before, the patients with PAD constitute the group of patients with significantly increased risk of the cardiovascular event occurrence. It should be taken into consideration that majority of these patients have no symptoms of the peripheral arterial disease, and half of them have not yet experienced the cardiovascular event. Medical history and preliminary clinical examination may result in underestimation of the actual number of patients with PAD. Cirkulation 2001’ published the article presenting positive correlation between coexisting PAD and the ankle-brachial index ABI ≤ 0.9 (11). Based on the article of A. Hirsch published in JAMA 2003’ (12), ABI measurement was recommended in all symptomatic patients, in all patients in the age of 60-69 years with coexisting risk factors for the cardiovascular disease, and in all patients in the age of over 70 years.
The article listed recommendations of Trans-Atlantic Inter-Society Consensus – its second edition (TASC II) (13), regarding diagnostics and treatment of the peripheral arterial disease. The article is a result of cooperation among fourteen scientific societies from Europe and North America involved in problems regarding vascular diseases.
Pharmacological modification of cardiovascular risk factors
The patients with PAD are frequently burdened with many risk factors for cardiovascular complications. Many broad-spectrum studies confirmed basic role of their modification.
Smoking cigarettes is associated with significant increase in risk of vascular complications and development of chronic ischemia of lower limbs at the background of atherosclerosis (14). Number of smoked cigarettes per year significantly correlates with increased risk of amputation, occlusion of the vascular graft, and death (15). In addition, during exercises on a treadmill, the smoking patients with PAD reported significantly less intensive pain in shanks than non-smoking patients (16). Therefore, smoking cessation is a significant factor for reducing cardiovascular complications, however, it has to be combined with formal program of nicotine replacement therapy (17) and administration of an antidepressant drug – bupropion (18). Introducing such regimen allows achieving 22% cessation rate within five years and if it is compared with 5% cessation rate achieved in patients with standard treatment, it becomes obvious how important is to apply aforementioned recommendations. The patients have to be informed about purpose of smoking cessation, which is not used in order to increase walking distance, but in order to significantly reduce risk factors for vascular and ischemic episodes. No broad-spectrum study explicitly proved that smoking cessation is associated with significant increase in walking distance (19, 20). The patients have to be aware of this fact in order to prevent losing effort put in therapy, if the patient is discouraged by noticing no increase in walking distance.
TASC II Recommendation 1. Smoking cessation in peripheral arterial disease
|Al patients who smoke should be strongly and repeatedly advised to stop smoking (B).|
All patients who smoke should receive a program of physician advice, group counseling sessions, and nicotine replacement (A).
Cessation rates can be enhanced by the addition of antidepressant drug therapy (bupropion) and nicotine replacement (A).
Independent risk factors for the lower limbs atherosclerosis include elevated level of total cholesterol, low-density lipoprotein (LDL) and triglycerides (TG) (21). Factor that is protective for the development of PAD is elevated high-density lipoprotein (HDL) (22). Current recommendations for the management of lipid disorders in patients with PAD are to achieve LDL level in serum < 100 mg/dL, however, in patients with PAD and other vascular disease (e.g. coronary heart disease), concentration of LDL in serum should be at the level of < 70 mg/dL. Administration of statins is the main method for lowering level of LDL and reducing risk of the cardiovascular episode. Fibrates are recommended in order to lower concentration of triglycerides. Data coming from broad-spectrum, randomized study including population of over 20 thousand patients – Heart Protection Study (HPS), emphasizes the role of lowering LDL concentration in order to reduce undesired cardiovascular events. Use of simvastatin (40 mg/day) over the period of five years was associated with a 12% reduction in total mortality, 17% reduction in vascular mortality, 24% reduction in undesired vascular events and 27% reduction in all strokes (23). Moreover, HPS study revealed that long-term therapy with statins was associated with reduction in incidence of myocardial ischemia, stroke, and vascular death in patients with PAD.
TASC II Recommendation 2. Lipid control in patients with peripheral arterial disease (PAD)
|All symptomatic PAD patients should have their low-density lipoprotein (LDL)-cholesterol lowered to < 2.59 mmol/L|
(< 100 mg/dL) (A).
In patients with PAD and a history of vascular disease in other beds (e.g. coronary artery disease) it is reasonable to lower LDL cholesterol levels to < 1.81 mmol/L (< 70 mg/dL) (B).
All asymptomatic patients with PAD and no other clinical evidence of cardiovascular disease should also have their LDL-cholesterol level lowered to < 2.59 mmol/L (< 100 mg/dL) (C).
In patients with elevated triglyceride levels where the LDL cannot be accurately calculated, the LDL level should be directly measured and treated to values listed above. Alternatively, the non-HDL (high-density lipoprotein) cholesterol level can be calculated with a goal of < 3.36 mmol/L (< 130 mg/dL), and in high-risk patients the level should be <2.59 mmol/L (< 100 mg/dL).
Dietary modification should be the initial intervention to control abnormal lipid levels (B).
In symptomatic PAD patients, statins should be the primary agents to lower LDL cholesterol levels to reduce risk of cardiovascular events (A).
Fibrates and/or niacin to raise HDL-cholesterol levels and lower triglyceride levels should be considered in patients with PAD who have abnormalities of those lipid fractions (B).
Hypertension is the next independent factor associated with a two- to three-fold increased risk of the lower limbs ischemia at the background of atherosclerosis (24). It is recommended to maintain the blood pressure in patients with atherosclerotic process at the level of 130/85 mm Hg (25). Beta-blockers are not contraindicated in therapy of the peripheral artery disease, as it was claimed in previous papers. Currently, it is believed that the patients qualified for surgical treatment of the peripheral artery disease should take beta-blockers due to their cardioprotective action in this group of patients (26). HOPE (Heart Outcomes Prevention Evaluation) study conducted on over four thousand of subjects proved positive effect of using ACE inhibitors on reduction of hypertension in the group of patients with PAD (27). Therefore, it is recommended to use ACE inhibitors in the group of patients with PAD and hypertension, who are at high risk of cardiovascular complications.
TASC II Recommendation 3. Control of hypertension in peripheral arterial disease (PAD) patients
|All patients with hypertension should have blood pressure controlled to <140/90 mmHg or <130/80 mmHg if they also have diabetes mellitus or renal insufficiency (A).|
JNC VII and European guidelines for the management of hypertension in PAD should be followed (A).
Thiazides and ACE inhibitors should be considered as initial blood-pressure lowering drugs in PAD to reduce risk of cardiovascular events (B).
Beta-adrenergic-blocking drugs are not contraindicated
in PAD (A).
In diabetes mellitus, there is approximately three-fold increase in risk of PAD and approximately five-fold increase in risk of intermittent claudication (28). Risk of other complications, such as peripheral neuropathies or skin infections leading to non healing ulcerations, is also a few times higher within the course of diabetes mellitus. Several studies of both type 1 and type 2 diabetes mellitus have shown that aggressive blood-glucose lowering can prevent microvascular complications, particularly retinopathy. However, explicit positive effect of blood-glucose lowering on reduction of cardiovascular events and PAD development has not been proven (29). The current American Diabetes mellitus Association guidance recommends hemoglobin A1C level of 7%, however, it is unclear whether achieving this goal will effectively reduce PAD development.
TASC II Recommendation 4. Control of diabetes mellitus in peripheral arterial disease (PAD)
|Patients with diabetes mellitus and PAD should have aggressive control of blood glucose levels with a hemoglobin A1c goal of < 7.0% or as close to 6% as possible (C).|
An elevated serum homocysteine level is an independent risk factor for PAD (30). However, no positive effect of using supplements with vitamin B on reduction of cardiovascular events has been proven.
TASC II Recommendation 5. Use of folate supplementation in peripheral arterial disease (PAD)
|Patients with PAD and other evidence of cardiovascular disease should not be given folate supplements to reduce their risk of cardiovascular events (B).|
Hypercoagulation is the most common cause of venous thrombosis, which has been proven in numerous studies (31). Pathologies associated with coagulation in patients with PAD have been evaluated in not many studies, which provided evidence of coexisting elevated concentration of platelet activation markers and PAD (32).
Acetylsalicylic acid (ASA) is a well-recognized antiplatelet drug that has clear benefits in patients with cardiovascular diseases. Antithrombotic Trialists’ Collaboration study proved efficacy of this drug in patients with ischemic heart disease (33). This study also proved that low doses of ASA (75-160 mg daily) are safe for the gastrointestinal tract. Thus, current recommendations would strongly favor the use of low doses of ASA in patients with cardiovascular diseases. Antiplatelet drugs are clearly indicated in the overall management of PAD, although the efficacy of ASA is shown only when PAD and cardiovascular disease coexist (34).
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