Screening Methods

The clinical exam and Rose questionnaire are useful though unfortunately fairly insensitive tools for the diagnosis of lower extremity vascular disease (163). Ancillary modalities include the ABI, toe systolic blood pressure, ultrasound duplex scanning, tissue PO2 measurement, and arteriography.

Ankle Brachial Index (ABI)

The ABI is a ratio of Doppler recorded systolic arterial blood pressures in the lower and upper extremities, (166) and is normally between 1.00 and 1.40 (167). PAD is defined as an ABI less than 0.9. Lower ABI values indicate more severe PAD.

The ADA consensus statement on PAD recommends that a screening ABI be performed in the following situations:

■ Individuals 49 and younger with type 1 diabetes mellitus and one other risk factor;

■ All diabetic individuals >50 years of age;

■ Any patients with symptoms of PAD.

The results of ankle brachial index measurements help to guide further management. An ABI less than 0.50 in any vessel should prompt expeditious referral for specialist vascular assessment, since these patients almost certainly have severe peripheral vascular disease. An ABI between 0.50 and 0.90 warrants a follow-up evaluation within 3 months, because these patients are likely to have mild to moderate peripheral vascular disease. If the subsequent ABI is less than 0.90, intensive risk factor modification and annual ABI follow-up is recommended. If the repeat ABI is greater than 0.90, further follow-up ABI may be performed every 2 or 3 years. Similarly if an initial ABI is greater than 0.90, repeat testing need only be done every 2 to 3 years since these patients are unlikely to have peripheral arterial disease.

ABI may have limited use in certain diabetic patients, such as those in whom the medial wall calcification may render the arteries non-compressible, resulting in unusually high ABI values (>1.40), even in the presence of occlusive disease (167). Under these conditions, the ABI is unreliable (165,168). However, an elevated ABI is still predictive of an increased risk of cardiovascular events, and other non-invasive tests should be considered to diagnose PAD (169).

Noninvasive Imaging Techniques

In patients with a confirmed diagnosis of PAD, further investigation of segmental pressures to localize the diseased vessel, and morphological features of the diseased area, usually in the context of a planned revascularization procedure is needed. This can be achieved by several non-invasive imaging modalities, such as ultrasound duplex scanning, pulse volume recording, MRA or CTA. Ultrasound duplex scanning can directly visualize vessels, providing information on arterial wall thickness, degree of flow turbulence and flow velocity (170). Contrast enhanced MRA produces images that are compatible with conventional angiography (171). Recent development in CTA has also dramatically improved image quantity, replacing conventional angiography in many centers (172,173).

Arteriography

Invasive arteriography has been the definitive procedure for diagnosing PAD. (Fig. 3) However, it is being replaced by noninvasive imaging methods in many centers as discussed before. Arteriography remains an important modality, particularly in the context of endovascular revascularization.

Management of PAD

Intensive Risk Factor Modification

The major cause of PAD is atherosclerosis. Atherosclerotic risk factors for PAD include cigarette smoking, diabetes, dyslipidemia and hypertension. Intensive risk factor modification is an essential component of PAD management.

Smoking Cessation

Cigarette smoking is the most important risk factor for the development of PAD. The amount and duration of tobacco use correlate directly with the development and progression of PAD (174). The effect of smoke cessation on the long-term survival should not be underestimated. In one study, the ten-year survival in former smokers was 82% as compared to 46% in active smokers (175). In a more recent study, the long-term mortality was improved by utilizing the following smoke cessation methods: physician advice, nicotine replacement therapy and counseling (176).

Diabetes

In the UKPDA study, each 1% reduction in the mean glycosalated hemoglobin (HbA1C) was associated with 21% reduction in risk for any endpoint related to diabetes, and 21% reduction in death related to diabetes, 14% reduction in MI and 37% reduction in microvascular complications (177). There is also strong evidence of an association between the duration of diabetes and the risk of PAD in men (178). However, direct evidence supporting aggressive glycemic control to reduce the risk associated with PAD is lacking. Current ADA guidelines recommended a target glycosylated hemoglobin level of <7.0% in diabetic individual (179).

Dyslipidemia

It has been well established that lipid lowering therapy decrease cardiovascular events in diabetic patients (103,104,180,181). However, there is a lack of direct evidence on treating dyslipidemia in patients with both diabetes and PAD. The Heart Protection Study randomized over 20,000 UK adults with occlusive arterial disease including coronary, cerebral and peripheral arterial disease and/or diabetes mellitus and a total cholesterol level greater than 135mg/dL to simvastatin or placebo (182). Among the 6748 patients with PAD, a 25% risk reduction over five years of follow-up was observed in the simvastatin group. In the classification system of the National Cholesterol Education Program/Adult Treatment Panel

III (NCEP/ATP III), individuals with lower extremity PAD are classified as either "high risk" or "very high risk" depending on associated risk factors. Based on these findings, the ACC/ AHA recommends that treatment with a hydroxymethyl glutaryl (HMG) coenzyme-A reductase inhibitor (statin) medication is indicated for all patients with PAD to achieve a target LDL cholesterol level of less than 100 mg/dL. When the risk is very high, such as for patients with PAD and diabetes, an LDL goal of less than 70 mg/dL is a therapeutic option.

Hypertension

Although the role of intensive blood pressure control in patients with diabetes and PAD has not been well studied, sufficient evidence supports the benefit of a lower target blood pressure. The UKPDA study showed that although diabetes end points were significantly reduced by strict blood pressure control, there was no effect on the risk of amputation due to PAD (183). Nevertheless, a significant reduction in vascular events in diabetic patients treated with aggressive hypertension management has been demonstrated in the hypertension optimal treatment (HOT) trial (184) and the appropriate blood pressure control in diabetes (ABCD) trial (185). In a more recent study, lowering blood pressure in normotensive diabetic patients with PAD was effective in preventing cardiovascular events (186).

Antiplatelet Therapy

Aspirin

Data from secondary prevention trials in non-diabetic subjects indicate that aspirin has a protective effect on subsequent cardiovascular mortality and morbidity (187). However, the only prospective study evaluating the efficacy of five-year aspirin treatment in diabetic patients with PAD is the Veterans Administration Cooperative Study. This study assessed the efficacy of aspirin (650mg/day) and dipyridamole in preventing the progression of cardiovascular and PAD in 231 diabetic men with limb gangrene or recent amputation for

Profunda And Sfa Arteriogram

FIGURE 3 Peripheral arteriogram of a patient with type 2 diabetes and symptomatic claudication. (A) The pigtail catheter is placed in the distal abdominal aorta (Ao). The right common iliac artery (RCIA) has mild aneurysmal dilatation before it bifurcates into the right external (REIA) and internal iliac arteries (RIIA). The right internal iliac artery is occluded (double arrows). The left common iliac artery (LCIA) bifurcates into the left external (LEIA) and internal iliac arteries (LIIA). The left internal iliac artery has a moderate ostial stenosis (single arrow). (B) The right common femoral artery (RCFA) has mild disease and bifurcates into the right superficial (RSFA) and profunda femoral arteries (RPFA). There is a high-grade stenosis involving the bifurcation extending into the ostium of the right SFA) (single arrow). The right SFA has a long segment of total occlusion (triple arrows). The left common fermoral artery (LCFA) bifurcates into the left superficial (LSFA) and profunda femoral arteries (LPFA). The LSFA has two discrete high-grade stensois (single arrow).

FIGURE 3 Peripheral arteriogram of a patient with type 2 diabetes and symptomatic claudication. (A) The pigtail catheter is placed in the distal abdominal aorta (Ao). The right common iliac artery (RCIA) has mild aneurysmal dilatation before it bifurcates into the right external (REIA) and internal iliac arteries (RIIA). The right internal iliac artery is occluded (double arrows). The left common iliac artery (LCIA) bifurcates into the left external (LEIA) and internal iliac arteries (LIIA). The left internal iliac artery has a moderate ostial stenosis (single arrow). (B) The right common femoral artery (RCFA) has mild disease and bifurcates into the right superficial (RSFA) and profunda femoral arteries (RPFA). There is a high-grade stenosis involving the bifurcation extending into the ostium of the right SFA) (single arrow). The right SFA has a long segment of total occlusion (triple arrows). The left common fermoral artery (LCFA) bifurcates into the left superficial (LSFA) and profunda femoral arteries (LPFA). The LSFA has two discrete high-grade stensois (single arrow).

ischemia. There were no differences in major endpoints such as atherosclerotic vascular death (22% vs. 19%, respectively), in treated and control subjects, or amputation of the opposite extremity (20% vs. 24% in treatment and control subjects) (188). Aspirin has been shown to significantly improve vascular graft patency by the Antiplatelet Trialsts' Collaboration (113). Aspirin is recommended for all diabetic individuals older than 21 years of age (189). However, its role in patients with either diabetes or PAD, but without clinical evidence of CAD or stroke, has not been established. A large secondary prevention trial of aspirin and/or other antiplatelet drugs in diabetic subjects with PAD is therefore needed (190).

Clopidogrel

Based on the results from the Clopidogrel versus aspirin in patients at risk for ischemic events (CAPRIE) study, the ADA consensus recommends that patients with diabetes should be treated with an antiplatelet agent, and those with PAD may benefit more by taking clopidogrel than Aspirin (191). The CAPRIE study evaluated aspirin 325 mg daily versus clopidogrel 75 mg daily in 19,000 patients with recent stroke, recent MI or established PAD (approximately 20% were diabetics). There was a significant 8.7% relative risk reduction in the annual risk of stroke, MI and vascular death in the clopidogrel arm as compared to the aspirin arm (192). In a subset analysis of 6452 patients with PAD, clopidogrel recipients had an annual event rate of 4.86% compared with 7.71% in aspirin recipients, representing a 23.8% relative risk reduction. Furthermore, in the PAD subgroup, clopidogrel was superior to aspirin in diabetic patients (193).

Pentoxifylline and Cilostazol

Pentoxifylline and cilostazol are the two medications currently approved in the U.S. for symptomatic treatment of intermittent claudication. Pentoxifylline is a hemorrheologic agent that decreases blood viscosity and improves erythrocytes flexibility (194). Evidence demonstrating the efficacy of pentoxifylline in improving treadmill walking distance has been equivocal, and therefore its general use in PAD cannot be justified (195). On the other hand, cilostazol, a phosphodiesterase inhibitor, has been shown to improve maximal walking distance by 40% to 50% when compared with placebo (196). In a study directly comparing pentoxifylline and cilostazol for treating claudication, patients treated with cilostazol for 24 weeks had significantly greater walking distance as compared to patients treated with pentoxifylline or placebo (197). Cilostazol is contraindicated in systolic or diastolic heart failure because of concerns about the potential risk of mortality (191).

Various trials have studied prostacyclin or prostacyclin analogues (iloprost and beraprost), and intravenous infusion of prostaglandin E1 for the treatment of claudication. However the results have been inconsistent, and therefore prostaglandin cannot be recommended for the treatment of PAD (198-200).

Endovascular and Surgical Revascularization Therapy

In patients with advance PAD resulting in critical limb ischemia, revascularization is the preferred treatment. Two methods of revascularization techniques include endovascular interventions and open surgical bypasses. In recent years, endovascular revascularization has increased more than five-fold from 1980 to 2000 (201). An endovascular procedure may be more appropriate in patients with relatively focal disease in the arteries above the knee; the best results have been achieved in the aorto-iliac vessels, where one-year patency rate has been reported to be 80 to 90% (202,203). Endovascular procedures carry generally low risk for complications and provide an excellent alternative to surgery in selected patients, particularly those deemed to be poor surgical candidate (204). However, because of its greater durability, surgical therapy remains the definitive therapeutic option in many diabetic patients (205). In addition, diabetes does not adversely affect the surgical treatment of aortoiliac disease (206).

Although most ischemic limbs can be revascularized, some cannot. Amputation is indicated when there is overwhelming infection or significant tissue loss. Despite increased rates of surgical and endovascular revascularization procedures, in the 1990s, there was no decrease in the rates of major amputation in the general population (207).

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