Peripheral Arterial Disease: Medical Care and Prevention of Complications

David L. Dawson, MD; William R. Hiatt, MD; Mark A. Creager, MD; Alan T. Hirsch, MD

Disclosures

Prev Cardiol. 2002;5(3) 

In This Article

General Management Issues

Drug therapies for patients with intermittent claudication are directed toward 1) slowing atherosclerotic progression; 2) reducing risk of myocardial infarction, stroke, and cardiovascular death; and 3) alleviating symptoms. Unless contraindicated, all patients with atherosclerotic disease should receive lifelong antiplatelet therapy. Management guidelines for PAD patients are summarized in Table I .[20,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]

Given that the presence of PAD is indicative of more generalized atherosclerosis, it is important to modify known risk factors that contribute to cardiovascular disease. Such factors include smoking, diabetes mellitus, obesity, hyperlipidemia, hypertension, and homocysteine elevation.[1] The continued use of tobacco products, for example, has been associated with progressive worsening of claudication, an amplified risk of critical-limb ischemia, greatly increased rates of amputation, failure of limb revascularization, increased rates of myocardial infarction and stroke, and heightened mortality.[20] Smoking cessation appears to decrease PAD symptom incidence and severity.[48] Although the magnitude of claudication improvement, if any, is uncertain in individual patients, the promise of decreased cardiovascular ischemic events and the lessened risk of other smoking-related diseases should provide an incentive to quit. Patient education and lifestyle changes to reduce smoking and other risk factors should be implemented as an important first step in any treatment of PAD.

Decreases in the rates of fatal and nonfatal myocardial infarction, stroke, and vascular death have been found when antiplatelet therapy is used for secondary prevention of cardiovascular events.[22] In men enrolled in the US Physicians' Health Study,[23] chronic administration of aspirin was found to reduce the need for subsequent peripheral artery surgery. The Antiplatelet Trialists' Collaboration[24] showed that aspirin reduced the risk of cardiovascular events; however, the data suggested that aspirin was less effective for the subgroup of patients with PAD, whereas ticlopidine did show benefit. More recently, the platelet inhibitor clopidogrel was tested in PAD patients at risk for ischemic events and found to be more effective and safer than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, and vascular death.[25,49] In the absence of contraindications, all patients with PAD, whether symptomatic or not, should be treated with antiplatelet therapy (aspirin or clopidogrel).[1]

Exercise therapy -- preferably a supervised walking program -- should always be considered as part of the initial therapy for patients with intermittent claudication.[1] Regular walking can be expected to result in an increase in the speed, distance, and duration of walking. The benefits accrue gradually, but are recognized by the patient after a few weeks.

The use of formal exercise programs to treat claudication has been studied over the past three decades. In fact, this is perhaps the best studied medical therapy for claudication, with demonstrated efficacy in improving exercise performance, quality of life, and functional capacity. Numerous types of exercise programs have been devised, but the most successful employ a supervised setting.[50,51,52,53]

A typical supervised exercise program is 60 minutes in duration, is given three or more times a week, and is monitored by a physical therapist, trained nurse, or experienced technician. Patients should be encouraged to walk on a treadmill, since this most closely reproduces walking in the community setting, is the best studied, and has been shown to be an effective intervention. The initial workload of the treadmill is set to a speed and grade that brings on claudication pain within 3-5 minutes. Patients walk at this work rate until they achieve claudication of moderate severity, then rest until the claudication abates. The exercise-rest cycle is repeated several times during the 1 hour of supervision. Patients should be reassessed clinically on a weekly basis as they become able to walk farther and farther at their chosen workload. This is followed by a regimen of increased speed or grade (or both) to allow patients to successfully walk at harder and harder workloads.

The general duration of an exercise program is 3-6 months. Typical benefits include more than 100% improvement in peak exercise performance on the treadmill,[54] significant improvements in walking speed and distance noted with the WIQ, and improvements in physical function and vitality on the SF-36 questionnaire. Despite the widespread documentation of efficacy, exercise programs are currently not reimbursed by most health care plans; however, this is expected to change in the years ahead due to the uniform consensus among vascular professionals and health care payers that supervised exercise is an effective primary therapeutic modality to improve claudication symptoms.

The mechanism of the exercise training benefit has been evaluated in several studies. In general, exercise training is not associated with significant changes in limb blood flow. Further, changes in blood flow have not been correlated with changes in exercise performance. However, it is possible that there may be better distribution of flow to exercising muscle. Several metabolic parameters have been evaluated. Improved extraction of oxygen has been documented with exercise training. Some studies have also shown increases in muscle enzyme activity, but these findings are inconsistent across trials. More important, there is no demonstrated relation between change in any enzyme activity and change in exercise performance. Patients with intermittent claudication accumulate intermediates of oxidative metabolism (acylcarnitines) in their skeletal muscle. Previous studies have shown that patients with the greatest accumulation have the most impaired functional performance. Exercise training has been shown to clear these acyl compounds, and the degree of removal from skeletal muscle is directly correlated with improved performance. Therefore, these data suggest some metabolic improvement as a result of exercise training. Finally, alterations in gait and walking efficiency may contribute to the exercise training response. Several studies have shown that at submaximal workloads, exercise training results in decreased oxygen consumption and therefore improved walking efficiency. This is also associated with the exercise training response. In summary, although exercise training is not associated with significant improvements in skeletal muscle blood flow, changes in skeletal muscle metabolism and walking efficiency may account for much of the observed benefit.

Although many drugs have been evaluated for their potential to relieve claudication symptoms, few have actually demonstrated efficacy in adequately designed clinical trials ( Table II ). Of these, cilostazol and pentoxifylline are the only drugs that have US Food and Drug Administration (FDA) approval for this indication. Other agents in diverse drug classes, such as anticoagulants, vasodilators, growth factors, prostaglandins, and prostaglandin analogues, have been suggested for this indication, but treatment outcomes with these agents have been variable and none are currently approved beyond investigational purposes.[55]

Currently Available Options. Cilostazol, an inhibitor of type III phosphodiesterase, inhibits platelet activation (aggregation and secretion) and relaxes vascular smooth muscle.[56] Other effects of cilostazol include inhibition of vascular smooth muscle cell proliferation, lowering of serum triglyceride levels, and an increase in high-density lipoprotein cholesterol levels.[57] The FDA approved this drug in 1999 on the basis of results from eight clinical trials that included 2702 patients with PAD and moderate to severe claudication.[57,58,59,60,61] These studies, 12-24 weeks in duration, showed that cilostazol increased both PFWD and MWD on standardized treadmill testing. The percent mean change from baseline MWD was 28% to 100%, whereas the percent change in the comparable placebo groups was -10% to 30%. A dose-response effect was also observed, with a greater effect seen with cilostazol 100 mg twice daily than with cilostazol 50 mg twice daily.[60] The positive treatment effect with cilostazol was independent of sex, age, race, smoking status, coexisting diabetes, or use of blockers or calcium-channel blockers.

The quality-of-life survey instrument, SF-36, was used in six US trials of cilostazol. This widely used general health questionnaire showed that cilostazol improved several patient-reported aspects of well-being. Scores for bodily pain, physical function, role -- physical, physical summary, and vitality were all significantly improved.[60] These data suggested that cilostazol improved the physical (but not the social or emotional) aspects of quality of life for patients with intermittent claudication. Also, in analyses of pooled data, cilostazol-treated patients reported improvements in walking speed and distance, as assessed by the WIQ. These data confirmed objective evidence obtained from treadmill testing. For example, data from a randomized, placebo-controlled trial[60] with 516 patients demonstrated a significant (p<0.001) improvement in PFWD (59% improvement vs. placebo) and MWD (51% vs. placebo) on a treadmill with cilostazol treatment.

Pentoxifylline, a trisubstituted xanthine derivative classified as a hemorrheologic agent, is the other currently available drug for intermittent claudication therapy. Although extensively evaluated for claudication therapy, most trials with pentoxifylline have been small, and many were compromised by design shortcomings, such as the lack of an adequate placebo-treated control group or failure to use treadmill testing to objectively assess walking ability. One major pentoxifylline study conducted in the United States[62] enrolled a total of 128 patients in a double-blind, placebo-controlled protocol and found significant differences between the treated and placebo groups in increased initial (PFWD) and absolute claudication distances (MWD). A 59% increase in PFWD and a 36% increase in MWD were noted in the pentoxifylline-treated patients in this study. However, the differences in percent change from baseline values were not significant at the end of the study (24 weeks), reflecting the magnitude of the observed placebo effect (36% increase in PFWD and 25% increase in MWD). Data from the Scandinavian Study Group[63] indicated an 80% increase in PFWD and a 50% increase in MWD in pentoxifylline-treated patients after 24 weeks of therapy, again with no significant difference between groups, reflecting a large placebo effect.

Hood et al.[64] performed a meta-analysis of results from pentoxifylline clinical trials that used treadmill testing as an end point. Evaluating a combined group of 612 patients with moderately severe claudication from 11 randomized, placebo-controlled, double-blind studies, they found that the weighted mean improvement in MWD with pentoxifylline therapy was 48.4 m (95% confidence interval, 18.3-78.6 m), which was significant compared with placebo. These pooled data suggested that pentoxifylline was better than placebo and may be efficacious in improving walking distances. Despite the results of the meta-analysis, however, the lackluster results in broad clinical use and critical reviews of the available data have left many skeptical about pentoxifylline's efficacy.[65,66]

Comparison of Cilostazol and Pentoxifylline. One multicenter, prospective, placebo-controlled trial has directly compared the safety and efficacy of cilostazol and pentoxifylline in the treatment of intermittent claudication and found cilostazol to be superior.[61] This study, with 698 patients randomized to three groups (including placebo), is the largest reported trial of drug therapy for claudication. In addition, with randomization of 232 patients to the pentoxifylline group and 239 patients to the placebo group, the study was the largest placebo-controlled trial of pentoxifylline for claudication, more than three times the size of the largest previous study of pentoxifylline efficacy.

Patients in each active treatment group demonstrated a progressive increase in walking distances over time, with the greatest improvement observed in patients who received cilostazol (Figure 1).[61] At 24 weeks, the mean improvement in PFWD was 94 m and the increase in MWD averaged 107 m in the cilostazol-treated patients. By comparison, pentoxifylline increased PFWD by 74 m and MWD by 64 m, the same change in walking distance observed in subjects treated with placebo.

Comparison of the effects of cilostazol, pentoxifylline, and placebo on maximal walking distance. In this study population (n=698), cilostazol improved treadmill walking performance more than either pentoxifylline or placebo. Pentoxifylline was equivalent to placebo. Reproduced with permission from Am J Med. 2000;109:523-530.[61]

Both cilostazol and pentoxifylline were generally well tolerated, though fewer patients (15.8%) in the cilostazol-treatment group withdrew due to adverse events than in the pentoxifylline group (18.5%). The most commonly reported side effects after starting cilostazol therapy were headache, diarrhea, and abnormal stools, but these symptoms were generally mild to moderate in severity and self-limited.

An exercise program should be viewed as a primary treatment modality, with adjunctive drug therapy provided in some cases (Figure 2). For PAD patients who are asymptomatic or who have only mild claudication, exercise alone may be sufficient. Provided there are no contraindications, drug therapy may be added for patients with function-limiting symptoms. There may be a beneficial synergy between drugs and exercise, but supporting data are lacking. Drug therapy may also be used in patients for whom invasive therapy is not indicated. Though drug treatment should complement, not replace, a program of exercise, drug therapy is still an option for those unable or unwilling to exercise regularly.[1]

PAD management algorithm. Adapted with permission from Pharmacol Ther. 1999;24:616-623.[67]

As with any medical intervention, it is important to provide appropriate patient education and counseling. Common side effects of drugs should be identified, and patients should know that many of the side effects experienced with initiation of drug therapy are self-limited. Drug therapy for claudication treatment generally has a gradual onset of action. Patients should be counseled that they will not recognize immediate benefit and should continue therapy for several weeks before considering how well the drug is working. Providers should know, however, that not all patients experience meaningful effects on their walking performance, and patients should be periodically evaluated to monitor their response to therapy. This may include use of treadmill tests, walking questionnaires, or consideration of the patient's opinion. In addition, adherence to therapy should be evaluated and possible side effects considered.

A trial of medical therapy is a reasonable option for patients with intermittent claudication, even though benefit is not assured. In a single-blind trial of withdrawal of therapy, neither the pentoxifylline- nor cilostazol-treated patients suffered harm by discontinuing therapy, though the benefits of the medication were lost in those who had responded -- as is true for any pharmacotherapeutic intervention.[68] This suggests that clinicians should consider a drug "holiday" -- a trial withdrawal of chronic pharmacotherapy for claudication if there is uncertainty about the benefits of continuing the medication. The effect of withdrawal should be evident within 6 weeks. Therapy should be restarted only in patients who demonstrated benefit from it. This approach may reduce the number of patients receiving a nontherapeutic, but moderately expensive, drug treatment.

Risks of Drug Treatment. Like all therapies, drug treatment for claudication may be associated with adverse effects. Cilostazol is generally well tolerated, but has recognized side effects, including headache, diarrhea, and palpitations.[60] These effects have generally been mild. The drug is contraindicated in patients with clinical congestive heart failure of any severity, as other phosphodiesterase inhibitors have been linked to increased mortality in patients with severe congestive heart failure. This potential "class effect" of adverse outcomes in heart failure is considered a risk for the subset with heart failure due to systolic (vs. diastolic) dysfunction. Since candidates for cilostazol may be expected to have a higher incidence of ischemic cardiovascular disease, all patients with PAD who are considered candidates for cilostazol use should be periodically evaluated for the presence of heart failure. If a treating physician suspects heart failure, a noninvasive measurement of left ventricular function, such as echocardiography or radionuclide ventriculography, may be performed. In this way, patients would benefit from definitive therapy for PAD, heart failure, or both.

Dyspepsia, nausea, vomiting, dizziness, and headache have been identified as common side effects of pentoxifylline use ( Table III ). Contraindications to this agent include evidence of recent cerebral or retinal hemorrhage and prior history of intolerance to methylxanthines.

Revascularization procedures should be considered for patients who present with critical-limb ischemia, i.e., pain at rest, ulceration, or gangrene (Figure 2). However, before any invasive therapy (catheter-based or surgical) for intermittent claudication is considered, it is important that several criteria be met.[1] First, the patient should have tried a program of exercise, risk factor modification, and claudication pharmacotherapy. Second, despite such therapy, there should have remained persistent, functionally disabling symptoms that impair the ability to perform normal work or other activities important to the patient. Third, the systemic risk of the invasive procedure must outweigh the functional benefit. In this regard, it is important to rule out other causes that may limit walking despite improvement of claudication. Such causes include angina, chronic pulmonary disease, neuropathy, or degenerative joint disease, any of which may result in decreased walking ability. Fourth, the anticipated natural history and prognosis for each patient should be considered on an individual basis to determine the appropriateness of achieved improvements or lack thereof. Last, a patient-specific, technically viable option with a high benefit vs. risk ratio should be available. In other words, the proposed intervention should have a low anticipated risk and a high probability of initial and long-term success.

Patients may be referred for vascular laboratory testing. Duplex scanning can often identify arterial lesions amenable to angioplasty. Other essential information can often be identified noninvasively, permitting a realistic risk-benefit discussion to be held with the patient prior to angiography.[69] For example, duplex scanning of the iliac arteries can augment the clinical finding of a normal femoral pulse, thus confirming the suitability of the common femoral artery as a source of inflow to a graft. Preoperative arteriography may not be necessary in all cases, as duplex scanning may provide the necessary information to guide subsequent interventions.[70]

Duplex scanning or intraoperative assessment with on-table angiography can identify a suitable target for the distal anastomosis. However, given the time-consuming nature of complete lower extremity arterial mapping with duplex scanning and the extensive nature of lower extremity arterial disease in patients with severe ischemia, preoperative arteriography remains a standard part of most surgeons' evaluation before elective lower extremity bypass procedures.

Definition of Vascular Specialist Care. The vascular specialist may be a vascular surgeon, vascular medicine or cardiovascular physician, or interventional radiologist with experience in the evaluation of PAD patients. Issues of diagnosis, education, pharmacotherapy, and evaluation are important for all vascular specialists. Few vascular specialists are individually capable of providing the full spectrum of diagnostic and therapeutics services; in most cases a collaborative approach is required. Appropriate care may require angiography or other imaging services, catheter-based interventions (including thrombolytic therapy, angioplasty, or stenting), surgical revascularization, amputations, reconstructive operations, and other procedures. Many revascularization procedures have uncertain long-term benefits. Care should be taken to avoid procedures for patients who do not demonstrate appropriate clinical indications.

After any interventional procedure, medical management should include continued monitoring of complications, if any, to prevent recurrence. All lifestyle changes to accomplish risk factor reduction should be maintained. Long-term follow-up of these patients is necessary, since many of them will require repeat procedures, for the same reasons that precipitated the intervention in the first place.

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