The medical therapy of intermittent claudication is founded on two fundamental precepts (Table 34-1). The most compelling of these is that peripheral arterial disease is evidence for systemic atherosclerosis. Affected patients most likely have concomitant coronary artery and cerebrovascular diseases. As a result, they are at increased risk for adverse clinical outcomes including myocardial infarction, stroke, and death. These patients also frequently manifest symptoms of intermittent claudication, resulting in impaired functional status, or symptoms of critical limb ischemia—rest pain, ulcers, or gangrene, which ultimately threaten the viability of the limb. Therefore, management of these patients must employ therapeutic strategies that decrease their risk of cardiovascular events, reduce mortality, improve functional capacity and quality of life, and preserve limb integrity. In contrast to the relative intangibility of vascular risk reduction, symptomatic improvement in peripheral arterial disease after the institution of appropriate medical therapy can often become apparent to the patient within a matter of weeks or a few months and can significantly enhance a patient’s quality of life.

Pentoxifylline was the first drug approved by the U.S. Food and Drug Administration (FDA) in 1984 for the treatment of claudication. It is a methylxanthine derivative that increases intracellular levels of cyclic adenosine monophosphate (cAMP). The drug improves red cell and white cell deformability, lowers plasma fibrogen concentrations, and possesses antiplatelet effects.¹ The drug’s clinical effects have however been somewhat lackluster. Although pentoxifylline increased maximal treadmill walking distance by 12% as compared with placebo in one randomized clinical US trial, there was no difference between the two groups in the increase in maximal treadmill walking distance when compared to baseline.² Another study found only a 21% (nonsignificant) increase in maximal treadmill walking distance in patients treated with pentoxifylline as compared to placebo.³ Most recently, a trial that compared pentoxifylline, cilostazol, and placebo found that cilostazol was the sole agent that improved pain-free and maximal walking distances compared with placebo.⁴ Patients randomized to pentoxifylline in this study fared as well as those randomized to the placebo arm in terms of symptom relief. A meta-analysis found a net benefit of only an additional 44 m in the maximal distance walked on a treadmill (95% CI, 14–74 m) in patients treated with pentoxifylline.⁵

In addition to the marginal clinical benefit afforded by pentoxifylline in improving exercise capacity, use of the drug is hobbled by a paucity of information with regard to its impact on function status and quality of life. Importantly, with the recent and now routine inclusion of quality of life questionnaires into clinical drug trial designs for claudication, pentoxifylline failed to demonstrate improvement in daily functional status as assessed by the Walking Impairment Questionnaire (WIQ) or Medical Outcomes Scale Health Survey (MOS SF-36), when compared to cilostazol.⁴

It has been recently postulated that pentoxifylline may possess the potential to alter the natural history of peripheral arterial disease (PAD). The facts supporting this hypothesis, however, deserve close scrutiny. Although the use of pentoxifylline was associated with a reduction in hospital expenditures without a greater overall cost of PAD-related care, the drug did not alter the risk of PAD-related hospitalization.⁶ Compliance with taking pentoxifylline reduced the frequency of invasive vascular procedures during the first year in a small group of claudicators.⁷

Pentoxifylline is administered in a dose of 400 mg 3 times daily with meals, but maybe reduced to 400 mg twice daily if gastrointestinal or central nervous system side effects occur. Because of its nearly complete absorption with some first-pass metabolism and renal excretion route, precaution needs be taken in patients with renal impairment, as metabolites may accumulate. It is relatively well tolerated with rare reported side effects, which include dyspepsia, nausea, vomiting, headache, and dizziness.

The results of clinical trials demonstrating the efficacy of pentoxifylline in improving treadmill walking distance have been equivocal and there are insufficient data to presently justify its generalized use in PAD (Table 34-1). The current ACC/AHA guidelines for the management of PAD advise that pentoxifylline maybe considered as second-line, alternative therapy to cilostazol to improve walking distance in patients with intermittent claudication (Class IIb, level of evidence: A). Furthermore, the guidelines clearly state that the clinical effectiveness of pentoxifylline as therapy for intermittent claudication is marginal and not well established (level of evidence: C).⁸

Cilostazol was the second agent approved by the FDA in 1999 for the symptomatic treatment of claudication. It functions as a phosphodiesterase type III inhibitor, thereby increasing the intracellular levels of cyclic AMP through its inhibition of proteolysis. This drug has a plethora of therapeutic mechanisms including the inhibition of platelet aggregation and arterial thrombogenesis, and the inhibition of smooth-muscle cell proliferation. Cilostazol amplifies the effects of prostacyclin and promotes direct smooth-muscle cell relaxation, leading to arterial vasodilatation.^9,10 The precise mechanism of this drug’s dramatic effects on reducing claudication symptoms and improving ambulatory capacity remains elusive and maybe multifactorial.

Cilostazol has undergone intensive clinical scrutiny, with no less than eight randomized controlled clinical trials examining its efficacy. Of these, four trials are large enough to warrant review; these were randomized, placebo-controlled enrolling a total of 1534 claudicants.^4,11,12,13 In all four trials, cilostazol improved pain-free and maximal walking distance by 35% to 50% as compared to placebo. In three of the trials, cilostazol demonstrated a significant improvement in functional status and walking performance compared to placebo using both the MOS SF-36 and walking impairment questionnaire criteria. The WIQ data from these trials indisputably established the superiority of this drug over placebo in improving both walking distance and speed over placebo.^12,13 In these trials, a significantly greater number of patients treated with cilostazol noted a dramatic subjective improvement in exercise capacity and quality of life, which ultimately is the most compelling indication for its “first line” use in claudication.

Cilostazol (50 mg twice daily) also has been shown to increase maximal walking distance on treadmill exercise testing. Cilostazol demonstrated a greater improvement in walking distance when compared to pentoxifylline and placebo in a large randomized clinical trial. The increase in the absolute claudication distance of 107 m (54%) with cilostazol eclipsed that observed with pentoxifylline of 64 m (30%) or placebo of 65 m (34%), after 6 months of treatment. Drug withdrawal in this study resulted in a rapid decline of the walking distance within 6 weeks, providing further evidence that the initial improvement in walking distance was solely the effect of cilostazol itself. In comparison, withdrawal of pentoxifylline therapy, like that of placebo drug in this study, resulted in no change in claudication symptoms or in exercise capacity from baseline.¹⁴

Ancillary benefits associated with cilostazol therapy in clinical trials include an increase in ankle-brachial indicies (ABI),¹² significant increases in high-density lipoprotein (HDL) cholesterol by 10%, and lowering of triglycerides by 15% with greater effects demonstrated in patients with higher baseline triglycerides.¹⁵ Patients with diabetes treated with cilostazol showed a significant reduction in carotid intimal-medial thickening on duplex ultrasound analysis.¹⁶ Once again in this study, as in many others, the modest increase noted in the ABI (9%) was not consonant with the dramatic and reproducible improvement in claudication symptoms in those patients randomized to the drug.

The standard cilostazol dosage of 100 mg twice daily provides the optimal efficacy, but patients who experience side effects may benefit from reducing the initial dosage to 50 mg twice daily.¹³

The pharmacokinetics of cilostazol are notable for its extensive hepatic metabolism by the 3A4 isoform of cytochrome P450 (CYP3A4) and by the 2C19 and 1A2 isoforms with the formation of active metabolites and predominant renal excretion.¹⁰ Although no recommendations have been put forward regarding the issue of dose adjustment in patients with renal or hepatic impairment, caution is advised in the use of this drug in the context of moderate or severe liver dysfunction.^17,18 Adjustment to dosage should be instituted during coadministration of agents that inhibit CYP3A4 or CYP2C19 such as ketoconazole, itraconazole, erythromycin, diltiazem, omeprazole, and consumption of large quantities of grapefruit juice, in excess of one quart daily.

The most frequent side effects are headache, which affects approximately 34% of patients as compared to 14% of patients taking placebo, followed by diarrhea, palpitations and dizziness.¹⁰ Despite the reported side effects, cilostazol has been well tolerated, as exemplified by the similar rates of discontinuation of the drug amongst patients receiving placebo or pentoxifylline in clinical trials.¹³ Although cilostazol is safe to be taken in conjunction with aspirin, there exists only limited safety data on combinations with clopidogrel.¹⁹

Cilostazol is contraindicated in patients with congestive heart failure, although it has not been shown in any clinical trial to precipitate or exacerbate this complication. The contraindication is based upon the fact that other phosphodiesterase 3 inhibitors such as milrinone, which was developed as an inotropic agent for the treatment of heart failure, have been associated with excess cardiac mortality in patients with New York Heart Association Class III–IV heart failure.²⁰ Cilostazol labeling is now accompanied by a “black-box” warning that it is contraindicated in patients with heart failure of any magnitude. In clinical trials involving more than 2000 patients treated with cilostazol followed for up to 6 months, no appreciable increase in cardiovascular death (0.6%) in cilostazol-treated vs. 0.5% in placebo-treated patients was observed. Myocardial infarction was also rare, occurring in 1.5% and 1.1% of cilostazol-treated and placebo-treated patients, respectively.⁹

The current ACC/AHA guidelines recommend cilostazol 100 mg twice daily as an effective therapy to improve symptoms and walking distance in patients with lower extremity PAD and intermittent claudication (in the absence of heart failure). The recommendations also state that a therapeutic trial of cilostazol should be considered in all patients with lifestyle-limiting claudication. Both these recommendations are class I, level of evidence: A.⁸

Given the theoretical concern regarding the risk of the drug in patients with heart failure, each individual physician needs to tailor his experience and comfort level as to the role of routine screening for evidence of congestive heart failure (CHF), interim assessment of risk–benefit ratio on subsequent ischemic events and monitoring of cardiac rate, and rhythm during commencement of therapy.²¹