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Can claudication be improved with medication?
Can Claudication Be Improved With Medication? By Michael S. Conners and Samuel R. Money Intermittent claudication is a common disabling condition that affects approximately 5% to 15% of patients with atherosclerotic disease. Recommended treatment involves lifestyle modification and physical conditioning through the adoption of a regular exercise program. These methods of treatment often have been unsuccessful in the past because of noncompliance, in large part related to the relatively minor degree of improvement experienced by the patient. However, some recent trials have resulted in greater relative improvements in both pain-free and maximal walking distances in some patients treated with medication. Surgical and endovascular options offer greater degrees of improvement but also greater morbidity and should be reserved as treatment for severe claudication. The efficacies, as well as common adverse reactions associated with current medications used to treat patients with intermittent claudication are reviewed. Copyright 2002, Elsevier Science (USA). All rights reserved.
ATHEROSCLEROTIC disease is a systemic that affects millions of Americans. Peripheral arterial disease (PAD) is only one manifestation of atherosclerotic disease, one that can limit an individual's capacity to carry out daily activities. Men and women are affected equally and the age-adjusted prevalence is approximately 12%.1 Of patients with PAD, only 5% to 15% suffer intermittent claudication. The accepted treatment for mild to moderate intermittent claudication is appropriately directed at lifestyle modification, control of atherosclerotic risk factors, as well as other comorbid medical conditions and attempting to lengthen pain-free walking distance by a structured (preferably supervised) exercise program, although many simply instruct the patient to walk to the point of claudication as often as they can on a daily basis. Modifications of lifestyle include smoking cessation and dietary restrictions aimed at hyperlipidemias. Comorbid illnesses that have been shown to increase the risk of PAD include hyperlipidemia, hypertension, diabetes mellitus, end-stage renal disease, and, more recently, hyperhomocysteinemia. Strict medical control of these risk factors has been shown to reduce the risk of coronary disease but its success in slowing the progression of PAD and improving intermittent claudication has not been proven by valid clinical trials. The only nonoperative treatment consistently shown to improve intermittent claudication has been the adoption of a structured exercise regimen. Discussion of therapy directed at the aforementioned risk factors and the beneficial effects achieved with exercise training are addressed in other sections of this monogram, so further
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discussion will be limited to the medical treatment of intermittent claudication. Enthusiasm for pharmaceutical treatments for claudication has waxed and waned since physicians first recognized that the painful cramping sensation was a result of impaired blood flow to the musculature of the lower extremities. Categorically, the medical treatment of claudication has included vasodilator therapy, antiplatelet agents, hemorrheologic agents, anticoagulants, and agents directed at improving metabolic reactions within the ischemic tissue. Most modem studies evaluating the efficacy of these agents usually are based on objective data related to improvements in walking ability on treadmill testing. Specifically, 2 end-points of interest are the patient's pain-free (PFWD) or initial claudication distance and the maximal (MWD) or absolute claudication distance. In addition, some studies have collected subjective data through the use of questionnaires regarding quality of life issues. Both generic and diseasespecific instruments are used, as well as functional questionnaires such as the Walking Impairment Questionnaire (WIQ). Improvements in both walking ability and subjective assessments of benefit are important to the patient's physical and psychological health. The following sections are directed at reviewing recent advances in the treatment of From the Department of Vascular Surgery, Ochsner Clinic Foundation, New Orleans, LA. Address reprint requests to Samuel R. Money, MD, MBA, Section Head, Vascular Surgery, Ochsner Clinic Foundation, 1514 Jefferson Hwy, New Orleans, LA 70121. Copyright 2002, Elsevier Science (USA). All rights reserved 0895-796710211504-0005$35.0010 doi: 10.1053/svas.2002.36259
Seminars in Vascular Surgery, Vol 15, No 4 (December), 2002: pp 237-244
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intermittent claudication with medication but also summarize some past treatments that have fallen out of favor. ASPIRIN
Aspirin has well established its role as a leader in the reduction of secondary events in patients with atherosclerotic disease. Additionally, some have reported reductions in the need for peripheral arterial procedures as well as improvements in vascular graft patency with the use of aspirin?,3 Despite these favorable results, the use of aspirin has not been shown conclusively to improve walking distances in patients with intermittent claudication. Aspirin is very effective in preventing secondary events (myocardial infarction and stroke) and accordingly should be considered in all patients with PAD (see Platelets-Is aspirin sufficient or do we really have to know how to pronounce abciximab? In this issue of Seminars) but is not currently indicated for the treatment of intermittent claudication. CLOPIDOGREL (PLAVIX)
Like aspirin, clopidogrel is an antiplatelet agent that has been shown to be effective in reducing secondary events in patients with atherosclerotic disease. In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, clopidogrel was associated with an overall reduction in primary endpoints (stroke, myocardial infraction, or death from other vascular causes) of 8.7%.4 This benefit was statistically different from that observed in patients receiving aspirin. In regards to treatment of claudication, clopidogrel has not been shown to offer any advantage. However, research into this field is ongoing. VASODILATORS
Initial attempts at improving blood flow to the extremities involved the use of vasodilators, mainly papaverine. s This was based on the concept that by dilating the blood vessels, the body would be able to provide more blood flow to the ischemic limb. However, unbeknownst to early pioneers, ischemic tissues release endogenous metabolic byproducts that lead to a maximal dilation of the local vasculature distal to the stenotic or obstructing lesion. The addition of vasodilator therapy has little effect on this already maximally dilated vas-
cular bed. In fact, vessels proximal to the lesion dilate and allow neighboring vascular beds to "steal" vital blood flow away from the deprived ischemic tissue. Vasodilators also have the capacity to reduce systemic vascular resistance potentially leading to a reduction in perfusion pressure. This reduction in perfusion pressure in conjunction with a steal phenomenon magnifies the ischemic insult to the underperfused muscle. As the understanding of the pathophysiologic mechanisms involved with peripheral vascular disease evolved, this concept of enhancing vasodilation fell out of favor. A relatively new concept, utilizing calcium channel blockers as vasodilators, involves increasing the oxygen extraction/utilization in the deprived skeletal muscle tissue. Bagger et al 6 conducted a randomized, double-blind, crossover study in which 44 patients had undergone a previous period of titration testing. 6 In the titration period, patients were given increasing doses of verapamil (120, 240, 360, and 480 mg) over 4 weeks to identify the drug dose that was associated with the longest MWD specific for each individual patient. After a washout period, each patient was given the drug dose that allowed that individual the longest MWD. Bagger et al 6 found that verapamil increased the mean PPWD 29% and the mean MWD 49% (P < .01 and P < .001, respectively) over placebo. Interestingly, the anklelbrachial pressure index (ABI) did not change suggesting it was not an increase in blood flow to the compromised tissue, but rather that oxygen extraction/utilization capacity was improved. Despite these recent data suggesting a beneficial effect with calcium channel vasodilator therapy, inconclusive data exist to support the use of vasodilators for the treatment of intermittent claudication in patients with peripheral arterial occlusive disease. PENTOXIFYLLINE(TRENTAL)
In 1984 the Food and Drug Administration (FDA) approved the first drug specifically indicated for treatment of claudication; pentoxifylline. This compound is a methylxanthine derivative that improves red blood cell deformability, decreases blood viscosity, and inhibits platelet aggregation. There have been numerous trials reporting mixed results concerning pentoxifylline's beneficial ef-
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fects in the treatment of intermittent claudication. The 2 largest multicenter randomized, doubleblind, placebo-controlled trials show these inconsistencies and are summarized in the following paragraphs. 7 ,8 The first of these 2 trials compared pentoxifylline (n = 67) with placebo (n = 61) treatment over a 24-week period. 7 Patients given pentoxifylline showed a 22% (45% v 23%; P = .02) greater improvement in mean PFWD from baseline when compared with placebo. In regards to MWD, patients treated with pentoxifylline had a 12% (32% v 20%; P = .04) absolute mean increase over patients given placebo. Despite significant improvements in PFWD and MWD, subjective assessments of cramping, tiredness, pain and the patient's overall condition were not found to differ between the 2 groups. The second large trial randomized 150 patients to 1,200 mg/d of pentoxifylline (n = 76) or placebo (n = 74).8 Unlike the findings of the previous study, investigators found no improvement in PFWD and only a trend that suggested an improvement in MWD in patients given pentoxifylline (P = .09). However, subset analyses identified certain subpopulations of patients (ABI <.80 and duration of disease> I year) that showed significant improvements in both PFWD and MWD when compared with patients receiving placebo. Ernst et al 9 likewise found no significant benefit in PFWD or MWD after 12 weeks of pentoxifylline therapy but did observe a significant increase in MWD at certain time intervals during the study period (at one and 8 weeks of treatment). This lead Ernst et al to speculate that the beneficial effects of pentoxifylline therapy may wear off with longterm administration. Although the above-mentioned trials failed to agree on the exact benefit gained with pentoxifylline therapy, their results do suggest a small beneficial effect offered to patients with intermittent claudication. Metaanalyses by Hood et allo and Girolami at ell I support these beneficial findings but agree that the magnitude of benefit is small. The major problem is that this questionable increase in walking distance is not subjectively appreciated by the patient. One must bear in mind that the purpose of this medication is to treat symptoms, so if the patient does not notice the improvement, the treatment is not useful. Use of pentoxifylline in patients receiving other
methylxanthine derivatives (aminophylline and theophylline) requires special attention. Concurrent use may result in increased active drug levels, so frequent monitoring of theophylline levels is recommended. CILOSTAZOL (PLETAL)
In January 1999 the FDA granted approval of a second drug, cilostazol, for the treatment of patients with intermittent claudication. The recommended dosage is 100 mg twice a day administered a half hour before meals or 2 hours after. Cilostazol is a phosphodiesterase type-3 inhibitor that is thought to exert its mechanism of action by inhibiting cyclic adenosine monophosphate (cAMP) phosphodiesterase. This leads to an accumulation of cAMP in platelets and blood vessels resulting in inhibition of platelet aggregation and promotion of vascular smooth muscle relaxation. Additional pharmacologic properties include a positive effect of increasing HDL cholesterol and decreasing serum triglycerides. 12 In vitro cell culture studies have also shown that it may reduce smooth muscle cell proliferation. 13 No claudication medication has been studied in as many prospective, placebo-controlled, doubleblind trials as cilostazol. The data presented are compiled from numerous studies involving 2,702 patients who were involved in phase-III double blind trials. 12 ,14,15 The mean age and ABI of the patients involved was 63.3 years and 0.64, respectively. As one would expect, approximately 76% of the patients were men with 92% of them being smokers (either previously or current). Approximately 60% of the patients had hypertension. Diabetes (25%) and coronary artery disease (22% with previous history of myocardial infarction) also were common in this group. When comparing percent change from baseline in patients who received cilostazol, 100 mg orally twice a day (v placebo), cilostazol was shown to be significantly more effective in increasing MWD across numerous studies. 12 ,14,15 It is interesting to note that the percent change from baseline in the cilostazoltreated group varied from a low of approximately 30% to a high of 100% improvement. Another way to look at this, in terms of increase distance walked, is that patients who receive cilostazol showed an improvement after 24 weeks of approximately 140 meters. What is essential in treating claudication is the
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subjective improvement perceived by the patient. It is interesting to note that approximately 30% of those patients who received placebo felt that they had a significant improvement in their walking ability. This is in comparison to a 51 % subjective improvement experienced in patients given cilostazol. When treating patients, it must be emphasized that not all patients will generate a significant subjective improvement, but a large part of the subjective improvement is what the patients perceive their improvement will be and what the patients are told they should expect before starting therapy. To go from one block claudication to 4-block claudication probably is not realistic. However, to improve walking distance from 2 blocks to 3 1/2 blocks, or from one block to 2 blocks is probably within the realm of what this drug is capable of achieving. As with many drugs, numerous side effects exist with the chronic use of cilostazol. The most common side effect is that of headache. Patients frequently will have a headache during the early stages of using this drug. The mechanism responsible for this is felt to be the drug's vasodilatory properties. Many of the headaches will respond to nonprescription medication such as acetaminophen. Another approach is to start with a lower dosage such as 50 mg twice a day, and after approximately 2 weeks increase to the recommended dosage. Gastrointestinal problems, especially diarrhea, are other common side effects. Most of the patients who suffer this side effect can tolerate it fairly well. Occasionally, there is a patient in whom the diarrhea is so severe that the drug needs to be discontinued. Palpitations are another important side effect. The average patient's heart rate typically will increase by approximately 4 beats per minute. Most patients will tolerate it without difficulty if they are warned in advance that palpitations may occur. Cilostazol and several of its metabolites are phosphodiesterase type III inhibitors. Other phosphodiesterase inhibitors, and not cilostazol specifically, have been shown to decreased survival rate compared with placebo in patients with class III to class IV congestive heart failure. 16 As a drug class consideration, cilostazol is contraindicated in patients with congestive heart failure of any severity. Cilostazol is partially metabolized in the liver by CYP3A4 or CYP2C 19 enzymes. As such, other drug classes that rely on such hepatic metabolism
CONNERS AND MONEY
may increase cilostazol levels. Examples include certain antifugals, calcium channel blockers, erythromycin, selective serotonin reuptake inhibitors, and omeprazole. Concurrent use is not discouraged but one may consider decreasing daily dosages to 50 mg twice a day. Cilostazol is a drug that can improve both PFWD and MWD in patients with claudication. Patient and physician expectations and perceptions must be realistic. A patient who responds to cilostazol should stay on the drug indefinitely. Patients should be reevaluated routinely for the development of congestive heart failure and, if it does occur, the drug should be discontinued. TICLOPIDINE (TICLlD)
Ticlopidine is a potent inhibitor of platelet aggregation that exerts its mechanism of action by blocking adenosine diphosphate receptors. Originally, this was theorized to lead to a reduction in blood viscosity and subsequent improvement in blood flow; however, others speculate it may improve red blood cell deformability as well.l? Balsano et al 18 conducted a randomized, double-blind, placebo-controlled trial in which 76 patients were given ticlopidine and 75 were selected randomly to receive placebo (n = 151). Using the intent-to-treat rule, Balsano et al found significant differences in PFWD and MWD in patients treated with ticlopidine. However, 25 patients violated protocol guidelines and subsequently were dropped from the trial. Secondary analysis of the remaining 126 patients (64 ticlopidine and 62 placebo) found only a significant increase in MWD in patients receiving ticlopidine. In another trial of similar size, Arcan et al 19 found significant increases in both mean PFWD and MWD in the ticlopidine treatment group. Additionally, ticlopidine was found to offer a cardiovascular protective benefit over placebo in patients with intermittent claudication. Fagher et al,zo however, found no benefit over placebo with long-term (5 years) treatment. In fact, significant improvements in walking at 5 years were experienced with placebo and not ticlopidine. Potentially fatal bone marrow suppression has been a concern with ticlopidine administration. A metaanalysis of 4 randomized trials found an overall 2.4% neutropenia rate with the majority of cases presenting within 3 months of drug initiation?1 In the study by Balsano, a significant reduction in the mean hematocrit level of patients taking ticlopi-
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dine was observed 12 and 15 months postrandomization. 18 However, this difference resolved by the end of the study period (21 months). Leukocyte counts also were found to be significantly less at 6 months, but differences in platelet count were never observed. In 2 of the aforementioned trials, patients receiving ticlopidine experienced significantly more gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation) than did the control patient population. 18 ,19 Similar to pentoxifylline and cilostazol, ticlopidine's metabolism is primarily accomplished by the liver. Patients concurrently receiving phenytoin or theophylline could potentially experience increases in drug serum levels, Serum drug level monitoring is recommended in these patients. Ticlopidine appears to offer a protective benefit from adverse cardiovascular events, but there is insufficient support to recommend use for the treatment of intermittent claudication. If ticlopidine is given, patients should be counseled with regard to gastrointestinal upset, and periodic hematologic monitoring should be initiated. PROSTAGLANDINS
The use of prostanglandins for the treatment of intermittent claudication has yielded promising results lately. A randomized, double-blind, placebocontrolled trial evaluating the efficacy of a prostaglandin E 1 prodrug (AS-013) found significant increases in MWD when compared with placebo treatment. 22 The study design consisted of 4 groups (total of 80 patients); 1 group receiving 25 ILg/wk intravenously, 2 groups receiving 10 ILg/wk but differing in dosing regimen, and 1 placebo group. Treatment was continued for 4 weeks followed by a 4-week observation period in which no therapy was administered. No statistical difference was found among the groups in regard to PFWD, but MWD was statistically different when all active treatment groups were compared with patients receiving placebo. This difference persisted over the 4-week observation period as well. Although no significant difference was found among the different active treatment groups, a trend existed that suggested a linear dose response. A subjective improvement also was seen in patients receiving the PGE 1 prodrug. A second multicenter, double-blind, placebocontrolled study showed similar improvements in MWD as well as improvements in PFWD?3 In this
study, patients were treated daily (5 d/wk) over a 4-week period followed by an interval treatment period (2 treatments per week) lasting 4 more weeks. PFWD increased 101 % over baseline for patients treated with PGE 1 • This compared favorably with the 60.1 % experienced in the placebo group (P < .05). Similarly, active treatment groups experienced significant improvements in MWD when compared with placebo (P < .05). Like the previous study, improvements in walking persisted beyond the treat period (3 months). Although these studies are encouraging, limitations exist with the use of PGE 1 for treatment of intermittent claudication. Despite outpatient use in these trials, intravenous administration is required. This has obvious limitations for long-term outpatient treatment. Adverse reactions include cardiac arrhythmias, hypotension, flulike illnesses, and gastrointestinal disturbances. The most common adverse reactions in the above-mentioned trials were injection site erythema and pain. A PGI2 analogue, Beraprost, may be a possible alternative to the intravenous administration of PGE 1. Lievre et al 24 conducted a large (n = 422) double-blind, randomized, multicenter phase III clinical trial evaluating the efficacy of Beraprost in patients experiencing intermittent claudication between the distances of 50 and 300 meters. In this study a significantly larger proportion of patients receiving Beraprost experienced an increase in PFWD (>50% above baseline) when compared with placebo (43.5% v 33.3%; P = .04). MWD increased a mean of 60.1 % in the active treatment group compared with a mean increase in the placebo group of only 35.0% (P = .004). Additionally, a significant improvement in global satisfaction related to changes in quality of life were reported in patients receiving Beraprost (P = .05). Adverse reactions did not appear to differ between the 2 cohorts. Beraprost currently is not available in the United States. NAFTIDROFURYL (PRAXILENE)
Naftidrofuryl is a serotonin antagonist that has been available in Europe for over 20 years. The proposed mechanisms of action include both vasodilatory effects as well as improvements in aerobic metabolism. An early multicenter, randomized, double-blind, placebo-controlled trial found a significant improvement in mean PFWD over placebo (35% increase) in patients treated for a 12-week
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period (P < .02).25 A later study duplicated these findings by showing a 32% increase in PFWD in patients treated with Naftidrofuryl for 6 months (P < .02).26 However, neither trial showed a significant increase in MWD with administration of Naftidrofuryl. Adverse reactions generally were related to gastrointestinal complaints but were not statistically different from placebo treatment. Currently, like Beraprost, Naftidrofuryl is not available for use in the United States. L-CARNITINE
Unlike the aforementioned pharmacotherapies, which achieve symptomatic relief by improving blood flow to the ischemic tissue by vasodilation, increased red blood cell deformability, improved blood viscosity, or reduced platelet adhesion, Lcarnitine improves the availability of substrates required for energy production. A small, doubleblind, cross-over trial by Brevetti et af 7 showed a significant improvement in PFWD in patients receiving oral L-carnitine. Pain-free walking distances improved by approximately 70% over baseline during L-carnitine therapy but diminished when patients were converted back to placebo treatment. Additionally, patients reported subjective improvements in symptoms while receiving L-carnitine. Investigators also found reductions in venous lactate and pyruvate levels with L-carnitine supplementation but significant differences over placebo were only suggested. In another study, a carnitine analogue, propionyl-L-carnitine, was found to increase MWD 27.1 % over placebo after 6 months of therapy (P = .03).2 8 Improvement in PFWD in patients receiving propionyl-L-carnitine almost doubled that experienced by patients in the placebo group but did not reach significance. A comparison study between equimolar doses of Lcarnitine and propionyl-L-carnitine showed greater increases in walking capacity in patients receiving the latter supplementation. 29 Improving metabolic efficiency of ischemic skeletal muscle is a unique treatment approach to intermittent claudication. Early results are encouraging and small but significant improvements in subjective assessments of quality of life appear to be possible with carnitine supplementation. 3D Carnitine supplements are available in most health food stores across the United States; however, recommended dosages for the treatment of inter-
mittent claudication is lacking. Further studies are needed to clarify the role of carnitine in the treatment of intermittent claudication. CHELATION
Chelation therapy refers to the administration of an agent (EDTA; ethylenediamine-tetraacetic acid), which forms complexes with divalent cations (Ca2 +), theorically preventing the progression of and possibly augmenting the regression of atherosclerotic disease. An early proponent of chelation therapy found an improvement in walking distance with a small patient population, but subsequent investigators have found no benefit in PFWD or MWD. 31 - 33 In addition, no difference in subjective assessments of quality of life has been identified. A more recent metaanalysis of randomized, placebo-controlled, double-blind clinical trials found that EDTA was not an effective treatment for intermittent claudication and concluded that chelation therapy should now be obsolete. 34 Despite these convincing results against chelation therapy, others continue to advocate its use for intermittent claudication. 35 Potentially fatal reductions in plasma cations are a concern, so close hematologic monitoring is recommended. L-ARGININE
L-arginine is an amino acid precursor for nitric oxide formation. A recent small (n = 39), randomized trial compared the effects of intravenous Larginine (8 g twice a day) and PGE 1 (40 p,g twice a day) in the treatment of patients with peripheral arterial occlusive disease. 36 Both treatments resulted in significant improvements in PFWD and MWD. This compared favorably with control patients who experienced no increase in walking ability. No difference was found between the 2 active treatment groups. The only adverse reaction was local injection site erythema and pain seen in the PGE 1 group. Further studies are needed to validate these encouraging results. Like carnitine, L-arginine is available in most health food stores as an oral supplementation. More controlled trials are needed before L-arginine can be recommended for the treatment of intermittent claudication. GINKGO BILOBA
The use of medicinal herbs as alternatives to conventional medicine has become fashionable.
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One of the most popular is Ginkgo Biloba extract. Review of the literature identified a recent metaanalysis of randomized, double-blind, placebocontrolled trials comparing Ginkgo to placebo for the treatment of intermittent c1audication. 37 Although metaanalyses are prone to criticism, this analysis suggested that Ginkgo biloba improved PFWD and MWD in patients with intermittent claudication. Overall, there did not appear to be a consistent adverse reaction, but occasionally gastrointestinal complaints were reported. More largescale clinical trials are needed before Ginkgo biloba can be recommended for the treatment of claudication (see Miscellaneous Medications: Mayhem or Miracle? In this issue of Seminars). BUFLOMEDIL
Buftomedil is a vasoactive drug that has reported effects on platelet inhibition, red blood cell deformability, and muscle cell metabolism. Trtibestein et al 38 have shown significant improvements in PFWD and MWD when compared with placebo in patients treated with 600 mg daily for 12 weeks (P < .001 and P < .01, respectively). Mild and transient side effects were experienced slightly more in the active treatment group and included gastric disorders, nausea, headache, dizziness, erythema, and pruritus. Buftomedil currently is only available in Europe.
KETANSERIN
Ketanserin is a serotonin-S z receptor antagonist whose ability to reduce cardiovascular events was tested on approximately 3,900 patients in Europe. A subset of these patients (n = 594) was evaluated for ketanserin effectiveness in increasing PFWD over I year of treatment. 39 No increase in walking distance occurred in patients receiving ketanserin. CONCLUSION
Mild to moderate intermittent claudication can be an extremely debilitating condition. Primary treatment should be aimed at lifestyle modification and, most importantly, at the implementation of a regular exercise program. Traditionally, these methods of management have been fraught with patient noncompliance. Treatment of claudication with medication is an effective way of improving PFWD and MWD but should be viewed as second line in patients capable of exercising. Currently only 2 drugs, pentoxifylline and cilostazol, are FDA approved for treatment of intermittent claudication. Cilostazol appears to be more effective with regard to increasing pFWD and MWD. There are a number of other medications, used mainly in Europe, that have shown some promising results but require further clinical evaluation. New treatment regimens should be accepted only after proven beneficial in appropriately conducted clinical trials.
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chronic arterial disease results of a six month controlled multicenter study using Naftidrofuryl tablets 200 mg. Angiology 37:160-169, 1986 27. Brevetti G, Chiariello M, Ferulano G, et al: Increases in walking distance in patients with peripheral vascular disease treated with L-camitine: A double-blind, cross-over study. Circulation 77:767-773, 1988 28. Brevetti G, Perna S, Sabba C, et al: Propionyl-L-camitine in intermittent claudication: Double-blind, placebo-controlled, dose titration, multicenter study. J Am Coli Cardiol 26:1411-1416, 1995 29. Brevetti G, Perna S, Sabba C, et al: Superiority of L-propionyl camitine to L-camitine in improving walking capacity in patients with peripheral vascular disease. An acute, intravenous, double-blind, cross-over study. Eur Heart J 13: 251-255, 1992 30. Brevetti G, Perna S, Sabba C, et al: Effect of propionylL-camitine on quality of life in intermittent claudication. Am J Cardiol 79:777-780, 1997 31. Olszewer E, Carter JP: EDTA chelation therapy in chronic degenerative disease. Med Hyp 28:41-49, 1988 32. Guldager B, Jelnes R, J0rgensen SJ, et al: EDTA treatment of intermittent claudication-a double-blind, placebo controlled study. J Intern Med 231:261-267, 1992 33. van Rij AM, Solomon C, Packer SGK, et al: Chelation therapy for intermittent claudication. A double-blind, randomized, controlled trial. Circulation 90: 1194-1199, 1994 34. Ernst E: Chelation therapy for peripheral arterial occlusive disease. Circulation 96: 1031-1033, 1997 35. Chappell LT, Miranda R, Hancke C, et al: EDTA chelation treatment for peripheral vascular disease. J Intern Med 237:429-434, 1995 36. Boger RH, Bode-Boger SM, Thiele W, et al: Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coli Cardiol 32: 1336-1341, 1998 37. Pittler MH, Ernst E: Ginkgo biloba extract for the treatment of intermittent claudication: A meta-analysis of randomized trials. Am J Med 108:276-281, 2000 38. Triibestein G, Balzer K, Bisler H, et al: Buflomedil in arterial occlusive disease: Results of a controlled multicenter study. Angiology 35:500-505, 1984 39. PACK Claudication Substudy Investigators: Randomized placebo-controlled, double-blind trial of ketanserin in claudicants. Circulation 80:1544-1548, 1989
ATHEROSCLEROTIC disease is a systemic that affects millions of Americans. Peripheral arterial disease (PAD) is only one manifestation of atherosclerotic disease, one that can limit an individual's capacity to carry out daily activities. Men and women are affected equally and the age-adjusted prevalence is approximately 12%.1 Of patients with PAD, only 5% to 15% suffer intermittent claudication. The accepted treatment for mild to moderate intermittent claudication is appropriately directed at lifestyle modification, control of atherosclerotic risk factors, as well as other comorbid medical conditions and attempting to lengthen pain-free walking distance by a structured (preferably supervised) exercise program, although many simply instruct the patient to walk to the point of claudication as often as they can on a daily basis. Modifications of lifestyle include smoking cessation and dietary restrictions aimed at hyperlipidemias. Comorbid illnesses that have been shown to increase the risk of PAD include hyperlipidemia, hypertension, diabetes mellitus, end-stage renal disease, and, more recently, hyperhomocysteinemia. Strict medical control of these risk factors has been shown to reduce the risk of coronary disease but its success in slowing the progression of PAD and improving intermittent claudication has not been proven by valid clinical trials. The only nonoperative treatment consistently shown to improve intermittent claudication has been the adoption of a structured exercise regimen. Discussion of therapy directed at the aforementioned risk factors and the beneficial effects achieved with exercise training are addressed in other sections of this monogram, so further
f t illness
discussion will be limited to the medical treatment of intermittent claudication. Enthusiasm for pharmaceutical treatments for claudication has waxed and waned since physicians first recognized that the painful cramping sensation was a result of impaired blood flow to the musculature of the lower extremities. Categorically, the medical treatment of claudication has included vasodilator therapy, antiplatelet agents, hemorrheologic agents, anticoagulants, and agents directed at improving metabolic reactions within the ischemic tissue. Most modem studies evaluating the efficacy of these agents usually are based on objective data related to improvements in walking ability on treadmill testing. Specifically, 2 end-points of interest are the patient's pain-free (PFWD) or initial claudication distance and the maximal (MWD) or absolute claudication distance. In addition, some studies have collected subjective data through the use of questionnaires regarding quality of life issues. Both generic and diseasespecific instruments are used, as well as functional questionnaires such as the Walking Impairment Questionnaire (WIQ). Improvements in both walking ability and subjective assessments of benefit are important to the patient's physical and psychological health. The following sections are directed at reviewing recent advances in the treatment of From the Department of Vascular Surgery, Ochsner Clinic Foundation, New Orleans, LA. Address reprint requests to Samuel R. Money, MD, MBA, Section Head, Vascular Surgery, Ochsner Clinic Foundation, 1514 Jefferson Hwy, New Orleans, LA 70121. Copyright 2002, Elsevier Science (USA). All rights reserved 0895-796710211504-0005$35.0010 doi: 10.1053/svas.2002.36259
Seminars in Vascular Surgery, Vol 15, No 4 (December), 2002: pp 237-244
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intermittent claudication with medication but also summarize some past treatments that have fallen out of favor. ASPIRIN
Aspirin has well established its role as a leader in the reduction of secondary events in patients with atherosclerotic disease. Additionally, some have reported reductions in the need for peripheral arterial procedures as well as improvements in vascular graft patency with the use of aspirin?,3 Despite these favorable results, the use of aspirin has not been shown conclusively to improve walking distances in patients with intermittent claudication. Aspirin is very effective in preventing secondary events (myocardial infarction and stroke) and accordingly should be considered in all patients with PAD (see Platelets-Is aspirin sufficient or do we really have to know how to pronounce abciximab? In this issue of Seminars) but is not currently indicated for the treatment of intermittent claudication. CLOPIDOGREL (PLAVIX)
Like aspirin, clopidogrel is an antiplatelet agent that has been shown to be effective in reducing secondary events in patients with atherosclerotic disease. In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, clopidogrel was associated with an overall reduction in primary endpoints (stroke, myocardial infraction, or death from other vascular causes) of 8.7%.4 This benefit was statistically different from that observed in patients receiving aspirin. In regards to treatment of claudication, clopidogrel has not been shown to offer any advantage. However, research into this field is ongoing. VASODILATORS
Initial attempts at improving blood flow to the extremities involved the use of vasodilators, mainly papaverine. s This was based on the concept that by dilating the blood vessels, the body would be able to provide more blood flow to the ischemic limb. However, unbeknownst to early pioneers, ischemic tissues release endogenous metabolic byproducts that lead to a maximal dilation of the local vasculature distal to the stenotic or obstructing lesion. The addition of vasodilator therapy has little effect on this already maximally dilated vas-
cular bed. In fact, vessels proximal to the lesion dilate and allow neighboring vascular beds to "steal" vital blood flow away from the deprived ischemic tissue. Vasodilators also have the capacity to reduce systemic vascular resistance potentially leading to a reduction in perfusion pressure. This reduction in perfusion pressure in conjunction with a steal phenomenon magnifies the ischemic insult to the underperfused muscle. As the understanding of the pathophysiologic mechanisms involved with peripheral vascular disease evolved, this concept of enhancing vasodilation fell out of favor. A relatively new concept, utilizing calcium channel blockers as vasodilators, involves increasing the oxygen extraction/utilization in the deprived skeletal muscle tissue. Bagger et al 6 conducted a randomized, double-blind, crossover study in which 44 patients had undergone a previous period of titration testing. 6 In the titration period, patients were given increasing doses of verapamil (120, 240, 360, and 480 mg) over 4 weeks to identify the drug dose that was associated with the longest MWD specific for each individual patient. After a washout period, each patient was given the drug dose that allowed that individual the longest MWD. Bagger et al 6 found that verapamil increased the mean PPWD 29% and the mean MWD 49% (P < .01 and P < .001, respectively) over placebo. Interestingly, the anklelbrachial pressure index (ABI) did not change suggesting it was not an increase in blood flow to the compromised tissue, but rather that oxygen extraction/utilization capacity was improved. Despite these recent data suggesting a beneficial effect with calcium channel vasodilator therapy, inconclusive data exist to support the use of vasodilators for the treatment of intermittent claudication in patients with peripheral arterial occlusive disease. PENTOXIFYLLINE(TRENTAL)
In 1984 the Food and Drug Administration (FDA) approved the first drug specifically indicated for treatment of claudication; pentoxifylline. This compound is a methylxanthine derivative that improves red blood cell deformability, decreases blood viscosity, and inhibits platelet aggregation. There have been numerous trials reporting mixed results concerning pentoxifylline's beneficial ef-
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fects in the treatment of intermittent claudication. The 2 largest multicenter randomized, doubleblind, placebo-controlled trials show these inconsistencies and are summarized in the following paragraphs. 7 ,8 The first of these 2 trials compared pentoxifylline (n = 67) with placebo (n = 61) treatment over a 24-week period. 7 Patients given pentoxifylline showed a 22% (45% v 23%; P = .02) greater improvement in mean PFWD from baseline when compared with placebo. In regards to MWD, patients treated with pentoxifylline had a 12% (32% v 20%; P = .04) absolute mean increase over patients given placebo. Despite significant improvements in PFWD and MWD, subjective assessments of cramping, tiredness, pain and the patient's overall condition were not found to differ between the 2 groups. The second large trial randomized 150 patients to 1,200 mg/d of pentoxifylline (n = 76) or placebo (n = 74).8 Unlike the findings of the previous study, investigators found no improvement in PFWD and only a trend that suggested an improvement in MWD in patients given pentoxifylline (P = .09). However, subset analyses identified certain subpopulations of patients (ABI <.80 and duration of disease> I year) that showed significant improvements in both PFWD and MWD when compared with patients receiving placebo. Ernst et al 9 likewise found no significant benefit in PFWD or MWD after 12 weeks of pentoxifylline therapy but did observe a significant increase in MWD at certain time intervals during the study period (at one and 8 weeks of treatment). This lead Ernst et al to speculate that the beneficial effects of pentoxifylline therapy may wear off with longterm administration. Although the above-mentioned trials failed to agree on the exact benefit gained with pentoxifylline therapy, their results do suggest a small beneficial effect offered to patients with intermittent claudication. Metaanalyses by Hood et allo and Girolami at ell I support these beneficial findings but agree that the magnitude of benefit is small. The major problem is that this questionable increase in walking distance is not subjectively appreciated by the patient. One must bear in mind that the purpose of this medication is to treat symptoms, so if the patient does not notice the improvement, the treatment is not useful. Use of pentoxifylline in patients receiving other
methylxanthine derivatives (aminophylline and theophylline) requires special attention. Concurrent use may result in increased active drug levels, so frequent monitoring of theophylline levels is recommended. CILOSTAZOL (PLETAL)
In January 1999 the FDA granted approval of a second drug, cilostazol, for the treatment of patients with intermittent claudication. The recommended dosage is 100 mg twice a day administered a half hour before meals or 2 hours after. Cilostazol is a phosphodiesterase type-3 inhibitor that is thought to exert its mechanism of action by inhibiting cyclic adenosine monophosphate (cAMP) phosphodiesterase. This leads to an accumulation of cAMP in platelets and blood vessels resulting in inhibition of platelet aggregation and promotion of vascular smooth muscle relaxation. Additional pharmacologic properties include a positive effect of increasing HDL cholesterol and decreasing serum triglycerides. 12 In vitro cell culture studies have also shown that it may reduce smooth muscle cell proliferation. 13 No claudication medication has been studied in as many prospective, placebo-controlled, doubleblind trials as cilostazol. The data presented are compiled from numerous studies involving 2,702 patients who were involved in phase-III double blind trials. 12 ,14,15 The mean age and ABI of the patients involved was 63.3 years and 0.64, respectively. As one would expect, approximately 76% of the patients were men with 92% of them being smokers (either previously or current). Approximately 60% of the patients had hypertension. Diabetes (25%) and coronary artery disease (22% with previous history of myocardial infarction) also were common in this group. When comparing percent change from baseline in patients who received cilostazol, 100 mg orally twice a day (v placebo), cilostazol was shown to be significantly more effective in increasing MWD across numerous studies. 12 ,14,15 It is interesting to note that the percent change from baseline in the cilostazoltreated group varied from a low of approximately 30% to a high of 100% improvement. Another way to look at this, in terms of increase distance walked, is that patients who receive cilostazol showed an improvement after 24 weeks of approximately 140 meters. What is essential in treating claudication is the
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subjective improvement perceived by the patient. It is interesting to note that approximately 30% of those patients who received placebo felt that they had a significant improvement in their walking ability. This is in comparison to a 51 % subjective improvement experienced in patients given cilostazol. When treating patients, it must be emphasized that not all patients will generate a significant subjective improvement, but a large part of the subjective improvement is what the patients perceive their improvement will be and what the patients are told they should expect before starting therapy. To go from one block claudication to 4-block claudication probably is not realistic. However, to improve walking distance from 2 blocks to 3 1/2 blocks, or from one block to 2 blocks is probably within the realm of what this drug is capable of achieving. As with many drugs, numerous side effects exist with the chronic use of cilostazol. The most common side effect is that of headache. Patients frequently will have a headache during the early stages of using this drug. The mechanism responsible for this is felt to be the drug's vasodilatory properties. Many of the headaches will respond to nonprescription medication such as acetaminophen. Another approach is to start with a lower dosage such as 50 mg twice a day, and after approximately 2 weeks increase to the recommended dosage. Gastrointestinal problems, especially diarrhea, are other common side effects. Most of the patients who suffer this side effect can tolerate it fairly well. Occasionally, there is a patient in whom the diarrhea is so severe that the drug needs to be discontinued. Palpitations are another important side effect. The average patient's heart rate typically will increase by approximately 4 beats per minute. Most patients will tolerate it without difficulty if they are warned in advance that palpitations may occur. Cilostazol and several of its metabolites are phosphodiesterase type III inhibitors. Other phosphodiesterase inhibitors, and not cilostazol specifically, have been shown to decreased survival rate compared with placebo in patients with class III to class IV congestive heart failure. 16 As a drug class consideration, cilostazol is contraindicated in patients with congestive heart failure of any severity. Cilostazol is partially metabolized in the liver by CYP3A4 or CYP2C 19 enzymes. As such, other drug classes that rely on such hepatic metabolism
CONNERS AND MONEY
may increase cilostazol levels. Examples include certain antifugals, calcium channel blockers, erythromycin, selective serotonin reuptake inhibitors, and omeprazole. Concurrent use is not discouraged but one may consider decreasing daily dosages to 50 mg twice a day. Cilostazol is a drug that can improve both PFWD and MWD in patients with claudication. Patient and physician expectations and perceptions must be realistic. A patient who responds to cilostazol should stay on the drug indefinitely. Patients should be reevaluated routinely for the development of congestive heart failure and, if it does occur, the drug should be discontinued. TICLOPIDINE (TICLlD)
Ticlopidine is a potent inhibitor of platelet aggregation that exerts its mechanism of action by blocking adenosine diphosphate receptors. Originally, this was theorized to lead to a reduction in blood viscosity and subsequent improvement in blood flow; however, others speculate it may improve red blood cell deformability as well.l? Balsano et al 18 conducted a randomized, double-blind, placebo-controlled trial in which 76 patients were given ticlopidine and 75 were selected randomly to receive placebo (n = 151). Using the intent-to-treat rule, Balsano et al found significant differences in PFWD and MWD in patients treated with ticlopidine. However, 25 patients violated protocol guidelines and subsequently were dropped from the trial. Secondary analysis of the remaining 126 patients (64 ticlopidine and 62 placebo) found only a significant increase in MWD in patients receiving ticlopidine. In another trial of similar size, Arcan et al 19 found significant increases in both mean PFWD and MWD in the ticlopidine treatment group. Additionally, ticlopidine was found to offer a cardiovascular protective benefit over placebo in patients with intermittent claudication. Fagher et al,zo however, found no benefit over placebo with long-term (5 years) treatment. In fact, significant improvements in walking at 5 years were experienced with placebo and not ticlopidine. Potentially fatal bone marrow suppression has been a concern with ticlopidine administration. A metaanalysis of 4 randomized trials found an overall 2.4% neutropenia rate with the majority of cases presenting within 3 months of drug initiation?1 In the study by Balsano, a significant reduction in the mean hematocrit level of patients taking ticlopi-
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dine was observed 12 and 15 months postrandomization. 18 However, this difference resolved by the end of the study period (21 months). Leukocyte counts also were found to be significantly less at 6 months, but differences in platelet count were never observed. In 2 of the aforementioned trials, patients receiving ticlopidine experienced significantly more gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation) than did the control patient population. 18 ,19 Similar to pentoxifylline and cilostazol, ticlopidine's metabolism is primarily accomplished by the liver. Patients concurrently receiving phenytoin or theophylline could potentially experience increases in drug serum levels, Serum drug level monitoring is recommended in these patients. Ticlopidine appears to offer a protective benefit from adverse cardiovascular events, but there is insufficient support to recommend use for the treatment of intermittent claudication. If ticlopidine is given, patients should be counseled with regard to gastrointestinal upset, and periodic hematologic monitoring should be initiated. PROSTAGLANDINS
The use of prostanglandins for the treatment of intermittent claudication has yielded promising results lately. A randomized, double-blind, placebocontrolled trial evaluating the efficacy of a prostaglandin E 1 prodrug (AS-013) found significant increases in MWD when compared with placebo treatment. 22 The study design consisted of 4 groups (total of 80 patients); 1 group receiving 25 ILg/wk intravenously, 2 groups receiving 10 ILg/wk but differing in dosing regimen, and 1 placebo group. Treatment was continued for 4 weeks followed by a 4-week observation period in which no therapy was administered. No statistical difference was found among the groups in regard to PFWD, but MWD was statistically different when all active treatment groups were compared with patients receiving placebo. This difference persisted over the 4-week observation period as well. Although no significant difference was found among the different active treatment groups, a trend existed that suggested a linear dose response. A subjective improvement also was seen in patients receiving the PGE 1 prodrug. A second multicenter, double-blind, placebocontrolled study showed similar improvements in MWD as well as improvements in PFWD?3 In this
study, patients were treated daily (5 d/wk) over a 4-week period followed by an interval treatment period (2 treatments per week) lasting 4 more weeks. PFWD increased 101 % over baseline for patients treated with PGE 1 • This compared favorably with the 60.1 % experienced in the placebo group (P < .05). Similarly, active treatment groups experienced significant improvements in MWD when compared with placebo (P < .05). Like the previous study, improvements in walking persisted beyond the treat period (3 months). Although these studies are encouraging, limitations exist with the use of PGE 1 for treatment of intermittent claudication. Despite outpatient use in these trials, intravenous administration is required. This has obvious limitations for long-term outpatient treatment. Adverse reactions include cardiac arrhythmias, hypotension, flulike illnesses, and gastrointestinal disturbances. The most common adverse reactions in the above-mentioned trials were injection site erythema and pain. A PGI2 analogue, Beraprost, may be a possible alternative to the intravenous administration of PGE 1. Lievre et al 24 conducted a large (n = 422) double-blind, randomized, multicenter phase III clinical trial evaluating the efficacy of Beraprost in patients experiencing intermittent claudication between the distances of 50 and 300 meters. In this study a significantly larger proportion of patients receiving Beraprost experienced an increase in PFWD (>50% above baseline) when compared with placebo (43.5% v 33.3%; P = .04). MWD increased a mean of 60.1 % in the active treatment group compared with a mean increase in the placebo group of only 35.0% (P = .004). Additionally, a significant improvement in global satisfaction related to changes in quality of life were reported in patients receiving Beraprost (P = .05). Adverse reactions did not appear to differ between the 2 cohorts. Beraprost currently is not available in the United States. NAFTIDROFURYL (PRAXILENE)
Naftidrofuryl is a serotonin antagonist that has been available in Europe for over 20 years. The proposed mechanisms of action include both vasodilatory effects as well as improvements in aerobic metabolism. An early multicenter, randomized, double-blind, placebo-controlled trial found a significant improvement in mean PFWD over placebo (35% increase) in patients treated for a 12-week
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period (P < .02).25 A later study duplicated these findings by showing a 32% increase in PFWD in patients treated with Naftidrofuryl for 6 months (P < .02).26 However, neither trial showed a significant increase in MWD with administration of Naftidrofuryl. Adverse reactions generally were related to gastrointestinal complaints but were not statistically different from placebo treatment. Currently, like Beraprost, Naftidrofuryl is not available for use in the United States. L-CARNITINE
Unlike the aforementioned pharmacotherapies, which achieve symptomatic relief by improving blood flow to the ischemic tissue by vasodilation, increased red blood cell deformability, improved blood viscosity, or reduced platelet adhesion, Lcarnitine improves the availability of substrates required for energy production. A small, doubleblind, cross-over trial by Brevetti et af 7 showed a significant improvement in PFWD in patients receiving oral L-carnitine. Pain-free walking distances improved by approximately 70% over baseline during L-carnitine therapy but diminished when patients were converted back to placebo treatment. Additionally, patients reported subjective improvements in symptoms while receiving L-carnitine. Investigators also found reductions in venous lactate and pyruvate levels with L-carnitine supplementation but significant differences over placebo were only suggested. In another study, a carnitine analogue, propionyl-L-carnitine, was found to increase MWD 27.1 % over placebo after 6 months of therapy (P = .03).2 8 Improvement in PFWD in patients receiving propionyl-L-carnitine almost doubled that experienced by patients in the placebo group but did not reach significance. A comparison study between equimolar doses of Lcarnitine and propionyl-L-carnitine showed greater increases in walking capacity in patients receiving the latter supplementation. 29 Improving metabolic efficiency of ischemic skeletal muscle is a unique treatment approach to intermittent claudication. Early results are encouraging and small but significant improvements in subjective assessments of quality of life appear to be possible with carnitine supplementation. 3D Carnitine supplements are available in most health food stores across the United States; however, recommended dosages for the treatment of inter-
mittent claudication is lacking. Further studies are needed to clarify the role of carnitine in the treatment of intermittent claudication. CHELATION
Chelation therapy refers to the administration of an agent (EDTA; ethylenediamine-tetraacetic acid), which forms complexes with divalent cations (Ca2 +), theorically preventing the progression of and possibly augmenting the regression of atherosclerotic disease. An early proponent of chelation therapy found an improvement in walking distance with a small patient population, but subsequent investigators have found no benefit in PFWD or MWD. 31 - 33 In addition, no difference in subjective assessments of quality of life has been identified. A more recent metaanalysis of randomized, placebo-controlled, double-blind clinical trials found that EDTA was not an effective treatment for intermittent claudication and concluded that chelation therapy should now be obsolete. 34 Despite these convincing results against chelation therapy, others continue to advocate its use for intermittent claudication. 35 Potentially fatal reductions in plasma cations are a concern, so close hematologic monitoring is recommended. L-ARGININE
L-arginine is an amino acid precursor for nitric oxide formation. A recent small (n = 39), randomized trial compared the effects of intravenous Larginine (8 g twice a day) and PGE 1 (40 p,g twice a day) in the treatment of patients with peripheral arterial occlusive disease. 36 Both treatments resulted in significant improvements in PFWD and MWD. This compared favorably with control patients who experienced no increase in walking ability. No difference was found between the 2 active treatment groups. The only adverse reaction was local injection site erythema and pain seen in the PGE 1 group. Further studies are needed to validate these encouraging results. Like carnitine, L-arginine is available in most health food stores as an oral supplementation. More controlled trials are needed before L-arginine can be recommended for the treatment of intermittent claudication. GINKGO BILOBA
The use of medicinal herbs as alternatives to conventional medicine has become fashionable.
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One of the most popular is Ginkgo Biloba extract. Review of the literature identified a recent metaanalysis of randomized, double-blind, placebocontrolled trials comparing Ginkgo to placebo for the treatment of intermittent c1audication. 37 Although metaanalyses are prone to criticism, this analysis suggested that Ginkgo biloba improved PFWD and MWD in patients with intermittent claudication. Overall, there did not appear to be a consistent adverse reaction, but occasionally gastrointestinal complaints were reported. More largescale clinical trials are needed before Ginkgo biloba can be recommended for the treatment of claudication (see Miscellaneous Medications: Mayhem or Miracle? In this issue of Seminars). BUFLOMEDIL
Buftomedil is a vasoactive drug that has reported effects on platelet inhibition, red blood cell deformability, and muscle cell metabolism. Trtibestein et al 38 have shown significant improvements in PFWD and MWD when compared with placebo in patients treated with 600 mg daily for 12 weeks (P < .001 and P < .01, respectively). Mild and transient side effects were experienced slightly more in the active treatment group and included gastric disorders, nausea, headache, dizziness, erythema, and pruritus. Buftomedil currently is only available in Europe.
KETANSERIN
Ketanserin is a serotonin-S z receptor antagonist whose ability to reduce cardiovascular events was tested on approximately 3,900 patients in Europe. A subset of these patients (n = 594) was evaluated for ketanserin effectiveness in increasing PFWD over I year of treatment. 39 No increase in walking distance occurred in patients receiving ketanserin. CONCLUSION
Mild to moderate intermittent claudication can be an extremely debilitating condition. Primary treatment should be aimed at lifestyle modification and, most importantly, at the implementation of a regular exercise program. Traditionally, these methods of management have been fraught with patient noncompliance. Treatment of claudication with medication is an effective way of improving PFWD and MWD but should be viewed as second line in patients capable of exercising. Currently only 2 drugs, pentoxifylline and cilostazol, are FDA approved for treatment of intermittent claudication. Cilostazol appears to be more effective with regard to increasing pFWD and MWD. There are a number of other medications, used mainly in Europe, that have shown some promising results but require further clinical evaluation. New treatment regimens should be accepted only after proven beneficial in appropriately conducted clinical trials.
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8. Lingiirde F, Jelnes R, Bjorkman H, et a1: Conservative drug treatment in patients with moderately severe chronic occlusive peripheral arterial disease. Circulation 80: 1549-1556, 1989 9. Ernst E, Kollar L, Resch KL: Does pentoxifylline prolong the walking distance in exercised c1audicants? A placebocontrolled double-blind trial. Angiology 42: 121-125, 1992 10. Hood SC, Moher 0, Barber GG: Management of intermittent claudication with pentoxifylline: Meta-analysis of randomized controlled trials. Can Med Assoc 1 155:1053-1059, 1996 II. Girolami B, Bernardi E, Prins MH, et al: Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline or nafronyl: A meta-analysis. Arch Intern Med 159:337-345, 1999 12. Money SR, Herd lA, Isaacsohn JL, et al: Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. 1 Vasc Surg 27:267-275, 1998 13. Takahashi S, Oida K, Fujiwara R, et a1: Effect of cilostazol, a cyclic AMP phosphodiesterase inhibitor, on the prolufera-
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