Drug treatment of claudication: Vasodilators, hemorrheologic agents, and antiserotonin drugs

Abstract

Intermittent claudication occurs when regional blood flow is inadequate to meet the metabolic demands of exercising muscle. The cause of the diminished flow in most claudicants is proximal fixed atherosclerotic arterial obstruction. Recent studies have suggested that local microcirculatory abnormalities resulting from the effects of anaerobic metabolites can play a significant facilitatory role in the production of claudication. The initial treatment of claudication in most patients has consisted of recommendation for walking exercise and cessation of tobacco use, a program which results in claudication stabilization or improvement in 70% to 80% of patients. The role of reconstructive arterial surgery is well established and will not be considered here. Interest in the drug treatment of claudication has historically centered about a diverse group of drugs collectively known as vasodilators. In recent years emphasis has shifted to several drugs that appear to exert their primary effect on the microcirculation. These drugs include pentoxifylline and ketanserin. Early clinicians seeing the blanched feet of claudicants intuitively, although erroneously, concluded that vasoconstriction must occur in ischemic areas. This impression, together with knowledge of the critical influence of vessel diameter on blood flow, as described by Poiseuille, quite naturally led to initial interest in the use of vasodilator agents for the drug treatment of claudication. Drugs evaluated in the past included direct acting agents such as papaverine, nicotinic acid, and cyclandelate; alpha-adrenergic neural and neuromuscular blocking agents such as tolazoline, guanethidine, reserpine, phenoxybenzamine, methyldopa, and ethanol; and beta-adrenergic stimulators such as nylidrin and possibly isoxsuprine. Although some anecdotal clinical benefit from use of these drugs has been reported, blinded controlled trials have not shown consistent beneficial drug effect. These agents are used on the assumption that vasoconstriction exists in areas of ischemia, an assumption repeatedly shown to be false.1Coffman JD Vasodilator drugs in peripheral vascular disease.N Engl J Med. 1979; 300: 713-717Crossref PubMed Scopus (18) Google Scholar Indeed, treatment of ischemic limbs with vasodilators may actually decrease blood flow in affected areas by a steal phenomenon resulting from dilation of normal vessels in nonischemic areas.2Coffman JD Pathophysiology of intermittent claudication.in: Pharmacologic approach to treatment of limb ischemia. American College of Clinical Pharmacology, Philadelphia1983: 43-52Google Scholar No vasodilator has been shown to increase blood flow to exercising muscle.1Coffman JD Vasodilator drugs in peripheral vascular disease.N Engl J Med. 1979; 300: 713-717Crossref PubMed Scopus (18) Google Scholar In view of these considerations, the U.S. Food and Drug Administration has not found any of these agents effective in treatment of intermittent claudication. However, it should be noted that several drugs currently classified as vasodilators have been recently found to have hemorrheologic properties. A careful review of several recently completed randomized, double-blind studies, with such agents as isoxsuprine and cyclandelate, has shown possible benefit. Therefore, the complete dismissal as ineffectual of all drugs classified as vasodilators may be premature. In recent years interest in the drug treatment of intermittent claudication has increasingly focused on drugs that alter blood flow characteristics, a field termed hemorrheology. An important factor affecting microcirculatory flow is erythrocyte flexibility. The importance of this is obvious, as normal erythrocytes with a diameter of 8 to 9 μm must routinely undergo considerable spherical deformation as they pass through the 4 to 5 μm diameter capillaries. Several investigators in 1976 independently showed that erythrocytes from patients with significant atherosclerotic peripheral vascular disease were considerably more rigid, or less flexible, than normal.3Ehrly AM Kohler HJ Altered deformability of erythrocytes from patients with chronic occlusive arterial disease.Vasa. 1976; 5: 319-322PubMed Google Scholar, 4Reid JL Dormandy JA Barnes AJ Lock PJ Dormandy TL Impaired red cell deformability in peripheral vascular disease.Lancet. 1976; 1: 666-667Abstract PubMed Scopus (180) Google Scholar The cause of the increased erythrocyte membrane rigidity in this setting is not known with certainty. The regional hyperosmolar acidosis associated with anaerobic muscle metabolism in ischemic limbs, through unknown mechanisms, appears to result in a reduction in intraerythrocyte adenosine triphosphate (ATP), which in turn is associated with specific membrane chemical changes resulting in diminished flexibility. Thus, the available evidence suggests that there are two complementary causes of muscle ischemia in the ischemic limb. First, the proximal atherosclerotic obstruction results in the entry of a reduced number of erythrocytes into the vascular system of the exercising muscle, which then must shift to anaerobic metabolism with the production of a localized area containing hyperosmolar acidic metabolic products. These products then alter the membranes of the erythrocytes present in the area, resulting in conformational changes with decreased flexibility. These changes then impede or prevent red blood cell (RBC) passage through muscle capillaries, further reducing muscle blood blow. In addition to having less erythrocyte flexibility, the blood of patients with peripheral vascular disease is more viscous than that of control patients, partly because of the erythrocyte changes, and partly because of increased platelet aggregation, both of which appear to result from regional hyperosmolar acidosis. These changes have suggested treatment with agents that affect these hemorrheologic factors.3Ehrly AM Kohler HJ Altered deformability of erythrocytes from patients with chronic occlusive arterial disease.Vasa. 1976; 5: 319-322PubMed Google Scholar, 4Reid JL Dormandy JA Barnes AJ Lock PJ Dormandy TL Impaired red cell deformability in peripheral vascular disease.Lancet. 1976; 1: 666-667Abstract PubMed Scopus (180) Google Scholar, 5Dormandy JA Hoare E Colley J Clinical hemodynamic and biochemical findings in 126 patients with intermittent claudication.Br Med J. 1973; 4: 576-581Crossref PubMed Scopus (204) Google Scholar, 6Janssen Pharmaceutica. Ketanserin: A novel serotonin S2-receptor blocking agent.Investigational New Drug Brochure. 7th ed. June 1983Google Scholar Two drugs that have attracted considerable attention recently in the treatment of claudication are pentoxifylline and ketanserin. Both appear to exert their most important effect in the microcirculation. Both drugs appear to improve the membrane flexibility of abnormally rigid RBCs found in claudicants, and both appear to have a platelet antiaggregant effect. Pentoxifylline was discovered in the 1950s in Germany by investigators evaluating theobromine derivatives for vasodilator activity. The drug was introduced for clinical use in Germany as a vasodilator in 1972. However, it soon became clear that the drug exerted its effects through a previously unencountered mechanism. Initial studies showed that oral administration of pentoxifylline in human beings did not change heart rate, arterial blood pressure, or systemic vascular resistance, confirming the absence of any significant vasodilator effect.7Baumann JC Erweiterte Moglichkeiten zur Konserviten. Behandlung arterieller. Durchblutungstor ungen.Therapiewoche. 1977; 27: 5872-5884Google Scholar Ehrly8Ehrly AM Improvement of the flow properties of blood. A new therapeutic approach in occlusive arterial disease.Angiology. 1976; 27: 188-196Crossref PubMed Scopus (97) Google Scholar was the first to demonstrate that the addition of pentoxifylline to human blood increased the filterability of the blood, indicating an increase in erythrocyte flexibility. This effect has since been confirmed by other investigators, both in vitro and in blood taken from patients treated with the drug.9Anglecort B Manion H Bouteng K Influence of pentoxifylline on erythrocyte deformability in peripheral occlusive arterial disease.Curr Med Res Opin. 1979; 6: 255-258PubMed Google Scholar, 10Schubotz R Muhlfellner O The effect of pentoxifylline on erythrocyte deformability and on phosphatide fatty acid distribution in peripheral occlusive arterial disease.Curr Med Res Opin. 1979; 6: 255-258PubMed Google Scholar In 1973 Hess et al.11Hess HV Franke I Jauch M Medikamentose Verbesserung der flieseigenschaften des blutes. Ein wirksames Prinzip zur Behandlung von arteriellen Durchblutungss torungen.Fortschr Med. 1973; 91: 743-748PubMed Google Scholar showed that oral treatment with pentoxifylline reduced whole blood viscosity. This finding has since been confirmed by data from placebo-controlled trials.12Volker D Behandlung von Arteriopathien mit Trental 400: Ergebnisse einer Doppelblid studie.Med Welt. 1978; 29: 1244-1247PubMed Google Scholar Although the decrease in viscosity appears to result primarily from increased erythrocyte deformability, decreases in plasma fibrinogen and in platelet aggregation also occur with pentoxifylline treatment.13Schmid-Setonbein H Microrheology of erythrocytes and thrombocytes, blood viscosity and the distribution of blood flow in the microcirculation.in: Microcirculation. Springer, New York1977Google Scholar, 14Muller R Hemorrheology and peripheral vascular diseases. A new therapeutic approach.J Med. 1981; 12: 209-235PubMed Google Scholar The relative contribution of these components to the change in viscosity is not yet known. Treatment with pentoxifylline has been shown to result in increases in limb blood flow as measured by plethysmography of toes and calf muscle, and as measured by xenon 133 clearance from calf muscle.15Accetto B Beneficial hemorrheologic therapy of chronic peripheral arterial disorders with pentoxifylline; results of a double-blind study versus vasodilator-nylidrin.Am Heart J. 1982; 113: 864-869Abstract Full Text PDF Scopus (69) Google Scholar, 16Rudofsky G Brock FE Ulrich M Nobbe F Behandlung von Patienten mit arterieller Verschlusskrankheit (Stadium II) mit pentoxifyllin. Hamodynamische und ergometrische Befunde.Med Klin. 1979; 74: 1093-1096PubMed Google Scholar, 17Pupita F Rotatori P Frausini G Farmacologia clinica della sostanze vasoattive: Studi sulla pentoxifyllina.Ric Clin Lab. 1981; II: 293-302Google Scholar, 18Angelkort B Doppelfield E Treatment of chronic arterial occlusive disease. Clinical study with a new galenic preparation of pentoxifylline. Trental 400.Pharmatherpeutica. 1983; 3: 18-29Google Scholar As the disappearance of injected xenon reflects capillary flow, the increased disappearance following pentoxifylline supports the proposed mechanism of action, that is, increasing the ability of erythrocytes to pass through capillaries. The critical question of whether increased blood flow results in increased oxygen availability for ischemic tissues has been addressed by direct micropipette measurements that show an increase in the tissue PO2 in ischemic muscle following treatment with pentoxifylline.19Ehrly AM Effects of orally administered pentoxifylline on muscular oxygen pressure in patients with intermittent claudication.IRCS Med Sci. 1982; 10: 401-402Google Scholar The potential usefulness of the drug in the treatment of intermittent claudication was further suggested by studies in animals demonstrating impairment in calf muscle contractility when perfused with erythrocytes that were artificially hardened, and a reversal of this effect when the muscles were perfused with normally flexible erythrocytes.20Dormandy JA Ernst E Bennett D Erythrocyte deformability in the pathophysiology of the microcirculation.Ric Clin Lab. 1981; II: 35-38Google Scholar, 21Dormandy JA Matrai A Assessment of pharmacological agents with hemorrheologic action.Ann NY Acad Sci. 1983; 416: 599-610Crossref PubMed Scopus (6) Google Scholar The actual mechanisms underlying alteration in erythrocyte membrane flexibility are not known with certainty. Several studies have shown that abnormally rigid erythrocytes of patients with occlusive arterial disease contain abnormally low levels of intracellular ATP. Intraerythrocyte ATP is increased by pentoxifylline primarily by the drug's inhibition of erythrocyte phosphodiesterase.5Dormandy JA Hoare E Colley J Clinical hemodynamic and biochemical findings in 126 patients with intermittent claudication.Br Med J. 1973; 4: 576-581Crossref PubMed Scopus (204) Google Scholar, 22Mueller R Lehrach F Grifolect HG Zum Wirkungs-mechanismus von pentoxifylline.Med Monatschr. 1975; 29: 487PubMed Google Scholar The drug also causes increased phosphorylation of erythrocyte membrane proteins.23Kramer JJ Swislocki NI Effects of pentoxifylline on membrane protein phosphorylation in rat erythrocytes.Vasc Med. 1983; 1: 159-174Google Scholar Although the precise mechanisms of action remain unknown, considerable evidence suggests that pentoxifylline produces improved blood flow and oxygen delivery to ischemic areas by improving blood flow in the microcirculation as a result of increased erythrocyte deformability, associated with a minor reduction in blood viscosity. Pentoxifylline has been in clinical use for more than a decade, although it was released for use in the United States only in 1984. To date, enough information has accumulated to allow a relatively clear picture of the drug's safety and efficacy. Because intermittent claudication improves with time in many patients, blinded, placebo-controlled trials are mandatory to ensure proper evaluation. The results of 11 separate double-blind controlled trials of pentoxifylline conducted in Europe are summarized in Table I.Table IEuropean studies on efficacy of pentoxifylline in intermittent claudicationDuration of treatment (wk)Dose of pentoxifylline (mg)No. of patients/clinical observationsReferences860013 pentoxifylline = 100% improved2413 placebo = 8% improved460027 pentoxifylline = 83% improved treadmill walking + 126%2528 placebo = 60% improved treadmill walking + 38%860027 pentoxifylline walking + 208%269 placebo walking + 52%4-680025 pentoxifylline = 84% improved walking + 120%2725 placebo = 17% improved walking + 20%6-8120020 pentoxifylline walking + 39%2820 placebo walking + 16%4120020 pentoxifylline = 71% improved walking + 45%2920 placebo = 24% improved walking + 28%2412008 pentoxifylline = walking initial + 12% walking absolute + 10%308 placebo walking initial + 28% walking absolute + 11%8120012 pentoxifylline walking + 38%3112 placebo walking + 3%1280018 pentoxifylline walking + 46%3218 placebo walking + 4%8120018 pentoxifylline = 83% improved walking + 80%3318 adenosine = 50% improved walking + 6%8800-120025 pentoxifylline = 73% improved treadmill walking + 47%1524 nylidrin = 46% improved treadmill walking + 5%+ indicates increase. Open table in a new tab The trials differed from one another in the dosage of pentoxifylline administered (600 to 1200 mg/day), in the therapeutic end points evaluated (treadmill walking, overall walking distance, coldness, paresthesias), in the duration of treatment (4 to 24 weeks), and in the nature of the control medication administered (placebo, adenosine, nylidrin). Despite these important differences, all these studies demonstrated significant benefit from treatment with pentoxifylline when compared with controls.15Accetto B Beneficial hemorrheologic therapy of chronic peripheral arterial disorders with pentoxifylline; results of a double-blind study versus vasodilator-nylidrin.Am Heart J. 1982; 113: 864-869Abstract Full Text PDF Scopus (69) Google Scholar In the United States, initial evaluation of pentoxifylline was in a double-blind placebo-controlled seven-center trial with treadmill walking as the evaluated end point. This study was designed to conform with the protocol recommended by the U.S. Food and Drug Administration for evaluation of agents for intermittent claudication.34Food and Drug Administration Peripheral vascular diseases—intermittent claudication study protocol. Draft guidelines from cardio-renal section.in: Food and Drug Administration, Washington, DC1976: 1-13Google Scholar The results of this study are depicted in Table II.Table IIResults of multicenter, double-blind comparison of pentoxifylline and placeboInitial claudication (m) or % changeAbsolute claudication (m) or % changePentoxifyllinePlacebop ValuePentoxifyllinePlacebop ValueBaseline111 m117 m172 m181 mTotal mean change at 24 weeks+45%+23%0.016+32%+20%0.035No. of patients showing improvement < 25%16201620 25%-49%4653 50%-100%98126 100%13696All0.0530.047+ indicates increase. Open table in a new tab In brief, patients with documented claudication for fixed atherosclerotic occlusive disease underwent a 2-week washout phase followed by a 4- to 6-week single-blind phase, followed by a 24-week double-blind randomization to treatment with pentoxifylline or placebo. The results demonstrated that pentoxifylline was significantly more effective than placebo in increasing walking distance as assessed by initial pain appearance and absolute walking distance. However, the benefit of drug over placebo averaged only 22%. As a result of this information, the U.S. Food and Drug Administration has classified pentoxifylline as effective in treatment of intermittent claudication, the first drug to be so classified. The side effects of the drug recognized in the double-blinded studies included gastrointestinal symptoms (nausea, vomiting, and bloating) and dizziness and required discontinuance of the drug in about 3% of patients. No other adverse effects were recognized. Although the effectiveness of pentoxifylline in the treatment of intermittent claudication appears to be real, statistically significant, and repeatedly confirmed, the ultimate usefulness of the drug in clinical practice remains to be determined. It is important to note that the 22% difference in treadmill walking distance between pentoxifylline-treated patients and placebo-treated controls, although statistically significant, was small. As an extreme example, assume that two patients began therapy with equal claudication at 70 meters (approximately one block). After 24 weeks of exercise training and drug ingestion, a patient treated with pentoxifylline might be expected to improve 45% to 101 meters, whereas a patient treated with placebo might be expected to improve 23% to 86 meters. Whether either patient would report any clinical improvement is problematic. It is similarly uncertain whether the small incremental walking distance of drug over placebo would justify the expense and inconvenience of long-term drug administration. Surgeons have noted for some time that procedures that only improve symptoms of claudication, rather than eliminate them, are infrequently regarded as successful by patients. Since pentoxifylline was released for general use in 1984, with the powerful endorsement provided by the Food and Drug Administration label of effectiveness, many patients have been treated. In our practice, results with the use of the drug have been unpredictable. Some patients report significant perceived improvement, although a number have noted no change. To date we have performed repeat treadmill tests in too few patients to reach any objective conclusions. It remains our opinion that the patients most likely to show benefit are those with extremely short distance claudication for whom a small increase in walking distance may represent the difference between home confinement and independent living. The ultimate importance of this drug may lie not in its therapeutic benefit but in its significance as the first in a new class of agents that improve blood flow through modifications of microcirculatory flow characteristics. Ketanserin is a new drug, not yet approved for clinical use by the U.S. Food and Drug Administration, that may be important in the treatment of claudication. The drug appears to exert its effect through selective blockage of peripheral S2 serotonin receptors. Serotonin is a powerful vasoconstrictor and platelet aggregator, which also has an important role in amplifying vasoconstriction and platelet aggregation induced by other agents such as catecholamines, prostaglandins, and angiotensin.35Porter JM Cutler BS Lee BY Reich T Reichle IA Scogin JT Strandness DG Pentoxifylline efficacy in the treatment of intermittent claudication: Multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients.Am Heart J. 1982; 104: 66-72Abstract Full Text PDF PubMed Scopus (353) Google Scholar Ketanserin antagonizes these effects and has the additional action of increasing RBC deformability.36DeClerck F David JL Janssen PAJ Serotoninergic amplification mechanisms in blood platelets.in: 5-Hydroxytryptamine in peripheral reaction. Raven Press, New York1982: 83-94Google Scholar, 37Van Neuten JM Janssen P Van Beck J Yonneux R Verbeuren TJ Vanhoutte PM Vascular effects of R 41 468, a novel antagonist of 5-HT2 serotonergic receptors.J Pharmacol Exp Ther. 1981; 218: 217-230PubMed Google Scholar As such, the drug has effects both as a vasodilator and as a hemorrheologic agent. These combined actions have suggested multiple therapeutic applications, many of which are currently being investigated. Among others, ketanserin is a powerful antihypertensive agent, and appears to improve blood flow in many types of peripheral vascular disorders including vasospastic conditions (e.g., Raynaud's disease, and acrocyanosis) and occlusive disease (e.g., intermittent claudication, ischemic ulcers, and rest pain).38DeCree J Leempoels J Geukens H DeLock W Verhaegen H Are serotoninergic mechanisms involved in high blood pressure?.in: 5-Hydroxytryptamine in peripheral reactions. Raven Press, New York1982: 183-192Google Scholar, 39Wenting GJ Man in't Veld AJ Wottiez AJ Boonsma F Schalekamp MA Treatment of hypertension with ketanserin, a new selective 5-HT2 receptor antagonist.Br Med J. 1981; 284: 537-539Crossref Scopus (88) Google Scholar, 40Strauden E Roald OK Krog K Treatment of Raynaud's phenomenon with the 5-HT2 receptor antagonist ketanserin.Br Med J. 1982; 285: 1069-1071Crossref PubMed Scopus (67) Google Scholar Abundant laboratory evidence indicates that ketanserin increases blood flow in ischemic limbs as measured by plethysmography, nuclear scanning, skin temperature, blood flow measurement by laser, and arteriography.41DeCree J Leempoels J Geukens H Verhaegen H Placebo-controlled double-blind trial of ketanserin in treatment of intermittent claudication.Lancet. 1984; 2: 775-779PubMed Google Scholar, 42Wiriz RAE Rens A Burema T The effects of a single IV dose of ketanserin on the continuing registered plethysmogram in intermittent claudication. Nov 13, 1982Google Scholar, 43Schoen A Scheijde E Vande Voort PLM Saat R The effects of a single IV dose of ketanserin on the microcirculation in intermittent claudication measured by TC scanning. An interim analysis of a double-blind placebo-controlled study. Nov 13, 1982Google Scholar The improved blood flow seen in ischemic limbs treated with ketanserin may result entirely from vasodilation and shunting without a true increase in nutrient flow to affected areas, although several studies with capillaroscopy have shown an improvement in stasis and sludging as well as decreased capillary pressure and increased RBC velocity. These observations suggest that the improved blood flow seen with ketanserin treatment is accompanied by a corresponding increase in nutritive blood flow at the capillary level.44Jacobs MJ Lemmens H Slaaf D Reneman R The effect of ketanserin on microcirculation in patients with ischemic hand syndromes (abstract), The XIII World Congress of the International Union of Angiology. Rochester, MinnSept 11-16, 1984Google Scholar These findings also support the proposal that ketanserin acts both as a vasodilator and as a hemorrheologic agent. The relative importance of each of the actions of the drug (vasodilation, decreased platelet aggregation, and increased RBC deformability) in producing the observed therapeutic benefits has not been determined. Ketanserin has been, and is being, evaluated in several double-blind placebo-controlled trials for treatment of claudication. DeCree et al.41DeCree J Leempoels J Geukens H Verhaegen H Placebo-controlled double-blind trial of ketanserin in treatment of intermittent claudication.Lancet. 1984; 2: 775-779PubMed Google Scholar randomized 20 patients with moderate claudication (mean initial walking distance, 200 meters) into treatment with ketanserin or placebo, and evaluated changes in treadmill walking, ankle/arm blood pressure ratio, several plethysmographic parameters, RBC deformability, and whole blood filterability. Beginning at 1 month after treatment, and continuing to the end of the study in an increasing fashion, there was significant advantage to the ketanserin-treated patients, with improvement in walking distance that averaged 140%. Ankle/arm blood pressure ratios, RBC-deformability, blood filterability, and pattern of reactive hyperemia also improved significantly in the treated patients. Although the number of patients evaluated by this study is small, the difference between the treated group and the placebo group was pronounced.41DeCree J Leempoels J Geukens H Verhaegen H Placebo-controlled double-blind trial of ketanserin in treatment of intermittent claudication.Lancet. 1984; 2: 775-779PubMed Google Scholar Other double-blinded studies have since been completed. When the results of analysis of patients from thirteen European centers are considered together, there was a significant advantage to treatment with ketanserin compared with placebo (Table III). Only 28% of the 134 ketanserin-treated patients increased walking distance more than 100%, however, and equal numbers of placebo- and ketanserin-treated patients were thought to be unchanged.Table IIIChange in walking distance (% of patients, 13 studies)Ketanserin (N = 134)Placebo (N = 134)No. of patients(%)No. of patients(%)p ValueUnchanged (0%-99%)74(55)71(53)Deteriorated (< 0%)39(29)26(19)< 0.001Improved > 100%15(11)37(28)Drop-out6(4)0(0) Open table in a new tab Although these studies generally confirm the beneficial effect of ketanserin on intermittent claudication suggested by the study of DeCree et al.,41DeCree J Leempoels J Geukens H Verhaegen H Placebo-controlled double-blind trial of ketanserin in treatment of intermittent claudication.Lancet. 1984; 2: 775-779PubMed Google Scholar the actual improvement in claudication distance, similar to pentoxifylline, was modest. It remains to be seen whether the statistically significant improvement in walking distance experienced by the treated patients is perceived by them as clinically significant. Naturally, since pentoxifylline and ketanserin both can be shown to improve blood flow to ischemic areas, considerable interest exists in the application of these agents to treatment of the entire spectrum of cardiovascular disorders, including vasospastic diseases, cerebrovascular disease, myocardial ischemia, severe limb ischemia, and hematologic sludging. At present, inadequate information exists to permit objective assessment of drug action in these areas. A finding that is currently generating extreme interest was noted in the data from the ketanserin-claudication studies summarized in Table III. In this study, a certain number of patients were withdrawn from the study groups because of adverse cardiovascular events (e.g., stroke, myocardial infarction, and angina) as might be expected in a population of patients suffering from atherosclerotic disease. Surprisingly, all these events occurred in the placebo-treated patients; there were none in the ketanserin-treated group. These results are statistically very significant. The intriguing possibility that treatment with ketanserin exerts some type of protective effect against adverse cardiovascular events in general has spawned widespread interest and is now the subject of a large multicenter study. In summary, both drugs described in this report appear to have a real and statistically significant effect in improving the walking distance in claudicants. The benefit derived is modest, however, and the clinical usefulness of neither agent has been established. The true importance of the drugs is probably that they represent the first drugs in a new class, that is, agents that have measurably beneficial microcirculatory effects. After more than 50 years of experimentation and therapeutic trials with multiple agents, the use of vasodilators for treatment of intermittent claudication has been largely abandoned. Current interest is focused on hemorrheology, or the study of the flow characteristics of blood. Pentoxifylline is a new drug, recently approved for use by the U.S. Food and Drug Administration for treatment of claudication. This drug alters the flexibility of the abnormally rigid erythrocytes found in patients with peripheral vascular disease, thus improving microcirculatory flow, muscle blood flow, and tissue oxygenation. The drug has been shown to be effective in treatment of claudication by multiple, carefully controlled, double-blind studies. Ketanserin is a new drug, not approved for clinical use, that acts by antagonizing the action of serotonin at peripheral receptor sites. In this manner, the drug causes vasodilation, decreased platelet aggregation, and apparently increased erythrocyte flexibility. These changes can be shown to result in increased limb blood flow. Several double-blind studies have shown benefit from ketanserin treatment of intermittent claudication. The overall therapeutic benefit of both these drugs appears to be modest, and their true clinical usefulness remains to be determined. The importance of both these agents probably lies in their role as the first hemorrheologic agents.