Pentoxifylline Treatment of Moderate to Severe Chronic Occlusive Arterial Disease

Transcription

1 Clin. Cardiol. 8, (1985) 0 Clinical Cardiology Publishing Co., Inc. Pentoxifylline Treatment of Moderate to Severe Chronic Occlusive Arterial Disease B. Y. LEE, M.D., F.A.C.S., P. BERKOWITZ, B.S., J. P. SAVITSKY, M.D., G. s. MAY, M.B., B. Chir., J. BROBST, M.S., W. J. MCCANN, JR.. M.D., F.A.C.S. Departments of Surgery, Veterans Administration Medical Center, Castle Point, and New York Medical College, Valhalla, New York. USA Summary: A pilot study of the effects of pentoxifylline in 19 patients with moderate to severe chronic occlusive arterial disease (COAD) is described. The severity of disease was assessed by the degree of limitation in the walking distance on the flat surface (< 100 m), the absence of peripheral pulses on palpation, the diminished Doppler tibiallbrachial pressure (the ischemic index) at rest, and by contrast arteriography, when available. After a 2-week washout phase, all subjects received pentoxifylline (1200 mg/day) in an open-label manner for a total of 12 weeks. Twelve of the nineteen patients showed a definite increase in exercise tolerance by the end of the study, with a concomitant reduction in ischemic symptoms. All except 3 patients felt they had derived benefit from the medication. In contrast to the clear improvements in walking distance and symptoms, only small effects on noninvasive vascular laboratory measurements were noted. Platelet aggregation, induced by, epinephrine, and collagen, gradually decreased over the study period. Pentoxifylline appears to be useful in the medical management of patients with moderate to severe chronic occlusive arterial disease; future controlled trials in such patients are now justified. Key words: peripheral vascular disease, pentoxifylline, first-line treatment Introduction Pentoxifylline, a trisubstituted xanthine derivative, is prescribed in many European and Asian countries for the treatment of intermittent claudication and the relief of other symptoms characteristic of chronic occlusive arterial disease (COAD). Surgery may be called for if the ischemic symptoms secondary to COAD are extreme, or if they progressively deteriorate over a short period of time. If surgical intervention or percutaneous transluminal angioplasty are not indicated, then pentoxifylline, in addition to advice on life-style changes such as tobacco abstinence, weight loss, and a graded exercise program is regarded in many European and Asian countries as one of the first-line treatments. The clinical benefit derived from pentoxifylline is currently thought to be due to its hemorheological properties; pentoxifylline increases microcirculatory capillary blood flow, secondary to enhanced erythrocyte flexibility (Angelkort et d., 1979). The resultant increase in tissue perfusion has been shown to improve the oxygenation of poststenotic ischemic muscle (Ehrly, 1982). The efficacy of pentoxifylline in treating intermittent claudication has been evaluated under double-blind controlled conditions both in Europe (Accetto, 1982) and in the United States (Porter et al., 1982). Response to treatment in these trials was assessed by measuring the im- Address for reprints: provement in the initial (ICD) and absolute (ACD) clau- Bok Y. Lee, M.D. dication distances elicited on treadmill ergometry under Chief, Surgical Service standard conditions. All patients enrolled were classified Veterans Administration Medical Center as having mild to moderate COAD, that is they were able Castle Point, NY 12511, USA to walk at least 50, but not more than 500 meters, on the Received: July 30, 1984 treadmill without experiencing claudication. Both trials Accepted: September 19, 1984 demonstrated that oral pentoxifylline, in doses up to 1200

2 162 Clin. Cardiol. Vol. 8, March 1985 mg/day for eight weeks or more, was significantly more effective than placebo in increasing the claudication distance. In addition, pentoxifylline was shown to be well tolerated, particularly when administered in a controlledrelease tablet formulation (Accetto, 1982). Most published reports have demonstrated the benefit of pentoxifylline in mild to moderate COAD. There have been few systematic studies of the effects of the drug in more severe grades of arterial disease. The present report describes the results of an open pilot study of the effects of pentoxifylline in patients with moderate to severe COAD; walking distances, clinical symptomatology, as well as various objective vascular laboratory measures have been evaluated. Methods Study participants were male in- or outpatients in the surgical service of the Veterans Administration Medical Center at Castle Point, New York. The diagnosis of moderate to severe COAD was based on the absence on palpation of one or more lower limb pulses and by the inability to walk more than 100 meters on a flat surface without claudication pain. COAD had to have been first diagnosed at least 6 months previously. Initially, 30 meters on treadmill ergometry, or 50 meters on a flat surface, were designated as the upper limits of exercise capability to qualify for the study. However, it was soon evident that these criteria excluded many patients with severe arteriographic lesions or with critically low Doppler ischemic indices that were indicative of severe disease. A revised maximum walking distance of 100 meters on the flat surface was therefore adopted. Patients with ischemic ulcers or gangrene were excluded from the study, but those with intermittent rest pain and mild trophic skin changes were eligible. Patients who had already undergone arterial revascularization were not excluded, nor were those who had had a previous lumbar sympathectomy, provided this had not been performed in the immediately preceding three months. A lower limb amputation of any degree precluded admission to the study, on the assumption that it would needlessly complicate the assessment of exercise tolerance. After giving informed consent to participate in the study, participants embarked on a 2-week washout phase during which all other medications prescribed specifically for their vascular symptoms were discontinued (e.g., cyclospasmol, papaverine). At the conclusion of this 2-week period, base-line walking distances as well as base-line vascular laboratory measurements of blood flow and tissue perfusion were made and the patients were clinically reassessed. They then entered a 12-week treatment phase during which pentoxifylline was prescribed in an open-label manner at a maximum dose of 1200 mg/day (400 mg t.i.d. controlled-release tablet). Vasoactive medications, as well as analgesics (e.g., aspirin), were discouraged for the duration of the study. During the treatment phase patients were evaluated at weeks 2,4,8, and 12. Clinical signs, symptoms, and the distance walked on the flat surface to the onset of claudication were recorded at every visit. Noninvasive vascular measurements of blood flow and tissue perfusion (Lee et al., 1981), as well as clinical laboratory evaluations, were carried out at monthly intervals only. The response to treatment with pentoxifylline was assessed by changm in the claudication distance and symptom severity over the course of the 12-week study. Measurements of blood flow and skin tissue perfusion were evaluated to detect any changes consistent with the walking distances and subjective assessments that may have been related to pentoxifylline therapy. Estimates of blood flow and pressures in the larger arteries were given by Doppler systolic blood pressure measurements at the ankle, electromagnetic flowmetry of the thigh and calf, and photoplethysmography of the toes. The Doppler systolic blood pressure in both posterior tibial arteries was measured before and after exercise. If the posterior tibial Doppler sounds were not audible, then the dorsalis pedis artery pressure was measured instead. Preexercise systolic blood pressures were determined after a minimum of 15 min rest in the supine position. While the patient was lying down, photoplethysmogmphic values of the systolic blood pressure were recorded from the plantar surface of all 10 toes. In addition, resting blood flow in the thigh and calf was determined by electromagnetic flowmetry. Subjects then walked on a flat surface until typical claudication developed; the distance covered was noted. Postexercise Doppler systolic blood pressures were taken at 2-min intervals for up to 20 min or until the systolic blood pressure returned to pre-exercise levels. Skin perfusion was assessed monthly by two methods. Slun temperatures at the toes, ankle, and calf of each limb were recorded by special thermistors, allowances were made for the general body temperature and the ambient temperature of the room. Transcutaneous oxygen partial pressures were measured from the pretibial region and at the dorsum of the foot bilaterally. The partial pressure of oxygen diffusing across the skin after warming is proportional to the cutaneous arterial blood flow and to the oxygen tension in the subdennal tissue. Clinical laboratory evaluations included routine hematology, serum chemistry, and whole blood coagulability using the thromboelastograph. Adenosine diphosphate (), epinephrine, and collagen-induced platelet aggregation were also measured. Results Of the 22 male subjects who consented to participate in the study, two complied poorly with the prescribed treatment regimen and were not evaluated after week 4. At the start of treatment, one patient developed nausea and diarrhea and, as this was thought to be probably due to

3 B. Y. Lee et al.: Pentoxifylline treatment of chronic occlusive arterial disease 163 pentoxifylline, the medication was discontinued. These three subjects are not considered further in this summary of the results. The remaining 19 patients (2 blacks, 17 whites) ranged in age from 48 to 74 years (mean age was 63 years). Two were inpatients, the other 17 were attending the outpatient surgical service. The severity of the COAD of this study population is indicated by the fact that 80% of the patients had previously undergone lumbar sympathectomy, angioplasty, and/or arterial revascularization, with the majority having had more than one procedure. Only 4 of the 19 patients did not have vascular surgery. Eighteen of 19 subjects were either current smokers or exsmokers. Associated conditions were as follows: hypertension (9), diabetes mellitus (7), angina (4), and a history of myocardial infarction (5). In published trials the most obvious benefit of treating COAD patients with pentoxifylline has been an improvement in the walking distance. Despite this study population having more advanced disease than those reported previously, comparable effects on exercise tolerance were observed. For all patients combined (n = 19), the mean claudication distance at baseline was 60 meters, increasing progressively at each visit to 112 meters a week 12; this is a mean improvement of 88% (Fig. 1, combined). However, it was clear that individual subjects fell into two quite distinct groups. In the minority (n = 7), each subject s walking distance at the end of the study had improved less than 50% over baseline. From previous experience (Porter el al., 1982), 50% improvement was a reasonable estimate of the likely placebo-response in these study participants. In the majority of patients (n = 12), each subject s walking distance by week 12 had improved considerably more than 50%; in only one case was the improvement less than 100%. A change of this magnitude appeared to represent a real response to the study therapy. For later reference, the probable placeboresponders are designated as Group 1 (n = 7) and the treatment-responders as Group 2 (n = 12). Figure 1 shows that the mean percent change from baseline in the walking distance for Group 1 remained remarkably stable over the course of the trial. The mean distance walked at baseline was 73 meters and it never improved more than 20% at any time in the study. At week 12 the mean walking distance for the placebo-responders had returned to the base-line level (72 meters). In contrast, the mean distance at baseline for Group 2 was 52 meters and it increased at every visit to reach a mean of 138 meters at week 12, an improvement of over 165%. For both Groups 1 and 2 the mean improvement in walking distance during the pretherapy washout phase, that is during the 2- week interval between the subject s first assessment and the base-line determination, was approximately 30 %. Over the 12 weeks of treatment with pentoxifylline the electromagnetic flowmeter did not detect any changes in the resting blood flow of the major arteries in either the thigh or the calf. The mean of the sum of the resting Doppler indices bilaterally showed only minimal changes over the course of the study when all patients (n = 19) were considered together. However, the results at 12 weeks did suggest a modest increase of the resting mean ischemic index over baseline in Group 2 patients (10%) compared a /-- -A+---,/-,,, m,-- ;----:A=.I>-.I -K /- ~ I I Baseline Weeks FIG. 1 The mean % change from baseline of the walking distance over the 12-week treatment period. - -, Combined groups (n = 19); V-, Group 1 (n -- -, Group 2 (n = 12).

4 164 Clin. Cardiol. Vol. 8, March 1985 to those in Group 1 (-4%). The postexercise Doppler measurements were difficult to interpret with any confidence; nevertheless, no apparent effects of pentoxifylline were observed. Digital artery pressures in the foot also appeared to be modestly improved by treatment. The mean of the sum of values from the great toes bilaterally did show a slight improvement (5%) over baseline at week 12 in the combined groups of patients (n = 19). However, differences were noted between Group 1 and Group 2 patients in the mean digital artery pressures in the big toe; Group 2 patients showed a mild increase (10%) compared to Group 1 (-4%). Neither of the two measures of skin tissue perfusion, transcutaneous oxygen partial pressure or the skin temperature, showed any consistent change after treatment. Of the laboratory measurements, only the effect of pentoxifylline therapy on platelet aggregation was of note. Platelet aggregation gradually decreased in all patients except one, whether the aggregation was induced by, epinephrine, or collagen. The mean reduction of platelet aggregation by these three agents for all patients (n = 19) was 41% after 12 weeks treatment (Table I). The severity of 7 symptoms characteristic of COAD were recorded at each clinical assessment on a five-point scale (i.e., absent, mild, moderate, severe, very severe). The means of the sum of symptom scores at baseline were 19.6 for all patients combined, and 18.9 and 20.1 for Group 1 and 2, respectively (Fig. 2). At the end of the study there was a reduction in the mean symptom score for all patients (13.4); this decreased symptom score was noted particularly for those in Group 2 (1 1.6). Examination of individual patient data suggested that improvement in walking distance appeared to be associated with overall symptomatic improvement. The patients who were treatment-responders (Group 2) were continuing to show improvement at week 12 (Figs. 1 and 2). After the 12 TABLE I Mean % platelet aggregation before and after 12- week treatment with pentoxifylline All Patients (n= 19) Group 1 (n=7) Group 2 (n= 12) Week 0 (Baseline) Week weeks of treatment, participants were asked to evaluate their own response to treatment: 16 of 19 felt they had improved on pentoxifylline; 3 of 19 said that there had been little noticeable change. In 12 of 19 patients the investigator evaluated the outcome as being better than anticipated, based on both the expected placebo response and disease progression. Pentoxifylline was well tolerated in all but one patient, who had medication discontinued early because of gastrointestinal adverse effects. Fourteen patients had an uneventful course for the entire study. Two patients developed mild skin conditions which were considered unrelated to treatment; they cleared spontaneously without a reduction in the daily dose of pentoxifylline. Three others experienced mild gastrointestinal upset (nausea, acid stomach, epigastric pain) which resolved with antacids and emphasis on pentoxifylline dosing with meals. Discussion There were two separate but interrelated objectives to this clinical trial. First, to determine whether pentoxifylline could safely reduce the claudication and symptomatology in patients with arterial disease more severe than reported in previous studies (Porter et al., 1982). Second, to find out whether any standard, noninvasive hemodynamic or tissue perfusion laboratory measurements (Lee et al., 1981) were affected by pentoxifylline. It was decided that a pilot open trial, conducted at one center, would best meet these objectives. Of course, the lack of a control group in this study made it difficult to quantify effects of treatment; no formal levels of statistical significance can be attached to the observed results. However, the findings have been interpreted conservatively by assuming that a 50% improvement in walking distance on treatment is attributable to a placebo response alone. The data presented show that pentoxifylline increased exercise tolerance and alleviated ischemic symptoms in 12 of 19 patients with moderate to severe COAD. These data confirm the earlier double-blind, controlled observations (Accetto, 1982; Porter et al., 1982), made in patients with mild to moderate intermittent claudication. In this study, all the participants at entry were prospective candidates for vascular surgery, but none had progressed to the point of requiring intervention during the trial. In contrast to the clear clinical and symptomatic improvements, pentoxifylline treatment produced only small effects on the noninvasive vascular laboratory measurements. No changes were observed in large arterial flow through the thigh and calf nor were any changes noted in skin tissue perfusion (skin temperature, transcutaneous Po2). However, small increases in the resting pressures of the more distal arteries (tibial, toes) were noted by Doppler and photoplethysmographic methods. These improvements in distal pressures, although present and measurable, were obviously less than those produced by successful

5 B. Y. Lee et al.: Pentoxifylline treatment of chronic occlusive arterial disease c g 21 rn s f 14 7 Baseline Weeks FIG. 2 The mean sum of symptom scores over the 12-week treatment period. -- -, Combined groups (n = 19); V-, Group 1 (n = 7); E L --_, Group 2 (n = 12). arterial revascularization. Gradual decreases of platelet aggregation, induced by, epinephrine, and collagen were noted over the 12-week treatment period. The physiologic mechanisms underlying the clinical improvements are unclear at present. Pentoxifylline has been described as a hemorheologic agent which improves erythrocyte deformability (Angelkort et al., 1979), microcirculatory capillary flow and muscle oxygenation (Ehrly, 1982). The data obtained in this study showed no improved flow through fixed arterial stenoses in the thigh and the calf and no improved perfusion of the skin. It is possible that improved microcirculatory flow produced by pentoxifylline is particularly characteristic of the capillary bed of the large muscles. This would account for the observed clinical benefit and perhaps explain why the measures of large arterial flows and skin perfusion showed little effect of the drug. Pentoxifylline apparently produces a more efficient oxygenation of muscle (Ehrly, 1982); greater numbers of more flexible erythrocytes reach the muscle capillary bed increasing oxygen availability to anoxic tissue. It is important to note that many noninvasive vascular laboratory measurements were developed to help evaluate surgical revascularization and the resulting major improvements in large arterial pressures and flows. It is possible that these standard vascular laboratory tests may not be sensitive enough for evaluating new hemorheologic pharmacologic agents, which can modify the microcirculation to produce clinical benefit. In summary, 12 of 19 patients with moderate to severe COAD showed increases in walking distance, as well as improvements of ischemic symptoms, after 12 weeks open treatment with pentoxifylline. Noninvasive vascular laboratory measurements, however, showed only small effects of the drug on flows and pressures. The apparent discrepancies between the clear clinical benefits and the small hemodynamic changes suggest that other laboratory approaches may be required for evaluating hemorheologic agents. Pentoxifylline appears to be useful in the medical management of patients with moderate to severe COAD; future controlled trials in such patients are now justified. References Accetto B: Beneficial hemorheologic therapy of chronic peripheral arterial disorders with pentoxifylline: Results of double-blind study versus vasodilator-nylidrin. Am Heart J 103 (3, 864 (1982) Angelkort B, Maurin N, Boateng K: Influence of pentoxifylline on erythrocyte deformability in peripheral occlusive arterial disease. Curr Med Res Opin 6(4), 255 (1979) Ehrly AM: Effects of orally administered pentoxifylline on muscular oxygen pressure in patients with intermittent claudication. IRCS Med Sci 10, 401 (1982) Lee BY, Trainor FS, Thoden WR, Kavner D: Handbook of Noninvasive Diagnostic Techniques in Vascular Surgery. Appleton-Century-Crofts, New York (1981) Porter JM, Cutler BS, Lee BY, Reich T, Reichle FA, Scogin JT, Strandness DE: 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 104(2), 66 (1982)