Treatment of claudication with pentoxifylline: Are benefits related to improvement in viscosity?

ORIGINAL ARTICLES From the Southern Association for Vascular Surgery Treatment of claudication with pentoxifylline: Are benefits related to improvement in viscosity? Willard C. Johnson, M.D., Joanna M. Sentissi, M.D., Donna Baldwin, R.N., Janis Hamilton, R.N., and Janice Dion, R.N., Boston, Mass. Forty-five patients with short-distance claudication were treated with pentoxifylline. The initial claudication distance increased significantly (32.5 m, p =.2) and the absolute claudication distance (ACD) increased significantly (49.5 m, p =.1) while the patients were receiving pentoxifylline. Patients with initial elevated viscosity levels were more likely to have decreased viscosity with pentoxifylline than were patients with normal viscosity levels (p =.1). No significant improvement in ACD or viscosity was noted in 51% of patients. Both ACD and viscosity improved in 15% of patients, viscosity improved without improvement in ACD in 9%, and ACD improved without improvement in viscosity in 25%. (J VASC SURG I987;6:211-6.) Pentoxifylline (Trental, Hoechst-Roussel Pharmaceuticals, Somerville, N.J.) is a trisubstituted xanthine derivative proposed to improve red blood cell flexibility and thus reduce whole blood viscosity. Recent control trials in the United States suggest improved treadmill walking in patients treated with this agent) '2 Although the magnitude of average improvement (45% for initial claudication distance [ICD] and 32% for absolute claudication distance [ACD]) was statistically significant, there remained some skepticism regarding the clinical significance of this improvement. In addition, only about 62% of patients had improved claudication with pentoxi~lline therapy. This suggests that not all patients treated with pentoxifylline had a reduction in viscosity. The purpose of this study was to evaluate improvement in claudication in patients treated with pentoxifylline and to determine whether improvement correlated with a decrease in viscosity. METHODS Patient population. To receive pentoxifylline therapy at the Boston Veterans Administration Med- From the Department of Vascular Surgery at the Boston Veterans Administration Medical Center and Tufts University School of Medicinc, Presented at the Eleventh Annual Meeting of the Southern Association for Vascular Surgery,, Scottsdale, Ariz., Jan. 28-31, 1987. Reprint requests: Willard C. Johnson, M.D., Surgical Service (112), 15 S. Huntington Ave., Boston, MA 213. ical Center, a patient must enter a drug evaluation program under the direction of the Vascular Surgery, Section. This program was initiated in August 1985 and has been continuous to January 1987. This article represents a prospective study of 45 consecutive patients who had the following characteristics: 1. Short-distance claudication as defined by an ICD of less than 12 m and an ACD of less than 24 m with symptoms stable for a minimum of 3 months 2. Absent or minimal angina 3. Ability to satisfactorily perform treadmill testing 4. Compliance to pentoxifylline therapy (4 mg taken orally three times a day) for 3 months (there was no placebo group) 5. Stable hematocrit level during the 3-month study period 6. Viscosity measuremcnts before and in the third month of pentoxifylline therapy 7. Anlde-brachial index of less than.75 8. No major change in other drug therapy Viscosity measurements. The Wells-Brookfield Cone/Plate Viscometer, a torque meter that max, be driven at discrete rotational speeds (Brookfield Engineering Laboratory, Inc., Stoughton, Mass.), was used to determine viscosity in 11 patients. The torque measuring system consists of a calibrated beryllium copper spring that senses the resistance to rotation caused by the presence of a sample fluid between the cone and a stationary flat plate. The stationad, plate 211

212 Johnson et al. Journal of VASCULAR SURGERY Fig. 1. Porous Plug Viscometer. is removed and filled with.5 ml of heparinized blood. Cone No. CP-4 and an.8 degree cone spindle were used at cone speeds of.3,.6, 1.5, 3, 6, 12, 3, and 6 rpm. The viscosity at each cone speed was determined from the readings on the torque scale and an appropriate correction factor supplied with the viscometer. The Porous Plug Viscometer (PPV), developed by E. W. Merrill in the Department of Chemical Engineering at the Massachusetts Institute of Technology (Merrill Medical Corp., Belmont, Mass.), was used to measure flow time in 45 patients, s'~ A cylindric plug of sintered polyolelin, approximately 4.6 1.1 cm, having communicating random channels with a mean pore diameter of approximately 4 gm is contained in a tight-fitting sleeve that connects to a transparent capillary column (lumen diameter 1.5 mm) with marks 53 mm apart. Because the cross-sectional area of the porous plug is nearly 1 times the cross-sectional area of the capillary, a descent of the meniscus in the capillary column of 53 mm corresponds to a net vertical displacement in the porous plug of approximately.5 mm. These geometric conditions lead to the result that the effective shear stress is approximately 1 dyne. cm -2 and allows blood to flow slowly so as to reveal its nonnewtonian properties. The PPV is mounted vertically on any convenient frame. Blood is drawn into a plastic syringe, without anticoagulant, by venipuncture. Two millimeters of blood is injected immediately through the syringe into the PPV. Blood flow through the porous plug is measured by recording the time interval for the blood meniscus to descend 53 mm. To determine flow time of a blood sample, three PPVs are filled and timed one after another. The three determinations are completed within 2 minutes after veni- puncture. The average value for these three determinations represents the flow time. Twenty-eight patients were evaluated by means of a viscometer filled through a stopcock at the junction of the colunm and 17 patients were evaluated by a viscometer filled through the inverted column (Fig. 1). Seven patients were measured by both viscometers, and each viscometer gave similar flow times; the Pearson correlation was significant (p =.2, r =.966). Treadmill testing. Patients were examined on a treadmill (model C-22, Trotter Treadmills Inc., Holliston, Mass.) set at 1.5 mph and a 12-degree incline. ICD was recorded as the onset of calf or thigh discomfort. ACD was recorded as that point at which significant discomfort occurred and would necessitate stopping for a rest. Symptomatic response. The patients were requested to score their response to pentoxifylline in the treatment of their claudication as follows: worse, no improvement, mild improvement (about one third increase in distance), moderate improvement (two thirds increase in distance), or maximal (free of claudication). Statistical analysis. The changes noted in ICD, ACD, and viscosity after pentoxifylline therapy were analyzed by paired Student t tests. Pearson's correlation analysis was used to compare the PPVs and the relationship of viscosity changes to daudicafion improvement. Chi-square analysis with Yates' correlation was used to compare different subgroups of patients. RESULTS Viscosity measurements. The Wells-Brookfield Viscometer and the PPV were both used to determine viscosity in 11 patients. With the Wells- Brookfield Viscometer, viscosity measured at 3. rpm

Volume 6 Number 3 September 1987 Pentoxifylline and viscosity measurements in daudicants 213 2O 18 16 y=o.242x-f 1.39 p=o.oi R=.735 14 ). j- o 12_ I_ 8-6_ 4. 2.,o' ;'s /o 5s' FILTRATION TIME (sec) Fig. 2. Correlation of viscosity as determined by the Wells-Brookfield Viscometer and the filtration time of Porous Plug Viscometer. The regression line is y =.242 1.39. (r =.735; p =.1.) Table I. Response to pentoxifylline therapy No. of patients Hematocrit Ankle-brachial index Initial claudication distance Before pentoxifylline (m) After pentoxifylline (m) % Patients improved >25% increase in ICD % Patients improved >5% increase in ICD % Patients improved >1% increase in ICD Absolute claudication distance Before pentoxifyuine (m) After pentoxifyuine (m) % Patients improved >25% increase in ACD % Patients improved >5% increase in ACD % Patients improved > 1% increase in ACD Viscosity evaluation Initial viscosity (cp) Posttherapy viscosity (cp) Viscosity reduction Moderate (>2. cp) Mild (1.1-2. cp) Small (.25-1. cp) None (<.25 cp) Subgroup Subgroup normal viscosity h~h viscosity (<9. q)) (>9. qo) Yotul Brou p 29 16 45 43.3 47.5 44.85.5.44.48 38.7 46.8 41.4 75.6 7.2 73.8 72 56 67 51 5 51 35 19 29 88.2 91.8 9 139.4 139.4 139.4 52 63 56 41 37 39 21 19 2 7.57 11.4 8.81 8.3 1. 8.73 1 (3.5%) 5 (31%) 13% 2 (7.%) 9 (12%) 9% 4 (14%) 3 (19%) 16% 22 (76%) 6 (38%) 62% (shear rate of 22.5 sec -1) was used to best represent the clinical condition of arterial occlusive disease. The computer-generated Pearson analysis showed a significant correlation (r =.735; p =.1). The regression equation was y =.242x + 1.39, where y was the viscosity (measured in centipoise and x was flow time measured in seconds) (Fig. 2). Reported viscosity values in this article represent the conversion of the flow times of the PPV to the Wells-Brooldield viscosity levels as determined by this correlation equation. The average viscosity for the 45 patients in this study was 8.81 cp. There was not a significant reduction in average viscosity associated with pentox-

214 Johnson et al. Journal of VASCULAR SURGERY 2OOO I~ ABSOLUTE CLAUOICATION INITIAL CLAUDICATION eo 6 4OO 2 35O IOOO" 8 6 MODERATE CHANGE "i' 55" MODERATE CHANGE uj 2 Z _~ eoo F 6o~ 8MALL CHANGE 2O 2 15"~1 I 1~ 8 6 I 4O 2 PRE TRENTAL THERAPY POST,~o ~ J 1 5 ~ PRE POST TRI~ITAL THERAPY Fig. 3. Changes in initial claudication distance (A) and absolute daudication distance (B) associated with pentoxifylline therapy. Improvement in viscosity was defined as none when the change was less than.25 cp, small if.25 to 1. cp, mild if 1.1 to 2. cp, and moderate if greater than 2. cp. ifylline therapy (Table I). If one separated the patients into groups compoged of those with normal viscosity (less than 9. cp) and those with elevated viscosity (greater than 9. cp) and evaluated pentoxifylline therapy, the group with elevated viscosity had a reduction from 11.4 to 1. cp. However, this change was not statistically significant (p =.76, n = 16). No change in viscosity was noted in the group with initially normal viscosity. Chi-square analysis of the subgroups noted that those patients with initially elevated viscosity (greater than 9. cp) had a decrease (more than 1 cp) in their viscosity more frequently (43%) than the subgroup with initially normal viscosity (1%) (p =.1). Claudicafion distance. The improvement in ICD and ACD after treatment with pentoxifylline is presented in Table I and Fig. 3. The average increases, 32.5 m for ICD and 49.5 m for ACD, are statistically significant (p =.2 and p =.1, respectively; Student's paired t test). Correlation analysis comparing the degree of change in viscosity to change in ACD did not show a good correlation (r =.4 for the entire group and r =.322 for the group with normal viscosity and r =.218 for the group with elevated viscosity). Fig. 4 represents the correlation between percentage of improvement in ACD to change in vis- cosity. Chi-square analysis showed a value of 5.7 (p =.46). In general, 51% showed less than 5% improvement in ACD or a viscosity reduction of more than 1 cp, 15% had improvement in both ACD and viscosity, 9% showed improvement in viscosity without improvement in ACD, and 25% had improved ACD without improvement in viscosity. Four of 12 patients who had improvement in ACD without an increase in viscosity showed an increase in their ankle-brachial index of more than.15, which might represent improved collateral circulation or improved cardiac function. Four patients with a significant decrease in viscosity (more than 1 cp) did not improve their claudication; two of these patients had a reduction in their ankle-brachial index (.59 to.4, and.37 to.23) suggestive of progression of their arterial occlusive disease. In general, when viscosity decreased more than 1 cp, 6% had improved ACD (more than 5%). In contrast, if viscosity did not improve, only 25% had improved ACD (more than 5%). The symptomatic response correlated with the treadmill testing is shown in Fig. 5. Chi-square analysis showed a value of 6.9 (p =.48) when one combined the subgroups with improvement of 5% to 1% and more than 1% increase in ACD. There was a good correlation between symptomatic

Volume 6 Number 3 September 1987 Pentoxifylline and viscosity measurements in daudicants 215 VISCOSITY CHANGE (z~c.p.) SYMPTOMATIC IMPROVEMENT None- z O m I-- I,- _o ua ttj O m ttj Ix Fig. 4. Correlation between improved viscosity and improved absolute claudication distances: dark boxes represent a good correlation;gray boxes a fair correlation; and white boxes a poor correlation. o z f- i- z ~ lu iu Iu J ~ 5C Ix,~ n~ Fig. 5. Correlation between symptomatic improvement and improved absolute claudicafion distances: dark boxes represent a good correlation; gray boxes a fair correlation; and white boxes a poor correhtion. improvement and improvement in ACD measurements in 24 patients (53%), fair correlation in 15 (33%), and poor in six (3%). Of the patients with a mismatch, 11 overrated their subjective response compared with treadmill testing, whereas seven tended to underrate their objective improvement. If symptomatic responses are compared with viscosity changes, the correlation is poor as 13 patients had significant clinical improvement (frequently supported by improvement in claudication distance) without change in viscosity. DISCUSSION Pentoxifylline is one of a new family of drugs to alter red cell rigidity and improve viscosity. In the randomized cooperative study of Porter et al.,1,2 31% of 42 pentoxifylline-treated patients had an increase of 1% or more in ICD and 21% of treated patients had an increase of 1% or more in ACD. In this study, comparable response rates were 29% and 18%. Sixty-two percent of patients in the cooperative study increased ICD and ACD by more than 25%, A similar response rate was seen in this study. Although the patients in this study had more severe claudication (an ICD and ACD of 42 and 1 m, respectively, compared with 111 and 191 m, respectively, in the cooperative study), the therapeutic responses to pentoxifylline were quite similar in both studies. A "bedside" technique, with the use of nonheparinizcd blood, that determines a reliable measurement of viscosity under low flow states as seen in arterial occlusive disorders would improve our assessment and possibly the therapeutic program for patients who have arterial ischemic syndromes. The PPV with a mean diameter of 4 Ixm in the bed of communicating porous channels is within a range relevant to arterioles and venules. The PPV has been previously calibrated by three standard silicone calibration oils, ranging from 5 to 2 cp. The flow time, in seconds, was approximately four times the viscosity (measured in centipoise) and was linearly proportional to the viscosity of the calibration fluid? This correlation is quite similar to that which we found for blood by means of the Wells-Brookfield Viscometer at 3 rpm. Schwartz, Keagy, and Johnson 4 have used the PPV in the evaluation of viscosity changes in animals subjected to hemodilution with dextran or crystalloid, as well as in nine patients who underwent infrainguinal reconstruction. They also validated the PPV with a rotational cone and plate viscometer. Their baseline canine viscosity, measurements of 5.9 cp and flow time of 23.8 seconds correlate well with our correlation equation (Fig. 1). Perego et al. S have measured whole blood viscosity with the Wells-Brookfield Viscometer in 25 clandicant patients who were receiving pentoxifyuine. They report a significant decrease (p +.1) in the average viscosity of 9. to 8.5 cp after 3 davs and to 8. cp after 9 days of therapy. (These vaiues were measured at a shear rate of 11.25 sec-~.) No information was presented on individual responses to pentoxifylline therapy. This reduction in viscosity was quite similar to that noted in our elevated viscosity group. One objective of this study was to evaluate viscosity changes associated with pentoxit~lline therapy and to see whether there was a correlation to objective changes in claudication distance. In general, the results suggest that when pentoxifylline increased

216 Johnson et al. Journal of VASCULAR SURGERY claudication distance, the viscosity decreased only minimally. This suggests that the benefit of pentoxifylline may be related to additional mechanisms other than viscosity changes, such as a direct skeletal or smooth muscle effect. Stefanovich 6 has noted that pentoxifylline inhibits cyclic adenosine monophosphate phosphodiesterase in vessels, implying a relaxing effect on vascular smooth muscle. The correlation between subjective and objective measurements of the therapeutic responses to pentoxifylline (Fig. 5) suggests that, in this study, approximately 25% of patients overrated the benefits ofpentoxifylline and approximately 15 / underrated their response. The authors recommend that patients who do not demonstrate objective improvement by treadmill testing (greater than 5% increase in ICD or ACD) or viscosity improvement (greater than 1 cp reduction) should have therapy discontinued and be monitored for a change in symptoms. If deterioration in symptoms does occur, reevaluation of viscosity, treadmill testing, and a "placebo" effect is warranted. REFERENCES 1. Porter JM, Cutler BS, Lee BY, et al. Pentoxifylline efficacy in the treatment of intermittent claudication: multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease in patients. Am Heart J 1982;14: 66-72. 2. Taylor LM Jr, Porter JM. Drug treatment of claudication: vasodilators, hemorrheologic agents, and antiserotonin drugs. J VAsc SURG 1986;3:374-81. 3. Ackerman RH, Burbank DM, Buxton RB, et al. Relationship between viscosity factors and CBF and porous bed viscometry in normal and stroke prone subjects. In: Hartmarm A, Kuschinsky W, eds. Cerebral ischemia, hemorheology. Berlin: Springer-Vedag, 1987. 4. Schwartz JA, Keagy BA, Johnson G Jr. Effects of the acute phase reaction in blood viscosity after infrainguinal arterial bypass. Am J Surg 1986;152:158-64. 5. Perego MA, Sergio G, Artale F, Guinti P, Danese C. Haemorrheological improvement by pcntoxifylline in patients with peripheral arterial occlusive disease. Curr Med Res Opin 1986;1:135-8. 6. Stefanovich V. Effect of 3,7 dimethyl- 1- (5-oxy-hexyl) xanthine and 1-hexyl-3,7-dimethyl xanthine on cyclic AMP phosphodiesterase of the human umbilical cord vessels. Res Commun Chem Pathol Pharmacol 1973;5:655-62.