REVIEW

Conservative Management of Intermittent Claudication Kenneth Radack, MD; and Richard J. Wyderski, MD

Objective: To review the evidence for efficacy of three contemporary treatments for intermittent claudication: pentoxifylline, exercise programs, and smoking cessation. Data Identification: English-language literature search using MEDLINE, Index Medicus, and bibliographic reviews of major texts and all pertinent articles. Study Selection: For pentoxifylline, randomized, double-blind controlled trials were selected. For exercise, all controlled trials were selected, because few randomized trials have been done. For smoking cessation, 26 pertinent studies were selected after an exhaustive search. Data Extraction: Study quality was evaluated; therapeutic efficacy was estimated for pentoxifylline and exercise using metaanalytic techniques. For smoking cessation, all outcomes were determined and described. Results: For pentoxifylline, insufficiently reported data led to marked disparity in effect sizes, preventing a meaningful pooled estimate of effectiveness. The results for exercise therapy suggested that dynamic exercise is beneficial (pooled effect size for pain-free walking distance = 1.03; 95% CI, 0.6 to 1.5; P < 0.0001). Finally, smoking cessation was associated with a reduced frequency of complications due to progressive disease and improved postoperative graft patency rates. Conclusions: The limited amount and quality of reported data precluded an overall, reliable estimate of pentoxifylline's efficacy. Structured exercise programs increased pain-free walking distance, and smoking cessation improved postoperative graft patency rates and reduced the complications of peripheral arterial disease. Annals of Internal Medicine. 1990;113:135-146. From the University of Cincinnati College of Medicine, Cincinnati, Ohio. For current author addresses, see end of text.

The Framingham study (8) reported a greater than twofold increase in 10-year mortality ratio in men and a fourfold increase in women. Even in nondiabetic subjects with claudication and verified peripheral arterial disease, 10-year mortality rates were reported to be two to five times increased, due mostly to myocardial infarction (9); the survival-corrected annual risk for amputation, however, was only 0.7%. Initial treatment decisions for intermittent claudications without resting pain are based on concurrent illnesses, health behaviors, and life expectancy. Recommendations are generally conservative and focus on symptomatic relief through risk factor modification, exercise and, in some cases, drug therapy. Although many enthusiastic reports of drug and other nonoperative treatments for intermittent claudication have been published, results are mixed and their clinical usefulness remains uncertain among clinicians. Do contemporary drugs such as pentoxifylline increase pain-free walking distance? Do regular physical exercise and cessation of cigarette smoking relieve symptoms and increase painfree walking distance? Does methodologic variability explain the mixed outcomes and limit the applicability of study results to the general population of claudicators? To answer these questions, we critically reviewed the available evidence from clinical trials on modern management of nondisabling, intermittent claudication without ischemic resting symptoms or signs. We specifically appraised the value of three frequently used treatment options: drug treatment with pentoxifylline, dynamic exercise programs, and cessation of cigarette smoking. Directly acting vasodilators and anticoagulants will not be discussed in our analysis; they were previously reviewed and considered not to be consistently effective for treatment of intermittent claudication (10, 11). Methods

Intermittent claudication is a major presenting manifestation of chronic obstructive peripheral arterial disease of the lower extremities. Claudication prevalence rates depend on the populations studied; for persons 60 years of age and older, rates vary from approximately 1.3% to 5.8% in men (1,2) and to as high as 1.7% in women (3). Incidence rates also rise sharply with age, leveling at approximately 75 years of age (4); after 26 years of follow-up, Framingham data (4) indicated biennial incidence rates of 7.1 per thousand for men compared with 3.6 per thousand for women across all ages (range, 35 to 84 years). Although the prognosis for the involved limb is relatively good (5) with rare progression to limbthreatening ischemia, claudication is an important clinical predictor of widespread atherosclerotic vascular disease and increased cardiovascular mortality (6-8).

Strategy for Literature Search. Overall Methodology For studies of pentoxifylline efficacy, we searched the English-language literature from that reported in 1976 (the date of the first controlled clinical trial reported in English) to that reported in April 1989 to identify all studies evaluating the treatment of intermittent claudication with hemorheologic agents. We used Index Medicus, the MEDLINE database, major surgical textbooks, reviews, editorials, and verbal and written communication with experts in the field. We used a similar approach to search for studies assessing the effects of physical activity and smoking cessation on intermittent claudication. For both, however, the search began with the literature from 1966 (the date of the first controlled trial of exercise reported in English). For our analysis of drug efficacy, only randomized, doubleblinded, controlled trials were eligible, and we used modified guidelines proposed by Sacks and colleagues (12) to assess and combine the results of these trials. We evaluated all reports independently for inclusion and exclusion criteria; in brief, we © 1990 American College of Physicians

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excluded reports without concurrent controls, reports with duplicate data, and any nonexperimental designs. For studies of physical activity, only controlled clinical trials were eligible for analysis. Unlike studies of drug efficacy, double blinding was not feasible, and randomization of treatment allocation was not always used. Therefore, to make our methodologic analysis of exercise therapy more comprehensive, nonrandomized studies were included for review to increase the sample size. We used no formal pooling techniques in our quantitative analysis assessing the effects of cigarette smoking cessation, because there were few controlled clinical trials that appropriately satisfied guidelines for validity and generalizability. We assessed the quality of eligible studies by recording the presence or absence of six comprehensive methodologic criteria modified from Chalmers (13) and DerSimonian (14). A weighting scale for the six criteria was developed, and a quality score was assigned to each study (scoring system and criteria are available on request). The study characteristics assessed included study design; patient characteristics (for example, demographic information, duration of intermittent claudication); details of treatment and control group interventions; objective outcome assessment; report of complications and compliance; and details of the statistical methods, including specification of steps used to control for carry-over effects and treatment-by-period interactions in crossover studies (applies to drug studies). Finally, we evaluated the methods used by investigators to analyze and present the outcome measures of effect for treatment and control groups.

Data Analysis Two quantitative methods were used to measure treatment effects within and across studies. The first method of estimating differences between treatment effects uses effect size, as described by Hedges (15). To be eligible for an analysis of effect sizes, studies had to report means and standard deviations (SDs), standard errors (SEs), or sufficient data to allow the calculation of these descriptive statistics. Difference in medians could not be computed due to the absence of necessary data. Effect size (15) is calculated as the difference between the mean improvement in walking distance in the treatment and control groups divided by the pooled SD. Effect size is appropriate for outcomes expressed on a continuous scale; it expresses the direction and magnitude of the difference in outcome between two groups in units of SD. For example, a study of pentoxifylline with a positive effect size of 0.5 suggests that the average effect of pentoxifylline is one half of an SD greater than the average effect in the control group. We computed this measure of effect, because most studies reported their results as group means of changes in walking distance, expressed as meters. Given the considerable variability, however, in claudication severity (indicated by the wide range of mean values for baseline and final walking distances), group averages may be misleading and may obscure individual treatment benefits. In addition, statistically significant changes in walking distance may not necessarily indicate clinically significant improvement. To translate results into a more clinically meaningful measure of treatment effect, we also determined the absolute effect of treatment, calculated as the absolute difference in frequency of clinically significant outcomes between the treatment and control groups. The absolute effect is the conceptual equivalent of expressing results as the therapeutic benefit attributable to the treatment (pentoxifylline). For this analysis, we defined the most clinically significant outcome as at least a doubling (of 100% or more) of baseline walking distance before onset of pain (pain-free walking distance). Because several investigators classified patients as "improved" if the change was at least 25% greater than baseline, we also included an evaluation of that outcome. Both measures of effect were examined for homogeneity across studies using chi-square tests of homogeneity (15, 16). Regression analyses were done to examine the influence of study quality on treatment results. For our review, we judged improvement in pain-free walking distance as the most clinically sensible outcome measure, although maximum walking distance (after onset of pain) was variably included in some studies. Because several studies reported either one or 136

both outcomes, we also present effect sizes for improvement in maximum walking distance. Results Drug Treatment for Vascular Disease Although Poseuille's law (flow = P x r4/v x L [where P = pressure, r = vessel radius, v = viscosity, L = vessel length]) describes the relation between a Newtonian fluid and vessel diameter, it also emphasizes the important indirect relation between viscosity and blood flow (blood is a non-Newtonian fluid). The relation is important in understanding the shift of interest from vasodilators to drugs that alter blood flow characteristics in the microcirculation of atherosclerotic vessels. Such drugs, known as hemorheologic agents, affect flow properties of blood components that influence viscosity. Patients with peripheral arterial disease have both decreased erythrocyte deformability (17, 18) and increased whole blood viscosity compared with normal controls (19). Of the pharmacologic agents that have beneficial hemorheologic properties, pentoxifylline has been the most extensively evaluated. Other drugs that function at the level of the microcirculation include ketanserin and naftidrofuryl. Pentoxifylline Pentoxifylline, a methylxanthine derivative, is the only hemorheologically active agent currently approved by the Food and Drug Administration (FDA) for treatment of intermittent claudication. In patients with peripheral arterial disease, pentoxifylline has been reported to improve abnormal erythrocyte deformability (20, 21), reduce hyperviscosity (22), and diminish platelet hyperreactivity and plasma hypercoagulability (22, 23). Although several studies have reported statistically significant results in favor of pentoxifylline, its clinical value remains undetermined. In assessing the usefulness of pentoxifylline, we identified 15 clinical trials (24-38), of which only 12 were randomized, double-blind, controlled trials (29-38). Reasons for exclusion were lack of randomization (24, 28), duplication of data (25-27), and no report of objectively measured walking distances (24). Methodologic Issues Descriptive data and quality scores for the 12 eligible trials are reported in Table 1. Only 1 study was conducted in the United States and, therefore, conformed to the strict FDA guidelines for eligibility criteria which are based on initial treadmill walking distances and relative stability of symptoms. All studies excluded patients with severe arterial disease as manifested by ischemic resting pain or ulceration. Unfortunately, explicit inclusion criteria were more variable; requirements for disease stability and a range of walking distances before enrollment were reported in only 7 studies (29, 31-34, 36, 38). All studies were placebo-controlled except 2 in which flunarizine (35) or nylidrin (36) was the comparative drug. Despite significant variation in study design (crossover or parallel), sample size (range,

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13 to 82 patients), dose (range, 600 to 1200 mg/d), treatment duration (range, 8 to 24 weeks), outcome assessment and endpoints reported (pain-free or maximum walking distance), 8 of 12 reports (29, 30, 33, 34, 36, 37 [contains 2 studies], 39) concluded that pentoxifylline was statistically significantly better than placebo for improving pain-free or maximal walking distance; 1 of the studies (38) reporting no significant difference in walking distance between groups reported statistically significant findings for pentoxifylline only after an analysis of the proportion of patients whose conditions improved at least 25% over baseline. Investigators expressed walking distances as either initial claudication distance (length in meters until onset of pain, referred to as pain-free walking distance) or absolute claudication distance (referred to as maximum walking distance). Analysis of Treatment Effectiveness Results of the data analysis using effect sizes are shown in Table 2 with 95% confidence intervals (CIs) and the range of improvement (in meters) for pain-free and maximum walking distance. Only seven studies provided sufficient detail for analysis of maximum walking distance and only five studies, for analysis of painfree walking distance. A positive effect size indicated that, on average, pentoxifylline was more effective than the control drug. Overall, the effectiveness of pentoxifylline varied considerably across all studies; 95% CIs were wide and frequently overlapped zero, indicating no significant difference from control group values. Effect sizes were not statistically significant for mean improvement in pain-free walking distance in three evalua t e studies (31, 37 [crossover study], 38) or for mean improvement in maximum walking distance in four evaluable studies (30-32, 37). The noticeable variability in treatment effects was reflected in the chi-square tests for homogeneity; for both maximum walking distance (X2 = 14.94, 6 degrees of freedom, P < 0.01) and painfree walking distance (x2 = 15.55, 4 degrees of freedom, P < 0.01), there was significant nonuniformity in effect sizes, indicating no consistent trend in treatment effects. Because of the marked disparity in outcome measurements, study results were not pooled. Overall study quality varied and was considered to be only fair (range, 6 to 15.5). Limitations included failure to exclude or report the absence of cointerventions (for example, concomitant exercise therapy, advice on smoking cessation), lack of full comparability at baseline, and failure to specify the number of patients with symptomatic deterioration on follow-up. Three crossover studies (27, 33, 37) lost statistical power by using only the first treatment period in their analysis (due to carry-over effects). There was no significant correlation between effect size and study quality (for maximum walking distance, r = 0.22; for pain-free walking distance, r = 0.39). In addition, we analyzed homogeneity of treatment effects based on subgroups of studies with common characteristics, including studies using only a placebo control group, those with 20 or more subjects, those whose treatment duration was more than 8 weeks, and those with comparable baseline variables. The chi-

square test showed homogeneity in effect size only for the outcome of pain-free walking distance for subgroups with a sample size of 20 or more subjects (31, 37, 38). The pooled effect size from those three studies, 0.14, was not statistically significant (CI, -0.22 to 0.50). Table 3 shows the results of the outcome analyses for pain-free walking distance expressed as absolute difference in treatment effect (benefit attributable to pentoxifylline). Unfortunately, for pain-free walking distance, only two studies reported sufficient detail for analysis (29, 38). For subjects whose conditions improved at least 25% over baseline, there was considerable improvement in both placebo- and pentoxifylline-treated groups. The pooled, absolute benefit attributable to pentoxifylline was only 0.16 (CI, 0.01 to 0.31). For subjects whose baseline walking distance before the onset of claudication improved by at least 100%, two studies specified pertinent data (29, 39); the benefit attributable to pentoxifylline was 0.16 (CI, 0.03 to 0.29). Table 3 also shows the therapeutic benefit attributable to pentoxifylline for maximum walking distance. For patients whose baseline maximum walking distance at least doubled, the pooled absolute benefit attributable to pentoxifylline was 0.27 (CI, 0.13 to 0.41). Application and Interpretation of Results To explain the wide variability in estimates of treatment effects, we assessed study characteristics that might affect outcomes. We identified several sources of variation that could plausibly account for the nonuniformity of outcome results and limit their generalizability to clinical practice. First, in most studies, there were strong placebo and Hawthorne effects associated with intense patient surveillance and extensive physician attention and counseling regarding changes in health behavior (better self-care, smoking cessation, control of diabetes mellitus). Moreover, variable improvements in exercise tolerance and treadmill performance are known to occur over time and with repeated examinations (40). In the placebo group alone, these effects may have directly or indirectly contributed to an improvement in walking distance of as much as 149% over baseline (38). By unpredictably influencing study outcomes, any of these methodologic difficulties could have led to imprecise treatment effects, thus limiting the reproducibility of the results. Second, selected study subjects may not be directly comparable with patients seen in general practice. The study patients had to be highly motivated, have stable comorbid conditions, and be compliant with the protocol. Because the endpoint of repeated treadmill testing is pain, outcomes such as maximum walking distance were likely to be strongly influenced by the study subjects' enhanced motivation and behavioral characteristics. Other characteristics, such as duration of severity of peripheral arterial disease, the presence or absence of diabetes, cigarette smoking, hypertension, age, and gender (4), also may have influenced outcome. Unfortunately, no study reported individual outcomes for any of these subgroups to allow a sensitivity analysis. Third, the methods used to analyze and present outcome data were not consistent across studies, limiting

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Table 1. Descriptive Data for Randomized Double-Blind Therapy on Patients with Intermittent Claudication Study (Reference)

Design

Subjects Entered (Subjects Completed)

Controlled Trials Assessing

Acetto et al. (36) Bollinger et al. (30) Dettori et al. (38) Di Perri et al. (34) Gallusetal. (31) Perhoniemi et al. (35) Porter et al. (29) Reilly et al. (32) Roekaerts et al. (37)tt Roekaerts et al. (37)tt Strano et al. (33) Tonak et al. (39)

Parallel Parallel* Parallel Crossover* Crossoverll Crossover^ Parallel Parallel Crossoverll Parallel Crossover^ Parallel

60(47) 26(19) 74 (59) 24 (24) 50 (38) 35(31) 128 (82) 30 (25) 20 (20) 16(16) 18(18) 60(55)

Pentoxifylline

Subject Type Included

Duration of Claudication

n

the Effects of

Patients with Diabetes

Patients with Hypertension

Active Smokers

Yes Yes Yes No Yes Yes Yes Not reported Yes Yes Not reported Yes

Yes Yes Yes Yes Yes Not reported Not reported Yes Yes Yes Not reported Yes

Yes Not reported Not reported No Yes Yes Yes Yes Yes Yes Not reported Yes

y Not 1.5 0.8 1 to 3 5 3 Not 3.5 4 Not 1 to

reported 5

reported

reported 6

* As concluded by the investigators in each study. t The maximum possible score was 21 point:s. $ No pretrial, stabilization run-in period was included. § Subjects were randomly assigned to treatment with pentoxifylline, acenocoumerol, pentoxifylline plus acenocoumerol, or placebo. Only results from subjects treated with pentoxifylline alone compared with those of patients treated with placebo were analyzed and presented || No significant difference between groups was reported for differences in percent improvement over baseline. However, the investigators found statistical significance only after a chi-square analysis of the proportion of patients whose pain-free walking distance improved by at least 25% over baseline. H No wash-out period between treatment periods was included. ** No significant difference between groups was reported for percent change from baseline at the end of the 24-week treatment period. The investigators reported statistical significance only after analyzing the sum of the individua 1 mean percent changes from baseline across weeks 2 through 24 (eight time points). tt Reference 37 (Roekaerts and colleagues) contains the results of two separate studies. $$ No significant difference between group*> was reported based on percent improvement over baseline. Investigators reported statistically significant findings only after analyzing the proportion of patients whose pain-free walking distance improved by at least 50% over baseline.

both the interpretation of clinical significance and the number of study results available for a comprehensive meta-analysis. For example, of 12 randomized controlled trials evaluable for a narrative analysis, only 5 provided sufficiently detailed data for pain-free walking distance to be analyzed. Limitations excluding study results from this meta-analysis included variation in reporting summary values for outcomes (10 studies reported means whereas 2 others reported medians [35, 39]); no report of any measures of variability (SD or SE) (29); and no report of the raw data necessary to compute means (or medians) and SDs (29, 35, 39). In addition, investigators were inconsistent in specifying the type of outcome variable, reporting sufficiently evaluable data for change in pain-free walking distance in only 5 of 8 studies (31, 33, 37, 38). Although similar limitations also apply to changes in maximum walking distance, this variable is an unrealistic outcome measure with little applicability to the average patient. Finally, the tendency to report improvements as mean changes from baseline conveys little information about actual gains made by individuals. Reporting results as proportions of patients with clinically significant outcomes, as previously described, may provide complementary information about clinical efficacy. Unfortunately, few studies presented data in this form. Conclusion Nine of twelve randomized controlled trials concluded that pentoxifylline was statistically significantly 138

more effective than placebo for improving one or another outcome variable reflecting change in walking distance. Unfortunately, variation in study characteristics and methods used to analyze and present the effects of treatment limit the generalizability of the results to clinical practice. Despite the statistical significance reported by some investigators, the actual improvement in walking distance attributable to pentoxifylline is often unpredictable, may not be clinically important compared with the effects of placebo, and may not justify the incremental cost for the average patient. Whether or not such therapy is useful for patients who have recent onset claudication and are unable to do daily physical activities due to comorbid conditions remains undetermined. An analysis based on all the raw data may provide a more conclusive estimate of the actual therapeutic effect of pentoxifylline. Exercise Therapy Potential Mechanisms for Benefit The benefits of regular physical training for subjects with intermittent claudication have been uniformly endorsed by most experts in vascular medicine (41-43). Despite this general agreement and many investigations, the precise mechanism for the reported improvement in pain-free walking capacity is still unknown. Suggested mechanisms include improved oxidative metabolic capacity of the involved limb (44), altered walking technique (45), and spontaneous fluctuations in pain toler-

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Table 1. Continued Range of Walking Distance

Duration of Treatment

Intervention

Pentoxifylline

100 to 400 Less than 750 50 to 500 50 to 510 Not reported 20 to 1000 80 to 360 Not reported 26 to 1500 paces

Yes Yes

13 8.5 15.5 12 13.5 9 12.5 10 11.5 12 6 12

wk 400 mg, three times daily 200 mg, three times daily 400 mg, three times daily 400 mg, three times daily 400 mg, three times daily 400 mg, three times daily 400 mg, three times daily Not reported 400 mg, three times daily 400 mg, three times daily 400 mg, two times daily 200 mg, three times daily

Nylidrin, 2 mg, three times daily Placebo, three times daily Placebo, three times daily§ Placebo, three times daily Placebo, three times daily Flunarizine, 5 mg, three times daily Placebo, three times daily Not reported Placebo, three times daily Placebo, three times daily Placebo, two times daily Placebo, three times daily

ance (46). More recent evidence suggests that physical activity may improve abnormal hemorheology in patients with peripheral arterial disease, leading to beneficial changes in blood flow (47). Regular physical exercise, compared with no exercise, was shown to be associated with a small but statistically significant decrease in whole blood and plasma viscosity and blood cell filterability (47). Finally, contrary to earlier data (48), it seems unlikely that physical training leads to any clinically important redistribution of blood flow or increased collaterization to the ischemic limb (49-53). Table 2. Summary of Mean Study (Reference)

Quality Scoret

Control

m 50 to 500 Not reported Not reported

Positive Treatment Effect*

Sample Size Treat- Conment trol Group Group

±11

Yes No No .+.**

No Yes Yes Yes ±tt

Study Selection In addressing the question of clinical efficacy, 84 references published since 1966 were evaluated. We identified eight controlled clinical trials (47, 53-59), of which only five were eligible for quantitative analysis. Reasons for exclusion included the following. One randomized, double-blind controlled trial compared physical training plus drug therapy (flunarizine) with physical therapy plus placebo, qualifying it as a drug study (58); no significant difference between treatment groups was re-

Improvements and Individual Treatment Effect Sizes for Changes in Walking

Pentoxifylline

Control

Not reported Not reported 176.7 (189)t Not reported 20.6 (76) 26 (19)§ 84 (59)|| Not reported 569 (124) 265 (137) 54 (45) 252 (126)1

Not reported Not reported 170.8 (142)t Not reported 19.6 (68) 26 (19)§ 63 (36)|! Not reported 123 (28) - 4 4 (-25) 5(4) 140 (38)1

Effect Size*

Distance

Mean Improvement in Maximal Walking Distance (Percent Change from Baseline)

Mean Improvement in Pain-Free Walking Distance (Percent Change from Baseline)

n Acetto et al. (36) 23 Bollinger et al. (30) 10 Dettori et al. (38) 29 Di Perri et al. (34) 12* Gallus et al. (31) 19* Perhoniemi et al. (35)> 14* Porter et al. (29) 42 Reilly et al. (32) 15 Roekaerts et al. (37) 10* Roekaerts et al. (37) 8 Strano et al. (33) 9* Tonak et al. (39) 27

8 8 52 8 8 12 24 12 24 24 12 4

Pentoxifylline

Control

Effect Size*

5.5 (3) 93 (53) Not reported 6(3) 11.9 (14) 109 (43)§ 69 (25)|| 90(89) 64(9) - 3 4 (-15) Not reported Not reported

0.753 (0.161 to 1.345) 0.748 (-0.182 to 1.678) NA 1.2% (0.416 to 2.176) 0.130 (-0.510 to 0.770) NA NA -0.364 (-1.154 to 0.426) 0.799 (-0.112 to 1.710) 1.80 (0.640 to 2.960) NA NA

•m 24 9 30 12 19 17 40 10 10 8 9 28

NA NA 0.022 (-0.492 NA 0.019 (-0.625 NA NA NA 0.728 (-0.177 2.00 (0.800 to 1.58 (0.520 to NA

60.8 (46) 471 (208) to 0.532) Not reported 136 (61) to 0.663) 22.6 (33) 44 (17)§ 75 (38)|| 37 (27) to 1.633) 618 (101) 304 (121) 3.200) Not reported 2.640) Not reported

* NA signifies not applicable due tc> lack of reported data necessary to calculate meansand standard deviations (SDs). Confidence intervals are 95%. t Original data wene reported in seconds. Mean change in distance walked was calculated by converting treadmill time at the reported rate (3 k/h) into distance expressed as meters. * These studies were crossover designs; therefore, sample size refers to the number of patients who either received treatment or were controls during the first treatment period only. In addition, three crossover studies (33, 34, 37) analyzed only the results from the first treatment period due to carry-over effects. Consistent with those investigators, treatment effect sizes for the data of Gallus and colleagues (31) were calculated from the first treatment period, as they did not include a wash-out phase in their crossover study. An analysis based on both treatment periods did not change the conclusion that there was 10 i statistically significant difference between groups. § Values refer to median change from baseline; no data were provided to calculate means. Therefore, no effect size based on means could be computed. || Values refer to mean change between the end of s tudy (week 24) and baseline. Values in parenthesis refer to geometric mean percent change from baseline. Because no data were provided to derive or calculate any measure of variability (SD or standard error), effect sizes based on means could not be calculated. 11 These values refer to median paces from baseline. The investigators did not report means or any data to calculate means or a measure of variability; therefore, effect sizes based on means or medians could not be calculated.

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Table 3. Number of Subjects Whose Pain-Free and Maximum Walking Distance Improved Due to Pentoxifylline Therapy Study (Reference)

Sample Size

Treatment Group

Proportion of Subjects with Improvement in Pain-Free Walking Distance*

Control Group

Treatment Group

24 30 12 40 28

Not reported 0.862 Not reported 0.619 Not reported

25% or Greater Increase over Baseline Attributable Control Group Benefitt

100% or Greater Increase over Baseline Treatment Control Group Group

n Acetto et al. (36) Dettori et al. (38) Di Perri et al. (34) Porter et al. (29) Tonak et al. (39)

23 29 12 42 27

Not reported 0.667 Not reported 0.500 Not reported

NAt 0.195 (-0.015 to 0.405) NA* 0.119 (-0.095 to 0.333) NAt

Not reported Not reported Not reported 0.310 0.741

Not reported Not reported Not reported 0.150 0.286

* The proportion of subjects is expressed throughout the tables in decimal notation. Therefore, when the proportion of subjects improving is stated as 0.862, specified walking distance improved in 86.2% of subjects. t Attributable benefit is a measure of treatment effect and refers to the absolute difference in proportion of subjects with improvement in walking distance (expressed in decimal notation). It indicates the actual improvements attributable to pentoxifylline that can be expected in terms of proportions of patients treated. For example, an attributable benefit of 0.295 indicates that 29.5% of the measured improvement in pain-free walking distance can be attributed to the effect of pentoxifylline. Statistical techniques for calculation of this measurement and their sampling variances are described in reference 16. Confidence intervals are 95%. X NA indicates not applicable due to lack of any reported data.

ported for changes in walking distance. The second excluded report was a randomized, controlled trial comparing surgical reconstruction with or without subsequent physical training with physical training alone (59). The investigators reported that surgery with or without subsequent exercise therapy was statistically significantly better than physical training alone for improving walking distance. Although both studies were well conducted, their design unfortunately prevents an unbiased estimate of the actual effect of physical training on walking distance. The third study (53) was excluded from the quantitative analyses because the "control group" inadvertently received exercise therapy. Study Characteristics The characteristics of the studies that were eligible for narrative analysis are shown in Table 4. All studies were parallel in design with small sample sizes (range, 13 to 42 subjects); only two studies had more than 20 subjects (47, 53). Exercise interventions were generally similar, consisting of some form of supervised, regularly scheduled group sessions of dynamic leg muscle exercises (47, 53, 55-57) that ranged from two to fi\t times per week in an outpatient setting. In addition, patients were advised to engage in a regular physical activity program at home. Treatment durations lasted 6 months or more in all but one study (47). Outcome assessment was also uniform, with most studies assessing walking distances with a standardized treadmill technique at various speeds and grades (47, 53-56). All five studies that were eligible for quantitative analysis reported a statistically significant improvement in walking distance for the exercise intervention group compared with the control group (47, 54-57); in a sixth study (53), the investigators noted that subjects in the control group could not be considered to be "real controls," as they had also received concomitant physical training; such training probably contributed to a spurious decrease in outcome differences leading to the investigators' con140

clusion that there was no significant difference between groups. Study subjects were generally middle-aged men with intermittent claudication for at least 2 years; claudication severity ranged from mild to moderate, with average baseline pain-free walking distances of less than 500 m in the three studies that specified baseline walking capacity. In three studies (53, 54, 57), the proportions of patients with hypertension, diabetes mellitus, or concurrent tobacco use were not stated. One investigation (57) provided no information on patient characteristics or eligibility criteria, used no objective method to assess outcome, and described no statistical methods. Only three studies randomly assigned subjects to treatment groups (53-55), none could be feasibly double-blinded, and adverse effects of the supervised training programs were specified in only one report (54). The earliest study (54) included an unspecified number of patients previously treated by vascular surgery. Despite the wide range in years of publication, study quality was fairly uniform, with quality scores ranging from 10.5 to 11.5 (total possible, 16). There was no correlation between study quality scores and outcome effects. Analysis of Treatment Effectiveness Table 5 shows the range of improvement in walking distances (in meters) for pain-free and maximal walking distance and effect sizes with 95% CIs. In contrast to the available studies on pentoxifylline, all studies measured both pain-free and maximum walking distance. Four of the five eligible studies provided sufficient data for analysis of effect sizes. The fifth report (55) specified no quantitative outcome data for the control group. Before pooling effect sizes, formal tests of homogeneity were done; no significant heterogeneity was found for either pain-free walking distance (x2 = 3.06, 3° of freedom; P > 0.40) or maximum walking distance (x* = 2.05, 3° of freedom; P > 0.40). The pooled estimate of overall treatment effect was 1.03 (CI, 0.58 to 1.48;

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Table 3. Continued Proportion of Subjects with Improvement in Maximum Walking Distance

Attributable Benefitt

NA* NA* NA* 0.160 (-0.018 to-0.338) 0.455 (0.220 to 0.690)

Treatment Group

0.609 Not reported 1.000 0.619 Not reported

25% or Greater Increase over Baseline Control Attributable Group Benefitt

0.375 Not reported 0.000 0.500 Not reported

0.234 (-0.044 to 0.512) NA$ 1.000 (0.887 to 1.13) 0.119 (-0.094 to 0.332) NAt

P < 0.0001) for pain-free walking distance and 1.17 (CI, 0.72 to 1.62; P < 0.0001) for maximal walking distance. Stated differently, for pain-free walking distance, the average patient receiving an exercise intervention had a response that exceeded approximately 85% of that of untreated control subjects (assuming normality and converting effect sizes into percentile rankings). Because no study provided the necessary raw data, however, differences in clinically successful outcomes (therapeutic benefit attributable to exercise) could not be calculated. Although two studies (54, 55) that were eligible for quantitative analysis used randomization, the absence of necessary data (55) precluded a subset analysis of pooled results from these reports. Based on our quantitative analysis, the results of four of five unambiguously controlled studies could be combined to provide an overall estimate of the treatment effect of physical training on intermittent claudication (total number of subjects, 109). The data strongly suggest that supervised, dynamic leg exercise programs combined with regular, home-based programs of similar activity are associated with improvement in pain-free and maximum walking distance in appropriately selected patients. Such benefit was generally noted within the first 3 months; thereafter, walking distance either remained unchanged or variably improved. Application and Interpretation of the Analysis Given the nature of the treatment protocols and the limitations noted, however, the reported clinical benefit from exercise therapy may have limited generalizability. For example, study data were derived almost exclusively from men with a mean age of less than 65 years and stable comorbid conditions. In addition, supervised exercise programs in hospital outpatient settings require highly motivated subjects and may not be accessible or acceptable to the average patient. Whether or not the results can be applied to the growing population of patients over 65 years of age with intermittent claudication accompanied by symptomatic cardiovascular disease (60-62), complicated diabetes mellitus, or chronic obstructive pulmonary disease (52) is unclear. In addition, the results from our analysis of controlled trials of physical training raise further issues, including the known spontaneous fluctuation (63) of symptoms

100% or Greater Increase over Baseline Treatment Control Attributable Group Group Benefitt

0.261 Not reported 0.083 0.214 Not reported

0.042 Not reported 0.000 0.150 Not reported

0.219 (0.022 to 0.416) NA$ 0.083 (-0.073 to 0.239) 0.064 (-0.102 to 0.230) Not reported

early in the course of peripheral arterial disease, potentially causing a bias in outcome measurement; the optimal intensity, frequency, and type (for example, walking, stationary bicycle) of physical training; patient compliance; and categories of patients who are most likely to benefit from physical training. Limited evidence from controlled (59) and uncontrolled studies (50, 62, 64) indicates that age, sex, the presence of diabetes mellitus, and the level of the atherosclerotic lesion may not adversely influence the success of physical training for improving pain-free walking distance. Fewer data from uncontrolled studies suggest that patients with angina pectoris, chronic obstructive pulmonary disease, or both (52, 62) may show improvement in walking distance but to a lesser extent than subjects without these conditions. Finally, it should be noted that compliance with any long-term physical activity regimen, similar to other health-related behavioral interventions, can diminish significantly with time (65). Additional, well-controlled studies (with intervention conducted under typical conditions) are necessary to determine strategies that maximize the effectiveness of and patient compliance with dynamic leg exercise therapy for intermittent claudication. Conclusion Given the potentially beneficial influence of regular physical training on some cardiovascular risk factors, neuromuscular function, and joint mobility in adults (66), it is reasonable to emphasize regular, individualized physical activity for selected patients with stable intermittent claudication. Despite the absence of adequate data, contraindications to a dynamic exercise program can be based on practical considerations; in general, reasons for exclusion would be unstable cardiorespiratory conditions (unstable angina, debilitating chronic obstructive pulmonary disease, symptomatic congestive heart failure) or severe manifestations of limb ischemia requiring surgery (gangrene or ulceration). The most successful programs are likely to be those that combine regular, supervised group sessions with daily home exercise programs (67, 68); regularity rather than intensity should be stressed by counseling physicians and other health professionals. In addition, the duration and specific content of an exercise program

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Table 4. Descriptive Data of Controlled Clinical Trials Evaluating the Effects of Dynamic Exercise Regimens Intermittent Claudication Study (Reference)

Randomization

Subjects Entered (Subjects Completed)

Mean Age

n

y

Duration of Claudication

on

Subject Type Included Patients with Diabetes

Patients with Hypertension

Active Smokers

y

Dahllofetal. (53)

Yes

34(21)

61.4

2

No

Yes

Yes

Dahllofetal. (55)

Yes

18(18)

61.4

2

No

Not reported

Not reported

Larsen et al. (54)

Yes

14(14)

57

5.3

Not reported

Not reported

Not reported

Ericsson et al. (57)

No

13(13)

63

Not reported

Not reported

Not reported

Not reported

Ernst et al. (47)

No

42 (42)

59

Yes

Yes

No

Mannarino et al. (56)

No

16(16)

62

Yes

Yes

No

4

Not reported

* Refers to conclusions; of the study investigators regarding whether the exercise intervention was more effective than the control group intervention for improving walking distance.

should be individualized; at least 30 minutes per day of dynamic leg exercise (walking, stationary bicycle, stairclimbing) is a reasonable goal. Limited evidence from descriptive reports (49, 69-71) suggests that components of an effective exercise program for intermittent claudication include comprehensive objectives (modification of other risk factors including smoking cessation); regular supervision and outcome evaluation; and exercises that are safe, simple, and convenient (for example, a daily walking program in a home-based environment). The ability to predict successful outcomes accurately for individuals, however, is limited (72-74). Cigarette Smoking Cessation The Relation between Smoking and Peripheral Arterial Disease Smoking is the most significant independent risk factor for chronic obstructive peripheral arterial disease of the lower extremities (75, 76). In an updated multivariate analysis of Framingham data (4), the biennial rate of development of intermittent claudication was approximately twice as great for smokers compared with nonsmokers in men and women ranging from 55 to 64 years of age. The risk extended to persons from 75 to 84 years of age, with the differences between rates for men and women narrowing as smoking intensity increased. The dose-response relation between the number of cigarettes smoked and increased rate of intermittent claudication was apparent for all age groups. In addition, for patients with any other cardiovascular risk factors (for example, elevated systolic blood pressure, diabetes mellitus), cigarette smoking further increased the rate of 142

development of intermittent claudication significantly. Other epidemiologic data have also supported the primary association between cigarette smoking and peripheral arterial disease of the lower extremities. Results from retrospective analyses have shown that the frequency of intermittent claudication may be as much as nine times greater among subjects smoking more than 15 cigarettes daily than among nonsmokers (61). Cigarette smoking after the onset of intermittent claudication also accelerated the progression of peripheral arterial disease; it was associated with an increased frequency of complications related to peripheral vascular disease, including life-threatening ischemia and risk for amputation (76-80). Moreover, continued cigarette smoking after arterial reconstructive surgery adversely influenced the patency rates of bypass grafts (77, 81-85). In general, continued postoperative smoking decreased the cumulative patency rates of both prosthetic (77, 81, 84, 85) and autologous saphenous (77, 84) vein grafts. Although the dose-response correlation between the number of cigarettes smoked and the rates of amputation or graft patency has been reported to vary (77, 82), the overall relationship was generally preserved when other variables were taken into account (age, graft type, and indication for operation). Myers and colleagues (77) reported 5-year cumulative patency rates of approximately 90% for aortofemoral reconstructions and 80% for femoropopliteal grafts for patients who either stopped smoking or smoked fewer than five cigarettes per day postoperatively. In patients continuing to smoke more than five cigarettes daily, the risks for occlusion for aortofemoral and femoropopliteal grafts were approximately 30% and 45%, respectively. There

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Table 4.

Continued

Baseline Walking Distance

Less than 400 Not reported 100 to 400

Not reported Not reported

Less than 500

Type of Intervention

Duration of Intervention

Positive Treatment Response*

Quality Score

Exercise Group

Control Group

Supervised program of various dynamic leg exercises in 30-minute sessions three times per week plus advice for home exercise Supervised program of dynamic leg exercises beyond onset of ischemic pain in 30-minute sessions three times per week Advised only to walk for 1 hour daily as far as claudication permitted, resting until pain subsided, then repeating; no supervision provided Supervised program of dynamic exercises in 45-minute sessions twice per week plus advice for 5-minute daily home dynamic exercise Supervised program of exercise on a treadmill at 3 km/hr, twice per day, five times per week, plus advice to walk twice per day at home until onset of ischemic pain Supervised program of various dynamic and isometric leg exercises in 1-hour sessions twice per week plus advice to increase daily walks at home until reaching 2 km in 1 hour

Placebo tablets

6

No

11.5

Placebo tablets

6

Yes

11.5

Placebo tablets

6

Yes

11.0

Not reported

11

Yes

6.0

Not reported

2

Yes

11.5

Not reported

6

Yes

10.5

was a dose-response relation between frequency of graft occlusions and number of cigarettes smoked per day. More recently, Ameli and colleagues (82) reported a statistically significant association between postoperative smoking and risk for amputation. Compared with nonsmokers and smokers of fewer than 15 cigarettes per day, subjects continuing to smoke more than 15 cigarettes per day postoperatively had an increased probability of limb loss. This probability was approximately fivefold greater after 2 years of follow-up (14.9% compared with 3.3%) and threefold greater after 5 years (28.1% compared with 10.9%). Data Identification and Methodologic Issues Despite strong observational evidence that continued smoking is associated with decreased graft survival, there are almost no available data from controlled clinical studies examining whether smoking cessation improves intermittent claudication. Most information on the effects of smoking cessation is derived from natural history studies of subjects with intermittent claudication (75, 76, 83, 86-89). Of the several sources of bias, noncomparability between smokers and former smokers for several variables (age, severity of disease, comorbid conditions) and misclassification of smoking status due to subjective reporting (83, 87-89) are of particular concern. Most studies used patient questionnaire data to classify smoking status; subjective evidence used in retrospective series, however, may inaccurately estimate both the degree of cigarette smoking and exposure to tobacco and nicotine (90-93). Nonetheless, the reports were generally consistent in reaching at least two conclusions: fewer than 50% of patients reported smoking cessation despite a supervised health behavior-modification program, and discontinuation or reduction of cig-

arette smoking as reported by subjects with intermittent claudication was associated with a reduced frequency of peripheral vascular complications (limb-threatening ischemia [76, 80, 86], surgery [76, 86], and cardiovascular disease-associated deaths [76, 86]). We identified only two controlled clinical trials that addressed whether smoking cessation improves the symptoms of intermittent claudication and pain-free walking distance (92, 93). Both studies were markedly different in terms of specific aims, design, and conduct. In the first study, Quick and colleagues (92) studied 61 consecutive patients with intermittent claudication for a mean period of 10.4 months. They concluded that patients who reported quitting cigarette smoking (n = 15) showed statistically significant increases in maximum walking distance (pain-free walking distance was not reported) compared with their own baseline values and with the values of a control group of smokers (mean improvement ± SD, 86.2 ± 124.7 m for quitters compared with 23.8 ± 117 m for smokers). Unfortunately, methodologic difficulties in subject allocation, group size and comparability (sex, degree of peripheral arterial disease), and compliance with reported smoking status biased the validity of the results. For example, groups were allocated according to smoking status after completion of the study; no objective evidence of cigarette exposure (serum thiocyanate or carbon monoxide levels) was obtained; it was unclear whether treadmill evaluations were done in a blinded fashion; and painfree walking distance was not measured. Long-term, randomized, controlled trials, however, are unlikely to be conducted due to ethical difficulties and problems of compliance associated with randomized allocation of smokers to groups of "continuers" or "quitters." In the second controlled clinical trial, Waller and col-

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Table 5. Outcome Results for Mean Improvements in Walking Distance and Treatment Effect Sizes for the Effect of Exercise on Intermittent Claudication Study (Reference)

Mean Improvement in Pain-Free Walking Distance (Percent Change from Baseline) Effect Size* Intervention Control Group Group

Sample Size Intervention Group

Control Group

m

n Dahllofetal. (53) Dahllofetal. (55) Larsen et al. (54) Ericsson et al. (57) Ernst et al. (47) Mannarino et al. (56)

15 10 7 9 22 8

6 8 7 8 20 8

Not reported (176) 173 (190) 163.2(155) 194(104) 61(103) 35 (88)

Not reported (126)t Not reported -21.9 (-14) - 4 1 (-22) 12(19) 10.7 (18)

0.025 (-0.83 to 0.88)t NA 2.06 (0.75 to 3.36) 0.82 (0.20 to 1.84) 1.01 (0.37 to 1.65) 0.68 (-0.33 to 1.69)

* NA indicates not applicable because the data from the control group were not reported, preventing calculation of treatment effect size. The investigators, however, stated that the control group had "unchanged walking capacity." Confidence intervals are 95%. t The investigators did not consider the control group in this study to be a true "control" group, as these patients also engaged in concomitant exercise therapy. t Effect sizes from this study were calculated using the raw data expressed graphically as a percent change from baseline and the reported mean baseline (pretreatment) values for walking distance.

leagues (93) primarily studied the acute effects of cigarette smoking and type of suggestion (whether smoking might lead to improvement or deterioration in walking distance) on treadmill walking distance in patients with intermittent claudication. They concluded that only the nature of the suggestion (either positive or negative), not cigarette smoking, acutely influenced treadmill walking times. The results, however, are unlikely to have clinically important relevance for long-term outcomes. Conclusion Most of the evidence on the effects of smoking cessation on intermittent claudication is primarily derived from observational studies (retrospective cohort and follow-up) of the natural history of peripheral arterial disease or the postoperative course of arterial reconstructive surgery. Several practical considerations are probably responsible for the absence of long-term controlled trials examining whether smoking cessation improves intermittent claudication. These considerations include the difficulties of smoking cessation for prolonged periods (94) and problems of ethics and compliance in randomized trials done in quitters and continue s . Nevertheless, the evidence strongly suggests that smoking cessation, compared with continuation, is associated with a reduced frequency of adverse events related to peripheral vascular disease. These adverse outcomes include complications due to progressive diseases (resting ischemic pain, worsening claudication, potential for amputation, need for reconstructive surgery), decreased patency rates after arterial reconstruction, and increased cardiovascular morbidity and mortality. Because of the known spontaneousfluctuationof symptoms (including subjective and objective improvement in pain-free walking distance) in patients with recent onset claudication (95), it is difficult to predict accurately which patients will improve after smoking cessation and the magnitude of improvement. However, smoking cessation clearly improves overall health status (96, 97) and beneficially affects the course of established peripheral arterial disease of the lower extremities and coronary artery disease (98, 99). 144

Overall Conclusions We conducted an analytical review of the three central components in a contemporary, nonoperative therapeutic approach to intermittent claudication. In assessing the efficacy of pentoxifylline and physical therapy for improving pain-free walking distance, we did both methodologic and quantitative analyses of controlled clinical trials. Based on the evidence from 12 randomized controlled trials of pentoxifylline, we conclude that the amount and quality of the data reported were inadequate to support or refute the efficacy of pentoxifylline therapy for intermittent claudication. Despite the positive conclusions reported by some investigators, differences in baseline severity of claudication, variation in the analysis and reporting of outcome variables, and incomplete data presentation allowed only a limited number of studies to be evaluated by meta-analytic techniques; the result was a wide scatter in treatment effect measures that precluded a meaningful pooling of study results. Given these limitations, the available data do not permit a definitive conclusion that pentoxifylline causes a significant and predictable improvement in pain-free walking distance for the average patient with intermittent claudication. Of six clinical trials with small sample sizes, we identified four that were eligible for a meta-analysis of dynamic physical exercise. Within the context of the previously discussed limitations, we conclude that a supervised, dynamic leg exercise program with similar, home-based exercises is strongly associated with improved pain-free walking distance. The data suggest, however, that the best results are associated with a regular, supervised program, risk-factor modifications such as smoking cessation, enhanced motivation, and continued evaluation of patient progress and satisfaction (objective assessment of improvement in distance walked, evaluation of program compliance). Practical considerations, including the benefits and costs (money, time, travel distance) of comprehensive, supervised vascular rehabilitation programs, need to be addressed by further studies before the combined results of our analysis of exercise therapy can be extrapolated to the

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Table 5. Continued Mean Improvement in Maximal Walking Distance (Percent Change from Baseline) Intervention Control Group Effect Size* Group m Not reported (136) 347(117) 400.9(178) 259 (95) 154(121) 51 (67)

Not reported (76) Not reported -14.2 (-6) 50(17) 20(16) 14.3(14)

0.72 (-0.16 to 1.60) NA 1.31 (0.16 to 2.46) 0.62 (-0.35 to 1.59) 1.46 (0.78 to 2.14) 1.03 (-0.01 to 2.07)

average patient with reliability. We recommend regular, individualized exercise programs as previously described, with the caveat that degree of improvement for individuals cannot be accurately predicted. No rigorously conducted controlled clinical trials were available for evaluating the efficacy of smoking cessation in improving intermittent claudication. Most available evidence is derived from observational studies that strongly suggest that smoking cessation is associated with improved outcomes in the natural history of peripheral arterial disease and for postoperative graft patency. Although the degree to which pain-free walking distance can be improved for individuals cannot be predicted, the overwhelming health benefits from smoking cessation strongly support its value in management of patients with intermittent claudication. Acknowledgments: The authors thank Suzanne Rase for manuscript preparation. Requests for Reprints: Kenneth Radack, MD, Division of General Internal Medicine, 231 Bethesda Avenue, Mail Location 535, Cincinnati, OH 45267. Current Author Addresses: Drs. Radack and Wyderski: University of Cincinnati College of Medicine, Division of General Internal Medicine, 231 Bethesda Avenue, Mail Location 535, Cincinnati, OH 45267.

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of Internal

Medicine

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