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(Circulation. 1997;95:411-414.)
© 1997 American Heart Association, Inc.

Articles

Effect of Verapamil in Intermittent Claudication

A Randomized, Double-Blind, Placebo-Controlled, Cross-over Study After Individual Dose-Response Assessment

Jens Peder Bagger, MD; Per Helligsoe, MD; Flemming Randsbaek, MS; Hans Henrik Kimose, MD; Bent Skov Jensen, MD

the Vascular Surgery Unit and Cardiology Department (J.P.B.), Skejby Section, Aarhus University Hospital, Aarhus, Denmark.

Correspondence to Jens Peder Bagger, MD, Cardiological Sciences, St George's Hospital, London SW17 ORE.

	Abstract

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Background The calcium antagonist verapamil is a vasodilator drug that has been shown to increase oxygen extraction of ischemic tissues in coronary and peripheral vascular disease.

Methods and Results Since the balance between the positive and the negative effects of vasodilation may be delicate in ischemic diseases a dose-response study (dose range, 120 to 480 mg) was established to determine optimal, individual dosages of slow-release verapamil in 44 patients with stable intermittent claudication (Fontaine classification stage II) with respect to walking capacity. A randomized, double-blind, placebo-controlled, cross-over study (4 weeks) was performed to assess clinical and hemodynamic effects of verapamil. The optimal daily dose of verapamil on maximal walking ability was 120 (8 patients), 240 (8 patients), 360 (14 patients), and 480 mg (14 patients). Walking distances were measured at a metronome-controlled speed of 60 steps per minute on level surface. Optimal individual doses of verapamil increased mean pain-free walking distance by 29% from 44.9 to 57.8 meters (P<.01) and maximal walking distance by 49% from 100.7 to 149.8 meters (P<.001) compared with placebo. The increase in maximal walking distance correlated positively only with initial systolic ankle pressure (r=.49, P<.001) and ankle/brachial pressure index (r=.37, P<.013). Verapamil had no effect on systolic ankle pressure, ankle/brachial pressure index, peripheral leg temperature, or blood pressure, which suggests that the drug may have extrahemodynamic effects, possibly brought about through improved oxygen metabolism.

Conclusions Verapamil showed significant clinical benefits in patients with moderate intermittent claudication in this short-term study. Individual optimization of drug dosage should be considered an option both in trials and in the clinical setting in these patients.

Key Words: calcium antagonists • vasodilation • claudication

	Introduction

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In patients with intermittent claudication, symptoms depend on the balance between oxygen supply and utilization of the diseased leg. Traditional surgical and pharmacological treatments seek to raise the flow of blood and hence the supply of oxygen to the ischemic legs.^{1 2 3} An alternative approach could be to induce increased oxygen extraction of the limb. The calcium antagonist verapamil has been reported to have this effect in both the ischemic myocardium⁴ and the ischemic lower limb.⁵ In a previous study of patients with intermittent claudication,⁶ a significant clinical effect of verapamil could not be established at a fixed dose of 240 mg/d; it was not investigated whether dose optimization through individual titration would have changed this outcome. However, the calcium antagonists nicardipine⁷ and nifedipine⁸ have shown clinical benefits in patients with ischemic heart disease when administered in individually optimal doses. We determined individual maximal walking distance in relation to increasing doses of verapamil in a group of patients with intermittent claudication. The clinical effect of the optimal verapamil dose was then evaluated in a randomized, double-blind, placebo-controlled, cross-over study in the same patient population.

	Methods

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Inclusion criteria comprised patients with stable intermittent claudication stage II according to the Fontaine classification. Exclusion criteria included ability to walk >200 meters, a variation of >20% between maximal walking distances during baseline recordings, severe rest pain or ulcerations/gangrene of the lower limb, previous operation for peripheral occlusive arterial disease, angina pectoris, heart failure, and heart block, ongoing treatment with vasodilators or ß-blockers, diabetes, severe hypertension, and other conditions limiting the patient's walking capacity. Among 195 patients admitted to our outpatient clinic in 1992 to 1993, 55 were eligible. Nine of these patients did not want to participate in the trial. Two of the remaining 46 patients were not able to continue the study after having participated in the dose titration because of a spontaneous compression fracture of an osteoporotic lumbar spine in one patient and development of unstable angina in the other. The 44 patients who participated in the cross-over study had a mean age of 59 years (47 to 70 years) and a mean disease duration of 24 months (6 to 84 months). Disease of one leg was seen in 24 patients; the rest had disease of both legs. All patients had had stable intermittent claudication for at least the last 6 months with a mean resting ankle/brachial blood pressure index of 0.54±0.13 of the diseased leg or of the most troublesome leg where both were diseased. Angiography confirmed vascular disease in all patients. The mean maximal walking distance was 100.4 meters (range, 32 to 190 meters) at study entry. Thirty-seven patients were smokers, 6 stopped smoking <1 year ago, and 1 patient was a nonsmoker. The patients were asked not to change smoking, dietary, or exercise habits during the study period. Medication (aspirin, n=17 and anticoagulants, n=0) was kept constant as well. All patients gave informed consent, and the study protocol was approved by the local ethics committee.

Experimental Protocol
The patients were examined 11 times in our outpatient clinic during a 13-week period (Fig 1). At each visit, patients were measured at rest for blood pressure, systolic ankle/brachial pressure index calculated from simultaneous ankle pressure (strain gauge plethysmography), and cuff brachial blood pressure; peripheral leg temperature, and heart rate (ECG recording). Patient weight was measured at the start and the end of the study. The patients then walked on a level surface at a metronome-controlled speed of 60 steps per minute, and pain-free and maximal walking distances were registered. The walking testing took place in a 300-meter-long corridor underneath the hospital with largely the same temperature and humidity all year round. Possible adverse events and signs and symptoms of the disease were registered. After the patients became accustomed to these methods of testing (1 or 2 tests without any registration during a 2-week run-in period), 3 baseline tests were performed within 2 weeks. During the following 4 weeks, the patients got 120, 240, 360, and 480 mg of slow-release verapamil (Isoptin Retard, Knoll AG) in one daily dose, maintaining each of the doses for 1 week. Before every dosage increment, blood pressure, ECG, and the clinical condition of the patients were evaluated. At the end of each treatment week, all the aforementioned measurements were performed. Then followed 1 week without medication with tests on the last day of this washout period before the patients entered the randomized, double-blind, cross-over part of the study, during which the patients received verapamil for 2 weeks and then placebo for another 2 weeks, or vice versa. Each patient received the dosage of verapamil (or equivalent amount of placebo) that allowed the longest maximal walking distance during the titration study. All pressure measurements were performed by the same technician and all exercise tests were conducted by two of the authors (P.H. and F.R.). Mean blood pressure was calculated as diastolic pressure times 2 added to the systolic pressure and divided by 3. Individual doses of verapamil and placebo tablets were packed and distributed by the pharmacy of another hospital (Aarhus Kommunehospital), which also held the randomization code. At the end of the study, the code and results were brought to an independent institution (UNI-C, Aarhus) for statistical evaluation. Patient compliance was ensured by pill counting at the end of the study. Sample size calculation was based on the fact that at least 40 patients were to be included to detect an increment of walking distance of >40%, a type I error of 5%, a power of 80%, and a possible withdrawal rate of 10% to 20%.¹ The primary effect variables were pain-free and maximal walking distances. The outcome was then related to patient age, sex, duration of disease, basal walking distances, ankle/brachial pressure index, peripheral temperature, systolic ankle pressure, and blood pressure.

View larger version (7K): [in this window] [in a new window]   Figure 1. At all visits (x), the following measurements were performed: pain-free and maximal walking distances, systolic ankle-brachial pressure index, peripheral leg temperature, blood pressure, and heart rate (ECG).

Statistics
The results were analyzed in accordance with "the simple cross-over design," as described by Armitage and Berry,⁹ taking treatment, period, and carry-over effects into account. Differences were evaluated by means of paired and unpaired t tests or Wilcoxon and Mann-Whitney tests as appropriate. Changes in walking distances were related to other variables by means of ANOVA and the Spearman rank correlation test. Statistical calculations were performed with the use of the BMDP statistical program package, 1990 version. The level of significance was 5% (two-sided).

	Results

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All 44 patients completed the study. Treatment did not affect mean patient weight (entry versus end of study, 69.6±1.9 kg and 69.6±2.0 kg, respectively; NS). The optimal dose of verapamil measured by maximal walking ability was 120 (8 patients), 240 (8 patients), 360 (14 patients), and 480 mg/d (14 patients). Thus, the maximal walking distance was related to the maximal drug dose in 14 patients (32%). There were no significant differences between the groups in terms of age, sex, duration of disease, smoking habits, initial pain-free and maximal walking distances, systolic ankle pressure, systolic ankle/brachial pressure index, and systolic, diastolic, and mean blood pressures, peripheral leg temperature, or heart rate. The individual optimal verapamil dosage caused both mean pain-free and maximal walking distances to rise significantly from 38.8±18.0 and 100.4±40.9 meters at baseline to 58.7±30.4 and 146.7±94.3 meters, respectively (P<.01 for both).

The cross-over study revealed an increase in mean pain-free walking distance of 12.9 meters (29%, P<.01) and in maximal walking distance of 49.1 meters (49%, P<.001) when verapamil and placebo phases were compared (Table). Also, pain-free and maximal walking distances increased significantly compared with both baseline and posttitration values after the drug. The mean maximal walking distance at study entry, 100.4 meters (range, 32 to 190 meters), did not differ from the value during placebo treatment, 100.7 meters (31 to 198 meters), indicating steady state of the disease throughout the study period. Verapamil had no effect on systolic ankle/brachial pressure index, systolic ankle pressure, peripheral leg temperature, heart rate, or systolic, diastolic, and mean blood pressures (only mean blood pressure is shown). Peripheral leg temperature rose and blood pressure fell minimally during both placebo and verapamil phases compared with posttitration and baseline values, respectively. Heart rate fell during verapamil administration in comparison with values at baseline and posttitration.

View this table: [in this window] [in a new window]   Table 1. Parameters for 44 Patients With Intermittent Claudication

Whether sequences were verapamil/placebo or placebo/verapamil, the groups were homogeneous and comparable regarding the initial walking distances, age, sex, duration of disease, weight, smoking habits, systolic ankle/brachial pressure index, systolic ankle pressure, peripheral leg temperature, heart rate, and systolic, diastolic, and mean blood pressures. No significant carryover or period effects were found. There were no differences between maximal walking distances at baseline, after 1 week's washout after titration, and during the placebo period (Fig 2), nor were there any differences between the maximal walking distance during the individually optimal verapamil dose and during the verapamil treatment phase. Pain-free walking distance showed a small (16%) but significant increase during the placebo phase compared with baseline but not with posttitration values. The study showed no correlation between the effect of verapamil on the walking distances and sex, age, initial pain-free and maximal walking distances, initial systolic, diastolic, and mean blood pressures, and initial peripheral leg temperature. Positive correlations were found between the treatment effect on maximal walking distance and initial systolic ankle pressure (r=.49, P<.001) and the initial systolic ankle/brachial pressure index (r=.37, P=.013). The former correlation was the most pronounced (F=13 versus F=6). No such correlations were found between the treatment effect on pain-free walking distance and all the variables measured.

View larger version (26K): [in this window] [in a new window]   Figure 2. Mean (SD) walking distance of the patients was stable throughout the study with and without medication.

There was no significant difference between verapamil or placebo in terms of side effects: six patients reported side effects on both verapamil and placebo. Eight patients had side effects on active medication only, and 8 had side effects on placebo only. The side effects were generally mild, comprising slight dizziness (verapamil/placebo, 3/6; NS), constipation (verapamil/placebo, 11/9; NS), and palpitations (verapamil/placebo, 0/1; NS).

	Discussion

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This randomized, double-blind, placebo-controlled cross-over study showed that individual optimal verapamil administration significantly improved pain-free and maximal walking distances in patients with intermittent claudication. Though not a long-term study, the improvement of walking performance after verapamil administration was of clinical relevance, with a 29% increase in pain free walking distance and a 49% increase in maximal walking distance. Verapamil had no verifiable effect on systolic ankle/brachial pressure index or peripheral leg temperature, indicating that verapamil did not increase blood flow to the arteriosclerotic limb despite its vasodilatory properties. This finding is in accordance with most randomized studies that fail to support any beneficial effect of vasodilator drugs per se in patients with intermittent claudication.^{1 2} It is also in agreement with our previous finding that intravenous verapamil does not influence the arterial blood flow to the arteriosclerotic limb.⁵ However, verapamil was chosen not for its vasodilating effect but because it reportedly raises the oxygen-extracting capacity of the ischemic lower extremity.⁵ Hence, a mean increase of 12% was achieved even in patients under general anesthesia, in whom the metabolic demands of skeletal muscles are absolutely minimized. Verapamil also augmented myocardial oxygen extraction by up to 9% during pacing-provoked ischemia in patients with coronary artery disease.⁴ The piperidine derivate perhexiline also may induce increased cardiac oxygen extraction during pacing studies in patients with ischemic heart disease.¹⁰ In contrast, the dihydropyridine drugs appear to decrease myocardial oxygen extraction, probably because they augment global tissue blood flow.¹¹ We chose to study patients with fairly advanced clinical symptoms because previous studies have established that the ability of verapamil to enhance oxygen extraction of the ischemic leg is comparatively greater, the poorer the patient's walking performance.⁵ Hence, in the present patient group, the initial pain-free walking distance was only 38.8 meters, maximal walking distance was 100.4 meters, and the mean ankle/brachial index was 0.54. Whether the verapamil-mediated effect on oxygen extraction of ischemic tissues is due to changes in the hemoglobin-oxygen affinity as seen after ß-blockade¹² or to improvements in deformability of erythrocytes with facilitated tissue oxygen transport¹³ remains speculative.

An additional effect of verapamil, as of other calcium antagonists, is that it affects cardiac energy metabolism. Thus, cardiac free fatty acids/carbohydrate uptake ratio has been reported to rise after administration of verapamil and nicardipine in patients with ischemic heart disease.^{4 11} The ability of a tissue to increase free fatty acid utilization at the expense of carbohydrates may be a sign of lessened ischemia.^{11 14} However, it is not yet known whether calcium channel–blocking drugs also change the metabolism of the ischemic limb.

Evaluation of clinical outcome of interventions in peripheral vascular disease requires reproducible, stable functional tests. Treadmill exercise has been suggested to be the method of choice,¹⁵ but we preferred plain walking, which imitates mostly the daily activity that has been limited. Our standardized walking test was highly reproducible and stable over time: There was no difference between maximal walking distances at baseline, after the titration part of the study, and during placebo treatment. Thus, there was no measurable training effect despite the number of walking tests carried out after the patients had become familiar with the testing procedures. We did not include any washout period between the placebo/verapamil phases since the measurements were done on the last day of each period after 2 weeks on either placebo or verapamil. The overall heart rate declined during active treatment only in comparison with values at baseline and after titration, the change in the individual patient fell short of significance, and treatment phase progression was not clear either to the patient or to the investigator. The same applied to side effects that occurred at the same rate during active and placebo periods.

The balance between positive and negative effects of nifedipine and nicardipine has been shown to be dose dependent in patients with coronary artery disease.^{7 8} A fixed daily dose of 240 mg of slow-release verapamil did not significantly modify walking distances in patients with intermittent claudication.⁶ The finding in the present study that only 8 patients (18%) showed the greatest progression of walking distance at that dosage stresses the importance of dose titration with these drugs also in intermittent claudication.

The delivery of blood (and oxygen) to tissues peripheral to an arterial stenosis depends on several factors, of which the pressure gradient is of importance. Verapamil is a well-known antihypertensive drug that also to some extent may lower blood pressure in normotensive persons.⁴ Drawbacks may arise by increasing verapamil dosages in patients to obtain possible vasodilatory or metabolic effects. It is therefore important to strike the right balance between the potentially dose-dependent positive and negative effects of this drug. Accordingly, we found an up to fourfold variation in the verapamil doses that caused the greatest improvement in walking ability. There were no corresponding augmented systemic or peripheral hemodynamic changes. This suggests that effects other than hemodynamic ones were responsible for the benefits seen after this drug (augmented tissue oxygen utilization?). The study opens the suggestion that the effect of other drugs also may be dose dependent and that individual dose titration may increase the therapeutic benefits in these patients.

	Acknowledgments

 
The Danish Heart Foundation and the Research Initiative of Aarhus County supported a research grant for this study. We are indebted to Chief Pharmacist Ulf Hammer, the Pharmacy at Aarhus Kommunehospital, Aarhus, Denmark, for packing tablets and performing randomization procedures, to Statistician Leif Spange Mortensen, UNI-C, Aarhus, Denmark, for his help with statistical analyses, and to Mrs A.M. Hansen for technical assistance. Statistical assistance and pharmacy expenses were supported by a grant from Meda A/S, Denmark. Medication was supplied courtesy of Knoll AG, Germany.

Received May 1, 1996; revision received August 5, 1996; accepted September 1, 1996.

	References

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