Extracorporeal Shockwave for Intermittent Claudication and Quality of Life

Key Points

Question

Can extracorporeal shockwave therapy improve quality of life in patients with intermittent lower limb claudication?

Findings

In this randomized clinical trial that included 138 patients, patients receiving extracorporeal shockwave therapy had statistically higher measures of quality of life compared to patients receiving placebo.

Meaning

The findings indicate that extracorporeal shockwave therapy may be considered as a safe and efficacious alternative therapy for patients with intermittent lower limb claudication, with comparable improvements in quality of life to supervised exercise.

This randomized clinical trial evaluates quality-of-life outcomes in patients with claudication following extracorporeal corporeal shockwave therapy.

Abstract

Importance

Intermittent lower limb claudication limits function and quality of life. Supervised exercise programs are not readily available, and a noninvasive alternative is needed.

Objective

To assess extracorporeal corporeal shockwave therapy in improving quality of life in patients with claudication.

Design, Setting, and Participants

In this double-blind, placebo-controlled randomized clinical trial, patients in the outpatient setting at a single tertiary center for vascular surgery were randomized in a 1:1 ratio to extracorporeal shockwave therapy or placebo therapy with no shockwaves delivered. Recruitment was between June 2015 and January 2020, with 12-week follow-up ending in March 2020. A convenience sample of patients with claudication and conservative treatment requirements who refused or were unable to participate in supervised exercise were eligible. Patients receiving anticoagulation therapy or with an active cancer were excluded. Of 522 patients screened, 389 were eligible, 138 were enrolled, and 110 completed follow-up and were included in the primary analysis. Statistical analysis was completed by May 2021.

Intervention

In the intervention group, patients received 100 impulses of 0.1mJ/mm/cm² in an area of the gastrocnemius muscle 3 times weekly for 3 weeks. The steps for treatment were replicated for the control group without delivering the treatment.

Main Outcomes and Measures

The primary outcome was the Physical Functioning domain of the 36-item Short-Form Quality of Life Questionnaire at 12-week follow-up. Secondary outcomes included walking distances, ankle brachial pressure index, and other quality-of-life measures.

Results

Of 138 patients recruited and randomized, 92 (67%) were male, and the mean (SD) age of the study population was 67 (9.6) years. The intervention group had a significantly higher physical function score at 12 weeks (estimated median difference 3.8; 95% CI, 0.0-7.7; P = .03). However, this significance did not remain when adjusting for covariates. At 12 weeks, the intervention group had significantly longer pain-free and maximum walking distances (pain-free estimated median difference, 34.1, 95% CI, 11.4-56.8; P = .004; maximum estimated median difference, 51.4; 95% CI, 10.7-86.5; P = .01).

Conclusions and Relevance

To our knowledge, this is the first double-blind, placebo-controlled, randomized clinical trial to consider extracorporeal shockwave therapy for the management of intermittent claudication. It demonstrated efficacy for walking distances, may have a positive effect on quality of life, and may provide a safe, noninvasive alternative therapy for patients with intermittent claudication.

Trial Registration

ClinicalTrials.gov Identifier: NCT02652078

Introduction

An estimated 237 million people worldwide experience lower limb peripheral arterial disease,¹ with this number expected to rise due to population aging.² Intermittent claudication is the most common symptomatic manifestation of peripheral arterial disease³ and limits physical function, walking distances, and quality of life.^4,5

Current first-line recommendations for the management of intermittent claudication consist of smoking cessation, best medical therapy, cardiovascular risk reduction, and supervised exercise.^6,7 Despite overwhelming evidence for clinical and financial effectiveness of supervised exercise,⁸ its utility is limited by suboptimal provision, uptake, and adherence rates.^3,9,10,11,12 A noninvasive, efficacious, and cost-effective intervention that is more appealing to patients and easy to implement may be an attractive alternative.

Extracorporeal shockwave therapy (ESWT) was originally used in urological lithotripsy and has since been implemented in the treatment of musculoskeletal disorders,¹³ wound healing,^14,15,16 and myocardial ischemia.^17,18 Its use in peripheral arterial disease is less established, with small studies reporting heterogenous outcomes.¹⁹ Our group conducted a pilot study^20,21 on the use of ESWT in patients with intermittent claudication, showing it to be safe and well tolerated with a likely benefit for pain-free walking distance. However, to date, there is no evidence of the effect of ESWT on quality of life in patients with intermittent claudication. The aim of this study was to address this evidence gap and assess the effect of ESWT on quality of life in patients with intermittent claudication.

Methods

A double-blind, placebo-controlled, randomized clinical trial was conducted at a university teaching hospital that is a tertiary referral center for vascular surgery. The trial was reviewed by a regional research ethics committee and full ethical approval was granted by the UK Health Research Authority. The protocol was compliant with the Declaration of Helsinki, and all participants provided written informed consent prior to any trial procedures. The trial was prospectively registered ClinicalTrials.gov (NCT02652078), and the protocol is presented in Supplement 1. This trial is reported in line with the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Participants

A convenience sample of participants were identified and screened at the outpatient vascular surgery service, where a diagnosis of stable calf intermittent claudication (Fontaine class II with no change in symptoms in a 3-month period prior to recruitment) was made by a vascular surgeon and treated conservatively with best medical therapy, smoking cessation advice, and exercise advice. All participants had been offered supervised exercise and had either declined participation or had already completed a 12-week program and did not experience a substantial reduction in symptoms. Participants were deemed eligible if they were 18 years and older, were able to provide written informed consent and adhere to the trial protocol, and had either unilateral intermittent lower limb claudication or, if bilateral, had an index leg that was symptomatically worse. Participants were not eligible if they had contraindications to the use of ESWT, including active malignancy, anticoagulation therapy, and known coagulopathies, or were pregnant at the time of screening.

Randomization

Participants were randomized in a 1:1 ratio using computer-generated numbers in random permuted blocks with allocation sequence concealed from all investigators via Sealed Envelope (Sealed Envelope Ltd) to either ESWT (intervention) or a placebo treatment (control). Randomization allocation was concealed from participants and outcome assessors.

Intervention

Participants in both groups received a total of 9 treatment sessions over a 3-week period. At each session, participants were positioned prone to expose their calf muscles for treatment and were facing away from the equipment.

The treatment and placebo protocol have been previously published.¹⁹ The intervention group received 100 impulses of 0.1mJ/mm/cm² in an area of 6 cm by 5 cm per head of gastrocnemius muscle of the index leg using the PiezoWave 2 shockwave system (Elevation Medical). Identical steps were replicated for the control group, including having the system display on with the correct settings, the application of ultrasonography gel, and the passage of the transducer over the same area, but without delivering the shockwave treatment. Instead, a recording of the sound of the active shockwave treatment was used to simulate the delivery of ESWT via an MP3 speaker mounted on the device. All participants were followed up with at 4 weeks, 8 weeks, and 12 weeks after the first treatment session.

Outcomes

All outcome measurements were assessed at all time points by assessors blinded to group allocation. The primary outcome was Physical Functioning as measured by the 36-item Short-Form Quality of Life Questionnaire (SF-36) at 12-week follow-up.

Secondary outcome measures were preplanned and included pain-free and maximum walking distance assessed via a standardized treadmill test. The treadmill protocol was constant load and was performed at 1.6 mph and 10% incline for a maximum of 10 minutes. Patients began walking on the treadmill and indicated when intermittent claudication pain occurred, which was recorded as the pain-free walking distance. Maximum walking distance was recorded when the patient could no longer continue due to maximal claudication pain or when 10 minutes had elapsed. For patients unable to walk at 1.6 mph, the speed was reduced by the outcome assessor and remained constant at all follow-up visits to ensure standardization. Ankle brachial pressure index was measured at rest and immediately following the treadmill protocol. Laser doppler flowmetry, used to assess microcirculatory blood flow of the skin on the medial aspect of the calf and the dorsum of the foot, was also undertaken for a period of 5 minutes at rest and immediately following the treadmill protocol using the moorVMS-LDF2 laser doppler monitor (Moor Instruments). Additional quality-of-life measures were assessed using the EuroQol 5-Dimension 3-Level survey, the remainder of SF-36 domains, and the disease-specific Vascular Quality of Life scale (VascuQoL).

Power Calculation and Sample Size

To demonstrate at least a 10-point difference in the SF-36 Physical Functioning domain with 80% power and 5% significance, 55 participants were required for each treatment group.²² Based on the completion rates of the local supervised exercise program and the results of the internal pilot study,²⁰ we allowed for a 20% attrition rate, resulting in a total sample size of 138 participants required to achieve power. Patients recruited in the pilot study^20,21 were included in the total number of patients analyzed for this trial.

Statistical Analysis

Data were analyzed using SPSS version 28 (IBM). A P value <.05 was considered statistically significant. Outcome measures were analyzed on an intention-to-treat basis according to the randomization group.

Baseline characteristics and outcome measures are presented as means and standard deviations for parametric data and medians and interquartile ranges for nonparametric data. The Shapiro-Wilk test was used to determine the normality of distribution. Mann-Whitney U and Kruskal-Wallis tests were used to estimate the difference in outcomes between groups. Hodges-Lehmann estimator used to provide an estimate of the median differences between groups with 95% confidence intervals. Secondary analysis by 1-way analysis of covariance using rank transformation of nonparametric data was carried out to compare outcomes at follow-up, controlling for baseline characteristics.

Results

Between June 2015 and January 2020, 522 patients were assessed for eligibility, and 389 (75%) patients were eligible. Of these, 138 (35.5%) consented to participate and were randomized (Figure). Of 138 patients recruited and randomized, 92 (67%) were male, and the mean (SD) age of the study population was 67 (9.6) years. Table 1 summarizes additional baseline characteristics of participants.

Figure. CONSORT Diagram.

Table 1. Baseline Characteristics.

Characteristic	Group, No. (%)
	Shockwave therapy (n = 68)	Placebo (n = 70)
Sex
Male	44 (64.7)	48 (68.6)
Female	24 (35.3)	22 (31.4)
Age, mean (SD), y	66 (10.7)	67 (8.5)
BMI, median (IQR)	27.9 (24.3-30.9)	27.8 (24.1-29.9)
Smoking status
Current	31 (45.6)	25 (35.7)
Former	33 (48.5)	38 (54.3)
Never	4 (5.9)	7 (5.6)
Diabetes	16 (23.5)	25 (35.7)
Hypertension	40 (58.8)	43 (61.4)
History of CAD/IHD	22 (32.3)	31 (44.3)
History of cerebrovascular injury	7 (10.3)	6 (8.6)
History of respiratory disease	16 (23.5)	17 (24.3)
Fontaine classification
IIa	5 (7.3)	9 (12.9)
IIb	63 (92.6)	61 (87.1)
Site of claudication
Calf	62 (91.2)	66 (94.3)
Calf and thigh	6 (8.8)	4 (5.7)
Bilateral claudication	7 (10.3)	8 (11.4)

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CAD, coronary artery disease; IHD, ischemic heart disease.

Throughout the study period there were no adverse effects or serious adverse events recorded that were related to the ESWT. One patient in the intervention group withdrew during the treatment period because they were unable to tolerate lying prone due to dyspnea.

Primary Outcome

Normalized medians (IQRs) of the Physical Functioning domain of the SF-36 at 12-week follow-up were significantly higher in the intervention group compared to the control group (41.3 [31.2-46.1] vs 34.6 [28.8-42.7], respectively; P = .03), with an estimated median difference of 3.8 (95% CI, 0.0-7.7). There were no statistically significant intragroup differences at any follow-up point.

Secondary Outcomes

Other Quality-of-Life Outcomes

No statistically significant intergroup differences in the other SF-36 domain scores were observed at baseline or at 8 or 12 weeks. At 4-week follow-up, the intervention group demonstrated significantly better median (IQR) scores than the control group in the SF-36 General Health (43.7 [38.7-53.2] vs 38.0 [33.2-46.1], respectively; P = .004) and Vitality (49.6 [45.9-55.6] vs 46.7 [34.8-55.6], respectively; P = .03) domains, as well as in the Physical Component Summary (39.7 [33.9-44.5] vs 35.9 [31.0-40.2], respectively; P = .02) (Table 2).

Table 2. Quality-of-Life Measures.

Measure	Group, median (IQR)		P value	Estimated median difference (95% CI)
	Shockwave therapy (n = 55)	Placebo (n = 55)
Baseline
SF-36 PF	36.5 (30.8 to 44.2)	33.0 (26.9 to 38.9)	.05	3.8 (0.0 to 5.7)
SF-36 RP	39.1 (31.3 to 48.2)	37.0 (30.2 to 43.1)	.18	2.3 (0.0 to 6.7)
SF-36 BP	38.2 (30.6 to 43.5)	38.2 (30.6 to 42.2)	.32	0.0 (0.0 to 4.0)
SF-36 GH	43.2 (35.2 to 50.8)	38.4 (30.8 to 47.5)	.07	3.3 (0.0 to 7.1)
SF-36 VT	46.7 (40.7 to 49.6)	43.7 (32.5 to 49.6)	.16	3.0 (0.0 to 5.9)
SF-36 SF	42.3 (32.3 to 53.6)	42.3 (32.3 to 47.3)	.06	5.0 (0.0 to 10.0)
SF-36 RE	45.7 (31.8 to 56.2)	42.2 (28.3 to 56.2)	.33	0.0 (0.0 to 7.0)
SF-36 MH	50.9 (42.4 to 58.7)	45.6 (37.8 to 56.1)	.11	2.6 (0.0 to 7.8)
SF-36 PCS	36.1 (31.3 to 41.7)	34.0 (27.6 to 39.8)	.09	2.5 (−0.5 to 5.3)
SF-36 MCS	49.5 (43.1 to 58.3)	45.6 (35.4 to 56.4)	.16	3.2 (−1.0 to 7.5)
EQ-5D-3L	0.7 (0.5 to 0.7)	0.7 (0.4 to 0.7)	.15	0
VascuQol	4.4 (3.3 to 5.5)	4.2 (3.2 to 4.8)	.13	0.4 (−0.1 to 0.8)
4-wk Follow-up
SF-36 PF	39.4 (32.6 to 44.6)	36.5 (28.8 to 44.2)	.11	2.4 (0.0 to 5.8)
SF-36 RP	40.3 (34.7 to 52.7)	39.2 (32.5 to 48.2)	.11	2.3 (0.0 to 6.7)
SF-36 BP	42.2 (37.3 to 51.5)	38.2 (34.2 to 46.3)	.19	3.2 (0.0 to 4.4)
SF-36 GH	43.7 (38.7 to 53.2)	38.0 (33.2 to 46.1)	.004	5.7 (2.4 to 9.5)
SF-36 VT	49.6 (45.9 to 55.6)	46.7 (34.8 − 55.6)	.03	3.0 (0.0 to 8.9)
SF-36 SF	47.3 (37.3 to 57.3)	42.3 (37.3 to 52.3)	.37	0.0 (0.0 to 5.0)
SF-36 RE	49.2 (35.3 to 56.2)	42.2 (31.8 to 56.2)	.26	0.0 (0.0 to 7.0)
SF-36 MH	56.1 (42.4 to 58.7)	50.9 (40.4 to 58.7)	.19	2.6 (0.0 to 5.2)
SF-36 PCS	39.7 (33.9 to 44.5)	35.9 (31.0 to 40.2)	.02	3.9 (0.8 to 6.5)
SF-36 MCS	53.5 (43.5 to 60.0)	49.3 (40.6 to 59.3)	.27	2.3 (−1.7 to 6.6)
EQ-5D-3L	0.7 (0.6 to 0.7)	0.7 (0.4 to 0.7)	.03	0.0 (0.0 to 0.1)
VascuQol	5.3 (4.2 to 5.9)	4.8 (3.9 to 5.6)	.14	0.3 (−0.1 to 0.8)
8-wk Follow-up
SF-36 PF	42.2 (31.2 to 46.1)	36.5 (30.3 to 42.7)	.08	3.8 (0.0 to 7.7)
SF-36 RP	39.2 (32.5 to 52.1)	39.2 (30.2 to 43.7)	.14	4.5 (0.0 to 9.0)
SF-36 BP	42.2 (34.2 to 49.9)	38.2 (34.2 to 46.3)	.17	3.6 (0.0 to 4.8)
SF-36 GH	43.7 (36.2 to 50.8)	40.4 (33.2 to 48.4)	.14	3.3 (−1.0 to 7.1)
SF-36 VT	49.6 (38.5 to 55.6)	43.7 (37.7 to 49.6)	.09	3.0 (0.0 to 8.9)
SF-36 SF	47.3 (37.3 to 57.3)	42.3 (37.3 to 52.3)	.17	5.0 (0.0 to 10.0)
SF-36 RE	45.7 (31.8 to 56.2)	42.2 (35.3 to 56.2)	.66	0.0 (−3.5 to 7.0)
SF-36 MH	53.5 (43.0 to 58.7)	48.3 (37.8 to 58.7)	.37	2.6 (−2.6 to 5.2)
SF-36 PCS	41.2 (35.9 to 46.0)	35.9 (30.7 to 40.9)	.02	4.2 (0.7 to 7.4)
SF-36 MCS	52.6 (39.9 to 59.0)	47.2 (39.7 to 57.5)	.53	1.5 (−3.0 to 6.5)
EQ-5D-3L	0.7 (0.6 to 0.7)	0.7 (0.5 to 0.7)	.10	0.0 (0.0 to 0.1)
VascuQol	5.2 (3.8 to 5.8)	4.6 (3.8 to 5.3)	.08	0.4 (−0.1 to 0.9)
12-wk Follow-up
SF-36 PF	41.3 (31.2 to 46.1)	34.6 (28.8 to 42.7)	.03	3.8 (0.0 to 7.7)
SF-36 RP	41.4 (32.5 to 48.2)	39.2 (32.5 to 48.2)	.39	2.2 (−2.2 to 6.7)
SF-36 BP	40.2 (34.2 to 46.7)	38.2 (30.6 to 46.7)	.48	0.0 (−0.8 to 4.4)
SF-36 GH	44.4 (35.6 to 50.8)	38.0 (33.2 to 46.1)	.06	4.8 (0.0 to 8.6)
SF-36 VT	49.6 (40.0 to 55.6)	43.7 (37.7 to 52.6)	.20	3.0 (−3.0 to 6.0)
SF-36 SF	47.3 (32.3 to 57.3)	42.3 (37.3 to 47.3)	.31	0.0 (0.0 to 10.2)
SF-36 RE	45.7 (35.3 to 56.2)	42.2 (28.3 to 56.2)	.42	0.0 (0.0 to 7.0)
SF-36 MH	52.2 (40.4 to 58.7)	48.3 (40.4 to 56.1)	.28	2.6 (−2.6 to 5.2)
SF-36 PCS	40.8 (33.5 to 45.4)	36.6 (31.4 to 43.7)	.12	2.8 (−0.7 to 6.0)
SF-36 MCS	48.7 (39.4 to 58.6)	46.4 (37.7 to 57.4)	.47	1.7 (−2.9 to 6.9)
EQ-5D-3L	0.7 (0.6 to 0.7)	0.7 (0.5 to 0.7)	.67	0.0 (−0.0 to 0.0)
VascuQol	4.9 (3.9 to 5.9)	4.9 (3.6 to 5.5)	.48	0.2 (−0.4 to 0.6)

Abbreviations: BP, Bodily Pain; EQ-5D-3L, EuroQol 5-Dimension 3-Level survey; GH, General Health; MCS, Mental Component Summary; MH, Mental Health; PCS, Physical Component Summary; PF, Physical Function; RE, Role Emotional; RP, Role Physical; SF, Social Functioning; SF-36, 36-item Short-Form Quality of Life questionnaire; VascuQol, Vascular Quality of Life questionnaire; VT, vitality.

The intervention group showed statistically significant improvement in multiple domains of SF-36 between baseline and follow-up. The median (IQR) Physical Component Summary score had a statistically significant increase between baseline and all follow-up points (baseline: 36.1 [31.3-41.7] vs 4 weeks: 39.7 [33.9-44.5]; P = .02; 8 weeks: 41.2 [35.9-46.0]; P = .01; 12 weeks: 40.8 [33.5-45.4]; P = .05). The median (IQR) score for Bodily Pain was significantly increased between baseline (38.2 [30.6-43.5]) and 4 weeks (42.2 [37.3-51.5]; P = .007) and 8 weeks (42.2 [34.2-49.9]; P = .02). The median (IQR) score for Vitality was significantly increased between baseline (46.7 [40.7-49.6]) and 4 weeks (49.6 [45.9-55.6]; P = .009). The control group had a statistically significant improvement median (IQR) score in only 1 component of SF-36, Bodily Pain, between baseline (38.2 [30.6-42.2]) and 4 weeks (38.2 [34.2-46.3]; P = .02).

No statistically significant intergroup differences in the EuroQol 5-Dimension 3-Level scores were observed at baseline or at 8 or 12 weeks. At 4 weeks, the intervention group demonstrated significantly better median (IQR) scores than the control group (0.66 [0.60-0.69] vs 0.66 [0.36-0.69], respectively; P = .03). There were no statistically significant intragroup differences. No statistically significant intergroup or intragroup differences in VascuQoL scores were observed at baseline or at any time during follow-up.

Pain-Free Walking Distance

No statistically significant intergroup differences in pain-free walking distance were observed at baseline. Thereafter, pain-free walking distances were significantly greater in the intervention group at 4, 8, and 12 weeks (estimated median difference, 34.1; 95% CI, 11.4-56.8; P = .004) (Table 3). Statistically significant intragroup improvements in pain-free walking distances were observed in both groups (intervention median [IQR]: baseline, 49 [32.7-82.4] m vs 12 weeks, 106 [67.5-157.6] m; P < .001; control median [IQR]: baseline, 40 [22.7-72.1] m vs 12 weeks, 70 [43.5-106.0] m; P < .001).

Table 3. Pain-Free and Maximum Walking Distances.

Walking distance, m	Group, median (IQR)		P value	Estimated median difference (95% CI)
	Shockwave therapy (n = 55)	Placebo (n = 55)
Baseline
Pain free	49.0 (32.7 to 82.4)	40.0 (22.7 to 72.1)	.10	8.8 (−2.1 to 19.0)
Maximum	84.6 (5.4 to 132.5)	93.4 (47.5 to 141.1)	.93	−1.0 (−22.0 to 17.8)
4-wk Follow-up
Pain free	86.6 (58.2 to 127.8)	57.5 (30.5 to 110.9)	.03	20.0 (2.1 to 38.3)
Maximum	142.0 (90.3 to 176.1)	103.0 (54.1 to 195.1)	.12	22.9 (−6.9 to 52.5)
8-wk Follow-up
Pain free	98.2 (56.1 to 147.1)	60.4 (37.1 to 91.2)	.006	32.0 (10.6 to 57.1)
Maximum	158.0 (107.5 to 256.8)	110.1 (62.4 to 200.6)	.04	38.3 (1.3 to 73.8)
12-wk Follow-up
Pain free	105.6 (67.5 to 157.6)	69.6 (43.5 to 106.0)	.004	34.1 (11.4 to 56.8)
Maximum	171.8 (118.6 to 239.3)	114.3 (68.7 to 200.9)	.01	51.4 (10.7 to 86.5)

Maximum Walking Distance

No statistically significant intergroup differences in maximum walking distance were observed at baseline or at 4 weeks. Thereafter, maximum walking distances were significantly greater in the intervention group at 8 and 12 weeks (estimated median difference, 51.4; 95% CI, 10.7-86.5; P = .01) (Table 3). Statistically significant intragroup improvements in maximum walking distances were observed in both groups (intervention median [IQR]: baseline, 85 [55.4-132.5] m vs 12 weeks, 172 [118.6-239.3] m; P < .001; control median [IQR]: baseline, 93 [47.5-141.1] m vs 12 weeks, 114 [68.7-200.9] m; P < .001).

Ankle Brachial Pressure Index

No statistically significant intergroup or intragroup differences in ankle brachial pressure index before or after exercise were observed at baseline or at any time during follow-up. Results are shown in eTable 1 in Supplement 2.

Laser Doppler Flowmetry

No statistically significant intergroup or intragroup differences in Laser Doppler Flowmetry before or after exercise were observed at baseline or at any time during follow-up. Results are shown in eTable 2 in Supplement 2.

Secondary Analysis

Secondary analysis of covariance, adjusting for baseline values, found that a history of coronary artery disease appeared to have a significant effect on the Physical Functioning domain of the SF-36. There was no statistically significant difference in the Physical Functioning domain at 12-week follow-up (F_1,94 = 3.39; P = .07). After adjustment for baseline values, SF-36 General Health and Vitality domains continue to be significantly higher in the intervention group compared to the control group at 4-week follow-up (General Health F_1,97 = 6.32; P = .01; Vitality F_1,97 = 6.21; P = .01).

After adjustment for baseline values, pain-free walking distances continue to be significantly higher in the intervention group compared to the control group at all follow-up points (4-week F_1,99 = 5.56; P = .02; 8-week F_1,81 = 9.77; P = .002; 12-week F_1,78 = 10.78; P = .002). After adjustment for baseline values, maximum walking distances continue to be significantly higher in the intervention group when compared to the control group at 12-week follow-up (F_1,92 = 9.46; P = .005).

Discussion

In this randomized clinical trial including patients with intermittent claudication who declined or completed a supervised exercise program, ESWT was safe, well tolerated, and efficacious in improving walking distances and quality of life. Supervised exercise is the recommended first-line treatment for intermittent claudication but is generally met with poor uptake and completion rates as low as 25% and 75% respectively.^3,9,10,11 Of the 389 patients eligible for this study, 138 (35.5%) agreed to participate and 110 (80%) completed the intervention and follow-up. Additionally, many of these participants had previously declined participation in an exercise program. Therefore, ESWT appears to be a potential alternative to supervised exercise for patients with intermittent claudication that can improve patient choice and increase access and engagement with noninvasive treatment.

With regard to the primary outcome, the median improvement in the SF-36 Physical Functioning domain at 12-week follow-up was similar to that associated with a 12-week supervised exercise program.⁸ However, post hoc secondary analysis revealed that this difference in physical functioning was no longer significant when accounting for baseline characteristics that can affect outcomes in lower limb peripheral arterial disease in general, though a trend did remain. In this cohort, a history of coronary artery disease or ischemic heart disease, significantly affected physical functioning score as well as a difference between groups at baseline, likely representing a chance imbalance at randomization.

Nevertheless, there were statistically significant differences between groups in the General Health and Vitality domains of the SF-36, which were not influenced by baseline differences. This suggests ESWT does have a positive effect on quality of life.

The remaining SF-36 domains and other measures of quality of life did not show statistically significant improvements. However, the median scores in the intervention group were consistently higher than in the control group. The lack of statistical significance may be due to the trial being powered to detect a significant change in the SF-36 Physical Functioning domain, therefore lacking the power to detect changes in other quality-of-life domains. It is also important to note that the aim of the intervention was not to eradicate claudication symptoms but to reduce them to enable patients to mobilize further. This means that there will be a continuing impact of intermittent claudication on quality of life, which can skew the results obtained from a disease-specific quality of life questionnaire, such as the VascuQol influencing the lack of a significant change. This will especially apply to patients with bilateral claudication, as the intervention only treated the index leg.

With regard to other secondary outcomes, walking distances improved at each time point, peaking at 12-week follow-up. The improvements in the intervention group were comparable to those provided by exercise therapy and represented a small to moderate minimal clinically important difference.^8,23 Importantly, the control group also had a significant increase in objective walking distances, suggesting adequate blinding, and validating our placebo treatment protocol.¹⁹ Another possible explanation for these increases is continuing to check that participants did not discontinue and were appropriately taking their statin and antiplatelet therapy at every follow-up point, ensuring strict adherence to best medical therapy. This, coupled with constant smoking cessation and exercise advice and encouragement throughout the trial period, is something that patients are unlikely to receive as part of routine clinical practice but can have a positive impact on intermittent claudication.

Nevertheless, given that the conservative management approach used within both groups conformed to latest guidance,^6,7 the significant increase in walking distances and quality-of-life measures in the intervention group can be attributed to the effects of ESWT. Future research should perhaps investigate various doses and durations of ESWT, compare ESWT with supervised exercise, investigate the potential additive effects of the 2 interventions, and consider the potential mechanism of action for ESWT. A previously postulated mechanism of action—that is upregulation of angiogenic factors²⁴—does not appear to be evident at a macrovascular level nor is it superficial enough to be adequately detected by laser doppler flowmetry. Other proposed mechanisms of action, such as neural stunning, that result in reduction in ischemic pain in patients with critical limb-threatening ischemia²⁵ might have a role in the effects of ESWT seen in this study. However, it is unclear from the current evidence whether this reduction in pain is due solely to neural stunning or due to angiogenesis and vasodilation.²⁴

A final but important consideration is that our findings support the suggestion that quality of life in patients with intermittent claudication cannot be solely assessed via the functional outcome of walking distance but requires generic and disease-specific quality-of-life tools. However, our findings also demonstrate the impact that concurrent comorbidities can have on such tools. As such, future research in patients with lower limb peripheral arterial disease should adopt patient-reported health-related quality-of-life measures as primary end points while stratifying for the impact of concurrent comorbidities.^4,26,27

Limitations

This study has limitations. First, post hoc secondary analysis revealed that the difference in physical functioning as measured by the SF-36 was no longer significant when adjusting for baseline characteristics, in particular a history of coronary artery disease. The study is also limited by the use of a constant load treadmill test for assessing walking distances. Though a reliable test, especially when assessing maximum walking distance in patients with intermittent claudication,²⁸ it has disadvantages in terms of test-retest reliability compared to a graded treadmill test and may not be as closely related to everyday walking as the 6-minute walking test.²⁹ Further, this is a single-center trial of a modest convenience sample. Future research should aim for a multicenter trial to allow for generalizability of results and will be of great interest for comparison with the current recommendation of supervised exercise therapy.

Conclusions

To our knowledge, this is the first adequately powered, double-blind, placebo-controlled randomized clinical trial to consider ESWT for the management of intermittent lower limb claudication. It has successfully demonstrated efficacy for improving walking distances within a comparable cohort of patients with intermittent claudication, while suggesting a potential positive effect on quality of life. Further trials are required to compare this treatment to the current available treatment, including a supervised exercise program, and identify the potential mechanism of action.

Supplement 1.

Trial protocol

Supplement 2.

eTable 1. Median Ankle Brachial Pressure Index at all trial time points

eTable 2. Median PU in Laser Doppler Flowmetry at all trial time points

Supplement 3.

Data sharing statement