Take-aways Adding supervised exercise to standard therapy (home walking and treatment with cilostazol) significantly improved walking ability among patients with peripheral artery disease (PAD). Supervised treadmill walking was more effective for increasing leg function than adding revascularization and stenting to standard therapy, even for patients with aorto-iliac PAD. While both supervised exercise and revascularization led to significantly improved quality of life than standard therapy alone, patient-reported quality of life was best with revascularization. A supervised exercise program is recommended for patients with PAD before revascularization.

Peripheral artery disease (PAD) affects about 8.5 million Americans 40 years of age and older and is associated with significant morbidity and mortality.¹ It profoundly limits physical functioning and results in a sedentary lifestyle and poor health-related quality of life. In terms of its impact on quality-of-life, its impact is somewhere between symptomatic HF and chronic lung disease.

However, in the general population, only about 10% of people with PAD have the classic symptom of intermittent claudication. Approximately 40% of individuals with PAD do not complain of leg pain, whereas the remaining 50% have a variety of leg symptoms different from classic claudication.

Prior prospective randomized clinical trials have demonstrated the efficacy of cilostazol, supervised exercise rehabilitation, and endovascular revascularization to improve objective measures of walking performance and quality of life in patients with claudication resulting from PAD.

Typically, these previous studies were pooled analyses comparing supervised exercise and percutaneous revascularization in patients with aorto-iliac and femoropopliteal PAD. While exercise programs were often associated with superior results at 6 months, there were questions as to whether the pooled populations were generalizable to patients with aorto-iliac PAD, a condition long considered ideal for stent revascularization.

CLEVER Trial

Investigators conducted the first multicenter randomized controlled trial to compare the benefits of optimal medical care (OMC) alone or OMC plus supervised exercise (SE; treadmill walking) or stent revascularization (ST) on both walking outcomes and measures of quality of life in 111 patients with claudication due to aorto-iliac PAD.^2,3 The CLEVER (CLaudication: Exercise Vs. Endoluminal Revascularization) Study was sponsored by the National Heart, Lung, and Blood Institute.

The study participants had relatively severe PAD, with 38% of the ST group having total occlusions in the aorto-iliac segment and all treatment groups showing low ankle-brachial indexes, poor treadmill test performance, and poor quality of life at baseline.

At 6-month follow-up, change in peak walking time (the primary endpoint) was greatest with supervised exercise, intermediate for ST, and least with OMC.

Specifically, compared to baseline, average walking time in each group improved by:

• 5.8 minutes: supervised exercise + cilostazol (p < 0.001 for the comparison of SE vs. OMC ; p = 0.04 for SE vs. ST)
• 3.7 minutes: stents + cilostazol (p = 0.02 for stenting vs. OMC)
• 1.2 minutes: home exercise + cilostazol (OMC)

In general, OMC alone led to minimal symptomatic improvement. Supervised exercise also was associated with an improvement in self-reported walking distance, an increase in HDL, and a decrease of fibrinogen.

Peak walking time on a graded treadmill test has been considered the most objective and reliable endpoint to evaluate improvements in functional status for patients with claudication. Secondary endpoints included changes in claudication onset time, change in community-based walking as assessed by pedometer measurements over 7 consecutive days, self-reported walking and quality of life, and biomarkers of CVD risk.

Patients in both the supervised exercise and revascularization groups scored better on a variety of quality-of-life measurements. However, patients in the revascularization group described a better quality of life compared to both the supervised- or home-exercise programs. The reasons for the dissociation between treadmill walking and quality-of-life improvements are not clear.

Exercise treatment improved leg function and symptoms, but not blood flow to the leg. "Perhaps this should not be surprising at all," said Alan T. Hirsch, MD, chair of the study and professor of medicine, epidemiology and community health at the University of Minnesota in Minneapolis. "Leg function can improve tremendously in almost any individual without any increase in blood flow past major artery blockages, as walking efficiency is dependent on much more than one blocked artery. Exercise is known to improve leg function and symptoms in numerous proven ways. Microscopic blood vessels that supply leg muscles and the nerves and muscles themselves all become much more efficient."

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References

1. Go AS, Mozaffarian D, Roger VL, et al. Circulation. 2013;127:e6-e245.
2. Murphy TP, Hirsch AT, Ricotta JJ, et al. J Vasc Surg. 2008;47:1356-63.
3. Murphy TP, Cutlip DE, Regensteiner JG, et al. Circulation. 2012;125:2649-60.

To listen to an interview with Emile R. Mohler, III, MD, about supervised exercise or revascularization for PAD, visit youtube.cswnews.org. The interview was conducted by Carl J. Pepine, MD.

Keywords: Intermittent Claudication, National Heart, Lung, and Blood Institute (U.S.), Follow-Up Studies, Ankle Brachial Index, Peripheral Arterial Disease, Tetrazoles, Stents, Biomarkers, Quality of Life, Sedentary Behavior, Fibrinogen, United States, Exercise Test, Lung Diseases

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