Improving Mobility After Revascularization in Peripheral Artery Disease

Lower extremity revascularization combined with supervised exercise significantly improves walking performance compared to revascularization alone in people who have PAD without limb threatening ischemia. However, supervised exercise is inaccessible or burdensome for most PAD patients. We hypothesize that home-based exercise combined with lower extremity revascularization will significantly improve walking performance compared to revascularization alone in patients with PAD undergoing revascularization for disabling PAD.

We further hypothesize that inorganic nitrate, a major source of nitric oxide (NO) abundant in beetroot juice, will improve walking performance after lower extremity revascularization, compared to placebo. In preclinical models, NO inhibits inflammation, neointimal hyperplasia, thrombosis, and vascular smooth muscle cell migration at sites of revascularization. NO increases angiogenesis and perfusion, repairs skeletal muscle damaged by ischemia, and stimulates mitochondrial activity.

In a randomized clinical trial with a 2 x 2 factorial design, we will test the following two primary hypotheses in 386 patients randomized within three months of a successful lower extremity revascularization for disabling PAD: First, that home-based exercise combined with lower extremity revascularization will improve six-minute walk distance more than revascularization alone at 6-month follow-up (Primary Aim #1). Second, that nitrate-rich beetroot juice combined with lower extremity revascularization will improve six-minute walk, compared to placebo combined with revascularization at 6-month follow-up (Primary Aim #2).

More than 300,000 surgical or endovascular lower extremity revascularization procedures are performed annually for Medicare beneficiaries who have lower extremity peripheral artery disease (PAD) without limb threatening ischemia, and rates of these procedures are increasing. In these patients, revascularization typically improves, but does not eliminate, PAD related walking impairment. Lower extremity revascularization combined with supervised exercise significantly improves walking performance compared to revascularization alone in people who have PAD without limb threatening ischemia. However, supervised exercise is inaccessible or burdensome for most PAD patients. We hypothesize that home-based exercise combined with lower extremity revascularization will significantly improve walking performance compared to revascularization alone in patients with PAD undergoing revascularization for disabling PAD.

We further hypothesize that inorganic nitrate, a major source of nitric oxide (NO) abundant in beetroot juice, will improve walking performance after lower extremity revascularization, compared to placebo. In preclinical models, NO inhibits inflammation, neointimal hyperplasia, thrombosis, and vascular smooth muscle cell migration at sites of revascularization. NO increases angiogenesis and perfusion, repairs skeletal muscle damaged by ischemia, and stimulates mitochondrial activity. A large body of evidence, assembled over more than 25 years, supports our hypothesis that inorganic nitrate (such as that in nitrate-rich beetroot juice) will improve walking performance and other lower extremity outcomes after lower extremity revascularization.

Effective, accessible, and safe therapies are needed to enhance the benefits and improve durability of lower extremity revascularization. Therefore, in a randomized clinical trial with a 2 x 2 factorial design, we will test the following two primary hypotheses in 386 patients randomized within three months of a successful lower extremity revascularization for disabling PAD: First, that home-based exercise combined with lower extremity revascularization will improve six-minute walk distance more than revascularization alone at 6-month follow-up (Primary Aim #1). Second, that nitrate-rich beetroot juice combined with lower extremity revascularization will improve six-minute walk, compared to placebo combined with revascularization at 6-month follow-up (Primary Aim #2). In Secondary Aims, we will establish whether home-based exercise, compared to control, and whether nitrate-rich beetroot juice, compared to placebo, improve the Walking Impairment Questionnaire and the PROMIS Mobility Questionnaire and prevent hemodynamic failure of the revascularized vessel. In exploratory aims, we will test the effects of the interventions on plasma nitric oxide bioavailability. If our hypotheses are correct, results of this trial will have a major impact on improving mobility in the large and growing number of people undergoing revascularization for disabling PAD.

Eligibility Criteria:
Inclusion Criteria:

1. Lower extremity revascularization for disabling PAD (endovascular or surgical revascularization and either femoropopliteal or aortoiliac revascularization) performed at least one month before baseline testing and less than 3 months before randomization.
2. Successful revascularization (assessed one month after revascularization), adjudicated by committee. A successful revascularization will be defined as:

   * Considered successful based on the surgical note and subsequent clinical visits (as relevant)

Exclusion Criteria:

1. History of leg amputation, not including toe and partial foot amputation.
2. History of gangrene.
3. History of critical limb ischemia.
4. Already exercising at a level consistent with exercise intervention, using investigator discretion.
5. Planning to engage in new exercise consistent with exercise intervention outside of the study.
6. Unstable angina.
7. Abnormal baseline stress test without subsequent clearance for exercise by physician.
8. Failure to complete study run-in.
9. Unwilling to adhere to the interventions and complete follow-up testing.
10. Mini-Mental Status Examination (MMSE) score \< 23. If the MMSE is \< 23 and the Principal Investigator evaluation determines that the lower score is related to language barriers or education level, the Principal Investigator has discretion to allow a participant with MMSE \< 23 to participate, as appropriate.
11. Dementia and psychiatric illness with sufficient impairment to prevent full engagement in all aspects of the trial will be an exclusion per the investigator's discretion.
12. Currently taking sildenafil, tadalafil, or related drugs.
13. Unwilling to accept randomization into either group (home-based exercise or attention control).
14. Currently consuming beetroot juice, oral nitrate or nitrite, or a beetroot supplement and/or unwilling to avoid beetroot juice during the study. Participants will be asked to discontinue these items for 30 days before baseline testing and throughout the clinical trial. If the potential participant is unwilling to refrain from taking these items, they will not be eligible for the clinical trial.
15. History of kidney stones that requires minimized intake of oxalate. Potential participants who need to minimize oxalate intake will be excluded from the trial.
16. Baseline blood pressure \<100/45.
17. Wheelchair confinement or requiring a walker to ambulate.
18. Walking is limited by a condition other than PAD.
19. Current foot ulcer on bottom of foot.
20. Planned major surgery during the next six months.
21. Major medical illness including lung disease requiring oxygen, Parkinson's disease, or a life-threatening illness with life expectancy less than six months.
22. Allergy to beetroot juice.
23. Currently consuming one cup or more of beets daily. Participants will be asked to discontinue beet ingestion of one cup or more of beets for 30 days before baseline testing and throughout the clinical trial. If the potential participant is unwilling to refrain from daily beet consumption of one cup or more for 30 days before the trial and during the trial, they will not be eligible for the clinical trial.
24. Participation in or completion of a clinical trial in the previous three months, using investigator discretion for trials that may not impact on study participation.
25. Visual impairment that limits walking ability.
26. Unable to communicate in English.
27. Planning to begin a supervised treadmill exercise program in the next 12 months.
28. In addition to the above criteria, investigator discretion will be used to determine if the trial is unsafe or not a good fit for the potential participant.