Improving Mobility After Revascularization in Peripheral Artery Disease

Official title

IMProving Mobility After revasCularizaTion in Peripheral Artery Disease: The IMPACT PAD Trial

Overview

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. Investigators 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. Investigators 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, the trial 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).

Detailed description

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. Investigators 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.

Investigators 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, the trial 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, the trial 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, the trial 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.

Interventions

• Behavioral Home Based Exercise
  This is a six month intervention where participants will walk at home for exercise with guidance from a study coach. They will attend two to four weekly meetings with the coach at the clinical site in the first 4 weeks following randomization, followed by once weekly telephone coaching calls for the remainder of the six-month intervention
• Drug Nitrate Rich Beetroot Juice
  Participants will drink one shot of nitrate rich beet-root juice twice daily for six months.
• Behavioral Attention Control
  Participants will be asked to participate in weekly meetings with the coach in the attention control group for weeks 1-26. A staff member will present a topic from the National Institute on Aging "age pages" relevant to health, such as cancer screening or blood pressure treatment. Calls will last approximately 5-15 minutes and will focus on educational topics such as diabetes, healthy eating, and Medicare Part D.
• Drug Placebo Beetroot Juice Without Nitrate
  Participants will drink one shot of placebo beetroot without nitrate juice twice daily for six months.

Primary outcome measures

• Six-Minute Walk Distance 6-month change [Time frame: Baseline to 6-month follow-up]

Secondary outcome measures (6)

• Walking Impairment Questionnaire (WIQ) Distance Score 6-month change [Time frame: Baseline to 6-month follow-up.]
• Walking Impairment Questionnaire (WIQ) Distance Score 12-month change [Time frame: Baseline to 12-month follow-up]
• PROMIS Mobility Questionnaire Score 6-month change [Time frame: Baseline to 6-month follow-up]
• PROMIS Mobility Questionnaire Score 12-month change [Time frame: Baseline to 12-month follow-up.]
• Prevention of Hemodynamic Failure of The Revascularized Vessel [Time frame: Baseline to 12 month follow-up]
• Change in 6-minute walk distance [Time frame: 12 month follow-up]

Eligibility criteria

Inclusion criteria

Successful lower extremity revascularization for disabling PAD performed at least 30 days before baseline testing and between 30 and 100 days before randomization.

Exclusion criteria

• History of leg amputation, not including toe and partial foot amputation
• Active gangrene
• Active limb threatening ischemia
• Already exercising at a level consistent with exercise intervention, using investigator discretion.
• Unstable angina
• Unwilling to drink study beverages
• Unwilling to adhere to the interventions and complete follow-up testing
• Currently taking sildenafil, tadalafil, or related drugs.
• Unwilling to accept randomization into either group (home-based exercise or attention control)
• 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.
• History of kidney stones that requires minimized intake of oxalate. Potential participants who need to minimize oxalate intake will be excluded from the trial.
• Baseline blood pressure <100/45.
• Wheelchair confinement or requiring a walker to ambulate
• Walking is limited by a condition other than PAD
• Current foot ulcer
• Planned major surgery, coronary revascularization, or lower extremity revascularization during the next 12 months
• Major medical illness including lung disease requiring oxygen, Parkinson's disease, or a life-threatening illness with life expectancy less than six months.
• Allergy to beetroot juice
• Currently consuming one cup or more of beets daily. Participants will be asked to decrease beet consumption to less than one cup of beets per day for 14 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.
• Participation in or completion of a clinical trial in the previous three months, using investigator discretion for trials that may not impact study participation or outcome measures of the IMPACT PAD Trial.
• Visual impairment that limits walking ability.
• Unable to communicate in English, unless the participant communicates in Spanish and is enrolled at a site that can deliver the intervention in Spanish. All sites with a Spanish speaking coordinator and interventionist will be able to enroll Spanish-speaking participants. While investigators aim to be as inclusive as possible, resources are not available to allow inclusion of people speaking languages that are not Spanish or English.
• Using a mouthwash containing chlorhexidine or cetylpyridinium chloride or a mouthwash determined to be bactericidal and unwilling to discontinue.
• Planning to begin a supervised treadmill exercise program in the next 12 months.
• Heart attack or stroke in previous three months prior to baseline testing.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 7 centers

• University of Arizona — Tucson
• Rancho Research Institute — Downey
• Emory University School of Medicine — Atlanta
• Northwestern University Feinberg School of Medicine — Chicago
• University of Chicago — Chicago
• Dartmouth Hitchcock Medical Center — Lebanon
• University of Pittsburgh — Pittsburgh

Identifiers

NCT: NCT06686121 · STU00222333

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗