Supervised Exercise Program for PAD vs CLI – Learn From the Expert

Critical limb ischemia (CLI) is as deadly as many other diseases, including coronary artery disease (CAD), along with many other malignancies. When we review the literature for medical therapy for CLI, we are faced with disappointments due to the lack of and scarce supportive data. Given that CLI is not new — it has been around for centuries — somehow it continues to escape the benefits of solid medical cocktails. On the other hand, over the course of 30 years, CAD medical therapy has evolved some very respectable treatment plans, including evidence-based medical therapy. This month, we are honored to discuss the issue at hand with Dr. Kevin Rogers, who has contributed to the available medical therapy for CLI. Dr. Rogers is also a strong advocate for a supervised exercise program for peripheral arterial disease (PAD) patients.

J.A. Mustapha, MD: Are you surprised to see that in 2016, we have not moved beyond only a few medical treatment options for the CLI patient?

Kevin Rogers, MD: Yes and no. On the one hand, medical therapy for systemic atherosclerotic disease has shown great progress. In particular, lipid-lowering therapies and novel anti-thrombotic therapies have made impressive advances in recent years. However, there is an evidence gap in limb-specific therapies. We do not yet know if advances in therapy for systemic atherosclerosis and thrombosis improve limb-specific outcomes, such as walking performance, wound healing, and amputation rates.  

Dr. Mustapha: You are currently involved in the VOYAGER PAD trial. What do you expect to learn from this trial?

Dr. Rogers: VOYAGER is an international, multicenter, randomized trial comparing low-dose rivaroxaban to placebo on a background of antiplatelet therapy in patients who have undergone lower extremity revascularization (surgical or endovascular). The primary outcome is time from randomization to the first occurrence of any of the following major thrombotic vascular events: myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia (ALI), and major amputation. Of note, 2 of the 5 components of the primary outcome are limb related. As such, I expect to learn substantially about ALI from VOYAGER. That is, we will learn about the natural history of patients with ALI in those who have undergone lower extremity revascularization, variables that predict ALI, and medical therapy that may alter that natural history.  

Dr. Mustapha: If you are able to get an NIH grant for CLI medical therapy trial, what would be your optimal primary and secondary endpoints and what would be your optimal study drugs?

Dr. Rogers: That’s a great and tough question. Critical limb ischemia is an end-stage atherosclerotic disease of the extremities that confers a high risk of amputation. There are also competing risks of myocardial infarction, stroke, and vascular death in this patient population. Optimal primary outcomes, in my opinion, would focus on “limb health”, defined as a pain-free, functional limb allowing an individual to perform daily activities without limitation. Ideal secondary outcomes, in my opinion, would include time-to-wound healing and quantification of the resources needed to achieve a functional limb compared to resources used in the setting of amputation. As for non-revascularization strategies to study in this setting, cell therapy and gene therapy are the most attractive, as are compounds that promote angiogenesis.  

Dr. Mustapha: Compared to CAD pathophysiology, do you believe we have enough knowledge on infrainguinal PAD pathophysiology to make sound medical decisions that can help our patients?

Dr. Rogers: Not really. There is an abundance of evidence on CAD. However, the pathophysiology relevant to CAD is undoubtedly different than that for PAD. For example, the CAPRIE trial suggested a benefit of clopidogrel over aspirin in a PAD population, which is not a described finding in CAD populations. In addition, PAD subgroups are under-represented as compared to patients with CAD. EUCLID was an exception. Patients with PAD were randomized to clopidogrel or ticagrelor; it was the largest PAD study to date. The trial was negative, but hopefully this result will not compromise increasing the evidence base for PAD and CLI. Regardless, I am optimistic that this evidence gap is being increasingly recognized and addressed by international societies and large trials, such as VOYAGER, as we discussed above.

Dr. Mustapha: How does a supervised exercise program help PAD patients?

Dr. Rogers: Supervised exercise clearly benefits patients with claudication, and perhaps even those with asymptomatic PAD. A major obstacle of supervised exercise therapy is the lack of reimbursement by third-party payers and Medicare. At the University of Colorado, we have a talented group of physical therapists who are passionate about limb health. We encourage all patients with PAD to engage in physical therapy for their limb health. However, we must recognize the challenges of a patient who has ambulatory dysfunction to attend multiple sessions a week at a tertiary care center. Promoting community-based or home-based walking programs might be a more pragmatic alternative to deliver this therapy.

Dr. Mustapha: Help us understand how a supervised exercise program can provide similar benefits to the CLI patients. And, how do we implement it?

Dr. Rogers: CLI is such a different disease than claudication. With claudication, a person must be ambulatory to experience symptoms. With CLI, I truly believe a treatment goal is for a patient simply to be ambulatory. Despite these fundamental differences between CLI and claudication, the limited evidence in patients with PAD often groups those with claudication and CLI, obscuring generalizable inferences to either group. Analogous to exercise therapy for patients with claudication, there should be a proven rehabilitative therapy for those with CLI.  

Dr. Mustapha: We all love to have a drug cocktail for our CLI patient. Please share with us your cocktails, and the when and where to use each drug.

Dr. Rogers: Medical therapy for CLI patients can be conceptualized in categories. The easiest category is for secondary prevention of atherosclerotic events. This entails smoking cessation, high-intensity “statin”, optimal blood pressure control, and antiplatelet therapy.  Each of these subcategories become more complicated and are in flux. At the University of Colorado:

• For patients willing to quit smoking, we refer to an accessible smoking cessation program.
• Current guideline recommendations for “statin therapy” for patients with PAD are posted in our outpatient work areas.  
• Hypertension is a weaker risk factor for PAD than smoking. Nonetheless, we consolidate antihypertensive therapy in concert with competing indications, such as PAD, CAD, and heart failure.  
• Antiplatelet therapy is also patient-specific. Mono-antiplatelet therapy is the default for stable patients without a history of coronary stenting. For CLI patients, a more aggressive approach is taken with dual antiplatelet therapy until wound healing or even indefinitely.  

In summary, my cocktail = nicotine replacement, high-intensity statin, aspirin or clopidogrel, adequate antihypertensive therapy (diuretic, calcium channel blockers, ACE inhibitor, spironolactone, and beta blockers), in that order as necessary (balancing competing cardiac, renal, hematologic, hepatic, and endocrinologic indications).  

Dr. Mustapha: Where do you see CLI medical therapy in 10 years?

Dr. Rogers: There are significant challenges to delivering care to patients with CLI. This population is marginally ambulatory, but needs care from multiple specialists. I would love to see CLI Centers of Excellence across the world where there is multidisciplinary, efficient, and effective treatment of patients with CLI. This program would need to encompass multiple specialties, reside in a common physical space, offer exemplary revascularization — endovascular and surgical, involve a robust foot and ankle surgery department, and participate in meticulous wound care systems. An emphasis should be placed on dissemination of skill sets for endovascular and surgical revascularization of the foot. Finally, cell and gene therapy is undoubtedly on the horizon, as well as novel angiogenesis therapies. 

Disclosures: Dr. Rogers reports he is on the adjudication committee for VOYAGER (Bayer). 
Dr. J.A. Mustapha can be contacted at jihad.mustapha@metrogr.org.
Dr. Kevin Rogers can be contacted at kevin.rogers@ucdenver.edu.