Key Studies for the Peripheral Vascular Disease Specialist
On Saturday, November 14, 2020 there was an interesting session evaluating new data that impacts the care of patients with lower extremity peripheral arterial disease. For those of us involved in the daily care of these patients, we welcome new insights to help improve outcomes in this high risk patient population.
First, Dr. Mary McDermott from Northwestern University presented the LITE randomized clinical trial which compared a low versus high intensity home based walking program for lower extremity PAD patients. While the benefits of supervised walking programs is well known from the literature (1), in practice we often have difficulty in convincing our patients to proceed even when experiencing lower extremity pain. Only recently has CMS approved reimbursement for supervised exercise programs (1). ‘
In this multicenter trial, 305 participants were randomized to low intensity exercise, high intensity exercise, and attention control groups. All groups received weekly telephone education. Both exercise groups consisted of exercise 5 days/week for upto 50 minutes/session with the low intensity intervention consisting of a comfortable walking pace without ischemic symptoms. In contrast, the high intensity group exercised to maximal ischemic leg pain. The primary outcome measure was 6 minute walk time at 12 months. The high intensity exercise group had a statistically significant increase in the 6 minute walk time (53.9 meters) versus the low intensity (11.7 meters) and the control group (4.0 meters). Similarly, there was improvement in the patient reported measures of walk distance based on the WIQ distance score in both the high intensity and low intensity groups.
These data suggest that we can prescribe high intensity exercise programs for our PAD patients and expect both objective and subjective improvement. An especially important finding when many options for supervised walking programs are restricted during the current pandemic.
Next in the session were a pair of important substudies from the VOYAGER PAD trial (2). First, Dr. Marc Bonaca from the University of Colorado presented an analysis evaluating the highest risk patients, those with critical limb ischemia (CLI). This subgroup of PAD tends to have the worse outcomes both from a standpoint of cardiovascular and lower extremity disease.
VOYAGER PAD randomized 6,564 patients with symptomatic lower extremity peripheral arterial disease who were undergoing peripheral revascularization. The patients were randomized 1:1 in a double-blind fashion to rivaroxaban 2.5 mg twice a day versus placebo. All patients received low dose aspirin with clopidogrel at the operator’s discretion. The main trial had a statistically significant benefit in the rivaroxaban group with a 15% relative risk reduction and 2.6% absolute risk reduction relative to control (19.9% versus 17.3%) (2). The number needed to treat (NNT) was 39 with a number needed to harm (NNH) due to TIMI major bleeding of 125.
The critical limb ischemia patients comprised nearly a quarter of the overall population (n=1533). Compared to the claudication patients, the CLI patients were at higher risk with more complex anatomy and a much higher baseline event rate (27% versus 17% at 3 years). Since the CLI patients were at higher risk, the benefit was greater with ARR of 4.5% in the CLI group. This was consistent across all subgroups and was primarily driven by less acute limb ischemia and lower extremity amputations. The NNT was 23.
Next, Dr. Manesh Patel presented an analysis from VOYAGER PAD evaluating rivaroxaban therapy plus aspirin versus aspirin alone after endovascular revascularization (3). Currently, we often use dual antiplatelet therapy in this population lasting anywhere from 1 month to 12 months post endovascular revascularization depending on the device used and patient risk profile.
With the results of COMPASS PAD (4) and VOYAGER PAD, it was unclear how to integrate this dose into the clinical care of patients receiving endovascular revascularization. Therefore, this analysis has been highly anticipated to understand the best post-treatment antiplatelet/antithrombotic regimen. About two-thirds of the patient population had endovascular revascularization versus one third in the surgical group. Clopidogrel was used in 69% of the patients. The endovascular patients had findings consistent with the overall trial with an absolute risk reduction of 1.7%. However, major adverse limb events were reduced by (ARR) 2.4% with an NNT of 42. There was an increase in TIMI major bleeding (NNT = 100), but not fatal bleeding. Clopidogrel didn’t change the MALE outcomes.
Taken together, this data certainly informs our clinical practice for a wide variety of lower extremity PAD patients. Dr. McDermott’s study reinforces the need for exercise therapy to improve walking distance and suggest that this can be done even in a home-based environment. The VOYAGER PAD substudies suggest that low dose rivaroxaban is especially beneficial in the highest risk patients, those with CLI and has a role to reduce long term adverse limb events in all patients undergoing endovascular revascularization. We should be strongly considering this therapy for those PAD patients that are at higher ischemic risk (diabetes, smoking, CLI) and do not have an excess in bleeding risk.
This is just a snapshot of some of the peripheral arterial disease-focused studies discussed at AHA Scientific Sessions 2020. I encourage everyone to utilize the on-demand content including many of the abstract sections for even more PAD focused content.
- Treat-Jacobson D, McDermott MM, Beckman JA, Burt MA, Creager MA, Ehrman JK, Gardner AW, Mays RJ, Regensteiner JG, Salisbury DL, Schorr EN, Walsh ME; American Heart Association Council on Peripheral Vascular Disease; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; and Council on Lifestyle and Cardiometabolic Health. Implementation of Supervised Exercise Therapy for Patients With Symptomatic Peripheral Artery Disease: A Science Advisory From the American Heart Association. Circulation. 2019 Sep 24;140(13):e700-e710. PMID: 31446770.
- Bonaca MP, Bauersachs RM, Anand SS, Debus ES, Nehler MR, Patel MR, Fanelli F, Capell WH, Diao L, Jaeger N, Hess CN, Pap AF, Kittelson JM, Gudz I, Mátyás L, Krievins DK, Diaz R, Brodmann M, Muehlhofer E, Haskell LP, Berkowitz SD, Hiatt WR. Rivaroxaban in Peripheral Artery Disease after Revascularization. N Engl J Med. 2020 May 21;382(21):1994-2004. PMID: 32222135.
- Hiatt WR, Bonaca MP, Patel MR, Nehler MR, Debus ES, Anand SS, Capell WH, Brackin T, Jaeger N, Hess C, Pap AF, Berkowitz SD, Muehlhofer E, Haskell L, Brasil D, Madaric J, Sillesen H, Szalay D, Bauersachs R. Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety. Circulation. 2020 Nov 3. PMID: 33138628.
- Kaplovitch E, Eikelboom JW, Dyal L, Aboyans V, Abola MT, Verhamme P, Avezum A, Fox KAA, Berkowitz SD, Bangdiwala SI, Yusuf S, Anand SS. Rivaroxaban and Aspirin in Patients With Symptomatic Lower Extremity Peripheral Artery Disease: A Subanalysis of the COMPASS Randomized Clinical Trial. JAMA Cardiol. 2020 Sep 30:e204390. PMID: 32997098.