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Key Studies for the Peripheral Vascular Disease Specialist

Sanjum Sethi, MD, MPH

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.

 

References:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
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When The Guidelines Need Guidance

Saurav Chatterjee, MD

I recently had the opportunity to be part of a team looking at the ‘evidence base and quality’ of recommendations enumerated in the current American Heart Association/American College of Cardiology guidelines for peripheral vascular interventions. The study led by my friend and colleague, Dr Partha Sardar, and Dr Herbert Aronow of the Warren Alpert Medical School at Brown University, found that the strength of evidence for the different recommendations vary significantly, underscoring the need for higher-quality evidence in this area as published in Circulation: Cardiovascular Interventions.

Our team identified 134 recommendations from five current full guidelines for endovascular and surgical procedures for peripheral vascular disease. For all peripheral vascular interventions, only 13% of recommendations were supported by level A evidence, whereas 48% were supported by level B evidence and 39% were supported by level C evidence.

The majority of recommendations were supported by level C evidence for pulmonary embolism or deep vein thrombosis interventions (76%) and inferior vena cava filter placement (69%), and level B evidence for renal artery stenosis interventions (67%).

However, levels of evidence were higher for endovascular therapy for stroke (level A, 24%; level B, 52%; level C, 24%), carotid revascularization (level A, 23%; level B, 52%; level C, 24%) and endovascular or surgical treatment for abdominal aortic aneurysm and lower-extremity aneurysm (level A, 26%; level B, 67%; level C, 7%). Quality of evidence for surgical revascularization for lower-extremity peripheral artery disease (level A, 18%; level B, 37%; level C, 45%) was also lower than for endovascular therapy (level A, 18%; level B, 55%; level C, 27%), which likely leads to greater emphasis on endovascular therapy in the current Appropriate Use Criteria (AUC for PAD) published by the national societies. (Bailey SR, Beckman JA, Dao TD, et al. ACC/AHA/SCAI/SIR/SVM 2018 appropriate use criteria for peripheral artery intervention: a report of the American College of Cardiology Appropriate Use Criteria Task Force, American Heart Association, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, and Society for Vascular Medicine. J Am Coll Cardiol. 2018;Epub ahead of print.)

Of significant surprise was the degree of variation in level of evidence supporting different procedural guideline recommendations. There was no level A evidence to support pulmonary embolism/deep vein thrombosis, inferior vena cava filter or renal artery stenosis intervention. In contrast, nearly 1 in 4 endovascular stroke therapy recommendations were supported by level A evidence.

 

Strength of recommendations

The researchers also noted that, overall, most recommendations were class II (54%), followed by class I (35%) and class III (11%).

For lower-extremity PAD endovascular revascularization, IVC placement, carotid revascularization and endovascular therapy for stroke, most recommendations were class II rather than class I or class III. For renal artery stenosis revascularization, recommendations were split evenly between class I and class II, with none falling into class III. For surgical or endovascular treatment of PE, there were no class I recommendations and 80% were class II. The classes of recommendation also varied for other peripheral vascular interventions, including DVT interventions, endovascular or surgical treatment for mesenteric artery disease, interventions for subclavian and brachiocephalic arteries, and endovascular or surgical treatment for AAA or lower-extremity aneurysms.

Results also showed significant variation in the strongest recommendation (class I, level of evidence A) between procedures:

  • 24% for endovascular therapy for stroke;
  • 18% for endovascular or surgical revascularization for lower-extremity PAD;
  • 20% for endovascular or surgical treatment for aneurysms of the abdominal aorta and the lower extremities; and
  • 0% for all other peripheral vascular interventions.

The most common recommendation for all peripheral vascular interventions was class II-C (C-‘expert’ opinion) (27%), followed by class II-B(B-Single RCT /multiple observational data) (26%).

 

Changes over time

From the 2005 to 2011 guidelines, the researchers observed some changes in the total number of recommendations.

For lower-extremity PAD, the number of recommendations decreased from 20 to 11 for endovascular therapy and from 29 to 11 for surgery. There were no increases in recommendations supported by level A evidence for either treatment, but the number of class I indications decreased from 10 to three for endovascular therapy (P = .27) and from 19 to five for surgical revascularization (P = .29).

For endovascular stroke therapy, there were no major changes in the number of recommendations or in level A evidence over time. However, level B evidence increased and level C evidence decreased.

The variation in the guidelines indicates that many recommendations in this area are based on lower quality of evidence or expert opinion.

 

Editorial Commentary

In an accompanying editorial, David W. Lee, MD, and Matthew A. Cavender, MD, MPH, both from the University of North Carolina at Chapel Hill, echoed the need for better evidence.

Research networks that facilitate comparative effectiveness studies in patients with peripheral vascular disease could help advance the field. Furthermore, the clinical trial infrastructure put in place for ongoing studies such as BEST-CLI and CREST-2 could provide a framework for additional studies in PAD, and multidisciplinary initiatives such as the Pulmonary Embolism Response Team Consortium can help secure funding for high-quality research. The use of existing registries, formulation of pragmatic trials nested in such registries, as well as improving data collection within these registries, could supply important information. The overarching goal of research in this field is to determine which treatments are most effective best on higher quality evidence.

 

References:

  1. Lee DW, Cavender MA. Guidelines for Peripheral Vascular Disease: Where Is the Evidence? Circulation: Cardiovascular Interventions. 2019;12(1). doi:10.1161/circinterventions.118.007561. Lee DW, et al. Circ Cardiovasc Interv. 2019;doi:10.1161/CIRCINTERVENTIONS.118.007561.
  2. Sardar P, Giri J, Jaff MR, et al. Strength of Evidence Underlying the American Heart Association/American College of Cardiology Guidelines on Endovascular and Surgical Treatment of Peripheral Vascular Disease: Circulation: Cardiovascular Interventions. 2019;12(1). doi:10.1161/circinterventions.118.007244. Sardar P, et al. Circ Cardiovasc Interv. 2019;doi:10.1161/CIRCINTERVENTIONS.118.007244.

 
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The Vascular Discovery Meeting Is This Week!

Wei Ling Lau, MD

Scientific knowledge is constantly evolving, and scientific meetings change over time to stay current with the target audience. Sometimes a revamp of the conference name is timely. For example, the American Society of Nephrology (ASN) retitled its annual Renal Week to Kidney Week in 2011 to move away from using nomenclature that might confuse the layperson (renal: late Latin adjective “relating to the kidneys”). This year, the AHA’s Arteriosclerosis, Thrombosis and Vascular Biology / Peripheral Vascular Disease (ATVB/PVD) meeting has been renamed Vascular Discovery and is happening in San Francisco May 10-12, 2018.

Thanks to the AHA Early Blogger program, I will be attending the ATVB conference for the first time, and will be live-tweeting for the Journal of the American Heart Association (JAHA). (Yes I still occasionally refer to the meeting as ATVB… not quite used to its snazzy new title yet!) I am totally stoked to be going to ATVB as vascular research has been a core interest of mine for several years, ever since fellowship training in the lab of Dr. Cecilia Giachelli at the University of Washington. Chronic kidney disease accelerates vascular disease at both the intimal and medial layers of arteries; i.e., atherosclerosis and medial vascular calcification. Medial vascular calcification is particularly intriguing as this is seen in the arteries of children on dialysis, without atherosclerosis (presumably because the children lack athero risk factors such as smoking, diabetes and aging). Dr. Giachelli identified a fascinating phenotype switch that occurs in the vascular smooth muscle cells of patients with chronic kidney disease; the cells start behaving like bone and deposit calcium-phosphate crystals in the artery wall, leading to vascular calcification and ultimately heart failure.

So, you may ask, why would a vascular cell decide to build bone in the wall of the blood vessel? This could be a defense mechanism, to avoid the cell imploding and dying. It turns out that too much intracellular calcium or phosphorus (an imbalance that can happen in chronic kidney disease) can trigger apoptosis (which also promotes vascular calcification!). By turning on genes that allow the cell to export calcium-phosphate mineral, the vascular cells avoid programmed cell death. Unfortunately, big picture-wise, this cell-centric ninja move fails the body as vascular calcification is associated with heart failure and sudden cardiac death. (Of note, Dr. Catherine Shanahan – one of the first to describe the role of apoptosis in uremic vascular calcification – will be a speaker at Vascular Discovery this week.)

ATVB is one of the smaller AHA conferences and thus the “concurrent sessions dilemma” is less of an issue. (Not like the AHA Scientific Sessions or ASN Kidney Week where one has to make a choice between 5-8 talks that are going on All At The Same Time.)  The Vascular Discovery program this week includes sessions on precision medicine, diabetes-vascular complications, lipid metabolism, gut microbiome and inflammation. For vascular biology enthusiasts, this meeting is a must.

Follow #JAHAMeetingReport and #AHAEarlyCareerBlogger for live tweets from Vascular Discovery. And don’t forget to show your support for vascular disease awareness and research by wearing red socks on Friday!

Red sock movement

Wei Ling Lau Headshot

Wei Ling Lau, MD is Assistant Professor in Nephrology at University of California-Irvine, where she studies vascular calcification and brain microbleeds in chronic kidney disease. She is currently funded by an AHA Innovative Research Grant, and has been a speaker for CardioRenal University and the American Society of Nephrology.