A Houston Methodist doctor is about to launch a potentially practice-changing trial aimed at pinpointing which peripheral artery disease (PAD) patients will benefit from open bypass surgery, and which will benefit from endovascular therapy — guidance badly needed to improve the field's high failure rate in severe cases.

Vascular surgeon-scientist Dr. Trisha Roy recently received a $3.3 million National Institutes of Health R01 grant to conduct the research, which combines advanced imaging technologies and her team's novel data-driven scoring system to better diagnose and treat the chronic circulatory condition that often leads to amputation and death.

"We hope the trial results prompt a shift from the current 'one-size-fits-all' approach to treatment to a more personalized strategy," says Dr. Roy. "By tailoring treatment strategies to individual patients and their unique types of peripheral artery disease, I think we can improve our results and save more legs and lives."

The grant is the culmination of preliminary research that Dr. Roy will present later this month at the European Vascular Society annual meeting, her second such presentation of the work there. In addition, the Journal of Vascular Society has also accepted and will soon publish a paper on the research.

Concern about the number of PAD-related leg amputations — there are now about 150,000 a year in the U.S. — recently prompted the American Heart Association to call for a 20% reduction in the rate by 2030. The appeal, made to regulatory body policymakers and health institutions, emphasized the need for greater preventive, diagnostic and research efforts. The association estimates 85% of PAD amputations are actually preventable.

Dr. Roy's NIH-funded study in that direction has two primary goals:

• Establish the utility of its MRI-histology scoring system to better identify plaque at risk of causing treatment failure
• Test orbital atherectomy's safety and effectiveness on certain types of plaque, particularly those characterized by concentric calcium

Plaque buildup is the primary cause of PAD, which affects about 12 million Americans, mostly diabetic end-stage renal disease patients, but also people with atherosclerosis stemming from hypertension, high cholesterol or smoking. In the most severe cases, known as critical limb ischemia, amputation is needed within one year in 20% of patients because plaque buildup has greatly reduced blood flow below the knee. Roughly 70% of such amputees die within three years.

Limits of the current approach to PAD treatment

The standard course of treatment is to employ percutaneous vascular intervention (PVI), favored by doctors and patients — roughly 1 million procedures are performed annually in the U.S. — because it's minimally invasive. If it's unsuccessful, doctors then perform open bypass surgery.

That status quo is increasingly considered untenable. For one, because of the impenetrability of some plaque, PVI is futile in 15%-20% of PAD patients. For another, patients who undergo bypass surgery after failed PVI have higher amputation rates and poorer long-term patency compared with patients who have primary bypass without a previous PVI intervention.

Even more alarming were the results of the landmark BEST-CLI trial in 2022. It reported that open surgical bypass generally yields better results than PVI.

The finding shook up the field: Was open bypass surgery really the best option?

"There's a lot of morbidity and mortality with open bypass, given the frail patients we operate on, so the thought of swinging back to it was a bit concerning," says Dr. Roy. "The question is, should we be treating everybody with bypass now or can we identify those patients best suited for a particular intervention?"

In 2023, the BASIL-2 trial pointed to the importance of patient selection. Focused on below-the-knee disease, a challenging and expanding subset of PAD, the trial showed improved outcomes with an endovascular-first approach.

But current approaches to preemptively identify the optimal intervention and devices are subjective and inadequate. Dr. Roy's study is an attempt to overcome that shortcoming and provide objective measures to determine which type of intervention is optimal based on plaque composition.

Identifying plaque composition, evaluating amputated legs

To that end, Dr. Roy's study will enroll 175 patients divided into two groups — 100 will undergo MRI scans to characterize their plaque before PVI intervention; and 75 will provide their amputated legs for an analysis of devices' impact on vessel walls.

The study's first part employs the team's unique MRI-histology protocol and scoring system to identify lesions at heightened risk of PVI failure. Specifically, it uses the MRI signal behavior of plaque components to differentiate hard from soft plaque components with faster or slower signal decay times, respectively. Soft plaque is a more natural candidate for endovascular therapy, while hard plaque is more natural for open bypass.

In preliminary research, Houston Methodist's MRI-histology scores were predictive of not only immediate technical failure of the ballooning or stenting procedures, but also three-month and six-month reintervention rates.

The study's second part will involve the recruitment of PAD patients undergoing above-knee amputation. Randomized to receive either plain balloon angioplasty or orbital atherectomy prior to angioplasty, these patients' legs will be imaged before the procedure and again after amputation.

Findings from the second part will be important because there's currently little evidence about the safety and effectiveness of atherectomy devices, the calcium-modifying tool whose use has grown exponentially in recent years. Investigative stories in the New York Times and ProPublica have raised questions about both safety concerns and widespread use of the devices.

The research team's program evaluating amputated legs, conducted at the Houston Methodist Institute for Technology, Innovation & Education (MITIE), has earned awards from the European Society of Vascular Surgery and the American Heart Association.

Dr. Roy says her research emphasis was motivated by the field's high failure rate and her own experience of PAD patients not being helped by the initial intervention and having to return for repeat procedures, each more futile than the last one, ultimately ending up in amputation.

"It's a very challenging field, its diverse patients understudied and underappreciated," says Dr. Roy. "We need to give physicians more confidence that their interventions will effectively unblock blood vessels without causing additional damage — that is, better identify the patients appropriate for open bypass because their vessels are like lead pipes, and the patients appropriate for endovascular treatment because their plaque is buttery and soft. Hopefully, this trial will achieve that."

The five-year grant began on July 1, 2024.