Collaboration to Conquer Critical Limb Ischemia

As prevalence rises, new treatment options and multidisciplinary solutions are key.

As the prevalence of critical limb ischemia reaches epidemic proportions, interventional cardiologists, radiologists and surgeons are seeking answers to questions about how best to treat the disease.

“CLI is a million-patient problem,” Michael R. Jaff, DO, FACP, FACC, FSCAI, president of Newton-Wellesley Hospital in Newton, Massachusetts, and professor of medicine at Harvard Medical School, told Cardiology Today’s Intervention. “Specifically, in the United States, approximately 10 million patients annually carry a diagnosis of peripheral artery disease. About 1% of those patients will have a new diagnosis of CLI and up to 10% will require treatment in the short term.”

These numbers are only likely to increase, he noted, due to the surging incidence of contributors to PAD, such as diabetes and chronic kidney disease. Therefore, determining strategies to curb the CLI epidemic is urgent. However, challenges in diagnosis and treatment of the disease as well as the need for high-quality research are big obstacles to effectively addressing the problem, experts told Cardiology Today’s Intervention.

“CLI is complex. We’re in the Middle Ages, so to speak, of knowing how to treat it,” Alik Farber, MD, chief of the division of vascular and endovascular surgery at Boston Medical Center and professor of surgery and radiology at Boston University School of Medicine, said in an interview. “We need more well-designed, unbiased studies, and clinicians from all areas of expertise need to be brought together to treat these complex patients.”

Complexities in Diagnosis

CLI is a disabling disease, with can lead to amputation and a reduced life span. Timely diagnosis is critical to preventing these adverse outcomes, but health care professionals caring for patients with CLI confront considerable challenges.

One issue is variation in definitions of CLI, according to Farber and Jaff. The 2016 American Heart Association/American College of Cardiology guideline on the management of patients with lower-extremity PAD states that CLI is characterized by chronic ischemic rest pain, nonhealing wound or ulcers, or gangrene in at least one leg attributable to objectively proven arterial disease. Farber noted, however, that definitions from the various medical societies are conflicting, and previous iterations have characterized the disease using different parameters (see Sidebar).

“I can identify a patient with CLI based on symptoms, physical examination and the results of objective tests, but it’s difficult to translate that across multiple providers in multiple systems around the United States and the world,” said Jaff, a member of Cardiology Today’s Intervention Editorial Board. “The competing definitions also make it difficult to come up with one aggregate series of diagnostic entities to make the disorder more clearly defined.”

One contributor to the complexity of defining CLI relates to testing, according to Jaff. The ankle-brachial index is a common, inexpensive and highly reliable test for identifying PAD, he said, yet it is not always useful in patients with CLI.

“Many of the patients who have CLI cannot have an ankle-brachial index because the arteries in their ankles and feet are calcified, usually due to diabetes and/or [chronic kidney disease]. Therefore, a meaningful pressure at the ankle or toe cannot be obtained, and that causes confusion,” he said.

A ‘Free-for-All’

Treatment of CLI also brings with it a host of challenges, experts told Cardiology Today’s Intervention.

“Given that the disease has multilevel and multivessel involvement, most of the time operators tend to be engulfed in the therapeutic modality for hours at a time to achieve an acceptable treatment outcome. That by itself creates a significant challenge for the operator and can be broken down into time spent, equipment and tools used, and radiation exposure. Adding all this together, you can see that CLI treatment is one of the most extremely challenging forms of therapy today,” Jihad A. Mustapha, MD, FACC, FSCAI, director of cardiovascular research at Metro Health University of Michigan Health in Wyoming, Michigan, wrote in an email to Cardiology Today’s Intervention.

Currently, revascularization performed via a surgical or endovascular procedure is the mainstay of treatment for patients with CLI, according to Farber. He noted, however, that questions persist about which approach is best.

In terms of surgical options, bypass with saphenous vein as a conduit yields positive outcomes for patients with CLI, Jaff said. Nevertheless, at least half of patients who are eligible for bypass do not have one continuous, healthy piece of saphenous vein, possibly because it has been harvested for use in CABG. Bypass surgeries using other conduits, such as composite vein grafts, prosthetic graft and grafts from cadaveric or umbilical veins, have been developed, but these procedures have been shown to be less effective, according to Jaff.

Endovascular interventions, although less invasive than surgery, are also not perfect, he said.

“There have been a number of publications using simple balloon angioplasty for focal lesions in patients with below-knee CLI, but the problem is that balloon angioplasty doesn’t provide durability. Additionally, most of these patients have long diffuse disease that affects all three arteries below the knee and distal disease that goes into the foot,” Jaff said.

Recently, researchers have started considering laser atherectomy, drug-eluting stents, bioresorbable stents and drug-coated balloons to treat CLI. Some research suggests these procedures may be beneficial, but the studies have generally been small, multiple-case series, according to Jaff.

One particularly vexing problem in treatment of CLI is the enormous variability in approach to the disease, Farber said.

For example, one study published in a 2011 issue of Circulation: Cardiovascular Quality and Outcomes showed that the proportion of patients who underwent revascularization in the year before amputation ranged from 32% in one region to 58% in another (P < .0001). Most patients who had an amputation did not have any vascular procedures in the year before, but among those who did, strategies varied greatly.

The multiple approaches to revascularization also complicate clinicians’ decisions regarding the best treatment strategy for a particular patient, Farber said. Several factors may contribute to this problem, including variability in clinicians’ skill sets and comfort with the different procedures, as well as changes in reimbursement. Payment for endovascular procedures performed in-office, for instance, may be higher than for bypass performed in a hospital setting.

Ultimately, though, the major driver is a lack of data comparing treatment strategies, according to Farber.

“There are multiple reasons why such variability in treatment of CLI exists, but the main basis is that there are no good data, and when there are no good data, it’s a free-for-all,” he said.

Addressing a Data Void

In light of these challenges, experts who spoke with Cardiology Today’s Intervention underscored the need for more high-quality data comparing treatment strategies for CLI.

“One meta-analysis of studies comparing open surgery with endovascular revascularization in CLI demonstrated no difference in amputation-free survival and mortality. The researchers also concluded that there were not enough data to make suggestions regarding treatment,” Farber said.

He also noted that the BASIL trial is currently the only randomized trial to date that compared open surgery vs. an endovascular treatment — in this case, balloon angioplasty — for CLI. However, the trial has been criticized for having multiple drawbacks. For example, Farber said, the primary efficacy endpoint — amputation-free survival — places more emphasis on mortality and less emphasis on the treated limb and, therefore, may not be best for assessing the effects of a specific treatment. Additionally, because angioplasty was the only endovascular therapy studied, the results may be less applicable to current clinical practice, which can include stents, atherectomy or other devices.

A number of issues complicate the gathering of data on treatment for CLI, such as variability in the patient population, according to William A. Gray, MD, system chief of the division of cardiovascular disease at Main Line Health and president of the Lankenau Heart Institute in Wynnewood, Pennsylvania. He said patients differ in terms of pedal loop outflow, whether direct revascularization is possible and comorbidities, such as diabetes, renal failure or infection — all of which can affect the success of a procedure.

“Furthermore, the data do not show differences in patient amputation outcomes. At 1 year, limb loss is approximately 8% to 12% regardless of which procedure or device we’re using,” he said.

The importance of patency also poses a dilemma, according to Gray. For one subset of the total population with CLI, sustained patency may not essential for wound healing in the first few weeks/months. For another subset of the population, however, continued long-term patency is important for healing a persistent wound or preventing the re-formation of wounds. At this point, he said, clinicians do not yet know how to readily identify these subsets of patients, and therefore assessing the clinical effects of new devices which promise — and may actually deliver — improved patency can be confounded.

Variation in wound care and assessment is another problem, according to Gray. To date, studies generally have not standardized wound care or the determination of wound status, which can muddle researchers’ ability to understand what effect a device, drug, or even cellular treatment is having on patient outcomes.

Taken together, designing trials and collecting data in CLI is challenging, he noted.

“As you start to winnow down some of these issues to remove confounders, you’re left with a trial that is difficult to enroll,” Gray said.

The potential for bias in studies evaluating treatment for CLI is an area of concern as well, according to Farber. For instance, although the data provided by industry-sponsored trials are good, these studies may be structured to answer questions relevant to the manufacturer as opposed to those relevant to clinicians, he said.

“It’s wonderful that industry has stepped up to develop new devices. However, their goal is not necessarily to conduct a completely unbiased study with appropriate endpoints,” Farber said. “These studies aren’t bad and the data are important, but we as specialists who treat CLI need to plan and participate in research that asks the relevant questions.”

On the Horizon

Despite these research challenges, clinicians have hope for future studies, experts told Cardiology Today’s Intervention.

The LIBERTY 360 study, for example, will provide useful data, according to Mustapha, a co-principal investigator. The prospective, observational, multicenter study aims to evaluate procedural and long-term clinical and economic outcomes of all FDA-approved endovascular device interventions in patients with symptomatic lower-extremity PAD, he said. A total of 1,204 patients were enrolled at 51 sites and will be followed for 5 years. Results for the 100 Rutherford class 6 patients enrolled, which were reported at the New Cardiovascular Horizons meeting in New Orleans in June, showed that 78% were discharged home, 2% were hospitalized and required additional therapy due to complications, more than 87% were free from major amputation and 85% survived to 6 months, Mustapha reported.

The 1-year data, which will be available later in 2017, should be revealing, according to Gray, who also is a co-principal investigator.

“We’re gathered comprehensive data on these patients and procedures without a preconceived premise on the outcomes and without the intent of testing any specific device. The study included all-comers, and clinicians treated patients with whatever they thought best,” he said. “We wanted a snapshot not only of treatment of CLI and claudication in America during this period, but also of what some of the challenges and the characteristics of these populations, as well as what some of the failure modes are.”

Other studies, including BASIL-2 and BASIL-3, which will compare various treatment paradigms such as DCBs, DES and regular stents, will also provide clinicians with more data on treatment options (see Table).

The BEST-CLI trial, however, may be the most highly anticipated, according to Jaff.

“This trial holds great promise for helping us learn what strategies are more effective in getting patients to heal and saving their legs,” he said.

The NIH-sponsored trial, which is currently enrolling, is a direct head-to-head comparison in patients with CLI who require revascularization. A total of 2,100 patients from 160 sites in the United States and Canada will be randomly assigned to a surgical or endovascular strategy. The primary efficacy endpoint is major adverse limb event-free survival. BEST-CLI is a pragmatic, real-world trial, and, as such, investigators are allowed to use any bypass techniques or endovascular devices that they usually use in clinical care.

“The BEST-CLI trial will help answer the question about who benefits most from surgery and who benefits most from endovascular therapy,” Farber, who is national co-principal investigator, told Cardiology Today’s Intervention.

Importance of a Team Approach

Certain strategies can help address challenges in CLI diagnosis, treatment and research.

Jaff said investigation into effective medical therapies would be beneficial. Clinicians use medical treatments, such as statins, antiplatelet agents and ACE inhibitors, to optimize risk factors for stroke and MI in patients with CLI, but little progress has been made in medical treatment for the disease itself.

“Revascularization procedures are taxing on the bodies of these ill patients, and it would be great if we had an effective treatment that did not put their systems at risk,” Jaff said. “So, the question is: With all of the advances in genomics, metabolomics and proteomics, is there an option from that standpoint?”

Raising awareness of CLI is essential as well, Farber said. At present, the disease often goes unrecognized, which prolongs treatment and leads to unnecessary amputations.

“It’s absolutely necessary to build awareness of the disease at hand with both the private sector (patients and community), health care providers and payers,” Mustapha told Cardiology Today’s Intervention. “Improvement is a must and, as of today, we are all evolving, either as individual practices or small fractions of groups trying to create algorithms for treatment. The hope is to one day move forward as a united front between all specialties, agreeing on the same diagnostic and treatment algorithms.”

The CLI Global Society — a medical society focused on advanced the prevention of amputation due to CLI — is one example of a multidisciplinary group trying to achieve this goal, he said.

Overall, though, the key to effectively addressing the CLI epidemic is teamwork, especially for research purposes and in clinical care. Farber said clinicians from all specialties must participate in well-designed studies to help yield the most robust data possible.

“Patients with CLI are complicated. Many interventionists are skilled at using catheters or scalpels, but they don’t have either the time, expertise or willingness to manage all aspects required for healing the wound, including managing a patient’s comorbid medical conditions,” Jaff said.

From a clinical practice perspective, collaboration allows a more comprehensive approach to treatment, according to Gray.

“An interdisciplinary team comprised of wound care specialists, surgeons, podiatrists and interventionists of any stripe will strengthen clinicians’ ability to care for these patients,” he said. – by Melissa Foster

• References:
• Gerhard-Herman MD, et al. J Am Coll Cardiol. 2017;doi:10.1016/j.jacc.2016.11.007.
• Goodney PP, et al. Circ Cardiovasc Qual Outcomes. 2012;doi:10.1161/CIRCOUTCOMES.111.962233.
• Jones WS, et al. Am Heart J. 2014;doi:10.1016/j.ahj.2013.12.012.
• Shishehbor MH, et al. J Am Coll Cardiol. 2016;doi:10.1016/j.jacc.2016.04.071.

• For more information:
• Alik Farber, MD, can be reached at alik.farber@bmc.org.
• William A. Gray, MD, can be reached at grayw@mlhs.org.
• Michael R. Jaff, DO, FACP, FACC, FSCAI, can be reached at mjaff@partners.org.
• Jihad A. Mustapha, MD, FACC, FSCAI, can be reached at jihad.mustapha@metrogr.org.

Disclosures: Farber reports no relevant financial disclosures. Gray reports consulting for Boston Scientific, Intact Vascular, Medtronic and Spectranetics. Jaff reports financial ties with Abbott Vascular (non-compensated), American Orthotics/Prosthetics Association, Boston Scientific (non-compensated), Cordis (non-compensated), Embolitech, Janacare Inc., MC10, Medtronic (non-compensated), Micell, Northwind Medical Inc., PQ Bypass Inc., Primacea, Sano V Inc., Valiant, Vascular Therapies Inc. and Volcano. Mustapha reports consulting for Cardiovascular Systems Inc.