New technology may give patients facing a major amputation a new treatment option
“We have failed to appropriately screen the populations at highest risk for PAD/CLTI and subsequent amputation,”
Fakorede | Endovascular Today
As an interventional cardiologist and limb salvage specialist, Foluso Fakorede, MD, was drawn to the South.
The Mississippi Delta is one of the poorest regions in the United States, with county-level poverty rates hovering between 30% and 40%, far surpassing the national poverty rate of 10.5%. Families in the region live in the shadow of generational poverty and lack basic resources like Wi-Fi and public transportation. The Delta is also a known food desert—lacking basic access to fresh and healthy food—which is associated with a long-documented obesity epidemic in the region.
Peripheral artery disease (PAD) is also endemic to the region. Data from 2017 estimate conservatively that 168,000 people in Mississippi are living with PAD, the third most common clinical manifestation of atherosclerosis. Nearly 19,000 of those people developed chronic limb-threatening ischemia (CLTI), a life-threatening arterial block that reduces blood flow in the extremities and leads to gangrene, ulcers, and amputation, in addition to increased mortality and decreased quality of life.
“We have failed to appropriately screen the populations at highest risk for PAD/CLTI and subsequent amputation,” wrote Fakorede in Endovascular Today. “These [populations] include the highest prevalence of cardiovascular disease or other risk factors.”
Understanding Peripheral Artery Disease
PAD is an occlusive disease of extremity arteries caused by reduced blood flow to the arms or legs. Symptoms typically include painful cramping, numbness or weakness in the leg, and sores on the feet, legs, or toes that won’t heal. For lower-extremity PAD, risk factors are the same as those associated with atherosclerosis, like smoking, diabetes, and hypertension. Perhaps most importantly, most patients—more than 50% according to one estimate—are asymptomatic and won’t learn that they have the disease until it’s too late.
PAD is caused by reduced blood flow to the arms or legs, and symptoms include painful cramping, numbness or weakness in the leg, and sores on feet, legs, or toes that won’t heal. Risk factors for lower-extremity PAD are associated with risk factors for atherosclerosis, like smoking, diabetes, and hypertension. However, most patients—up to 4 in 10 people with PAD—have no symptoms at all.
Some patients experience progression to CLTI, which requires urgent intervention—typically by a vascular interventionalist for limb salvage efforts. These limb salvage experts can choose the proper tests, interpret the results, and order imaging studies to diagnose and manage CLTI.
One 2020 study found that roughly 11% of patients with PAD will develop CLTI, with a prevalence of 1.28% in adults over 40 years of age—representing approximately 2 million individuals. In a different study that included patients with untreated, severe CLTI, researchers found that within one year of CLTI diagnosis, amputation and mortality rates were roughly 22% each.
Patients with diabetes and renal failure experience even worse outcomes: over a 10-year period, the mortality risk for those living with diabetes and PAD was 58%, compared with age- and sex-matched adults diabetes alone, for whom the 10-year mortality was only 19%. Among patients with renal failure, the 6-year overall mortality rate hovers around 45%; this is compared with patients with chronic kidney disease alone and peripheral artery disease alone, which have 6-year mortality rates of 28% and 26%, respectively.
Compared with cancer, these outcomes are devastating. In fact, more patients die within 5 years of a CLTI diagnosis than with a diagnosis of any type of cancer except lung cancer, including pancreatic cancer (51,000 deaths), colorectal cancer (49,000 deaths), and liver cancer (35,000 deaths). A 2021 study found patients with diabetic foot complications have a 5-year mortality rate of 56.6% for major amputations. Compared with a 31% mortality rate for all reported malignancies, it’s easy to see how CLTI is an urgent public health crisis.
“All patients with CLTI should be afforded [the] best medical therapy,” they wrote, followed by long-term limb surveillance.
When limb salvage fails, the next step is amputation. But in underserved and rural areas, amputation is startlingly common—even among patients who might otherwise benefit from procedures like limb revascularization. In Mississippi, for example, Fakorede pointed out that 90% of patients who underwent a limb amputation never had an angiogram—a simple diagnostic X-ray used to evaluate arterial blockages—before their surgeon started to cut.
When PAD and CLTI progress to amputation, the lack of racial equity is amplified. Data show that PAD and CLTI disproportionately affect minorities. A 2017 study used a nationally representative Healthcare Cost and Utilization Project inpatient data sample of patients diagnosed with PAD between 2006 and 2013. Of the 34,612 African American and 15,277 Hispanic patients included in the study, 27.9% and 20.8%, respectively, underwent any leg amputation; 18.2% and 15.7%, respectively, specifically underwent lower leg amputation. African Americans, the researchers concluded, were twice as likely to be amputated compared with Caucasian patients, and account for “about 50% to 55% of the disparities in amputation rates.”
“[The] lack of awareness of the clinical, economic, and human impact of this epidemic at the patient, provider, payor, hospital, and community levels has significantly contributed to this attitude of indifference toward limb loss,” Fakorede said, “particularly in racial [and] ethnic minorities. We have normalized the inhumane act of removing a limb despite its disabling and deadly impact.”
Peripheral Artery Disease: A Global Problem
The PAD problem transcends the borders of both Mississippi and the United States: globally, PAD is considered a major public health concern, affecting roughly 202 million people worldwide—primarily in low- and middle-income countries. Among high-income countries, Germany, Italy, Spain, the United Kingdom, and France represent 75% and 78% of the PAD and CTLI burdens, respectively, in Western Europe.
When these data are broken down further, the picture painted for racial and ethnic minorities can feel grim. Data from population-based studies—of which there are few—show that compared with Caucasians, racial and ethnic minorities worldwide are more likely to experience PAD. People living in low- and middle-income countries also bear a disproportionate burden of PAD at a younger age than people living in high-income countries—45 to 49 years compared with 65 to 69 years, respectively—representing nearly 73% of all global PAD cases.
Globally, these risks are compounded by poor access to healthcare resources: socioeconomic status is a major determinant of cardiovascular disease in general and has been directly related to PAD development and hospitalization. A 2017 study published in the Journal of the American Heart Association found that compared to people with high household income, those with the lowest household income had a risk of PAD and PAD-related hospitalization that was nearly double.
Back in the United States, approximately 8.5 million Americans are living with PAD, 6.5 million of whom are, according to the US Centers for Disease Control and Prevention (CDC), adults 40 years or older. Here, too, racial and ethnic minorities bear a disproportionate burden of disease, with African Americans, Hispanic Americans, and Native Americans experiencing higher rates of PAD and subsequent limb amputation than white Americans. African Americans, in particular, bear the highest burden, with a roughly 30% lifetime risk for PAD development and two to three times higher rates of diabetes and hypertension-related mortality compared to white adults in rural areas.
Aside from patient outcomes like amputation, cardiovascular events, and death, PAD and CLTI are associated with a significant economic burden on patients and the healthcare system at large.
Many patients with Type 2 diabetes go on to develop PAD—roughly 1 in 3 over the age of 50, according to the American Diabetes Association. Type 2 diabetes already creates a financial burden, particularly for patients living in underserved areas. The estimated total economic cost of type 2 diabetes was roughly $327B in 2017, with individual-level healthcare costs more than 2.3 times higher for people with diabetes than people without.
When these patients develop PAD—whether due to uncontrolled blood sugar, poor diet and exercise habits, or a lack of access to insulin and other necessary medical care—these financial burdens are compounded. In 2016, combined annual costs for lower-extremity PAD exceeded $21B; on an individual level, estimates place the average per-patient healthcare expenditure for a person with PAD at $11,553 per year. Costs, of course, vary by insurance type but generally factor in spending on increased prescription medications, inpatient and outpatient hospital-based care, and office-based care, as well as out-of-pocket medication costs.
Frequent hospitalizations are another PAD-associated cost, with many PAD patients requiring hospitalization. Among the 286,160 hospitalizations recorded through the National Inpatient Sample, 48% were for severe Stage 3 or 4 diseases associated with CLTI. These patients may experience major adverse limb events, major or minor nontraumatic amputations, or death, and generally required a longer median length of hospital stay, associated with a median cost of $18,984 per stay and an annual burden of roughly $3.5 billion.
Outside of hospitalizations and utilization of care, amputation contributes significantly to the economic burden associated with PAD. Major amputation is the most expensive treatment available for CLTI, and despite this, is still the most popular. Treatment with major amputation is one of the primary factors increasing CLTI costs, according to Mary L. Yost, MBA, president of the Sage Group, LLC. Direct medical costs of major amputation, said Yost, were $13.4B in 2020, most of which were associated with inpatient spending. Follow-up costs typically exceed $160,400 per patient, with lifetime costs topping $11.1B. This, according to Yost, adds up to $24.5B.
And because many patients who undergo major limb amputation are insured through Medicare and Medicaid—two insurers who pay almost 80% of the bill for major amputation—this outsized spending is financed by public tax dollars.
Comparatively, the direct medical costs—that is, the total cost of all healthcare—associated with cancer is only $80.2B, illustrating just how financially devastating PAD and CLTI can be.
Fighting PAD Through Law and Policy
When Foluso Fakorede set up his practice, Cardiovascular Solutions of Central Mississippi, in 2015, he was well aware of the impact of health disparities and racial biases on patient outcomes. Health inequities loom large in minority communities across the country. For example, African Americans, Hispanic Americans, and Native Americans are less likely to have health insurance and access to local healthcare and more likely to experience chronic health conditions than their white counterparts. And although CDC data show that the death rate for African Americans, in particular, has declined by 25% over the last 17 years, they are still more likely to develop chronic diseases like diabetes—a leading risk factor for PAD.
Between 2015 and 2018, Fakorede and his team decreased nontraumatic PAD-associated amputation rates in Bolivar County, Mississippi, by 88% through a multipronged strategy of patient education, prevention, angiogram screenings, and nonsurgical treatment. Following these local successes, Fakorede took his advocacy to the national stage.
In 2019, Fakorede testified in Congress on behalf of the Association of Black Cardiologists, of which he is the PAD Initiative Co-Chair. His testimony led to the creation of the bipartisan Congressional Peripheral Artery Disease Task Force, led by Representatives Donald M. Payne, Jr, a Democrat from New Jersey, and Gus Bilirakis, a Republican from Florida. Since its creation, the Caucus has been hard at work to prevent non-traumatic amputations, identifying four key priorities for Congress:
- Addressing how Medicare handles multidisciplinary review of patients with PAD
- Addressing the lack of arterial testing before nontraumatic amputations
- Creating an intragovernmental working group responsible for developing a comprehensive PAD amputation prevention program
- Encouraging the US Preventive Services Task Force (USPSTF)—a group of nationally recognized experts responsible for publishing evidence-based guidelines—to review screening recommendations for PAD in patients considered at-risk.
Representative Payne and his co-sponsors first introduced a bill—The Amputation Reduction and Compassion (ARC) Act—in October 2020. The bill has been reintroduced to the 117th Congress as H.R.2631: The Amputation Reduction and Compassion (ARC) Act of 2021. The bill’s co-sponsors hope to amend two titles of the Social Security Act to ensure financial coverage for PAD screening in at-risk Medicare and Medicaid beneficiaries—a group of patients usually excluded from preventive screening due to current USPSTF recommendations, which found “inadequate evidence” to conclusively say whether PAD screening in asymptomatic individuals provides a clinically meaningful benefit. In other words, programs like Medicare and Medicaid aren’t required to financially cover these screenings because there’s no hard data showing that screening those who are at-risk or asymptomatic can prevent either PAD progression or later cardiovascular events.
Representative Payne and his co-sponsors introduced H.R.2631 on April 16, 2021. Since then, the bill has been referred to the House Energy and Commerce and Ways and Means Committees to determine which committee is a better fit.
In the meantime, advocacy groups like the CardioVascular Coalition have applauded the bill, writing in a press release that expanded coverage for PAD screening can go a long way in preventing PAD complications in vulnerable populations that include racial and ethnic minorities. The Society for Cardiovascular Angiography and Interventions (SCAI) also commended the bill, releasing a statement on behalf of the PAD Task Force—which includes members from the Association of Black Cardiologists, the CardioVascular Coalition, the Preventive Cardiovascular Nurses Association, and the Society of Interventional Radiology—calling the ARC Act “historic.”
Treating PAD and CLTI:
on the Cutting Edge
Cindy & Doctor
Wilhemina & Doctor
At the forefront of innovation around amputation prevention is LimFlow, Inc.—a pioneer in minimally-invasive CLTI treatment technology—is hard at work developing their Percutaneous Deep Vein Arterialization System. This minimally invasive device was initially evaluated in the United States as part of the completed PROMISE I trial and is currently under investigation as part of the larger PROMISE II trial. The LimFlow System is designed to bypass arteries and restore blood flow to the leg and foot, which could resolve patient pain, promote wound healing, and avoid the need for a nontraumatic major amputation. It is not commercially available in the US.
In severe cases of PAD and CLTI, diseases can progress until patients are “no-option patients.” These individuals have a poor prognosis and poor quality of life, typically requiring surgery, endovascular interventions, and hospitalization. In addition, these patients frequently undergo unnecessary limb amputation—nearly 200,000 of these surgeries are performed annually—with skilled vascular interventionalists who can perform alternative revascularization procedures thin on the ground in some areas of the country.
Results from the PROMISE I study were recently published in the Journal of Vascular Surgery and highlighted limb salvage and survival rates at 12 months in a no-option patient population.
“One-year outcomes demonstrate that the benefits from treatment with the LimFlow System are durable,” said Daniel Clair, MD, PROMISE I principal investigator and chair of the department of surgery at the University of South Carolina (USC) and Prisma Health-USC Medical Group. “One of the greatest challenges in the treatment of CLTI is to achieve long-lasting outcomes due to disease progression. In this study, the vast majority of patients who would otherwise be facing major amputation were able to avoid it and, at the same time, heal their previously non-healing wounds. This type of lasting result in such a challenging, no-option patient population offers tremendous hope to CLTI patients and the physicians who treat them.”
An economic analysis, published in the Journal of Critical Limb Ischemia, demonstrated remarkable economic outcomes—good news for hospital systems and insurers who place a premium on price. Using the PROMISE I 12-month data, the analysis compared the cost-effectiveness of the LimFlow system with the “status quo” for no-option CLTI patients, indicating that expected outcome improvements justify fully the incremental costs associated with LimFlow, categorized as a “high-value” therapy based on established willingness-to-pay thresholds.
“This research highlights the health economic benefits of reducing amputations and the need to offer a better alternative worldwide,” said Peter A. Schneider, MD, Professor of Surgery at the University of California, San Francisco, and co-author of the paper.
Through the ongoing PROMISE II trial, LimFlow investigators are hoping to give no-option patients new options—that is, patients who are at the end stages of PAD who are experiencing chronic limb-threatening ischemia, and are facing a lower limb amputation. Unfortunately, not all patients with CLTI are candidates for revascularization; these patients often have little to no blood flow, progressive tissue loss, and previous unsuccessful attempts at halting disease progression.
LimFlow’s technology is the first and only deep venous arterialization (DVA) system under clinical evaluation in the United States and may provide an alternative therapy for patients who have no other revascularization options. Rather than remove the limb, the LimFlow technology is designed to restore blood flow and critical oxygen supplies to starved tissues, which may lead to wound healing and improved quality of life.
“Avoiding major amputation is a key treatment goal in CLTI due to its associated high costs, loss of functional status and quality of life, and high mortality,” added LimFlow CEO, Dan Rose. “The analysis…demonstrates [that] our technology can provide significant clinical and health-economic value to patients and healthcare providers who are drastically underserved by the status quo.”
Keep reading to meet just a few of the patients LimFlow has helped, and click here to learn more about this ground-breaking technology.