Peripheral Artery Disease Treatment: Changing the Status Quo

Chronic limb-threatening ischemia (CLTI), previously known as critical limb ischemia, is the most advanced form of peripheral artery disease (PAD). People with CLTI have dramatically reduced blood flow to their legs and feet due to narrowed arteries caused by atherosclerotic plaques, which can cause pain and tissue damage.

A new paper from Yale researchers investigates the factors that impact mortality in patients with CLTI. The paper, Long‐Term Mortality Predictors Using a Machine‐Learning Approach in Patients With Chronic Limb‐Threatening Ischemia After Peripheral Vascular Intervention, was published in the Journal of the American Heart Association (JAHA).

In the following conversation, the first and senior authors of the paper, Santiago Callegari, MD, postdoctoral fellow (cardiovascular medicine) and current internal medicine resident at Yale, Carlos Mena-Hurtado, MD, associate professor of medicine (cardiovascular medicine) and co-director of the Vascular Medicine OutcomeS program (VAMOS), and Kim Smolderen, PhD, MSc, associate professor (cardiovascular medicine and psychiatry) and co-director of VAMOS, highlight the findings of their new paper and discuss why the field of medicine should adjust its approach to caring for patients with CLTI.

What prompted you to conduct this research?

SC: More than one million people in the United States and 20 million globally have CLTI. Patients with CLTI have a dramatic reduction in their quality of life, an overall high psychological and medical comorbidity burden, and very high rates of amputation and mortality. It’s important to understand which factors are most highly associated with mortality rates so that we can better care for these patients.

KS: The rates of vascular disease are increasing rapidly, especially in younger populations. We must get this right.

What were some of the key findings from your paper?

SC: We found that the factors most highly correlated with mortality rates for patients with CLTI included stage 5 chronic kidney disease (CKD), advanced age, congestive heart failure, dementia, and dysrhythmia.

We also found the factors that predict mortality in CLTI are significantly broader than just medical comorbidities and CLTI characteristics. Other factors include functional limitations, demographics, and behavioral variables that we don’t frequently look for or address when making a care plan for people with CLTI.

My main takeaway from this research is that we need to take a step back and consider all of these variables in patients’ health plans if we are to improve outcomes.

How did you conduct this research?

SC: We used a machine learning model called a random survival forest, which builds decision trees and ultimately provides a highly accurate relative ranking of each variable. This type of model can handle a lot of data and overcomes statistical limitations of traditional logistic regression models, which allowed us to look at more than 65 variables that could play a role in predicting mortality. All of this work would not be possible without the expertise of Dr. Gaëlle Romain, the second author of the manuscript and biostatistician for the VAMOS Lab.

What is the current standard of care for patients with CLTI?

CMH: Currently, the cornerstone of CLTI treatment has been medical therapy. Unfortunately, we’ve shown in prior publications, including in JACC and the JAHA, that medical therapy is underused in our country.

Much of the emphasis has been on revascularization, meaning opening those blockages through minimally invasive or surgical procedures.

Why is it important to rethink how we care for CLTI patients?

CMH: Despite the treatment options available for patients with CLTI, health outcomes remain poor, and patients do not have a high quality of life. CLTI mortality rates are incredibly high. We want to figure out why this happens and how we can improve care for patients with CLTI and other vascular diseases.

KS: Clinicians caring for patients with CLTI tend to focus on fixing the local perfusion (increasing the volume of blood moving through the arteries and capillaries), but we may overlook that patients often have bad long-term outcomes even with that treatment. We need to transition to a multidisciplinary and integrative approach to managing vascular disease. We also need individuals suffering from the condition to articulate what they prefer for their care and treatment goals, which may differ from what their insurance approves, and make sure their treatment plan reflects their wishes and approaches the disease from a holistic point of view.

What do you hope other researchers and clinicians take away from this paper?

KS: It’s important for all of us who are interested in improving options for individuals with CLTI and other forms of PAD to work together. We recently held a conference focused on building some of these relationships across fields so that we can all work together to care for every aspect of the patient—not just the revascularization. More work is needed, but I’m optimistic we can get there.

Other Yale authors of the paper include Gaëlle Romain, PhD, MSc, biostatistician (cardiovascular medicine), Jacob Clemen, MD, clinical fellow, Lindsey Scierka, MD, MPH, clinical fellow (cardiovascular medicine), and Francky Jacque, MD, MSCE, postdoctoral fellow (cardiovascular medicine).

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