August 06, 2018
6 min read

Q&A: The problem of CLI

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Alik Farber
Alik Farber
Chronic limb-threatening ischemia, also referred to as critical limb ischemia, is a condition that affects 1% to 2% of the population and up to 11% of patients with peripheral artery disease. However, this common problem remains a mystery to many physicians.

In a paper published in The New England Journal of Medicine, 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, reviewed diagnosis and treatment options for the growing population of patients with CLI.

As our population ages and the incidence of diabetes, obesity and chronic kidney disease increases, so will the incidence of PAD and, consequently, CLI. Therefore, the need to be aware of and understand the various ways in which to evaluate and treat this disease is important.

Farber spoke with Cardiology Today’s Intervention about the critical aspects of caring for patients with CLI.


Q: What is CLI?

A: Chronic limb-threatening ischemia, or critical limb ischemia, is a condition in which there is insufficient blood flow to the extremity to allow for normal metabolic function of that extremity.

It is important to note that CLI is a chronic process. Whereas acute limb ischemia is typically diagnosed if symptoms are within 14 days, the condition is referred to as CLI when the symptoms persist beyond 14 days. However, there are a lot of issues with nomenclature. Some people refer to CLI as severe limb ischemia, chronic critical limb ischemia, CLI and more. I have started using the term chronic limb-threatening ischemia because, more recently, people are thinking it may be a better way to describe the condition.


Q: How is CLI diagnosed?

A: The diagnosis of CLI starts with clinical evaluation. Basically, the clinical presentation is either pain or numbness in the foot at rest or tissue loss, including ulcers, wounds or gangrene. Therefore, diagnosis is based on history and physical examination. Then, noninvasive vascular studies are used to show and/or confirm ischemia.  

There are a number of noninvasive studies, but in our article in NEJM, we describe at least five of the more commonly used studies. Typically, people use ankle-brachial index (ABI), toe pressures, pulse-volume recordings, Doppler waveforms or transcutaneous oximetry.

It must be emphasized, however, that no one test on its own is perfect. ABI, for instance, is a measurement of pressure at the ankle divided by pressure at the upper arm. In many patients with CLI, though, pressure cannot be measured at the ankle because the arteries are calcified. We often see this in patients with diabetes and kidney failure, which are common in patients with CLI. In these cases, ABI isn’t as useful because the ABI may appear normal or elevated because the pressures are not compressible. Toe pressure can also be useful because the toe arteries are not as calcified, but again, it may not be the best measurement for every patient.

In general, we typically obtain a number of these different noninvasive studies for any given patient because a well-supplied, well-functioning vascular lab can perform a battery of these tests simultaneously so that the interpreting physician can get a better sense of what is happening. It’s more complicated and nuanced that just obtaining an ABI.


Q: What are the current treatment options for patients with CLI?

A: I like to think of treatment of CLI in three domains.

The first domain is medical management. Because atherosclerosis is the most common cause of PAD and CLI in many of these patients in most countries and because atherosclerosis also affects other vascular beds in the heart, brain and neck, medical risk factor optimization is essential. Patients are advised to quit smoking; they are often started on antiplatelet agents such as aspirin if they’re not already taking them; and they initiate statin therapy. Patients are also started on antihypertensives. ACE inhibitors in particular have been shown to improve outcomes in patients with PAD. Additionally, if patients have diabetes, there is evidence to suggest that controlling blood glucose can improve outcomes as well.

These data are based on PAD — not necessarily CLI — but medical therapy is important to deliver to these patients.

The second domain of treatment is soft tissue therapy. Patients may present with an ulcer, infected toenails or an abscess in the foot. If an abscess develops, it must be drained. Sometimes, but not always, soft tissue therapy involves amputation of the toe or several toes.

The third domain is revascularization, or restoring blood flow to the leg. The patient may have an imaging study, such as MR angiography or CT angiography, to assess the location and extent of occlusive disease. More often than not, the patient will need contrast catheter-based angiography. Once imaging studies are completed, the decision is made to perform endovascular therapy or surgical bypass to improve blood flow to the foot. 


Q: Is one therapy more appropriate for a certain type of patient?

A: The BEST-CLI trial, for which I am a national co-primary investigator, is being conducted to answer this question. As of today, the trial is more than two-thirds of the way done. The BASIL-2 trial, which is being conducted in the United Kingdom, also seeks to answer a similar question. We eagerly await the results of these landmark trials.

Before these data are available, however, the basic answer is that patients who are at high surgical risk, those with limited life expectancy, those with minor tissue loss or discrete lesions and those who do not have good veins are typically thought of as being better candidates for endovascular therapy. Conversely, patients who are at average surgical risk have major tissue loss, diffuse disease and a good single saphenous vein are thought to be better suited for surgical bypass.

However, it’s important to bear in mind that there is an enormous amount of bias and disagreement. The same patient could be offered two different treatments — surgery vs. endovascular therapy — if they went to two different doctors within the same group, not to mention two different hospitals in the same city.


Q: Are there new therapies on the horizon?

A: Endovascular therapy is evolving, so there are new devices becoming available that have promise to improve outcomes. Drug-coated balloons and drug-eluting stents have moved the needle in terms of outcomes but more data are needed to tell us when and where to best use these technologies. The hope is that, as the technology advances, endovascular therapy will improve significantly.

Researchers are also investigating stem cells and gene therapy as ways to increase angiogenesis or formation of the blood vessels around blockages to try to improve circulation. The studies thus far have yielded mixed results, and the jury is still out as to whether they are a viable option.


Q: What is the biggest challenge facing physicians caring for patients with CLI?

A: The biggest challenge is definitely the lack of good science to drive decision-making. We don’t have much information about what treatment works best for which patient. There is plenty of research being done, but many of the studies are not necessarily answering questions that are relevant to clinical practice. For instance, DCBs have been studied, but they were tested against plain balloon angioplasty, which is what the FDA requested. Although those results are helpful and important, knowing that DCB is better than plain balloon angioplasty does not exactly help me as a practicing vascular specialist. What helps me more is knowing how one DCB performs against stents or another DCB, under what circumstances we should use DCB or for what sort of lesions we should use DCB and in what kind of patient.


Q: Do you have any advice for physicians treating patients with CLI?

A: I urge physicians to continue doing what’s best for their patients. These are complicated patients. Many are sick or may even be at the end of life, so physicians must balance what’s right for the patient and what’s right for society in terms of the effort that is placed. For example, some patients may be better off with amputation than with multiple interventions. All of this is nuanced and complex, especially against the backdrop of a fee-for-service health system in which people are paid for procedures.

We also need to participate in trials and be open to learning more so we can find answers to these important questions regarding treatment.


Q: Is there anything else you would like to discuss?

A: CLI is a condition that many doctors do not feel comfortable managing. Our article shines light on this disorder and I hope it will allow for increased awareness of and conversation about how to best manage these patients. In this way, we can demystify the condition and help improve treatment overall. – by Melissa Foster


Farber A. N Engl J Med. 2018;doi:10.1056/NEJMcp1709326.

For more information:

Alik J. Farber, MD, can be reached at

Disclosure: Farber reports no relevant financial disclosures.