PAD widely prevalent, consequences could be dire

New reports have suggested that the prevalence of peripheral artery disease is increasing sharply. According to a recent meta-analysis, an estimated 202 million people worldwide had peripheral artery disease in 2010, up 23.5% from 164 million in 2000.

“There is a general lack of awareness of this condition among health professionals, yet it is an indicator of high risk for major cardiovascular events and death, requiring preventive measures,” said F. Gerald R. Fowkes, PhD, FRCPE, FFPH, one of the researchers of the meta-analysis that was published online by The Lancet in August.

In the United States and other developed countries, research and development is being invested for ways to better diagnose and treat PAD. Patients who 20 years ago would have had limbs amputated because of PAD are now having their limbs saved because physicians are better able to recognize symptoms of PAD and have more numerous and advanced treatments at their disposal. Additional treatments, including drug-coated balloons and stem cell therapy, are on the way.

“PAD is out there much more so in the public eye than it had been before,” Peter Schneider, MD, chief of vascular therapy at Kaiser Foundation Hospital, Honolulu, told Cardiology Today. “We have many more people interested in it, more people studying it and more dollars to pay for studies to look at it.”

The question for many is whether advancements in PAD awareness, diagnosis and treatment can keep up with the increasing prevalence.

Widespread prevalence

Several factors may help explain why there has been a sharp growth in PAD rates since 2000.

“There are four major reasons,” 
Michael R. Jaff, DO, chair of the Institute for Heart, Vascular and Stroke Care and medical director of the Vascular Center at Massachusetts General Hospital, said in an interview. “First, the population is getting older. Most PAD is atherosclerotic in nature, and that occurs in an older population. Second, diabetes is out of control. If you look around the world for places where PAD prevalence is rising, those are also places where diabetes is highly prevalent. Third, in many places around the world, tobacco use continues to be a major risk factor for PAD, and it continues to be highly prevalent. Fourth, people are looking for PAD more. There are more therapies available now that weren’t before. The ability to make this diagnosis is easier than it was in the past.”

However, Fowkes said “none of the increase in PAD in our study can be attributed to increased detection because the results are all based on population surveys using the same detection technique.”

More likely, according to the experts, is that PAD was always prevalent but, because of shorter lifespans, symptoms did not present before death as often in earlier generations. “I cannot prove this, but this population with PAD in an earlier generation might have died young of heart disease,” Schneider said. “With better medical management [and intervention techniques], you have this whole population that has lived for many years with all the risk factors for cardiovascular death. In the United States, the cardiovascular mortality rates have dropped significantly, and a lot of those people who would have passed away in a previous generation are now turning up with these signs and symptoms of atherosclerosis in other beds.”

Fowkes agreed, citing better survival rates for MI and stroke in high-income countries and better survival rates for infectious diseases in low- and middle-income countries.

Better detection, communication

Many are left asking what health professionals can do to combat the increasing number of patients with PAD.

First, increase efforts to detect PAD during routine examinations, as symptoms in the early stages are easier to alleviate than those in the later stages, which may require surgery or amputation.

“These patients benefit dramatically from early therapy, evaluation and intervention as appropriate,” said John H. Rundback, MD, FAHA, FSVM, FSIR, medical director of the Interventional Institute at Holy Name Medical Center and managing partner at Advanced Interventional Radiology Services LLP, both in Teaneck, N.J.

Second, take quick action to confirm a diagnosis if PAD is suspected and communicate across disciplines, as outcomes tend to be better when the disease is treated in a comprehensive way. Third, keep up with the rapidly evolving advances in treatment.

There are simple ways to assess for PAD, but not everyone uses them, Rundback said.

“The primary care doctors need to do a complete vascular exam,” he said. “Only one in four doctors feels for peripheral pulses. Only one in three doctors feels for abdominal aortic aneurysm. Only one in two doctors listens for carotid bruits. These need to be part of the routine physical examination to identify patients. Podiatrists should be screening these patients routinely. Doctors have to regularly take off the patient’s shoes and socks and evaluate for PAD and identify ulcers early in the diabetic and renal failure populations because those ulcers can quickly turn bad and result in amputation. Nephrologists deal with a population at high risk for PAD, but gloss over PAD routinely in their evaluations of patients. If they can make it a practice where they take off shoes and socks of patients with chronic kidney disease and patients on dialysis for periodic regular evaluation and further referral as appropriate, that would go a long way toward stopping the rise of amputation in this brittle population.”

Another simple and common way to screen for PAD is to use resting ankle-brachial index (ABI). However, a study by the US Preventive Services Task Force found that drawbacks of using ABI as a screening mechanism included false-positive results, exposure to gadolinium or contrast dye if CT or MR angiography is used to confirm the diagnosis, and adverse events from medications unnecessarily prescribed. The USPSTF team called for large, population-based, randomized trials to determine whether screening for PAD with ABI improves clinical outcomes.

Also crucial are quick evaluation and testing and, especially for patients who may have advanced PAD, timely referral to vascular specialists and wound care centers, Gary M. Ansel, MD, FACC, system medical chief for vascular services at OhioHealth, Columbus, told Cardiology Today.

“The typical norm [was] you were seen for an ulcer, and you need some noninvasive testing, which takes a week or two, and then it is discovered it’s really bad, so you need to see a specialist in another couple of weeks. Before you know it, you’re 5 or 6 weeks down the road, and the ulcer turns into gangrene,” Ansel said. “We created a center where everything is done within 24 to 36 hours. You get your initial consultation, you get point-of-care noninvasive testing and, if that’s abnormal, even that day you’d get your specialist consultation. If there’s a need for an angiogram or revascularization, it’s usually done very early the next day. A lot of centers are moving toward a similar approach.”

Increased discussion of cases across disciplines is also being utilized for better and earlier diagnosis and treatment, Schneider said.

“My hospital started a diabetic limb treatment program in 1995,” he said. “It’s staffed by internal medicine, podiatry and vascular surgery, with consults from orthopedics, ID, endocrinology and others. It meets twice a week. We have the ability to do vascular studies right in the diabetic limb treatment clinic, so if a patient comes in as a new referral and there’s a question about the perfusion, they can get a noninvasive study right at the same time. One of the challenges with diabetics with open lesions in particular is that so many things have to happen right for them to keep the leg. They have to show up to someone who understands what they’re looking at [and] how complicated it can be.”

Such efforts have led to a dramatic decrease in PAD-related amputations in some parts of the United States. Researchers at the Mayo Clinic analyzed data from the Rochester Epidemiology Project (773 patients undergoing 1,906 limb procedures; 58.5% men; 96.5% white) and found a 40% decline in PAD-related amputations from 1990 to 2009. The researchers, who presented their findings at the Society for Vascular Surgery’s 2013 Vascular Annual Meeting, mainly attributed the improvement to increased limb revascularization.

However, Jaff said those data may not apply globally. “I don’t think the rates of amputation are decreasing around the world, particularly in the areas where diabetes is so prevalent,” he said. “Maybe there are parts of the United States where there’s a better system of care, in which amputation rates would be decreasing, but I doubt that’s the case around the world.”

Most PAD-related amputations are preventable if the disease is detected early enough, Rundback said.

“Half the amputations in this country are performed without ever undergoing a vascular evaluation,” said Jaff, who is a member of the Cardiology Today Editorial Board. “If you do have vascular disease, which is predominant, 80% of the limbs can be salvaged. But early identification and referral is critical.”

Conservative therapies

More US patients with PAD may be spared from amputation than in previous years, but there are still many who are not treated until the disease has progressed to the point of severe symptoms. Therefore, experts said, it is important to keep up with the latest treatments, for both early- and advanced-stage PAD.

For patients who have mild symptoms such as claudication or are asymptomatic, antiplatelet therapy and exercise can be an effective course of treatment, Rundback said. Although there are not many medications dedicated to the treatment of PAD, cilostazol (Pletal, Otsuka Pharmaceuticals) has shown benefit in some cases, according to Jaff and Rundback. Newer medications for lipid control and BP control can also help prevent PAD symptoms.

After identifying the atherosclerosis burden in other vascular beds and assessing whether a patient is at risk for MI, stroke or death, physicians should counsel patients who are not at high risk “on exercise, walking, foot care and shoe care,” Jaff said. “And, I’d put them on an aggressive walking program for a period of 3 to 6 months. If their symptoms improve, I’d continue them on that program. If they feel that despite all efforts their symptoms are not improving or in fact are worsening, then I would consider evaluating where their anatomic disease is located and, based on that, make a decision about how to improve their blood flow.”

Encouraging smoking cessation is also crucial. “That is the absolute most important thing” to help prevent PAD from getting worse, Schneider said.

Interventional, surgical options

Should a patient have a more severe form of PAD, such as critical limb ischemia, superficial femoral artery disease or femoral-popliteal disease, there are a number of interventional and surgical options, and more in development.

“The majority of [these] patients appear to be best served by considering an endovascular percutaneous approach first,” Ansel said. “There are variables that we’ll take into account. One, how much blockage is there? Is there blockage behind the knee and then all the way down to the foot? Do they have a conduit, a bypass material like a vein that could be utilized? What’s their kidney function? Can they tolerate a dye or catheter-based approach?”

However, not everyone has appropriate expertise in all options, Ansel said. “The interventional operators are being much better educated, but there’s still a deficit in the United States and the other major developed countries in the number of physicians that have enough of an advanced skill set to fully revascularize these patients.”

A noteworthy new tool available in the United States, Jaff and others said, is the Zilver PTX drug-eluting peripheral stent (Cook Medical), which received FDA approval in November 2012 after trials showed superior performance compared with percutaneous transluminal angioplasty and bare-metal stents. Cook Medical issued a recall in April after reports of delivery system tip separation, but began shipping the product again in August.

The recall aside, based on results from registry studies, real-world performance of Zilver PTX has been “significantly better than what people have expected, and very similar to what was reported in the trial,” Jaff said. “People seem to be optimistic about this technology.”

Several nitinol stents have received or are seeking approval for use for superficial femoral artery disease, including the S.M.A.R.T vascular stent system (Cordis), the EverFlex self-expanding stent (Covidien/ev3) and the SUPERA Veritas self-expanding nitinol stent system (Abbott Vascular), Jaff said.

Balloons are useful for treating long tibial blockages, Ansel said. “It has only been in the last 8 years or so that we’ve had long balloons to be able to treat blockages, which are oftentimes at least half the length of the knee to the ankle,” he said. “Many of the patients who have diabetes will have kidney failure as well, and those patients tend to have foot blockage. We are trying to develop the technology to open those vessels.”

Drug-coated balloons are approved in Europe and have been praised by interventionalists using them there, Ansel and Jaff said. However, they are not yet approved in the United States. “In drug-coated balloons, the FDA has been concerned about the amount of debris that goes downstream, even though we haven’t seen anything worrisome in Europe,” Ansel said. “We have to think outside the box because it’s a population where the amputation risk is significant and we need to be able to try to cut down on the number of repeat procedures for these patients.”

Examples of drug-coated balloons include the Lutonix drug-coated balloon (Bard), the IN.PACT Admiral drug-eluting balloon (Medtronic) and the Cardiovascular Ingenuity (CVI) paclitaxel-coated percutaneous transluminal angioplasty balloon catheter (Covidien/ev3).

There are also several options for support catheters and guidewires, Ansel said. “We tend to use a lot of hydrophilic wires, which have revolutionized getting across these long tibial blockages,” he said. Effective products in this area include the CXI support catheter (Cook Medical) and the Quickcross support catheters (Spectranetics), Ansel said.

“The procedures are becoming faster and more effective,” he said. “We just need to get something that allows us to maintain the staying-open rate for a longer time period.”

Another interventional option is atherectomy. “There are many who believe that atherectomy is going to be an important component to the treatment of patients with PAD,” Jaff said. Among the atherectomy devices available are the SilverHawk atherectomy catheter (Covidien), the Turbo Elite laser atherectomy catheter (Spectranetics), the Orbital atherectomy system (CSI) and the Jetstream Navitus system (Bayer/Pathway Medical Technologies), he said.

Bypass performed less often

There are still plenty of patients, however, who cannot be helped by intervention and for whom bypass surgery is the only option before amputation. Schneider estimates that 10 years ago, about 80% of patients needing surgery received bypass and the rest received balloon angioplasty or another intervention, but now the ratio has reversed.

Data published in August in the Journal of Vascular Surgery by Malas and colleagues showed that femoral popliteal bypass was associated with a higher rate of reintervention compared with stenting. Researchers found that patients receiving stents showed improved primary patency at 24 months compared with patients undergoing bypass (67% vs. 49%; P=.05), and patients receiving stents had a 31% reintervention rate vs. 54% for those receiving bypass (P=.02). Schneider said, however, these results must be considered in the context of previous studies showing better long-term patency for bypass compared with stenting, and the value of bypass should not be discounted just because there are less risky options now.

“The challenge is this: We have an existing technology, bypass, which works fairly well but has morbidity associated with it,” he said. “So, now we have new endovascular technologies. We think it works, or at least it works in most patients. But in those patients where it doesn’t work, it would be awful if those patients went on to lose limbs despite the fact that we already had an existing technology that would have saved them. We don’t know which patients, if any, would be better off treated right off the bat with a bypass.”

There are more treatments in development for patients with PAD that may ultimately help those who are unable to benefit from current interventional and surgical procedures. Bioresorbable devices are in development that could cut reintervention rates even further. And, PAD is a focus for some researchers working on genetic and stem cell solutions.

“For patients who have critical limb ischemia, non-healing, there’s a tremendous amount of work being done with gene therapy and stem cell therapy and injection of precursor cells from the bone marrow to help restore blood vessels and muscles and allow ulcer healing, when otherwise it would have … resulted in amputation,” Rundback said.

Outlook for the future

There are no signs that the prevalence of PAD is going to decline any time soon.

“If I’m right, and diabetes and cigarette smoking are major culprits here, the consequences are going to be dire,” Jaff said. “Because patients who have PAD in combination with either diabetes or tobacco abuse tend to have a more diffuse pattern of disease, that affects more of the arteries of the leg as opposed to one focal area.”

However, Schneider said, better recognition of the disease and better technology could make the outlook less alarming.

“You could match up this dramatic increase in the number of procedures we’ve seen in the past years … with what appears to be a spike in the number of patients with PAD, and become extremely worried about how we are going to keep up with this,” he said. “But I don’t necessarily think that’s going to happen. We have a much larger workforce who understands PAD more than we did even 5 or 10 years ago. That, coupled with the fact that people are choosing healthier lifestyles as a first choice, and not some type of intervention as a first choice, I suspect that we will have enough people power to deal with what will be a slow but steady increase in the number and types of procedures.”

Disclosure: Ansel serves on medical advisory boards for Abbott, Bard, Boston Scientific, Cook Medical, Cordis Vascular, CSI and Medtronic and receives a royalty on some Cook Medical interventional devices. Fowkes receives fees from AstraZeneca as co-chair of the EUCLID trial. Jaff is an unpaid consultant for Abbott Vascular, Boston Scientific, Cordis, Covidien and Medtronic, and has an equity interest in PQ Bypass Inc. Jaff and Rundback are board members of VIVA Physicians, a not-for-profit 501(c)(3) organization. Rundback is a consultant for Biotronik, Covidien/ev3, St. Jude Medical and Simbionix, an unpaid consultant for Bluegrass Technologies, Boston Scientific and Ekos, and receives institutional research support but no compensation from Atrium, Bard/Lutonix, Cardiovascular Systems Inc., Celo-Nova, Cordis/Flexible Stenting Solutions, Daiichi Sankyo and Terumo/Harvest. Schneider is chief medical officer for Intact Vascular and receives a royalty for intellectual property from Cook Medical.