Time for PAD to Come Out of the Shadows, Say GetABI Researchers

September 7, 2007 (Vienna, Austria) — Screening for peripheral arterial disease (PAD) should be performed routinely in all elderly patients and younger ones with cardiovascular risk factors, says Dr Curt Diehm (Affiliated Teaching Hospital, Karlsbad-Langensteinbach, Germany), who reported the results of the German epidemiological study on ankle brachial index (getABI) during the hotline session at the European Society of Cardiology congress today. And those found to have PAD should be treated in the same way as patients with coronary artery disease (CAD), he said, stressing that PAD patients are currently undertreated.
GetABI shows that PAD patients have a substantially increased risk of death — dying, on average, 10 years earlier than their peers — and that asymptomatic PAD patients are as much at risk as symptomatic ones, a vital fact that was not previously appreciated, he said. This latter point is very important; "This is the first time, in such a big study, that we have found no difference in mortality between asymptomatic and symptomatic PAD patients. We learned that PAD patients are usually asymptomatic, and we say in the guidelines that symptomatic patients have to be treated in a different way, but now we need to change the guidelines."
It is also imperative that the traditional view of PAD is changed, he said. "It used to be considered a disease of impaired walking distance, quality of life, or of amputation, or just a smoker's disease — so-called smokers leg," Diehm said. But they found that half of the patients who had PAD had never smoked: "Today we see this disease in a new light."
Mortality Almost Twice as High in PAD Patients
GetABI began in 2001 and included a total of 6,880 unselected patients who underwent ankle brachial index (ABI) testing by their primary care physician in 344 offices. The mean age of the patients was 72.5 years, 46% were past or current smokers, 74% had hypertension, 24% diabetes mellitus and 52% lipid disorders. The study is ongoing, but so far visits have occurred at baseline and six, 12, 36 and 60 months, and outcomes include death and severe vascular events — myocardial infarction (MI), coronary/carotid/peripheral revascularization, stroke or amputation due to PAD.
The study is of high quality, he added — being monitored, which is unusual for an epidemiological study, with the supervision of centers by experts. In addition, very few patients have been lost to follow-up — so far, the survival status of 99.5% of patients is known.
Diehm explained that in healthy individuals, the systolic blood pressure at the ankle should be at least as high as the pressure in the arm — ie, ABI should be 1 or greater. An ABI of < 0.9 indicates PAD, and an ABI of < 0.5 indicates severe PAD. In the study, asymptomatic PAD was defined as an ABI of < 0.9 and symptomatic PAD as ABI < 0.9 with intermittent claudication or PAD-related amputation or revascularization.
At the end of the five-year observation period, all-cause mortality was 23.9% in the 596 patients with symptomatic PAD (hazard ratio 1.8; p < 0.001), 19.1% in the 835 patients with asymptomatic PAD (HR 1.6; p < 0.001) and 9.4% in the 5390 patients without PAD. Even after adjusting for all other known cardiovascular risk factors, PAD has the best ability to predict future death, stroke or MI, Diehm said.
ABI: An Important Prognostic Factor — Simple, Quick, and Cost-Effective
Diehm said that although it has been known for five years that the lower the ABI, the greater the mortality, this study replicated the finding, indicating that ABI is an important prognostic factor.
Screening for PAD using ABI is very simple, he explained — measurement is quick, taking just eight minutes, the equipment costs only a few hundred dollars and nurses can be trained in its use "within 15 minutes." It is also highly specific for leg artery stenosis (> 50%) and highly sensitive (> 95%), he noted.
Diehm added that in this trial, they used the higher of the two values for blood pressure in the leg, as per the American Heart Association recommendations, "but in our opinion, this is absolutely wrong because you miss distal occlusions." He said if the lower of the two leg values is used, the prevalence of PAD comes out as much higher.
The new results illustrate the feasibility of using ABI in primary care, he says. "The good news is that the ABI test is not limited to expert use but can be performed in general practice. We need to implement ABI as a screening tool in GPs [general practitioners'] offices to identify high-risk patients, and we have to change this very quickly now."
Discussant of the study, Dr Don Poldermans (Erasmus Medical Center, Rotterdam, the Netherlands) added that it is imperative to screen PAD patients for disease in additional affected vascular beds. "Only a very small number of patients will have only one affected vascular bed. We are only seeing the tip of the iceberg," he noted. PAD patients should primarily be screened for aortic aneurysms, carotid disease and CAD, he said.
Treat PAD Patients as You Would CAD Patients
Diehm explained that PAD patients are severely undertreated compared with CAD patients. Most PAD patients should be on aspirin or clopidogrel, he said, plus a statin, beta-blocker and angiotensin-converting enzyme inhibitor. Sub-group analyses of large trials such as 4S with a statin, or HOPE-2 with an angiotensin-converting enzyme inhibitor, have shown the benefit of these agents in patients with intermittent claudication, he noted.
Despite this data, "many doctors are still afraid that beta-blockers are contra-indicated in this disease, which is absolute nonsense," Diehm said. Poldermans agreed wholeheartedly. "We have known since 1990 that beta-blockers are not contra-indicated in PAD. We all know that these patients will benefit from medical therapy, but we just don't do it. We need to keep medical therapy optimized."
Diehm concluded: "Family physicians can identify high-risk patients and initiate and maintain effective treatment in this large group. PAD patients should no longer be treated as second-class atherothrombotic patients — whether you are asymptomatic or symptomatic, you die 10 years early. A huge number of lives could be saved if patients with atherosclerosis would be identified with ABI and treated timely."
GetABI was funded through an unrestricted educational grant from Sanofi-Aventis. Diehm reported no conflict of interest with regard to present data.
European Society of Cardiology (ESC) World Congress 2007. Presented September 4, 2007.

WAVE: Give Antiplatelets in PAD, Hold the Warfarin

July 20, 2007 — The addition of oral anticoagulation to antiplatelet therapy for peripheral artery disease (PAD) doesn't further reduce the likelihood of cardiovascular (CV) events, but it does raise the risk of serious bleeding complications, including hemorrhagic stroke, according to a randomized study appearing in the July 19, 2007 New England Journal of Medicine.
The Warfarin Antiplatelet Vascular Evaluation (WAVE) also cautions against extrapolating therapies that have passed clinical-trial muster in one arterial bed to the treatment of disease in another, its investigators say.
In this case, for example, combined antiplatelet and oral anticoagulant therapy has been found effective and safe for myocardial infarction (MI) secondary prevention, but in WAVE it raised the risk of life-threatening complications, observed the trial's principal investigator, Dr Sonia S Anand (McMaster University, Hamilton, ON). The trial, she told heartwire, "points to the need for doing carefully conducted trials within each vascular subgroup rather than assuming the risk-benefit ratio is the same when you go from coronary to peripheral to cerebrovascular disease."
But the trial's primary message, she said, is that "In patients with PAD who don't have a clear indication for oral anticoagulants, such as a mechanical heart valve or atrial fibrillation, using an oral anticoagulant on top of antiplatelets as a prevention method is not indicated at this point."
In an accompanying editorial, Dr Emile R Mohler (University of Pennsylvania, Philadelphia) agrees. WAVE, in combination with other, smaller studies, "shows clearly that the addition of an anticoagulant to an antiplatelet drug results in increased rates of bleeding complications," and that outcomes are superior with antiplatelet therapy alone in the long-term management of PAD.
As previously reported by heartwire, Anand presented WAVE in preliminary form at the World Congress of Cardiology 2006.
The seven-country trial had randomized 2161 patients with PAD to receive antiplatelet therapy (primarily aspirin) either with or without an oral vitamin-K antagonist (primarily warfarin). The PAD could be in the lower extremities, the carotids, or the subclavian arteries.
An attempt had been made to exclude patients with a propensity for bleeding or who were unlikely to tolerate combined therapy, according to the authors. To that end, eligibility required that patients first receive both agents without untoward side effects for two to four weeks and achieve a stable international normalized ratio (INR) of 2.0 to 3.0. Randomized patients also could not have a specific indication for anticoagulation, active or recent bleeding, recent stroke, renal failure, or chronic nonsteroidal anti-inflammatory drug (NSAID) use.
Even with those entry criteria plus INR monitoring that was probably more careful than what is generally done in clinical practice, Anand said, "we observed this excess risk of bleeding. In the real world, it's likely to be much higher."
No significant difference was seen in the primary endpoint of MI, stroke, or CV death over a follow-up averaging 35 months, nor in a second primary composite endpoint that consisted of the first one or severe ischemia in the coronary or peripheral arterial beds. Nor were there significant differences for primary endpoints' individual components; a closer look, however, showed a significant increase in hemorrhagic strokes with combination therapy. In addition, rates of minor, moderate, and "life-threatening" bleeding complications were significantly higher with double antithrombotic therapy.
Although WAVE doesn't address why its combination therapy caused more serious bleeding complications than has been observed in secondary-prevention MI and stroke trials, Anand speculated that the PAD patients were older and sicker. "They had more comorbid conditions, such as diabetes or other vascular disease, and were more likely to be smokers," she said. "All of those comorbid conditions increase both the vascular event risk and bleeding event risk."
WAVE "was sponsored by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Ontario, and the Population Health Research Institute. Donations were also provided by Roche Diagnostics (in kind) and DuPont Pharma. In Hungary, acenocoumarol was provided by ICN Pharma." Mohler reports receiving lecture fees from Bristol-Myers Squibb, Sanofi, and Astra-Zeneca and grant support from Bristol-Myers Squibb and Sanofi.
N Engl J Med. 2007;357:217-227, 293-296.