Severe asymptomatic heart disease may accompany narrowing in leg arteries

CHICAGO,06 dec 2009 – Results of a randomized, controlled clinical trial presented today at the annual meeting of the Radiological Society of North America (RSNA) reveal that one in five patients with narrowing or blockage in arteries that supply blood to the legs and other parts of the body also have significant but silent coronary artery disease.

Peripheral arterial disease (PAD) occurs when plaque, a combination of fat, cholesterol and other substances, builds up in the arteries, limiting the flow of oxygen-rich blood throughout the body. PAD usually affects arteries that carry blood to the legs, causing poor circulation, discomfort and pain. More than eight million Americans have PAD, according to the American Heart Association.

According to the National Heart, Lung and Blood Institute, coronary artery disease is the most common type of heart disease and the leading cause of death in the U.S.

"PAD patients, including those experiencing no symptoms of heart disease, are known to be at high risk for cardiovascular events such as a heart attack or stroke," said Rozemarijn Vliegenthart Proenca, M.D., Ph.D., radiology resident at the University Medical Center Groningen in the Netherlands. "The purpose of our clinical trial was to investigate whether noninvasive imaging of the heart and subsequent treatment of PAD patients result in a decrease in cardiac events compared to standard care."

In the clinical trial, a total of 231 PAD patients from four participating hospitals in the Netherlands were divided into one of two groups: one in which 108 patients received standard care—consisting of lifestyle changes and medication—for their condition, and a second group in which 115 patients underwent cardiac imaging of the heart in addition to standard care.

"With new, noninvasive cardiac imaging techniques, asymptomatic coronary atherosclerosis can be readily detected and treated," Dr. Vliegenthart Proenca said.

Among the 115 patients who received cardiac imaging, computed tomography (CT) revealed that 53, or 46 percent, had at least one significant narrowing of a coronary artery. Of those 53 patients, 22 had significant narrowing in the left main coronary artery or its equivalent, and were referred for treatment. Eight of those patients subsequently had bypass surgery, and three underwent coronary angiography with stent placement. The remaining patients were treated with medication.

Cardiac stress MRI was then performed on 76 patients. Cardiac stress MRI, in which a drug is infused into the patient's bloodstream to make the heart work harder, helps determine if the heart muscle is receiving adequate blood flow. Results of the cardiac stress MRI exams identified two additional patients with signs of coronary artery disease, one of whom underwent angiography and stent placement.

In total, 24 (21 percent) of the 115 patients who underwent imaging had evidence of asymptomatic but severe coronary artery disease that required additional treatment.

"In PAD patients experiencing no cardiac symptoms, we found a strikingly high rate of severe coronary artery disease," Dr. Vliegenthart Proenca said. "The results of our trial stress that PAD patients without a history of cardiac symptoms should undergo extensive cardiovascular risk factor management."

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Coauthors are Alexander de Vos, M.D., Ph.D., Matthijs Oudkerk, M.D., Ph.D., Mathias Prokop, M.D., Ph.D., Michiel Bots, M.D., Ph.D., Willem Mali, M.D., Ph.D., Annemarieke Rutten, M.D., Ph.D., Gonda de Jonge, M.D., Daniel Lubbers, M.D., Jan van den Dungen, M.D., Ph.D., Maarten Cramer, M.D., Ph.D., Pieter Doevendans, M.D., Ph.D., Benno Rensing, M.D., Ph.D., Hester van der Zaag-Loonen, M.D., Ph.D., and Felix Zijlstra, M.D., Ph.D.

Note: Copies of RSNA 2009 news releases and electronic images will be available online at RSNA.org/press09 beginning Monday, Nov. 30.

Peripheral Arterial Disease Linked to Recurrence of Stroke

Ankle brachial index measurement screening for stroke and TIA patients may be merited

30 aug 2009-- Patients who have asymptomatic peripheral arterial disease after a stroke or transient ischemic attack are more likely to have another stroke or vascular event, according to a study published online on Aug. 27 in Stroke.

Souvik Sen, M.D., of the University of North Carolina in Chapel Hill, and colleagues evaluated 102 patients and used ankle brachial index measurements to detect peripheral arterial disease. The patients were followed up for a mean of 2.1 years.

Among the 102 patients, 26 percent had asymptomatic peripheral arterial disease, the researchers found. During follow-up, 84 percent of those without asymptomatic peripheral arterial disease remained free of vascular events, compared with only 48 percent of those with asymptomatic peripheral arterial disease, the investigators discovered. The association remained, even after adjusting for confounding factors.

"Ankle brachial index measurement may be appropriate for screening patients with stroke and those with transient ischemic attack who may be at high risk for vascular events," the authors write. "Further studies are needed to determine if the screened high-risk patients may benefit from aggressive monitoring, risk factor modifications as well as possibly selecting patients for a more effective clinical trial design."

The study was funded by BMS/Sanofi Pharmaceuticals. A co-author reported a financial relationship with the pharmaceutical industry, including BMS/Sanofi.

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Personality Type Linked to Increased Mortality

Type D personality assessment may identify high-risk patients with peripheral arterial disease

20 aug 2009-- In patients with peripheral arterial disease, Type D personality -- which is characterized by negative emotions and inhibited self-expression during social interactions -- is an independent predictor of all-cause mortality, according to a pilot study published in the August issue of the Archives of Surgery.

Annelies E. Aquarius, Ph.D., of Tilburg University in the Netherlands, and colleagues conducted a baseline psychological assessment of 184 patients (mean age, 64.8 years), of whom 16 died during a follow-up of up to four years.

The researchers found that independent predictors of all-cause mortality included traditional clinical risk factors such as age, diabetes, and renal disease (odds ratios, 1.1 to 2.3). Even after adjusting for these risk factors, however, they found that Type D personality was associated with more than a tripled risk of death (odds ratio, 3.5).

"Hence, in light of the challenge of optimizing risk management in peripheral arterial disease, a personality-based approach may be useful," the authors conclude. "Previous research has already shown that Type D personality predicts prognosis in cardiac patients and impaired quality of life. This study suggests that attention on personality variables may also improve the detection of high-risk patients with peripheral arterial disease."

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PAD Frequently Undiagnosed in Heart Disease Patients

Condition is overlooked in up to 15 percent of patients; systematic screening recommended

10 may 2009-- As many as one in six patients with coronary artery disease (CAD) may have overlooked peripheral arterial disease (PAD) despite specialist cardiovascular care, according to a study published in the May issue of Catheterization & Cardiovascular Interventions.

Issam D. Moussa, M.D., of the New York Presbyterian Hospital/Weill Cornell Medical Center in New York City, and colleagues assessed 800 patients without known PAD who were referred for coronary angiography.

Overall, the researchers found that the prevalence of overlooked PAD was 15 percent, and that the prevalence was highest among subjects over age 70 years and women (25.2 and 23.3 percent, respectively). They also found that subjects with multi-vessel CAD were twice as likely to have previously unrecognized PAD as those with single-vessel CAD.

"These findings extend the results of previous research and not only suggest a greater burden of atherosclerotic disease and later presentation, but also provide a possible explanation for the worse outcome of patients with concomitant CAD and PAD compared with those without PAD," the authors write. "Therefore, making a diagnosis of PAD in a patient with CAD should prompt the clinician to be more aggressive with risk factor intervention, foot protection, and a high clinical index of suspicion for progressive PAD symptoms. These patients must be viewed as exceptionally 'high risk.' Systematic, ankle-brachial index-based, PAD screening programs should be implemented in all patients with CAD."

This study was supported by Sanofi-Synthelabo.

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Arterial disease of the leg frequently overlooked in patients with heart disease

Study shows peripheral arterial disease is under diagnosed in patients who are under a cardiologist's care

New York, N.Y. , 30 april 2009– Peripheral arterial disease (PAD) of the legs, in which the arteries become blocked with plaque and blood supply to the legs is reduced, affects eight million people in the U.S. Early detection of PAD is important because it can limit the ability to walk and exercise, it may place patients at greater risk for limb loss and it increases the chance of having a heart attack or stroke. Coronary artery disease (CAD) is prevalent in patients with PAD and it is known that PAD is under diagnosed in the primary care setting, but a new study found that it is often overlooked even in patients with known heart disease who are under a cardiologist's care. The study was published in the May issue of Catheterization and Cardiovascular Interventions, the official journal of The Society for Cardiovascular Angiography and Interventions (SCAI).

Led by Dr. Issam D. Moussa of New York Presbyterian Hospital/Weill Cornell Medical Center, the study involved nearly 800 patients with ischemic heart disease who were to undergo coronary angiography and/or intervention and were either at least 70 years old, or between the ages of 50 and 69 and had a history of diabetes mellitus and/or tobacco use. Researchers determined if patients had PAD by calculating the Ankle-Brachial Index, the ratio of the blood pressure in the lower legs to blood pressure in the arms, which is normally the first test administered to patients in cases where PAD is suspected. Patients also answered questionnaires on PAD awareness and functional status.

The results showed that approximately one out of six patients had previously unrecognized PAD, despite being under the care of a cardiovascular specialist. The researchers point out that this includes only those with previously undiagnosed PAD and does not represent the total prevalence of PAD in patients with heart disease, which is actually much higher. Most patients with PAD did not limp or have leg pain, two symptoms of the disease. "The combination of physician lack of awareness and lack of symptoms among patients results in failure to diagnose PAD, even in patients who are at high risk," the researchers state. "Furthermore, clinical evaluation alone often lacks the sensitivity and specificity to optimally identify PAD particularly in less advanced stages and in hospitalized patients with CAD."

The study also found that previously missed PAD was more frequent in older patients and women, which goes against the conventional wisdom that PAD is more prevalent in men and suggests that PAD is more frequently overlooked in women than men in outpatient settings. In addition, the study showed that patients with PAD had a more severe form of CAD, which may account for the worse outcome of heart patients who also have PAD compared to those who do not. The authors note that "making a diagnosis of PAD in a patient with CAD should prompt the clinician to be more aggressive with risk factor intervention, foot protection and a high clinical index of suspicion for progressive PAD symptoms," adding that these patients should be viewed as exceptionally high risk.

They also note that establishing an early diagnosis of PAD promotes the preservation of functional status in the lower limbs, which is particularly important in patients CAD, since PAD may limit active participation in cardiovascular rehabilitation following coronary interventions. Many physicians cite the lack of space, time and resources as barriers to implementing a systematic PAD screening program, however new guidelines by the American Heart Association and the American College of Cardiology advocate screening for PAD in patients with CAD. The authors conclude that their findings present a compelling argument that screening for PAD should become standard of care in these patients.

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This study is published in Catheterization and Cardiovascular Interventions. Media wishing to receive a PDF of this article may contact medicalnews@bos.blackwellpublishing.net

Issam D. Moussa, M.D., FSCAI is the Director of Endovascular Services in the Division of Cardiology at New York Presbyterian Hospital/Weill Cornell Medical Center and Associate Professor of Medicine at Weill Medical College of Cornell University in New York. Dr. Moussa can be reached for questions at ism9003@med.cornell.edu.

Borderline Arterial Pressure Linked to Mobility Loss

Observed in patients with peripheral arterial disease

22 mar 2009-- Patients with peripheral arterial disease and even a borderline or low normal ankle-brachial index (ABI), a measure of relative arterial pressures in the lower and upper extremities, are at higher risk of later mobility loss, according to a study published in the March 24 issue of the Journal of the American College of Cardiology.

Mary M. McDermott, M.D., from Northwestern University's Feinberg School of Medicine in Chicago, and colleagues studied the association between low ABI -- a ratio of systolic pressures in the lower and upper extremities -- and functional decline in 666 patients, where 412 had mild-to-severe peripheral arterial disease.

After a follow-up of five years and after adjusting for confounding variables, the researchers found that the rates of mobility loss were higher for patients with lower ABI values. Even patients with borderline ABI (0.90 to 0.99) had higher rates of mobility loss and higher rates of becoming unable to walk continuously for six minutes, and patients with low normal ABI (1.00 to 1.09) also had higher rates of mobility loss. The study notes that the clinically important ABI threshold is normally considered less than 0.90.

"At five-year follow-up, persons who have borderline and low normal ABI values are at higher risk for mobility loss compared with persons who do not have peripheral arterial disease," McDermott and colleagues conclude. "Participants with borderline ABI values are also at higher risk for becoming unable to walk for 6 min continuously at five-year follow-up," according to the study.

Summit Doppler Systems, Inc. provided support for the editorial.

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'Seeing' stem cells helps in fight against peripheral arterial disease

Unique interventional radiology research puts puzzle pieces together in regenerating blood vessels to open clogged arteries, uses firefly-like bioluminescence imaging agent

SAN DIEGO, Calif., 12 mar 2009—Interventional radiologists are fitting together the puzzle pieces of how to use stem cells to create new or more blood vessels to treat peripheral arterial disease (PAD) in those individuals with extensively narrowed or clogged arteries. That puzzle may be closer to being solved in light of recent successful techniques that use simple imaging to view and locate transplanted stem cells and to confirm that they remain alive in the body once injected, notes a study presented at the Society of Interventional Radiology's 34th Annual Scientific Meeting.

PAD, which affects about 10 million Americans, is a chronic disease that progressively restricts blood flow causing poor blood circulation (generally in the legs) and if left untreated can lead to serious medical complications, including heart attack, stroke, amputation and death. Many people can manage the symptoms of PAD and stop its progression through lifestyle changes. If lifestyle changes are not enough, additional medical treatment may be needed, including prescribed medicine to prevent blood clots, lower blood pressure and cholesterol and control pain.

Interventional radiologists treat severe cases of PAD with minimally invasive treatments, including angioplasty and insertion of stents. "However, some patients have extensive disease—with so many blood vessels affected—that they're difficult to treat," said Frank Wacker, M.D., interventional radiologist at Johns Hopkins School of Medicine in Baltimore, Md. That's where stem cells—and image-guided stem cell therapy—come in. "One day, stem cells may enable the targeted delivery of cellular treatments to PAD patients who may be facing amputation and death. It will be important to deliver the right amount of drug treatment to the right place, thus allowing tailored treatment for individual patients," said Wacker. "The use of C-arm CT for image-guided delivery in the angio lab enabled us to precisely target cell delivery in relationship to blood vessels without transferring to a separate CT scanner to obtain the similar information," he added. Stem cell therapy may provide interventional radiologists with a new weapon to fight PAD, a disease that affects 12 to 20 percent of Americans age 65 and older.

"To develop new stem cell treatments for PAD, we need suitable noninvasive methods to track the fate of stem cells clearly inside the body," said veterinary radiologist Dara L. Kraitchman, V.M.D., Ph.D., an associate professor at Johns Hopkins School of Medicine. Transplanting stem cells derived from bone marrow (not embryonic stem cells), accompanied by necessary immune-suppressing drugs, has had mixed results. Rejection by the body's immune system is a likely reason for transplant failure. Because X-ray agents are toxic to stem cells, tracking of stem cell therapy cannot be done by directly labeling the stem cells themselves. Hopkins researchers used a new technique that encloses stem cells in an alginate capsule or "bubble" made from seaweed that contains stem cells to create factors to recruit the building of new vessels along with an X-ray–visible contrast agent. Tested in a rabbit model for the first time, the bubble prevents the body's immune system from reaching and attacking the transplanted cells. "We needed to figure out how to protect transplanted stem cells that are vulnerable to attack by a recipient's immune system and 'see' the cells to determine if they remained alive or not," said Kraitchman. "By making sure our protective covering for stem cells stayed intact, we were able to track where we put the stem cells and confirm whether they could survive," explained Kraitchman.

"These bubbles, which can be transplanted into a leg, can then be placed accurately at blocked blood vessels that need intervention," said Kraitchman. However, even visible with X-ray imaging, researchers could not determine if the stem cells within the bubble remained alive. Researchers then induced the stem cells within the bubble to produce luciferase, a bioluminescence imaging agent produced by fireflies—to "see" living stem cells. "We could 'see' the bubble via X-ray and tell if the stem cells remained alive as they lit up much like a firefly at night," said Kraitchman, who added that all agents used to form the bubble are approved by the Food and Drug Administration.

The future hope is to use adult stem cells extracted from a healthy donor's bone marrow and inject the cells into the patients' legs where circulation problems exist, stimulating the growth of new or more blood vessels in the leg, thus improving circulation, said Wacker. Previous studies in animals and other laboratory tests show that the injections of stem cells have such an effect and have prompted human trials, she added. Hopkins researchers took rabbit stem cells—separated from bone marrow in the lab—and injected them into the animal's hind quarter to track them. "Our research could eventually help PAD patients by providing a process for stem cells to thrive in the body and make more blood vessels or new blood vessels," he noted. "Using an animal model, we found that our research opens the door to delivering stems cells exactly where they are needed, allowing them to 'recruit' new blood vessels," added Wacker.

Bone marrow stem cells, which have the ability to renew themselves, could unlock the door to treat PAD with cell-based treatments. Stem cells are master or undifferentiated cells that have the ability to continuously divide and develop into other specialized types of cells. When conditions are just right, stem cells can begin to develop into specialized tissues and organs or turn into more specialized cells that are self-sustaining by replicating through cell division. Once healthy stem cells are harvested like blood for blood tranfusions, they could be injected into a diseased part of the body for growing healthier new blood vessels. Because of their uniqueness, researchers are exploring the use of stem cells for the treatment of life-threatening diseases.

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More information about peripheral arterial disease and interventional radiology can be found online at www.SIRweb.org.

Abstract 133: "Using X-ray Trackable Encapsulated Stem Cells to Guide Reporter Probe Delivery with C-Arm CT," D.A. Kedziorek, P. Walczak, Y. Fu, F. Wacker, D.L. Kraitchman, Johns Hopkins University, Baltimore, Md., SIR 34th Annual Scientific Meeting March 7-12, 2009. This abstract can be found at www.SIRmeeting.org.

Exercise improves leg pain caused by arterial disease

OAK BROOK, Ill., 03 feb 2009 – Patients with leg pain caused by arterial disease may be able to forego treatment of the affected artery by participating in hospital-supervised exercise, according to a new study published in the February issue of Radiology.

Intermittent claudication is a painful leg condition affecting some patients with peripheral arterial disease. Various treatments are available, including drug therapy or endovascular revascularization, a minimally invasive technique that widens and restores blood flow to the affected artery.

"The results from our clinical trial demonstrate that after six and 12 months, patients with intermittent claudication benefited equally from either revascularization or supervised exercise," said the study's lead author, Sandra Spronk, Ph.D., researcher in the Department of Epidemiology and Radiology at Erasmus MC, University Medical Center in Rotterdam, Netherlands. "However, improvement is more immediate following revascularization."

For the study, 151 patients with intermittent claudication were randomly assigned to undergo revascularization or hospital-supervised exercise. Supervised exercise consisted of 30-minute, semi-weekly sessions of walking on a treadmill. Follow-up was performed after six and 12 months.

The patients who had undergone revascularization showed more immediate improvement. However, no significant differences were observed between the two groups after six months or 12 months with functional capacity and quality of life scores increasing for all patients.

"Revascularization is increasingly being performed as a first line of treatment," Dr. Spronk said. "This study emphasizes that all patients with intermittent claudication should initially be treated with exercise training, and that invasive procedures should be considered only if symptoms fail to improve."

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"Intermittent Claudication: Clinical Effectiveness of Endovascular Revascularization versus Supervised Hospital-based Exercise Training—Randomized Controlled Trial." Collaborating with Dr. Spronk were Johanna L. Bosch, Ph.D., Pieter T. den Hoed, M.D., Ph.D., Hermanus F. Veen, M.D., Ph.D., Peter M. T. Pattynama, M.D., Ph.D., and M.G. Myriam Hunink, M.D., Ph.D. Journal attribution requested.

Radiology is edited by Herbert Y. Kressel, M.D., Harvard Medical School, Boston, Mass., and owned and published by the Radiological Society of North America, Inc. (RSNA.org/radiologyjnl)

Treadmill Exercise Recommended for Peripheral Arterial Disease

Physicians should prescribe treadmill exercise for patients with peripheral arterial disease, a JAMA study concludes

18 jan 2009--Some 150 patients with peripheral arterial disease, with or without intermittent claudication, were randomized to one of three groups: treadmill exercise, lower-extremity resistance training, or a control group. (The active treatment groups exercised three times a week for 6 months under supervision.)

By the end of the trial, treadmill exercise resulted in greater improvement in the 6-minute-walk test than resistance training, and it also improved brachial artery flow-mediated dilation. For its part, resistance training improved several measures of functional performance, such as stair-climbing ability.

The authors say their results "suggest ... treadmill exercise confers a favorable systemic vascular effect that may reduce cardiovascular events" in these patients, regardless of the presence of intermittent claudication.

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ATVB: Too Little Vitamin D May Increase Risk of Peripheral Arterial Disease

By Todd Neale
ATLANTA, 17 April 2008 -- Low levels of vitamin D were associated with an increased risk for peripheral arterial disease (PAD) in a large, cross-sectional study.
Participants in the lowest quartile of 25-hydroxyvitamin D levels were 80% more likely to have peripheral arterial disease than those in the highest quartile (prevalence ratio 1.80, 95% CI 1.19 to 2.74), Michal Melamed, M.D., M.H.S., of Albert Einstein College of Medicine in Bronx, N.Y., and colleagues, reported at the American Heart Association's Arteriosclerosis, Thrombosis, and Vascular Biology meeting here.
The results were published simultaneously online in Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the American Heart Association.
For every 10 ng/mL that vitamin D levels decreased, the risk was increased by 35% (PR 1.35, 95% CI 1.15 to 1.59).
However, because a causal relationship could not be determined, "we would not recommend people start taking vitamin D supplements without talking to their doctors," Dr. Melamed said in a statement.
Because there are conflicting results in the literature about the association between levels of vitamin D and cardiovascular disease, the researchers evaluated the relationship between the nutrient and peripheral arterial disease in a large, population-based sample, the National Health and Nutrition Examination Survey 2001-2004.
They looked at data from 4,839 participants ages 40 and older with values calculated for ankle-brachial index.
Peripheral arterial disease was defined as a score of less than 0.9 on the index.
The participants were divided into quartiles of vitamin D levels -- less than 17.8 ng/mL, 17.8 to 23.4 ng/mL, 23.5 to 29.1 ng/mL, and 29.2 ng/mL or more.
Prevalence of peripheral arterial disease decreased with each successive quartile from lowest to highest: 8.1%, 5.4%, 4.9%, and 3.7%, respectively (P<0.001 for the trend).
Those who had peripheral arterial disease were older, less physically active, and more likely to be a former smoker, to have diabetes, hypertension, chronic kidney disease, or a history of myocardial infarction, and to use statins (P<0.001 for all).
Also, mean 25-hydroxyvitamin D level was lower in those with peripheral arterial disease compared with those without PAD (21.5 versus 24.6 ng/mL, P<0.001).
In a secondary analysis, higher levels of serum calcium, phosphate, and intact parathyroid hormone were not associated with peripheral arterial disease, despite findings from previous studies that suggested high levels of these markers were related to increased risk of cardiovascular disease, the researchers said.
The cross-sectional nature of this study could not prove a causal effect of vitamin D levels on risk of peripheral arterial disease, Dr. Melamed said, and a large, randomized clinical trial will be needed to confirm the association.
An alternative explanation for the results, she said, was that patients with peripheral arterial disease do not go outside as much and, therefore, have less exposure to the sun.
However, Dr. Melamed said, that is unlikely to explain the findings because all of the participants were ambulatory and able to get to the mobile examination centers used in the study.
The authors noted some potential limitations of the study, including the cross-sectional design, the lack of data on sun exposure, geographic location, and season during which examinations were conducted, and the fact that angiography was not used to detect peripheral arterial disease.
As strengths of the study, the researchers mentioned that the use of the ankle-brachial index detected subclinical disease, the study included a broad range of and quality control for data collection, and the sample was large and nationally representative.
Dr. Melamed's work was funded by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases and by an American Heart Association Heritage Affiliate Clinically Applied Research Award. One of her co-authors was supported by the PJ Schafer Memorial Cardiovascular Research award at Johns Hopkins and has served as a consultant to Abbott.
Additional source: Arteriosclerosis, Thrombosis, and Vascular BiologySource reference: Melamed M, et al "Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004" Arterioscler Thromb Vasc Biol 2008; DOI: 10.1161/ATVBAHA.108.165886.

Solo Antiplatelet Therapy Sufficient in Peripheral Arterial Disease

HAMILTON, Ontario, July 18 -- Antiplatelet therapy alone is as effective in peripheral arterial disease as adding an oral anticoagulant, and it's safer, researchers reported.
The two-drug combination was not more effective than single drug treatment in preventing major cardiovascular complications and was associated with a more than three-fold increase in life-threatening bleeding, according to a report in the July 19 issue of the New England Journal of Medicine.
Antiplatelet drugs reduce the risk of myocardial infarction, stroke, and death from cardiovascular causes associated with atherosclerotic peripheral arterial disease, said Sonja Anand, M.D., Ph.D., of McMaster University here, but the role of oral anticoagulant agents in the prevention of cardiovascular complications has been unclear.
To explore it, she and fellow investigators conducted the randomized open-label Warfarin Antiplatelet Vascular Evaluation (WAVE) trial.
They assigned 2,161 patients with peripheral arterial disease to combination therapy with an antiplatelet agent and an oral anticoagulant or to antiplatelet therapy alone.
The patients, ages 35 to 85, came from 80 centers in Canada, Poland, Hungary, Ukraine, China, the Netherlands, and Australia.
Antiplatelet agents used in the trial included aspirin, ticlopidine (Ticlid) and clopidogrel (Plavix). Warfarin was used for oral anticoagulation in five countries and acenocourmarol was used in Poland and Hungary.
At a mean follow-up of 35 months, myocardial infarction, stroke, or death from cardiovascular causes occurred in 132 of 1,080 patients (12.2%) receiving combination therapy and in 144 of 1,081 patients (13.3%) receiving antiplatelet therapy alone (relative risk, 0.92; 95% confidence interval, 0.73 to 1.16; P=0.48), the authors said.
When taking severe ischemia of the peripheral or coronary arteries that required urgent intervention into account, the researchers noted that the number rose to 172 patients (15.9%) receiving combination therapy compared with 188 patients (17.4%) receiving antiplatelet therapy alone (relative risk, 0.91; 95% CI, 0.74 to 1.12; P=0.37).
Life-threatening bleeding, including hemorrhagic stroke, occurred in 43 patients (4.0%) receiving combination therapy compared with only 13 patients (1.2%) receiving antiplatelet therapy alone (relative risk, 3.41; 95% CI, 1.84 to 6.35; P<0.001), the authors said.
Moderate bleeding was also increased in the patients on the combination therapy (2.9% versus 1.0%, relative risk 2.82, P=0.002).
The rates of serious bleeding among patients getting combination therapy were higher than in a trial of patients with coronary artery disease, the researchers noted.
The reason for this difference, they said, may be that patients with peripheral arterial disease are older and have more systemic atherosclerosis, including cerebrovascular disease, and more co-existing conditions.
A potential limitation of the trial, they noted, was its open-label design, which permitted patients and physicians to know the treatment given. However, they added, all trial endpoints were centrally judged by a blinded committee.
According to their data, the researchers said, treating 1,000 patients with combination therapy compared with antiplatelet therapy alone for three years would lead to 24 fewer cardiovascular events but 28 more episodes of life-threatening bleeding. This would result in a net increase in serious adverse outcomes, they said.
Their findings highlight the need to evaluate alternatives to vitamin K antagonists in patients with peripheral arterial disease, they added.
In an accompanying editorial, Emile R. Mohler III, M.D., of the University of Pennsylvania, wrote that the risks of serious bleeding and hemorrhagic stroke in the WAVE trial were higher than those seen in the post-myocardial infarction studies that used combined treatment.
The reasons for the increased likelihood of bleeding in patients with peripheral arterial disease are unknown, he noted, but, as the WAVE researchers suggested, may include advanced age, more widespread atherosclerosis, as well as decreased integrity of the vessel wall and increasing microvascular fragility.
Although there may be some patients for whom the bleeding risks are lower, resulting in a risk-benefit ratio that favors adding an anticoagulant, the data from the WAVE trial do not provide any evidence for this, Dr. Mohler wrote.
At this time, he said, the data indicate that antiplatelet treatment alone affords a better outcome than does combined therapy.
Further information, he added, about the pathobiologic basis for bleeding in these patients is needed to develop successful clinical strategies to prevent bleeding and to devise safer antiplatelet and anticoagulant drugs.
The Wave researchers reported no relevant conflicts of interest. The study was supported by grants from the Canadian Institutes of Health, the Heart and Stroke Foundation of Ontario, and the Population Health Research Institute. Roche Diagnostics, DuPont Pharma, and ICN Pharma provided drugs for the study but had no role in the design and conduct of the trial or the analysis of the data.
Dr. Mohler reported receiving lecture fees from Bristol-Myers Squibb, Sanofi, and Astra-Zeneca and grant support from Bristol-Myers Squibb, and Sanofi. He reported no other potential conflicts of interest.Primary source: New England Journal of MedicineSource reference: Anand S et al "Oral Anticoagulant and Antiplatelet Therapy and Peripheral Arterial Disease" N Engl J Mrf 2007; 357:217-227. Additional source: New England Journal of MedicineSource reference: Mohler III ER "Atherothrombosis -- Wave Goodbye to Combined Anticoagulation and Antiplatelet Therapy?" N Engl J Med 2007; 357:293-296.