BiDil reduces mortality in blacks with heart failure

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DALLAS ? Nov. 8, 2004 ? A new medication has dramatically reduced mortality among African-American patients suffering from heart disease, according to results of a study including UT Southwestern Medical Center at Dallas researchers.

The results were so favorable that investigators halted the multi-center trial so that all the 1,050 study participants suffering from advanced heart failure, including those on a placebo, could be given the combined drug treatment, said Dr. Clyde Yancy, a study author and director of the Congestive Heart Failure/Transplant Program at UT Southwestern/St. Paul University Medical Center.
"We discovered that patients were indeed living longer and that their incidence of death was dramatically less," said Dr. Yancy, professor of internal medicine.
A 43 percent decrease in the one-year mortality rates among African-Americans in the study receiving the combined treatment was observed by Dr. Yancy and his UT Southwestern colleagues, working in conjunction with University of Minnesota researchers. Participants, which included patients 18 years of age and older who had a heart failure diagnosis for at least three months, were recruited from 161 medical centers.
Dr. Yancy said the findings, published in the Nov. 11 edition of The New England Journal of Medicine, will have a substantial impact on the treatment of cardiovascular disease for African-Americans.
"Heart disease is the leading cause of death in the African-American community," Dr. Yancy said. "We were trying to find the best treatment for a disease that happens to be in a specific population."
The clinical trial, called the African-American Heart Failure Trial, or A-HeFT, used a combination of hydralazine and isosorbide dinitrate, two older drugs that had been used in the past to treat various heart conditions and are now being used in a new combination called BiDil.
In addition, study participants must have received standard therapy for their heart disease including beta blockers and diuretics.
The study began in June of 2001 and was discontinued on July 19, 2004, because the results were markedly favorable in decreasing mortality in the group taking BiDil as opposed to the group taking placebos.
By narrowing the focus of the study to a specific group of patients, Dr. Yancy said, the researchers could better assess the medicine's efficacy within that group. The findings, he added, provide strong evidence BiDil can slow the progression of heart failure in addition to decreasing death rates among African-American patients. Earlier heart drug studies have shown a marked difference in the drugs' effects in African-Americans and other ethnic population groups.
"Heart disease affects so many people and adds such a tremendous burden on the quality of life," Dr. Yancy said. "It is our hope that this treatment will allow patients with heart disease to enjoy a higher quality of life."

Celebrex and heart attacks - increased risk halts NCI study

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The National Institutes of Health (NIH) announced today that it has suspended the use of COX-2 inhibitor celecoxib (Celebrex? Pfizer, Inc.) for all participants in a large colorectal cancer prevention clinical trial conducted by the National Cancer Institute (NCI).

The study, called the Adenoma Prevention with Celecoxib (APC) trial, was stopped because analysis by an independent Data Safety and Monitoring Board (DSMB) showed a 2.5-fold increased risk of major fatal and non-fatal cardiovascular events for participants taking the drug compared to those on a placebo.
Additional cardiovascular expertise was added to the safety monitoring committees at the request of the Steering Committees for this trial after a September 2004 report that the COX-2 inhibitor rofecoxib (Vioxx?) caused a two-fold increased risk of cardiovascular toxicities in a trial to prevent adenomas. The APC is a study of more than 2,000 people who have had a precancerous growth (adenomatous polyp) removed. They were randomized to take either 200 mg of celecoxib twice a day, 400 mg of celecoxib twice a day, or a placebo for three years. The trial began in early 2000 and is scheduled to have been completed by Spring 2005.
Investigators at the 100 sites in the APC trial located primarily in the United States, with a few additional sites in the United Kingdom, Australia, and Canada, have been instructed to immediately suspend study drug use for all participants on the trial, although the participants will remain under observation for the planned remainder of the study.
"Data from the report on rofecoxib (Vioxx?) informed us of the need to focus on specific cardiovascular issues, and our Institutes brought in the experts to do so, said Elias A. Zerhouni, M.D., NIH Director. "Our overwhelming commitment is to advance the health and to protect the safety of participants in clinical trials. We are examining the use of these agents in all NIH-sponsored clinical studies. In addition, we are working closely with our colleagues at FDA to ensure that the public has the information they need to make informed decisions about the use of this class of drug."
"The rigor of our clinical trials system has allowed us to find this problem," said NCI Director Andrew C. von Eschenbach, M.D. "We have a strong system that provides us with the opportunity to both find ways to effectively treat and prevent disease and to do so in a way that protects the lives and safety of the participants."
However, another ongoing study looking at whether Celebrex can prevent colon cancer has not found any increased risk of heart attacks in patients taking the drug. This trial, the PreSAP trial, used the same heart measures and the same safety monitoring board as the APC trial.
"Pfizer is taking immediate steps to fully understand the [APC study] results and rapidly communicate new information to regulators, physicians, and patients around the world," Pfizer CEO Hank McKinnell says in a news release.
Because the two studies came up with opposite findings -- and because earlier studies showed no obvious sign of heart problems linked to Celebrex -- the FDA has not yet decided whether to ban Celebrex, to add additional warnings to the drug's label, or to wait for more information. But Acting FDA Commissioner Lester Crawford, MD, says the agency won't drag its feet.
"We will evaluate this information and may make statements very soon with regard to Cox-2 drugs in general and this product in specific," Crawford said today in a joint FDA/National Institutes of Health news conference.
NIH sponsors over 40 studies using celecoxib for the prevention and treatment of cancer, dementia and other diseases. In light of these new findings, NIH Director Zerhouni requested:
  • a full review of all NIH-supported studies involving this class of drug.
  • NIH Institutes to inform the principal investigators for all of these studies and will ask them to communicate directly with their study participants and explain the risks and benefits
  • NIH to ask each investigator to inform us of the their plan to analyze their data in light of the information
  • the Institutional Review Boards (IRBs) for all related trials to assess the new information and to conduct a safety review as well

Insulin increases mortality in heart failure patients

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UCLA researchers for the first time showed that advanced heart failure patients with diabetes who are treated with insulin faced a mortality rate four times higher than heart failure patients with diabetes treated with oral medications.

The new study may help raise awareness among physicians and patients of this previously unknown relationship between insulin use and increased mortality in advanced heart failure patients. More research is needed to explore the mechanisms of how insulin use may be contributing to the higher mortality rate.
The research appears in the January issue of the peer reviewed American Heart Journal.
Previous studies have shown a connection between type 2 diabetes, heart failure and insulin. The UCLA study is the first to identify a high mortality rate for advanced heart failure patients who use insulin to manage diabetes. "Further studies into what is the best strategy to control blood sugar levels in patients with diabetes and heart failure are urgently needed," said Fonarow. Dr. Gregg Fonarow, senior study author; professor of cardiology, David Geffen School of Medicine at UCLA; and director, Ahmanson-UCLA Cardiomyopathy Center.
Researchers assessed the history of diabetes and insulin treatment in 554 patients with advanced heart failure after adjusting for various risk factors. One year survival rates were 89.7 percent for non-diabetic patients, 85.8 percent for non-insulin-treated diabetic patients, and only 62.1 percent for insulin-treated diabetic patients.
Heart failure affects 5 million in the United States and is the most common cause of hospitalization for those 65 years and older. Between 25 to 44 percent of heart failure patients also have diabetes.
The study is funded by the Ahmanson Foundation and was conducted at UCLA. Fonarow is a research consultant and speaker for GlaxoSmithKline, Bristol-Myers Squibb, Pfizer and Merck.

Low-dose aspirin and anti-ulcer medications better than Plavix

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DALLAS ? Jan. 20, 2005 ? Heart patients with gastrointestinal complications should use low doses of aspirin combined with drugs that treat stomach ulcers rather than taking the anti-platelet drug Plavix, which has been thought to reduce bleeding ulcers, according to a gastroenterologist at UT Southwestern Medical Center and the Dallas Veterans Affairs Medical Center.

Physicians are challenged in treating heart patients who may be at high-risk for gastrointestinal bleeding from aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Factors that place patients at high-risk include a history of ulcers or gastrointestinal complications such as bleeding, increased age and congestive heart failure.
Low-dose aspirin (325 milligrams or less daily) has been shown to lower the risk of cardiovascular and cerebrovascular blood clots. It can, however, cause gastrointestinal ulceration and major bleeding, thereby limiting its overall usefulness even at the lowest effective amount. In an editorial in the current issue of The New England Journal of Medicine, Dr. Byron Cryer, associate professor of internal medicine at UT Southwestern, said current cardiology guidelines suggest patients who cannot take aspirin because of previous bleeding ulcers be given the drug clopidogrel (Plavix), which has been found to be marginally better than low-dose aspirin in preventing heart attacks and reducing bleeding ulcers. But, Plavix's effectiveness has not been proven in heart patients at greatest risk due to their history of gastrointestinal bleeding, and recent research indicates it actually may impair ulcer healing and markedly increase rates of bleeding.
"Clopidogrel inhibits new growth of small blood vessels in ulcers ? which is important for ulcer healing," said Dr. Cryer, a VA physician. "Although Plavix may not primarily cause gastrointestinal ulcers, through inhibition of new blood vessel growth, it may impair healing of background ulcers. When combined with the propensity to increase bleeding, these agents may convert small, silent ulcers into large ulcers that bleed profoundly."
Consequently, Dr. Cryer recommends that patients at high-risk for gastrointestinal complications who require blood clot-preventing therapy should consume the lowest effective dose of aspirin combined with drugs used to treat stomach ulcers (such as Aciphex, Nexium, Prevacid, Prilosec or Protonix) rather than take clopidogrel.
The New England Journal of Medicine editorial accompanies a study in the same issue of the journal by researchers from Hong Kong. The study evaluates the use of antiplatelet therapies in patients with a history of aspirin-induced upper gastrointestinal bleeding and found those who took clopidogrel had a 900 percent increase in recurrent bleeding from ulcers when compared to patients who took aspirin with esomeprazole (Nexium).

Diabetes a bigger heart disease risk for women than for men

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ORLANDO, Feb. 18 ? Women with diabetes have a significantly greater risk of dying from coronary heart disease (CHD) than men with diabetes, researchers reported today at the Second International Conference on Women, Heart Disease and Stroke.

Diabetes is a well-established CHD risk factor known to double a person's chance of dying from heart disease. There has been much debate, but no large studies of whether diabetes carries different heart risks for women than for men, said Mark Woodward, Ph.D., professor of biostatistics at The George Institute for International Health at the University of Sydney, Australia.
Using data on more than 450,000 people, which included participants in the Asia Pacific Cohort Studies Collaboration, researchers found that men with diabetes had about 90 percent higher risk of dying from CHD as men without diabetes. Women with diabetes had more than two and a half times the risk of women without diabetes. That translates to a greater than 50 percent excess relative risk for women than for men, he said.
The data came from two previous meta-analyses of 16 studies and a collaborative overview of 44 studies in nine countries in the Asia-Pacific Region (China, Japan, South Korea, Taiwan, Hong Kong, Singapore, Thailand, New Zealand and Australia).
About 5 percent of all the participants had diabetes. Diabetes was defined according to self-reported history with or without fasting glucose evidence as an alternative. The researchers were able to adjust for age, systolic blood pressure, total cholesterol and cigarette smoking in most of the data sets, he said.
Perhaps better monitoring and control of blood glucose levels in women with diabetes would reduce their CHD risk compared with men with diabetes, Woodward said.
"There is some evidence to suggest that people with diabetes benefit from treatment with aspirin, cholesterol-lowering drugs and blood pressure-lowering agents," he said.
This meta-analysis has similar drawbacks to most overviews including the possibility of publication bias (in this case the exclusion of studies that did not report sex-specific results), misdiagnosis of diabetes, lack of information on an individuals' medical treatment, no information on menopause status or on whether subjects had Type 1 diabetes, due to the body's inability to produce insulin, or Type 2 diabetes, initially caused by the inability to use the insulin produced. Data from randomized trials of individuals with diabetes would clarify these issues.
Besides continuing to seek data on the sex-specific relative risk for CHD related to diabetes, researchers at the George Institute are leading a large scale randomized trial Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) on 11,140 people. They are trying to ascertain whether more intensive glucose control combined with blood pressure lowering reduces cardiovascular mortality in people with Type 2 diabetes. The trial, which will follow participants for 4 ? years on average, will end in 2006.

Women with heart attacks benefit from stenting

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DALLAS. Female heart attack patients undergoing angioplasty have a higher risk of death than men, but stenting may improve their outcomes, according to a study reported in Circulation: Journal of the American Heart Association.

A new analysis of the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial examined gender differences in outcomes after treatment with angioplasty compared to stenting, with and without the antiplatelet agent abciximab, when women and men arrive at the hospital after a heart attack. The trial investigated the safety and efficacy of stents compared to angioplasty alone in heart attack patients.

In angioplasty, a small balloon-tipped catheter is inserted into a blocked artery, and then the balloon is inflated to open the artery. Stenting is performed in conjunction with angioplasty, wherein a mesh tube ? called a stent ? is positioned to help keep the unblocked artery open.

?Angioplasty is known to save lives in the setting of a heart attack and saves more lives of women than men,? said lead author Alexandra J. Lansky, M.D. ?For every 1,000 patients treated with percutaneous coronary interventions, an estimated 56 deaths are prevented for women compared to 42 deaths prevented for men. There is a larger absolute benefit for women because of their higher risk profile.?

Lansky is director of clinical services for interventional cardiology at New York-Presbyterian Hospital/Columbia and associate professor of clinical medicine at Columbia University Medical Center in New York City and director of the Women?s Health Initiative at the Cardiovascular Research Foundation.

Based on the CADILLAC findings, Lansky suggested that stenting may be the preferred treatment choice for women with heart attack.

?Stenting is the best alternative among excellent treatment options for women,? she said. ?There is no difference in the death rates between stenting and angioplasty, but stenting offers a substantial benefit by decreasing the recurrence rate of new blockages.?

The study involved 2,082 heart attack patients who arrived at the hospital within 12 hours after symptoms began. Patients were randomized into four treatment groups: 518 received balloon angioplasty, 528 received balloon angioplasty plus abciximab, 512 received stenting alone, while 524 received stenting plus abciximab. Women represented 27 percent of the study population, and their average age was 66. The average age for men in the study was 57.

Lansky said that more than 1 million Americans undergo angioplasty each year, but only 35 percent of these procedures are performed on women.

In this analysis, death rates were higher for women: 7.6 percent of women had died one year later compared to 3 percent of men. Also, rates of major adverse cardiac events were also higher for women at one year: 23.9 percent for women compared to 15.4 percent for men.

For the first time in a randomized, controlled clinical trial, stent use was found to significantly reduce major adverse cardiac events in women at one year, 19.1 percent for stents compared to 28.1 percent for balloon angioplasty. The need to re-intervene was reduced from 20.4 percent with balloon angioplasty to 10.8 percent with stents, a significant reduction.

Women in the study had more diabetes, hypertension and high cholesterol than men and were older than men.

The women represented a high-risk population with higher short and long-term death rates compared to men. This was explained by their older age, smaller body surface area, increased frequency of other diseases and risk factors, and the greater occurrence of in-hospital complications. Major adverse cardiac events remained greater in women than men.

The fact that the women had a smaller body size and smaller vessels ?appears to be a critical factor that confers higher mortality risk in women,? Lansky said.

The study also noted that women waited longer by an average of 22 minutes to go to the hospital than men, and women had as much as a 15-minute longer delay once they arrived at the hospital until the time treatment was started.

Lansky called on women to go to the hospital as soon as they suspect the symptoms of heart attack. She urged the medical profession to speed evaluations and the time to treatment from the emergency room to the catheterization lab. This will help optimize treatment for women, she said.

Co-authors are Cody Pietras, BSc; Ricardo A. Costa, M.D.; Yoshihiro Tsuchiya, M.D.; Bruce R. Brodie, M.D.; David A. Cox, M.D.; Eve D. Aymong, M.D.; Thomas D. Stuckey, M.D.; Eulogio Garcia, M.D.; James E. Tcheng, M.D.; Roxana Mehran, M.D.; Manuela Negoita, M.D.; Martin Fahy, M.S.; Ecaterina Cristea, M.D.; Mark Turco, M.D.; Martin B. Leon, M.D.; Cindy L. Grines, M.D. and Gregg W. Stone, M.D.

The study was supported in part by Guidant Corporation and the Cardiovascular Research Foundation.

Editor?s note: The American Heart Association?s Go Red For Women program offers information and educational tools for women about heart disease. For more information, visit the Go Red For Women Web site or call 1-888-MY-HEART.

Statements and conclusions of study authors that are published in the American Heart Association scientific journals are solely those of the study authors and do not necessarily reflect association policy or position. The American Heart Association makes no representation or warranty as to their accuracy or reliability.

Guidelines to focus on atrial fibrillation following cardiac surgery

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(NORTHBROOK, IL, August 8, 2005) - The American College of Chest Physicians (ACCP) released today the first evidence-based clinical practice guidelines for the prevention and management of postoperative atrial fibrillation (AF) after cardiac surgery. Published in the August issue of CHEST, the peer-reviewed journal of the ACCP, the guidelines offer specific recommendations on cardiac pacing, anticoagulation therapy, pharmaceutical prophylaxis, intraoperative interventions, and pharmacologic control of ventricular rate and rhythm. Atrial fibrillation, or irregular heartbeat, is a common condition that occurs increasingly with age and is one of the most frequent complications of cardiac surgery.

"Over one third of patients suffer from AF after cardiac surgery, which is associated with a higher risk of operative morbidity, increased hospital stay, and increased hospital cost," said Guidelines Co-Chair Peter P. McKeown, MBBS, MPH, MPA, FCCP, Veterans Affairs Medical Center, Asheville, NC. "Although previous guidelines have focused on the management of chronic AF, our guidelines are the first to address AF associated with cardiac surgery."
Through the Health and Science Policy Committee of the ACCP, the guidelines were developed by a multidisciplinary panel of experts in the fields of cardiothoracic surgery, cardiology, anesthesiology, and epidemiology. The panel included representatives from the ACCP, the American College of Cardiology, the Society of Thoracic Surgeons, and the American College of Surgeons. Based on a systematic review of randomized, controlled trials, panel members made graded recommendations based on the quality of evidence available and the net benefit of the intervention.

Recommendations center on the main issues that arise in managing patients with postoperative AF, including overall prevention; control of ventricular response rate; restoration of normal sinus rhythm; and prevention of thromboembolism and the role of anticoagulation. Overall, guidelines recommend the use of beta-blockers over calcium channel blockers, a standard therapy for chronic AF, for general prevention of postoperative AF and control of ventricular rate. Guidelines also recommend against the routine use of magnesium and digitalis for the prevention of postoperative AF. Amidarone may be considered for patients in whom beta-blockers are contraindicated and as therapy for postoperative sinus rhythm control. Atrial pacing, the use of a pacemaker to control arrhythmia, was found to reduce the incidence of AF after cardiac surgery; however, biatrial pacing is recommended over single atrial pacing. Additionally, mild hypothermia and heparin-coated circuits are recommended to reduce the occurrence of AF during intraoperative procedures. In regard to the prevention of thromboembolism, the guidelines recommend cautious anticoagulation therapy for patients in whom AF has persisted for more than 48 hours.
"Atrial fibrillation that develops after cardiac surgery places the patient at risk for thromboembolism and stroke, both which may require anticoagulants or blood-thinning agents to treat. Yet, cardiac surgery may increase a patient's tendency to bleed," said Guidelines Co-Chair David D. Gutterman, MD, FCCP, Medical College of Wisconsin, Milwaukee, WI. "Therefore, anticoagulation therapy should be carefully considered in the treatment of postoperative AF, with the risks of bleeding balanced with the risk of embolic stroke."
"The development and implementation of clinical practice guidelines allow clinicians to practice medicine based on the highest quality of data available," said Paul A. Kvale, MD, FCCP, President of the American College of Chest Physicians. "Although recommendations for the prevention and management of postoperative atrial fibrillation are intended to guide clinicians in their health-care decisions, they can be adapted to address issues of individual patient circumstance."
To order a copy of American College of Chest Physicians Guidelines for the Prevention and Management of Postoperative Atrial Fibrillation After Cardiac Surgery, or for more information, contact the ACCP at (800) 343-ACCP (2227).