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National Heart, Lung, and Blood Institute (NHLBI)

National Institute of Diabetes and
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Optimal Medical Therapy As Beneficial As Elective Revascularization Procedures in Patients with Type 2 Diabetes and Stable Coronary Heart Disease

Landmark Study Also Finds No Difference Between Insulin-Providing and Insulin-Sensitizing Drugs

Optimal medical therapy for patients with diabetes and stable coronary heart disease is equally effective at lowering the risk of death, heart attack, and stroke as prompt revascularization procedures with either coronary bypass surgery or angioplasty, according to results from an international multicenter clinical trial supported by the National Institutes of Health. Optimal medical therapy includes intensive drug therapy and lifestyle interventions, such as dietary changes and smoking cessation.

The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) simultaneously compared two cardiovascular treatment approaches and two diabetes control strategies to improve survival and to lower the risk of heart attacks and strokes. The findings are published online by the New England Journal of Medicine today, in conjunction with the researchers' presentation at the American Diabetes Association's 69th Annual Scientific Sessions in New Orleans, La.

BARI 2D also found — and is the first study to suggest — that patients who had prompt bypass surgery in addition to optimal medical therapy had significantly fewer non-fatal heart attacks or strokes compared to similar patients who initially received optimal medical therapy alone. No such benefit was seen in patients who received prompt angioplasty, most of whom also received stent placement (a wire mesh scaffold to keep the affected artery open), versus similar patients who initially received optimal medical therapy alone. However, participants in the bypass surgery group were more likely to have more extensive coronary artery disease (CAD) than those in the angioplasty group; more research is needed to confirm these findings. Both angioplasty and bypass surgery are revascularization procedures to relieve or bypass blockages in the coronary arteries.

Researchers also discovered that, overall, strategies using drugs that aim to make insulin work better by lowering the body’s resistance to insulin (called insulin sensitization) are as effective as a strategy emphasizing drugs that provide insulin or that stimulate insulin production (insulin provision drugs).

"By comparing different strategies for both blood sugar control and prevention of cardiovascular events such as heart attack and stroke, we aim to provide physicians with evidence-based guidance to help them identify the safest and most effective therapies for their patients," said Elizabeth G. Nabel, M.D., director of the National Heart, Lung, and Blood Institute (NHLBI), the primary funder of the study.

Adults with type 2 diabetes are two to four times more likely to develop heart disease. In addition, heart attacks and stroke often occur earlier than in people without diabetes — and are more likely to be fatal. Sixty-five percent of people with diabetes die from cardiovascular disease.

BARI 2D was conducted in 49 clinical sites in the United States, Canada, Brazil, Mexico, the Czech Republic, and Austria. The study was coordinated by the Epidemiology Data Center at the University of Pittsburgh Graduate School of Public Health. Participants were 2,368 adults (average age 62 years) with established type 2 diabetes (average duration of 10 years) and stable CAD. One component of the study compared optimal drug treatment to control blood sugar levels, cholesterol, and blood pressure with prompt (within four weeks of the start of the study) coronary revascularization by either bypass surgery or angioplasty to optimal drug treatment alone. In angioplasty, blocked arteries are opened by inflating a small balloon inside a narrow vessel and often followed by the placement of a stent. Of the 798 BARI 2D participants selected to receive prompt angioplasty, 91 percent had a stent inserted, of whom about one-third received a drug-eluting stent.

At enrollment, all participants’ CAD had to be stable enough so that the patients could be safely managed with optimal medical therapy without immediate revascularization. Participants were selected to be in either the bypass or the angioplasty group based on whether (in the judgment of their physician), the extent and severity of blockages in their coronary arteries would be best treated by coronary bypass surgery or angioplasty. As reflective of standard medical practice, patients with more extensive and severe CAD were more likely to be candidates for bypass surgery than angioplasty. When they were screened to enter the trial, approximately two-thirds of BARI 2D participants were considered suitable candidates for elective angioplasty, while the remaining one-third were considered candidates for elective bypass surgery.

Within the bypass surgery and angioplasty groups, participants were randomly assigned to either promptly receive the designated revascularization procedure or to receive optimal medical therapy alone. Thus, the two coronary revascularization procedures were not compared to each other; rather, patients receiving either revascularization procedure were independently compared to their own control groups receiving optimal medical therapy alone.

Participants randomized to promptly receive revascularization underwent the designated procedure within four weeks from the start of the study while also receiving optimal medical therapy. Participants in the medical therapy alone group could undergo revascularization during the study if needed; about 40 percent of participants in the medical therapy groups did so.

Overall, researchers found that after an average follow up of five years, there were no differences in mortality rates, the primary endpoint of the study, which was about 12 percent in both groups. In addition, deaths combined with nonfatal cardiovascular events — a principal secondary outcome — between the combined revascularization groups who received early coronary procedures compared to those in the medical therapy alone groups were similar (23 percent versus 24 percent, respectively). However, among the subgroup of participants who were pre-identified as candidates for coronary bypass surgery, there were significantly fewer subsequent major cardiovascular events (death or nonfatal heart attacks or strokes) among those who had bypass surgery within the first month of being in the study compared to those who initially received optimal medical therapy alone (22 percent versus 30 percent, respectively).

In the diabetes control component of the study, researchers randomly divided the same participants into two blood sugar control strategy groups. One strategy emphasized insulin-sensitizing drugs, such as biguanides (metformin) and thiazolidinediones (primarily rosiglitazone), which lower the body's resistance to insulin. The other strategy group emphasized insulin-providing drugs — insulin treatment or drugs that stimulate the body to make more insulin, including sulfonylurea drugs (such as glipizide) and meglitinides (such as replaginide). These two drug strategies address two different problems in type 2 diabetes.

Participants in both groups were treated to targeted levels of glycated hemoglobin (HbA1c) levels of less than 7.0 percent, which is consistent with current diabetes care guidelines. HbA1c is a measure of blood sugar control over a period of several months. On average, participants in the insulin sensitizing group had an HbA1c level of 7.0 percent, and participants in the insulin providing group had an HbA1c level of 7.5 percent.

"Other studies have suggested that insulin resistance contributes directly to the development of coronary artery disease," noted Suzanne Goldberg, R.N., M.S.N., NHLBI project officer of the study and program director in the Atherothrombosis and Coronary and Artery Disease Branch in the Division of Cardiovascular Diseases. "Our study was an opportunity to directly compare the effects of drugs that enhance the body's ability to use insulin to the more traditional drugs that increase the amount of insulin."

Overall, the numbers of deaths and cardiovascular events were about the same in both diabetes treatment strategy groups. In addition, because of safety concerns raised in other studies, BARI 2D researchers conducted an in-depth analysis of cardiovascular disease rates in patients receiving rosiglitazone (Avandia) versus other diabetes drugs, and found no evidence of increased risk of heart attacks in participants receiving rosiglitazone.

"We found some indications that insulin-sensitizing drugs might be beneficial for certain patients with diabetes, especially those with more extensive coronary artery disease who undergo bypass surgery, but more research is needed," noted Sheryl F. Kelsey, Ph.D., professor of epidemiology at the University of Pittsburgh Graduate School of Public Health, and a principal investigator and coauthor of the study.

In addition to the NHLBI, BARI 2D received support from the National Institute of Diabetes and Digestive and Kidney Diseases. Supplemental funding was provided by GlaxoSmithKline, Lantheus Medical Imaging Inc., Astellas Pharma US Inc., Merck & Co. Inc., Abbott Laboratories Inc., and Pfizer Inc. Additional support came from Abbott Laboratories Ltd.; MediSense Products; Bayer Diagnostics; Becton, Dickinson, and Company; J.R. Carlson Labs; Centocor, Inc.; Eli Lilly and Company; LipoScience Inc.; Merck Sante; Novartis Pharmaceuticals Corporation; and Novo Nordisk Inc.

Further information about this trial (NCT00006305) can be found at www.clinicaltrials.gov.

To arrange an interview with an NHLBI spokesperson, please contact the NHLBI Communications Office at (301) 496-4236 or email nhlbi_news@nhlbi.nih.gov. To interview Dr. Kelsey, please contact Clare Collins, manager of media relations, University of Pittsburgh Medical Center, at (412) 648-9725.

Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at www.nhlbi.nih.gov.

NIDDK, part of the NIH, conducts and supports basic and clinical research and research training on some of the most common, severe and disabling conditions affecting Americans. The Institute's research interests include diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic and hematologic diseases. For more information, visit www.niddk.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

BARI 2D study: http://www.bari2d.org/

Your Guide to Living Well With Heart Disease: http://www.nhlbi.nih.gov/health/public/heart/other/your_guide/living_well.htm

Coronary artery disease: http://www.nhlbi.nih.gov/health/dci/Diseases/Cad/CAD_WhatIs.html

National Diabetes Information Clearinghouse: http://diabetes.niddk.nih.gov/

National Diabetes Education Program: http://ndep.nih.gov/

NHLBI Statement on Use of Rosiglitazone in Two NHLBI-Funded Clinical Trials (June 15, 2007): http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=287

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