Late reperfusion fails to reduce cardiovascular complications

American Heart Association Scientific Sessions Late-Breaking News:

CHICAGO, Nov. 14 — Balloon angioplasty plus stenting failed to reduce major cardiovascular complications in patients who had the procedure three to 28 days after a heart attack, researchers reported today at the American Heart Association’s Scientific Sessions 2006. 

Results of the Occluded Artery Trial (OAT), a National Heart, Lung, and Blood Institute (NHLBI) funded international, randomized clinical study, were presented in a late-breaking clinical trials session.

The trial included 2,166 people and is the largest and longest study to compare very late reperfusion (reopening blocked arteries) to medication alone.

“OAT was designed to help resolve a controversy about treatment of over one hundred thousand heart attack survivors in the United States alone each year: whether late opening of blocked coronary arteries would provide any long-term benefits to stable patients,” said Judith S. Hochman, M.D., OAT study chair and Harold Snyder Family Professor of Cardiology, clinical chief and director of the Cardiovascular Clinical Research Center at the New York University School of Medicine in New York City.

“Treatment to reopen totally blocked arteries reduces damage and improves survival if given during the first 12 hours of a heart attack, and up to 36 hours in selected unstable patients.    However, an estimated one-third of eligible patients do not receive reperfusion therapy in that timeframe because many of them arrive at the hospital after the treatment window has closed.”

In the United States, many physicians favor mechanical opening of totally blocked, or occluded, arteries in stable patients even after the treatment window has closed — despite the lack of evidence based on large, randomized, controlled trials on the issue, said Gervasio A. Lamas, M.D., study co-chair and director of Cardiovascular Research and Academic Affairs at Mount Sinai Medical Center in Miami, Fla.

OAT tested the hypothesis that percutaneous coronary intervention (PCI) with stenting would be better than medication alone if performed three to 28 days after a heart attack in stable patients who were at increased risk of long-term events — death, repeat heart attack and heart failure — and who had a completely blocked (totally occluded) coronary artery causing the heart attack.   Most of these patients had only one coronary artery with severe disease.  The primary endpoint was a composite of death, repeat heart attack or heart failure after an average of three years of follow up.  

Stenting (placing a metal tube in the artery to keep it open) was required when feasible, with investigators free to choose bare-metal (traditional) or drug-eluting stents.   Most patients did not receive drug-eluting stents.  The researchers followed the patients for an average of three years by telephone or through clinic visits and used medical records to check on the clinical events of interest.  The endpoints were verified by an independent classification central committee.  Maryland Medical Research Institute was the data coordinating center, led by Genell L. Knatterud, Ph.D.

The study results show no statistically significant differences between the late PCI and medication group in the occurrence of death, heart attacks or heart failure.   However, the researchers found an unsettling trend toward more heart attacks in the late PCI group than in the medication group.  PCI-assigned patients tended to have excess rates of repeat heart attack, including non-procedure-related events.  In addition, elevation of cardiac markers, chemical indicators of heart damage, was significantly more common in the PCI group soon after randomization to that treatment arm. 

“Although the rate of repeat heart attacks did not reach the level of statistical significance, the trend is worrisome," Hochman said.  "Further analysis and longer follow-up is required to understand the clinical consequences of these heart attacks.  These unexpected results are remarkably consistent among all subgroups, including those at highest risk of adverse left ventricular remodeling, such as those with low ejection fraction (a measure of the heart’s pumping ability).

“There were fewer patients with angina (chest pain) in the PCI-assigned group at four months and at one year.   However, the overall occurrence of angina was low and declined in both groups, and at three years there was no significant difference between groups in the proportion of patients with angina.”

OAT included a substudy called the Total Occlusion Study of Canada (TOSCA)-2 Trial.  It used repeat pictures of the coronary arteries and left ventricle (the heart’s main pumping chamber) in the hearts of a subgroup of 381 subjects in the PCI and medication groups, which was led by Vladimir Dzavik, M.D., University Health Network, Toronto General Hospital, Canada and Christopher E. Buller, M.D, Vancouver General Hospital, Canada.   This study found that the opened artery stayed open at one year in most patients who had the angioplasty but their heart function was not better than the medication group.   A subset of those who had additional measurements showed less adverse enlargement of the heart in the PCI group. However, this did not translate into clinical benefit.   There may be competing processes whereby repeat heart attacks offset this potential benefit.

“Results of the 2,166-patient OAT Trial found no reduction in major cardiovascular events over an average follow-up of three years and a signal of excess non-fatal heart attack when routine PCI was performed on stable patients who still have an occluded IRA following a heart attack,” Hochman said.   “Our findings should lead to lower rates of unnecessary coronary interventions in this specific group of stable patients, which should result in substantial healthcare cost savings.  Early treatment of heart attacks remains a critically important therapy.”

Other co-authors are: Harmony R. Reynolds, M.D.; Staci J. Abramsky, M.P.H.; Sandra Forman, M.A.; Witold Ruzyllo, M.D.; Aldo P. Maggioni, M.D.; Harvey White, M.D.; Zygmunt Sadowski, M.D.; Antonio C. Carvalho, M.D.; Jamie M. Rankin, M.D.; Jean P. Renkin, M.D.; P. Gabriel Steg, M.D.; Alice Mascette, M.D.; George Sopko, M.D.; Matthias E. Pfisterer, M.D.; Jonathan Leor, M.D.; Viliam Fridrich, M.D.; and Daniel B. Mark, M.D., M.P.H.

Supported by grants from: the NHLBI, National Institutes of Health.   Corporate Donations (funds totaling <5 percent of OAT grants): Boston Scientific Corporation (Argentina): stents donated for Argentine sites; Cordis Corporation, a Johnson & Johnson Company: stents donated for OAT sites; Eli Lilly and Company: ReoPro replacement doses, funding for meetings in 2001, 2002 and 2006 (monetary donation equivalent to 1.09 percent of total funding); Guidant Corporation: funds for pilot phase and stent reimbursement for one site (monetary donation equivalent to 0.40 percent of funding), stents donated for OAT sites; Medtronic of Canada Ltd. (Canada): stents donated for Canadian sites; Merck & Co., Inc.: funding for pilot phase and funding for training meetings (total monetary donation equivalent to 0.50 percent of total funding); Millennium Pharmaceuticals, Inc. and Schering Plough Corporation: Integrilin replacement doses and funding for pilot phase (total monetary donation equivalent to 0.25 percent of total funding).

Disclosure statement:  Dr. Hochman, Dr. Lamas, Dr. Knatterud, Dr. Reynolds, Dr. Mark, Ms. Forman and Ms. Abramsky report having current grant support for OAT from NIH/NHLBI.  Dr. Lamas reports having been paid speaking fees by Medtronic and Guidant and consultant fees by Medtronic.  Dr Hochman reports having received a consultant fee from Eli Lilly, Merck, and Sanofi Aventis and speaker fees from the Network for Continuing Medical Education speaker program, supported by Bristol Myers Squibb/Sanofi.   Grants from Eli Lilly, Millennium Pharmaceuticals, Inc. and Schering Plough Corporation, Guidant and Merck to support OAT were awarded to Dr Hochman’s institution.  Dr. Lamas reports having been paid speaking fees by Medtronic and Guidant and consultant fees from Medtronic.   Dr. Buller reports having served as a consultant for Guidant.  Dr. Dzavik reports having served as a consultant for Cordis Johnson & Johnson and Boston Scientific and having been paid speaking fees by Cordis Johnson & Johnson. Dr. Dzavik also reports having current grant support from Cordis Johnson & Johnson and from Medtronic.  Dr. Ruzyllo reports having served as a consultant for Cordis Johnson & Johnson and Proctor and Gamble. Dr. Ruzyllo also reports having been paid speaking fees by Eli Lilly and Merck.   Dr. Maggioni reports having been paid speaking fees by Guidant.  Dr. White reports having served as a consultant to, and having been paid speaking fees by, Sanofi Aventis and The Medicines Company. Dr. White also reports having received grant support from Fournier, Johnson & Johnson, Proctor and Gamble, Schering Plough, Alexion, Sanofi Aventis, Lilly, Merck, The Medicines Company, Neuron, Glaxo Smith Kline, Pfizer, and Roche.  Dr. Rankin reports having received an unrestricted educational grant from Cordis Johnson & Johnson.   Dr. Renkin reports having been paid speaking fees by Guidant.  Dr. Steg reports having served as a consultant and having been paid speaking fees by Merck. Dr. Steg also reports having received honoraria as a national coordinator for a Schering Plough trial.  Dr. Leor reports having served as a consultant to BioLineRx.  Dr. Mark reports having served as a consultant and having been paid speaking fees by Medtronic. Dr. Mark also reports having current grant support from Eli Lilly.

Statements and conclusions of abstracts presented at American Heart Association scientific meetings are solely those of the 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.

NR06-1123 (SS06/Hochman/OAT)

Note: This abstract will be presented at 11:25 a.m. CST, Tuesday, Nov. 14.

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