NHLBI Working Group

NHLBI Working Group: Translation of Therapies for Protecting the Heart from Ischemia, Exec. Summary

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NHLBI Working Group Translation of Therapies for Protecting the Heart from Ischemia Executive Summary The National Heart, Lung, and Blood Institute convened a Working Group of investigators on June 23-24, 2003, in Bethesda, Maryland to review the reasons for the failure to effectively translate potential therapies for protecting the heart from ischemia and reperfusion and to make recommendations for future approaches that would help to accomplish this task. Working Group members included basic scientists and physicians whose work has focused on the need for new therapies to protect the heart from ischemic and reperfusion injury. The major goals for the Working Group were to: (1) evaluate the gaps and barriers in basic research which have delayed the clinical implementation of cardioprotective therapies; (2) identify clinical settings in which cardioprotective therapies may be useful; (3) identify basic science findings that are ready for translation into clinical research; and (4) provide prioritized recommendations to facilitate the advancement of both basic and clinical research and identify approaches to applying therapies to protect the heart from ischemic injury. The two-day Working Group meeting was organized into three sessions covering the following topics: Session 1: Protection in Cardiac Interventions z z z

Adjuncts to Cardiac Surgery Mechanical vs. pharmacological approaches Alternative approaches to preconditioning

Session 2: Treatment of Stable Angina z z z

Pharmacological approaches to chronic protection Gene therapy for prolonged protection Identification of ‘High Risk' patient populations

Session 3: Acute Coronary Syndromes and Out-of-Hospital Arrest z z z z z

Predicting ischemia and preventing sudden death Preventing/reversing ischemia induced arrhythmias Strategies for limiting infarct size Nuclear and MR assessment of infarction Clinical Trials, lessons and opportunities

The Working Group concluded that the field of cardioprotection in the setting of acute myocardial ischemia, cardiac surgery, and cardiac arrest is at a crossroads. The process that has been used thus far to identify cardioprotective therapies at the basic research level is often inefficient, wasteful, and ultimately counterproductive. For three decades, pharmaceutical companies and federal funding agencies have invested significant resources in single-center studies of cardioprotection that have often yielded inconclusive results that have failed to be translated to clinical practice. The Working Group believed that opportunity presently exists for a new paradigm that can obviate many of the unreproducible, conflicting, contradictory, and unconfirmed results of single-center studies. As such, they indicated that the time has come to focus on translational research using clinically-relevant outcomes in addition to mechanisms of action. Their recommended approach was to establish a system for rigorous preclinical testing of promising cardioprotective agents using methods analogous to those used in clinical trials (i.e., blinded, randomized, multicenter, and adequately powered studies using standardized methods). In addition, they indicated that continued efforts are justified in pursuing the interventions that have been identified as promising in preclinical studies and, in some cases, in phase I and II clinical trials. A preclinical research consortium would advance the ability to rationally and progressively translate important findings from the basic science laboratory into eventual clinical use. In addition, such a consortium would increase opportunities for productive collaborations with industrial partners

http://www.nhlbi.nih.gov/meetings/card_prot.htm

12/18/2007

NHLBI Working Group: Translation of Therapies for Protecting the Heart from Ischemia, Exec. Summary

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Finally, the Working Group believed that the investment in cardioprotection made by the pharmaceutical industry and federal government during the past three decades could and should be developed into clinically effect therapies. They, therefore, recommended that the NIH proactively intervene to remedy the problems that have impeded the translation of cardioprotective therapies. Their specific recommendations include a short-term, low-risk project (preclinical consortium) and two medium-term, clinical studies with a high likelihood of demonstrating effectiveness (phase III clinical trials of adenosine in AMI and cardiac surgery). Among these recommendations, the Working Group assigned the highest priority to the preclinical consortium, because such an entity would serve as a source of potentially useful therapies to be tested in subsequent clinical trials. The Working Group believed that with these initiatives, the NIH could catalyze the translation of improved cardioprotection into clinical reality. A summary of the meeting is available in the journal, Circulation Research: Roberto Bolli R, Becker L, Gross G, Mentzer R, et al. Myocardial Protection at a Crossroads: The Need for Translation into Clinical Therapy. Circ Res. 2004;95:125-134. (The f ull article is available online.) Working Group Members Chair: Roberto Bolli, MD, Department of Medicine, University of Louisville Session Moderators:

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Lance Becker, MD, Emergency Resuscitation, University of Chicago Garrett Gross, PhD, Department of Pharmacology & Toxicology, Medical College of Wisconsin

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Robert M. Mentzer, Jr., MD, Department of Surgery, University of Kentucky

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Participants:

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Christopher B. Granger, MD, Duke Clinical Research Institute Dara Kraitchman, VMD, PhD, Department of Radiology, Johns Hopkins University School of Medicine Rakesh Kukreja, PhD, Medical College of Virginia Robert J. Myerburg, MD, Department of Medicine, University of Miami Karin Przyklenk, PhD, Department of Emergency Medicine, University of Massachusetts Medical School Jakob Vinten-Johansen, PhD, Department of Surgery, Emory University Richard D. Weisel, MD, Toronto General Hospital, University Health Network James Weiss, MD, Department of Medicine, UCLA School of Medicine

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Sir Magdi Yacoub, MD, Harefield Heart Science Centre, Middlesex

z z z z z z z

NHLBI Staff: z z z z

David M. Balshaw, PhD, Heart Research Program, Division of Heart and Vascular Diseases David A. Lathrop, PhD, Clinical and Molecular Medicine Program, Division of Heart and Vascular Diseases Jerome Fleg, MD, Clinical Trials Research Group, Division of Epidemiology and Clinical Application Ahmed Hasan, MD, Division of Blood Diseases and Resources

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Department of Health and Human Services

http://www.nhlbi.nih.gov/meetings/card_prot.htm

National Institutes of Health

National Heart, Lung, and Blood Institute

12/18/2007

CORONARY ARTERY DISEASE NHLBI Workshop on the Translation of Therapies for Protecting the Heart from Ischemia

Overview of Ischemia and Cardioprotective Therapies

• Caused 459,841 deaths in the United States in 1998 -- 1 of every 5 deaths

• Every 29 seconds an American suffers a coronary event, and every minute someone dies from one

Roberto Bolli, M.D. June 23, 2003

• An estimated 1,100,000 Americans will have a new or recurrent myocardial infarction this year

NHLBI WORKSHOP

NHLBI WORKSHOP

Translation of Therapies for Protecting the Heart from Ischemia

Translation of Therapies for Protecting the Heart from Ischemia Objectives

• Define the problem

Why are we here?

• Identify the causes • Recommend strategies for moving forward

NHLBI WORKSHOP Translation of Therapies for Protecting the Heart from Ischemia Objectives

• Define the problem • Identify the causes • Recommend strategies for moving forward

Factors Influencing Infarct Size Following Experimental Coronary Artery Occlusions By PETER R. MAROKO, M.D., JOHN K. KJEKSHUS, M.D., BURTON E.. SOBEL, M.D., TAN WATANABE, M.D., JAMES W. COVELL, M.D., JOHN ROSS JR., M.D., AND EUGENE BRAUNWALD, M.D. SUMMARY The purpose of this study was the determination of whether hemodynamic and pharmacologic factors influence the extent and severity of myocardial necrosis produced by coronary occlusion. In 48 dogs, 10 to 14 epicardial leads were recorded on the anterior surface of the left ventricle in the distribution and vicinity of the site of occlusion of a branch of the left anterior descending coronary artery. The average S-T segment elevation for each animal was determined at 5-min intervals after occlusion. This elevation was used as an index of the presence and severity of myocardial ischemic injury. The number of sites showing this elevation provided an additional measure of the size of the injured area. Occlusion alone raised the average S-T segment elevation from 0.22 ± 0.04 to 3.32 ± 0.37 mv (SEM). Isoproterenol, ouabain, glucagon, bretylium, and tachycardia given prior to a repeated occlusion increased the severity and extent of ischemic jnury, while propranolol decreased it. Elevation of arterial pressure with methoxamine reduced the occlusion-induced S-T segment elevation, and lowering of the mean arterial pressure by hemorrhage had the opposite effect. In 19 additional experiments, propranolol, isoproterenol, and alterations in arterial pressure produced similar alterations in S-T segment elevation when these interventions were applied as long as 3 hr after ligation. In a third group of dogs, myocardial creatine phosphokinase (CPK) activity was determined 24 hr after occlusion at the same sites at which epicardial electrocardiograms were taken. Depression of myocardial CPK activity in injured portions of the left ventricle 24 hr after coronary artery ligation correlated well with S-T segment elevation in the same sites 15 min after ligation. Moreover, isoproterenol increased and propranolol decreased the area of depression of myocardial CPK activity. We conclude that the hemodynamic states and neurohumoral background at the time of occlusion and for up to 3 hr thereafter can alter the extent and severity of myocardial ischemic injury and myocardial necrosis. Additional Indexing Words: Coronary occlusion, S-T segment elevation, Myocardial necrosis, Myocardial oxygen consumption, Myocardial creatine phosphokinase

Epicardial electrocardigram,

(Circulation. 1971;43:67-82.)

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PROTECTION OF ISCHEMIC MYOCARDIUM:


Experimental Success vs. Clinical Failure?


During the past 30 years, hundreds of drugs have been claimed to reduce myocardial infarct size in experimental models. However, few of these results have been reproducible and none has been translated into clinical therapies.

Numerous interventions have been tested in patients with AMI. All of them were started late into ischemia or after reperfusion, and the results have been disappointing. • hyaluronidase • steroids • recombinant superoxide dismutase • prostacyclin • fluosol • magnesium • poloxamer 188 (RheothRx) (positive with 114 pts, negative with >3,000 pts • trimetazidine • eniporide (positive with 162 pts, negative with 638 pts) • cariporide (positive with 100 pts, negative with >500 pts) • nitrates • antileukocyte interventions (anti-CD18 mAb)

NHLBI WORKSHOP Translation of Therapies for Protecting the Heart from Ischemia

Cardioprotection: The eternal promise

• Define the problem ¾

There is a chasm between the enormous number of therapies claimed to be cardioprotective in experimental studies and the lack of any cardioprotective therapy in the clinical arena

NHLBI WORKSHOP

NHLBI WORKSHOP



Objectives

• Define the problem • Identify the causes

• Identify the causes ¾

Why have experimentally successful interventions not been successful in patients?

• Recommend strategies for moving forward

2





Reasons for inability to translate experimentally successful treatments into clinical treatments:

Reasons for inability to translate experimentally successful treatments into clinical treatments:

• Methodological problems in experimental studies

• Methodological problems in experimental studies

• Difficulties inherent in studying cardioprotection in patients


• Timing of treatment in clinical studies


• Selection bias for positive studies


METHODOLOGICAL PROBLEMS IN EXPERIMENTAL STUDIES

• Use of in vitro models (isolated hearts, isolated cells, etc) • Use of in vivo models with short (< 24 hours) reperfusion • Failure to use conscious animal models • Inadequate attention to basic physiologic parameters (arterial pH, PO2, temperature, etc)

• • •

Differences in mortality not taken into account

•

Mouse model

In dogs, collateral flow not taken into account End-points (ST segment, infarct size without region at risk assessment, use of tetrazolium < 24 h after reperfusion, etc)

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PROTECTION OF ISCHEMIC MYOCARDIUM: Experimental Success vs. Clinical Failure? Reasons for inability to translate experimentally successful treatments into clinical treatments: • Methodological problems in experimental studies • Difficulties inherent in studying cardioprotection in patients • Timing of treatment in clinical studies • Selection bias for positive studies

DIFFICULTIES INHERENT IN STUDYING CARDIOPROTECTION IN PATIENTS Numerous confounding variables (duration of ischemia, continuous vs. intermittent ischemia, ischemic preconditioning, size of region at risk, collateral circulation, preexisting infarctions, medications, adrenergic tone, etc)

• •

Reasons for inability to translate experimentally successful treatments into clinical treatments: • Methodological problems in experimental studies

Pretreatment usually impossible


Infarct size estimated from nuclide uptake; limited resolution


(subendocardial vs. transmural infarction)

•



Even if infarct size is reduced, showing improvement in clinical outcome is difficult

REPERFUSION INJURY

HYPOTHETICAL ROLES OF ISCHEMIA AND REPERFUSION INJURY

Definition

A

B

C Ischemic injury Reperfusion injury

Injury that can be prevented by modifying the conditions under which reperfusion occurs.

INJURY

•


TIME

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TIMING OF TREATMENT IN CLINICAL STUDIES

• Even in experimental animals, in order to achieve reproducible cardioprotection treatments must be started before ischemia or in the early phase of ischemia. No treatment has been reproducibly shown to limit infarct size when started at the time of reperfusion. • It is usually impossible to treat patients before the onset of acute myocardial infarction. Thus, in the clinical arena, treatments are started after a significant part (perhaps most) of the damage has occurred.

PROTECTION OF ISCHEMIC MYOCARDIUM: Experimental Success vs. Clinical Failure? Reasons for inability to translate experimentally successful treatments into clinical treatments: • Methodological problems in experimental studies • Difficulties inherent in studying cardioprotection in patients • Timing of treatment in clinical studies • Selection bias for positive studies

NHLBI WORKSHOP

NHLBI WORKSHOP



Objectives


• Define the problem

¾ What should be done to translate basic research findings into clinical therapies?

• Identify the causes

• Use of relevant experimental models and


• Use of appropriate clinical settings and methods

reliable methods

• Use of effective therapies

NHLBI WORKSHOP Translation of Therapies for Protecting the Heart from Ischemia • Recommend strategies for moving forward ¾ What should be done to translate basic research findings into clinical therapies? • Use of relevant experimental models and reliable methods • Use of appropriate clinical settings and methods • Use of effective therapies

CLINICAL SETTINGS TO STUDY CARDIOPROTECTION IN HUMANS • PTCA • Cardiac surgery • Angina (chronic, unstable) • Acute myocardial infarction • Cardiac arrest

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CLINICAL SETTINGS TO STUDY CARDIOPROTECTION IN HUMANS • PTCA • Cardiac surgery • Angina (chronic, unstable) • Acute myocardial infarction • Cardiac arrest

EFFECT OF NITROGLYCERIN PRETREATMENT ON ST-SEGMENT DURING PTCA

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