Ancillary Studies in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial: Synergies and Opportunities

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The definitive power of randomized controlled trials (RCTs) to characterize the efficacy of putative therapeutic approaches cannot be overestimated. Such trials are expensive, and their implementation requires prolonged and intensive commitments by both investigators and subjects. Accordingly, enhancing their value, in a sense increasing the “scientific return on investment,” is a laudatory objective. Ancillary studies afford a great opportunity to do so. They permit acquisition of new knowledge, elucidation of cause/consequence relation, and delineation of pathogenetic mechanisms at a much lower cost than would be possible if they were performed independently of the parent RCTs. In addition, their utility is enhanced by internal consistency under the rubric of the parent trial and the presumed external validation of the parent trial. Several ancillary studies undertaken in conjunction with the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial provide cogent examples. They seek to delineate causal connections linking the accelerated coronary disease typical of diabetes with phenomena such as genetic predisposition to altered expression of cytokines and fibrinolytic system proteins, inflammation, procoagulation, insulin-induced impairment of fibrinolysis, insulin resistance, and the response to insulin-sensitizing and insulin-providing treatment strategies.

Section snippets

The Value of Ancillary Studies

Several types of ancillary studies are being performed in conjunction with the BARI 2D trial. One comprises substudies designed to address mechanistic questions that focus on a particular segment of the parent study population or on patients from a subset of clinical sites participating in the parent study. In another type of ancillary study, results are obtained from a single center or a subset of centers by using already collected data or new assays of stored blood or urine samples with

The prominence of procoagulation in diabetes

Impaired fibrinolysis has been implicated as a contributor to acceleration of CAD in type 2 diabetes, attributable to elevated blood concentrations of the primary physiologic inhibitor of fibrinolysis, plasminogen activator inhibitor–1 (PAI-1).3 Impaired fibrinolysis is thought to potentiate persistence of microthrombi and their propensity to initiate and sustain intense thrombosis. Activation of the coagulation system leads to the generation of thrombin and fibrinopeptide A (FPA), released

BARI 2D Ancillary Studies Addressing These Phenomena

Several BARI 2D ancillary studies23 are designed to determine whether inflammation, procoagulation, and progression of CAD, independently or in combination, are ameliorated in patients with type 2 diabetes who are treated with insulin-sensitizing regimens, insulin-providing regimens, or both. Another is designed to delineate the effects of the 2 insulin treatment regimens on the progression of coronary vasculopathy and cardiac events associated with diabetes with respect to expression of PAI-1.

Significance

Reduction of the toll due to CAD in the >16 million Americans thought to have type 2 diabetes will, perhaps, best be achieved by preventing and retarding the evolution of lesions into the vulnerable atherosclerotic plaques that may rupture and precipitate acute coronary syndromes. Through identification of specific mediators of the development of such plaques and targeting them for prophylactic pharmacologic intervention, morbidity and mortality may be ameliorated. The possibility that

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  • Cited by (0)

    The core laboratories for electrocardiography (Dr. Bernard Chaitman, St. Louis University), economics (Dr. Mark A. Hlatky, Stanford University), and fibrinolysis (Dr. Burton E. Sobel, University of Vermont) were funded, respectively, by Grant Nos. U01 HL061746, U01 HL061748, and U01 HL063804 from the National Heart, Lung, and Blood Institute. The Nuclear Cardiology Core Laboratory (Dr. Ami E. Iskandrian, University of Alabama at Birmingham) received funding from Astellas Pharma US, Inc.

    A complete list of the BARI 2D Investigators appears in the Appendix.

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