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The following published critique was sent with a cover letter to many leaders of the cardiology academic community in addition to the physicians leading this flawed study. The goal was to have the failings of this study widely known in the cardiology community prior to its publication so it would not inappropriately adversely affect the care of patients presenting with unstable angina or non-Q-wave MIs.

A Critique of Selected Aspects of the Thrombolysis in Myocardial Infarction IIB (TIMI IIB) and the Thrombolysis in Myocardial Infarction IIIB (TIMI IIIB) Trials.  Roehm E. Jl. Invas. Cardio 1992: 4;145-154

ABSTRACT: The Thrombolysis in Myocardial Infarction IIB trial (TIMI IIB) compared a particular invasive treatment strategy to a particular conservative strategy.1 A single 80mg dose of aspirin was routinely used in the invasive strategy patients prior to undergoing angioplasty. This low dose of aspirin, which results in suboptimal inhibition of platelet aggregation, may have adversely affected the outcome of the patients undergoing angioplasty.Both the TIMI IIB trial and the Should We Intervene Following Thrombolysis trial (SWIFT) showed a trend for a higher early adverse cardiac event rate for the invasive strategy group, subsequently followed by a trend for a lower adverse outcome rate.2,3 A short duration of follow up potentially biases the outcome data against the invasive strategy group. Additional follow-up data beyond one year is needed to definitively determine the relative outcome of the invasive and conservative groups.The ongoing Thrombolysis in Myocardial Infarction IIIB trial (TIMI IIIB) compares an invasive treatment strategy to a conservative treatment strategy for patients with unstable angina and non-Q-wave myocardial infarction.4,5 The TIMI IIIB trial, similar to the TIMI IIB trial, uses a suboptimal dosage of aspirin prior to angioplasty and has a relatively short duration of follow-up.

J INVAS CARDIOL 1992; 4:145-154

full article (3mb download)

The following was the cover letter:

Eric Roehm, M.D.
2300 Round Rock Ave., Suite 204
Round Rock, Texas 78681

April 20, 1992

Eugene Braunwald, M. D.
Chairman,Department of Medicine
Brigham and Women's Hospital
Dear Dr. Braunwald,

The TIMI trials have substantially impacted the treatment of patients presenting with a myocardial infarction. The completed TIMI IIB trial compared an invasive strategy to a conservative strategy for patients with an acute myocardial infarction with ST elevation. The ongoing TIMI IIIB trial includes a similar comparison of therapy for patients with unstable angina and non-Q-wave myocardial infarction.

Unfortunately, the TIMI IIB and IIIB trials have an unintended bias against the outcome of the invasive strategy patients by virtue of protocol design. Aspirin is given to the invasive strategy patients in a suboptimal fashion prior to angioplasty. In the TIMI IIIB trial, the initial patients received a single 80 mg. dose of aspirin prior to angioplasty. Currently, the prevailing mode of aspirin administration in the TIMI IIIB trial prior to angioplasty consists of a single 325mg enteric coated aspirin swallowed whole. The resulting suboptimal inhibition of platelet aggregation can potentially adversely effect the angioplasty success rate. In addition, the invasive strategy patients in the TIMI IIIB trial may be adversely affected by a relatively short duration of pretreatment with heparin and aspirin prior to the performance of angioplasty.

The short interval of follow up for the trials also potentially biases the results against the invasive strategy. An invasive strategy tends to have much of its adverse outcome occur relatively early. The appropriate duration of follow up for a trial comparing a PTCA strategy to a conservative strategy needs to be more critically examined. Why should the CASS trial comparing coronary bypass surgery to medical therapy be followed for five years, and the TIMI IIB and IIIB trials have mortality and reinfarction endpoints reported at six weeks and one year?

A full discussion of the strengths and weaknesses of these trials, including the ongoing TIMI IIIB trial is warranted. The GISSI II investigators have previously suggested that the criticism they received for instituting heparin as a subcutaneous dose many hours after tPA administration had been completed was less valid, since it was made only after the trial outcome data was reported. Hence, critical evaluation of a protocol of an ongoing trial protocol is appropriate.

The TIMI trials will continue to have a major influence on the current standards of cardiology care. These trials warrant careful examination.

Thank you for your time and consideration.

Sincerely yours,

Eric Roehm, M.D.

Encl: Critique of TIMI IIB & IIIB, Roehm, J Inv Cardiol. 1992: 4:145-154

cc: Jeffrey Anderson, M.D.
Arnold E.R. Arnold, M.D.
George Beller, M.D.
Eugene Braunwald, M. D.
Robert Califf, M.D.
D. A. Chamberlain, M. B.
James Chesebro, M.D.
Rory Collins, M.B. C.
Richard Conti, M.D.
Simon Dack, M.D.
D. P. de Bono, M.D.
Anthony DeMaria, M.D.
Steve Ellis, M.D.
Charles Fisch, M.D.
James Forrester, M.D.
Robert Frye, M.D.
Valentin Fuster, M.D.
Bernard Gersh, M.B.
Raymond Gibbons, M.D.
Cindy Grines, M.D.
Geoffrey Hartzler, M.D.
Frank Hildner, M.D.
Adolph Hutter, Jr., M.D.
J. Ward Kennedy, M.D.
Spencer King, M.D.
Richard Myler, M.D.
William O'Neill, M.D.
Bertram Pitt, M.D.
Albert Raizner, M.D.
Robert Roberts, M.D.
William C. Roberts, M.D.
Allan Ross, M.D.
Thomas Ryan, M.D.
R.C. Schlant, M.D.
Sol Sherry, M.D.
Peter Sleight, M.D.
Burton Sobel, M.D.
Simon Stertzer, M.D.
H. Jeremy Swan, M.D.
Eric Topol, M.D.
Frans Van der Werf, M.D.
Sylvan Weinberg, M.D.
Harvey White, M.B.
James Willerson, M.D.
David Williams, M.D