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Specific guide to this web site for:


 1.  Medical School
      Educators 
      in Statistics

 2.  Medical Students
 3.  Science media writers

 4.  High School & College
     Statistic Teachers


   Misadventures:


1. Harvard led MI study

2. JACC study 
   (J. of Amer. Coll.
   Cardio.)

3. NEJM cath study
4. Amer. J. of Cardio.
    review of literature
5. ALLHAT
     controversy 

6. Oat bran study
7. Pregnancy & Alcohol
8. Are Geminis really
    different?
      
9. Columbia 'Miracle' Study  
                                                 

Additional Topics:

Celebrex

Limitations of Meta-Analyses

Large Randomized Clinical Trials

Tale of Two Large
Trials

Advocate meta-analyses

Network meta-analyses


 

 

 

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A Flawed Medical Trial: Inappropriately low single dose of aspirin potentially resulting in an excess of heart attacks with angioplasty (balloon dilation).  

By trial design, the study was seriously biased against one of the two treatment strategies the trial was designed to evaluate.

    A trial led by Harvard Medical School faculty was designed to compare initail treatment with angioplasty (balloon dilatation) of heart arteries to a treatment strategy initiated with medication.  However, by the initial flawed protocol design, patients prior to undergoing angioplasty received only a single low dose of aspirin, 81 mg.  A single low dose of aspirin of this strength does not give the full effect of aspirin in inhibiting platelet aggregation.  It takes numerous days of administration of 81 milligram of aspirin to potentially achieve the full effect of aspirin.1

    Hence, the initial trial protocol called for patients undergoing angioplasty to receive an insufficient dose of aspirin which would result in an increased risk of heart attack occurring in the angioplasty group.  At the time the balloon is dilated with angioplasty, the platelets need to be maximally inhibited.  The patients treated with medication initially did not suffer from this protocol pitfall because they did not receive angioplasty after only a single low dose of aspirin. The prior randomized trials that established the benefit of aspirin with angioplasty used a high dose of aspirin.2,3

    The trial investigators after already entering some patients initially at the 81 milligram dose changed the aspirin dose to a single enteric coated dose of aspirin 325 milligrams.  Unfortunately, a single dose of enteric coated of aspirin swallowed whole also does not reliably achieve the full effects of aspirin at the time the angioplasty was performed in the study.4,5

In addition, the trial protocol called for an inappropriate short duration of follow up that could also bias trial results.5  The short interval of follow up for the trial 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.    The CASS study6, as an example, showed a significant reduction in mortality in patients undergoing patients coronary bypass surgery who had decreased left ventricular function and triple vessel coronary artery disease. This difference in outcome was not present at one year, but developed in later subsequent follow up. 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?

Summary:  Hence, by trial design, the study was seriously biased against one of the treatment strategies the study was designed to evaluate.  The patients in the angioplasty arm were being treated in a substandard fashion not in keeping with the clinical standard of the time which was full dose aspirin.  The trial was initially designed for the primary endpoint assessed at six weeks which was premature and also would tend to bias the outcome results against the angioplasty group.

1  Kuster L, Frolich J. Platelet aggregation and thromboxane release induced by arachidonic acid, collagen, ADP, and platelet-activating factor following low dose acetylsalicylic acid in man. Prostaglandins 1986;32:415-423

2. Barnathan E, Schwartz J, et al. Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circulation 1987;76:125-134

3. Schwarz L, Bourassa M, et al. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty.
N Engl J Med 1988;318:1714-1719

4. Brandon RA, Emmett J, et al.  Peripheral venous plasma aspirin concentrations and platelet aggregation inhibition produced by enteric-coated aspirin formulation. Thrombosis and Haemostasis 1986:55:222-227.

5. Roehm E.  A Critique of Selected Aspects of the Thrombolysis in Myocardial Infarction IIB (TIMI IIB) and the Thrombolysis in Myocardial Infarction IIIB (TIMI IIB) Trials. J Invas Cardiol 1992:4:145-154 (p. 151)

6. Passamani E, Davis K, et al. A randomized trial of coronary artery bypass surgery; survival of patients with a low ejection fraction. N Engl J Med 1985;312:1665-1671.

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