November 6th, 2012

What Tack to Take in Thinking about TACT?

Several Cardiology Fellows who are attending AHA.12 in LA this week are blogging together for CardioExchange. The Fellows include Tariq AhmadReva Balakrishnan, Megan Coylewright, Eiman Jahangir, Amit Shah, and John Ryan (moderator). Read the previous post here. Find the next one here. For related CardioExchange content, go to our AHA 2012 Headquarters page.

In my short experience at AHA.12, I have noticed several differences this year, most notably that several presentations at the early Late-Breaking Clinical Trials sessions left us with mostly negative results and more questions.

During the first session, one presentation with a positive result seemed to catch the fellows (and perhaps many others in the audience) off guard — TACT (Trial to Assess Chelation Therapy). When the introductory slide appeared, we all seemed to be thinking,  “What is chelation? And why is this important?” Although some presentations at these conferences can seem beyond our knowledge base or secondary to our personal experiences within the specialty and training, it is rare that during a major session a therapy is presented that only few of us are even remotely familiar with. Except for reading about chelation therapy for lead poisoning in medical school, the most experience I have had with it was seeing an old enrollment binder sitting in the back of one of the fellows rooms and asking an attending about it (who quickly dismissed it with an “oh, nobody does that anymore, don’t worry about it” type of statement). 

The surprising trial results raised more questions than answers, showing that chelation therapy was significant (HR 0.82, with an upper limit of 0.99) in reduction of the primary composite endpoint of all-cause mortality, MI, stroke, revascularization, and anginal hospitalization, with what appeared to be a stronger benefit in the subgroup of diabetics (39% reduction in events, p=0.002).  

I searched the internet for some information on plausible mechanisms of action — and could find no strong evidence, instead seeing mostly theories.  

Later that night, our fellowship program convened for a reception. One aspect that makes the conference valuable for fellows is the opportunity to discuss the presented results with a diverse group of people at different levels of training, plus researchers and clinicians, which allows us to more fully synthesize the data and explore different approaches to thinking about the information. 

At the reception, I was able to discuss the trial with more senior faculty with extensive research backgrounds. One highlighted thought-provoking point was that our impression of a major finding is oftentimes shaped by the bias of the presenter. Although this trial had a significant result, the overall tone from the panel was negative, and the author at an AHA press conference even called for caution in interpretation. The attending at my evening reception believed that if similar results were presented on a new drug or stent, people would likely be more excited about it and the study might change their practice. Yet, given that biologic plausibility is not established and closer analysis of the data remains to be seen, it seems appropriate to approach these results with a critical eye.

As a fellow, have you had any exposure to the practice of chelation therapy for CAD, either first-hand or through the grapevine? More generally, how do you think about studies with surprising results?

3 Responses to “What Tack to Take in Thinking about TACT?”

  1. Dan Hackam, MD PhD says:

    I just had a patient ask me about this today. He has intractable angina.
    Questions I have:
    1) Was the test of interaction for DM vs non-DM statistically positive? If not, was it underpowered?

    2) What have prior trials suggested? I believe all have been negative at the randomized trial level.

    3) Was the result the fact that they gave glucose in the “placebo” arm? That might explain the worsened outcomes in diabetics who received “placebo” therapy.

    4) What effect did truncating enrollment and prolonging follow-up (trial amendment agreed by NIH) have on statistical power? Wasn’t this only supposed to be a one year trial, with one year of treatment?

    5) What happened to the hard endpoints – MI, stroke, cardiac death, etc.

    6) Can this be replicated?

  2. Thank you for your comments. You bring up some very valid points.
    1) The statistical analysis does warrant a closer look, and unfortunately the data is not published yet, and the full slide set is not available yet for review on the AHA website.
    2) Prior “randomized” studies have been done, albeit small – initially in the 1950’s then 1990 – but were very small (N=10!). The PATCH study was published in JAMA in 2002 which was a negative trial in 84 patients evaluating the effect of chelation in stable CAD v. placebo on time to ischemic changes in ECG stress testing. This is a systematic review in BMC cardiovascular disorders from 2005:
    3) The fact that there was some glucose added to the placebo is a good point; during the presentation it was not specified how much glucose was added. It would be interesting to see how diabetes was defined and what the degree of diabetic control was in this group over the study period.
    4) This was addressed in the presentation, although again – slides are not available for review of power calculation – they adjusted to a more conservative prespecified p-value of p less than or equal to 0.036 for their final analysis
    5)Hard endpoints – awaiting more information upon full presentation review. OF note, the quality of life presentation (can review here: did not show any significant improvements in quality of life measures (SF-36, DASI score, seattle angina questionnaire) at 2 yrs.

    A larger question is not only “can this be replicated”, but should it be replicated? Given the difficulties with enrollment, the length of the trial, the lack of improvement in quality of life, the task of even evaluating this in a diabetic subpopulation would need careful consideration

  3. Dan Hackam, MD PhD says:

    It is striking that a trial that found a substantial near-significant improvement in revascularization (15.5% vs 18.1%, p=0.076) and hospitalization for angina (1.5% vs 2.1%, p=0.359), yet showed no improvement in quality of life. Don’t hospitalizations and need for revascularizations at least transiently worsen QoL? There is an odd disconnect here – almost as if two separate trial datasets were being examined here rather than the same patients and procedures.

    As well, improvement in something other than softer, subjective endpoints like revascularization (which are often guided by clinician/patient preferences and oculostenotic reflexes) would be ideal before supporting this therapy.