Be More Critical April 9, 2010

Josh Cooper recently discussed the shortcomings of the gold standard we use to generate new knowledge and understanding: the randomized controlled trial. He pointed out that patient populations may be significantly divergent from the patient sitting in front of us, and study findings may not be right for our particular patients.

I agree with Josh’s comments, and propose a solution to deal with the randomized controlled trial, and all studies for that matter. No matter what your grandmother told you, or what you’ve been working on with your therapist, when it comes to research, BE MORE CRITICAL.

Critical appraisal of research doesn’t mean criticism of the table layouts, or the trial sponsor, or the study PI. Critical appraisal means a careful look at the patient population, study design, and research intervention. Did the conditions in the study look like the conditions that I’m facing when I treat my patient? If not, are they similar enough that I can learn something that will help me take care of the patient in front of me? (more…)

Taking Clinical Trials with a Grain of Salt March 30, 2010

I must confess that I am not a big fan of clinical trials, given the many ways that they can provide misleading information. In my opinion, the fatal flaw of clinical trials is the assumption that the enrolled subjects are biologically homogeneous. And a close second is the belief that we understand and have accounted for all the variables that impact the study hypothesis. In virtually every trial, there are patients who benefit from the therapy and those who are harmed. While the aggregate results may point toward benefit or harm, how do we know if the solitary patient sitting in the office will be in the majority? It might be exciting to the statistician to discover how a group of 5,000 heart failure patients would best be treated, but to the clinician, it can remain agonizingly unclear what to do with the individual.

Here are a few examples of how I believe trials may lead us astray.

1) A simple randomized trial of  beta-blocker use in patients with vasovagal syncope may show no statistical difference in the number of syncopal events on or off the drug.  I cringe when I hear someone proclaim that “Beta-blockers do not work for vasovagal syncope!”  How foolhardy. Of course beta-blockers work for vasovagal syncope – but not in everyone. I have treated many patients where daily pindolol or acebutolol has been life-changing. The biologic heterogeneity in the mechanisms of vasovagal syncope and response to pharmacologic intervention can easily account for a negative trial and, regrettably, the inappropriate unconditional rejection of beta-blockers by the naive clinician.

2) A large randomized trial of biventricular pacing in heart failure patients with a wide QRS overwhelmingly shows a benefit in both morbidity and mortality. Practice guidelines declare a solid indication for bi-v pacing in cardiomyopathy/CHF patients with a wide QRS.  And yet, we are learning that not all bundle branch blocks portend a vigorous response to CRT.  The right bundle branch block patient minority (who probably derived much less benefit, if any) might have been carried along with the triumphant left bundle branch block majority (who likely had an even greater response than the mean result would suggest).  And the same goes for those patients who squeaked into the trial with a QRS of 125ms.  The heterogeneous response of trial subjects to CRT is under-appreciated when only the average result is considered, and, consequently, a subset of patients who are now being implanted (supported by guidelines) will derive no benefit and may be harmed by the treatment. (more…)