Monday, February 10, 2014

CABANA Trial Morphs from Mortality Trial to Composite Endpoint Trial

Major changes are underway for one of the signature comparative effectiveness research trials promoted by government interests on Capitol Hill as a critical path forward to controlling costs in health care. It seems such research might not be so easy and "cost-effective" as some had hoped.

The Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial was slated to have total mortality as its primary endpoint, but with the trial's most recent revision, the primary endpoint will instead become a composite endpoint of 1) total mortality, 2) disabling stroke, 3) serious bleeding, or 4) cardiac arrest.

While some may not see this as a significant development, we should understand that clinicians will be left without a definitive answer to which therapy, catheter ablation or anti-arrhythmic drug therapy, will prolong life the best in symptomatic patients with atrial fibrillation. Instead, doctors will have to read tea leaves based on a composite score of several endpoints to make their own personal judgment.

Changes to the protocol from its original design have occurred because (1) there was a lower-than-expected mortality rate seen in the trial so far and 2) (and perhaps most importantly) accrual of patients worldwide was occurring at a lower rate than expected. Careful consideration of these issues led to a decision by the study leadership to (a) change the primary endpoint in the trial from total mortality to the new composite endpont described above and (b) to reduce the sample size from 3000 to a number (2000-2200) with longer follow-up (5-7 yrs) to shorten the study duration and more realistically achieve the new endpoint within the study's funding.

While these develops are disappointing to many of us who serve as regional investigators for this trial, this study remains our best chance to get closer to determining which therapy for symptomatic patients with atrial fibrillation and CHA2DS2-Vasc scores > 2 is most likely to reduce death AND/OR stroke.

As the CABANA Trial has now clearly shown us, the realities of conducting proper research to make definitive claims about patient care are much more difficult to prove than our politicians and policy wonks on Capital Hill would like us to believe.

On a larger scale, we should remain skeptical that comparative effectiveness research (CER) is necessarily the best and most cost-effective means to determine the best therapies for our patients. This is especially important to grasp since the Patient Care Outcomes Research Institute (PCORI), formed by the 2009 Stimulus Bill and quietly funded by patient fees attached to their new insurance premiums, necessarily involves insurers and other "stakeholders" in this CER research initiative. Their participation worries me that spectrum, reporting, analytical and data-snooping bias can be introduced when interpreting such imperfect CER trial results. After all, the fox is irrevocably in our CER research henhouse.


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