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Randomized controlled trials: Read the “fine print”!

Most randomized controlled trials (RCTs) can appear deceptively simple. Study subjects are randomized to experimental therapy or placebo—simple as that. However, this apparent simplicity can mask how important subtle aspects of study design—from patient selection to selected outcomes to trial execution—can sometimes dramatically affect conclusions. Given how much influence large RCTs can have in medical practice, it is important for doctors to be familiar with the “fine print” of how the landmark studies in their specialties are conducted.

In neurology, one of the most prominent case studies of the impact of RCT “fine print” is the story of endovascular therapy for acute ischemic stroke patients. Ischemic stroke involving clots within the large vessels of the brain can be absolutely devastating for patients with regards to their ability to walk, talk, think, and eat. When experimental catheter-based procedures began emerging over the past two decades that made possible the direct removal or lysis of large vessel occlusions (with what appeared to be acceptable rates of complications), a controversy developed within the stroke community. How could quickly removing a clot with a relatively safe catheter ever be the wrong thing do to? Why even subject such patients to a randomized trial, especially if insurance companies seem willing to pay for the procedure to be done?

With this mentality, the stroke community struggled for years with enrollment of severe ischemic stroke patients into formal RCTs of endovascular therapy. Surprisingly, the pendulum of medical opinion swung wildly in 2013, when the New England Journal of Medicine published three large RCTs of endovascular therapy that were actually unable to prove any benefit of such catheter-based procedures for improving patient recovery from large-vessel strokes. The sheer scope of the three well-publicized, simultaneous studies was enough to reverse the question many doctors were asking in these situations from, “How could we possibly consider enrolling an endovascular candidate in a randomized clinical trial?” to “How can we even bring stroke patients to the endovascular suite, with three negative trials?”

However, as the stroke community became more familiar with the “fine print” of the three 2013 trials, it became clear that many of these details were absolutely critical in unpacking the trials’ negative results. The International Management of Stroke III Trial (IMS III), one of these three landmark trials, has now been dissected perhaps as much as any stroke trial in history. On the surface, the trial design seemed straightforward: 58 centers randomized patients who (1) presented early with severe stroke symptoms and (2) had already received intravenous tissue plasminogen activator (IV t-PA, an IV clot-busting agent, the accepted standard of care for acute stroke) to either endovascular therapy or conservative management. IMS III was stopped early for futility and found no difference between groups in terms of patients who were functionally independent at 90 days. Simple as that?

Image CreditL CT scan of a normal human brain by Andrew Ciscel. CC BY-SA 2.0 via Wikimedia Commons.
Image Credit: CT scan of a normal human brain by Andrew Ciscel. CC BY-SA 2.0 via Wikimedia Commons.

The “fine print”: Less than half of the patients enrolled in IMS III underwent a CT angiogram prior to IV t-PA. A CT angiogram is the best test for non-invasively identifying a large vessel occlusion for an acute stroke patient, and thus it is possible that a large number of patients enrolled in the study didn’t have a large-vessel clot to remove. A substantial proportion of patients enrolled in IMS III already had evidence of significant stroke on the initial head CT scan, meaning that much of their brain had already suffered irreversible damage before they were even potentially randomized to a clot retrieval. Many patients who were good candidates for the study were likely kept out of the study by doctors who were uncomfortable with not guaranteeing endovascular therapy for them, a bias that could have disproportionately left poorer endovascular candidates as the patients who were randomized. The length of the IMS III trial resulted in the fact that, by the time the trial was completed, the technologies that it studied were essentially out of date and replaced by catheters that had a much higher success rate of clot removal.

These limitations of the IMS III trial and the other two negative trials published in 2013 ultimately paved the way for the current era of stroke treatment. A series of RCTs published in the past two years have since shown overwhelming clinical benefit for endovascular therapy in large vessel stroke—provided that patients are shown to have actual large vessel clots before the procedures, that their initial irreversible stroke burden is small, and that patients undergo procedures using cutting-edge catheter technology. Although it was a “failed” trial, IMS III has a large legacy in stroke and in neurology—simple aspects of study design of execution can make all the difference in your RCT results. It’s important for all clinicians to read the “fine print”!

Featured image credit: Bethesda Naval Medical Center by tpsdave. CC0 Public Domain via Pixabay.

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