Acute stroke trials: strengthening the underpowered.

In this issue of Stroke, Muir 1 addresses the looming crisis in acute stroke clinical trial design by illustrating why neuroprotective trials have been seriously underpowered. Unfortunately, this is not a new observation. Samsa and Matchar2 pointed out 3 statistical reasons neuroprotective stroke trials have been underpowered: (1) Sensitivity of power to small changes in outcome rates. (2) Overestimation of true treatment effect. Typically, neuroprotective stroke trials are powered to detect absolute treatment effects of 10%. This is likely wishful thinking. Phase III neuroprotective stroke trial sample sizes are usually based on optimistic phase II treatment effects. Furthermore, endpoints vary from trial to trial and may be erroneously selected on the basis of phase II data (eg, citicoline used an unconventional NIHSS analysis and lubeluzole Europe chose mortality). There is little reason to believe that neuroprotective stroke therapy alone will demonstrate the same magnitude of efficacy as reperfusion stroke therapy with intravenous tissue plasminogen activator under 3 hours (13% absolute benefit) or intra-arterial thrombolysis at 6 hours (15% absolute benefit). (3) Underestimation of the minimum clinically important difference. Since stroke is disabling with high long-term care costs, even a very modest treatment benefit on the order of 2% may result in a net benefit from a population viewpoint. Cardiology trials have employed this type of analysis to demonstrate the cost-effective benefit of new therapies that improve mortality by only 1%. Others3–5 have emphasized the need for standardization of baseline stroke severity, a shorter time window, and combination therapy. Adding to this list, Muir emphasizes what may be the most neglected problem of all—stroke pathophysiological heterogeneity. Using the most optimistic assumptions about treatment effect based on available data, Muir estimates that neuroprotective stroke trials require about 4000 total patients. Using more conservative (ie, realistic) estimates of treatment effect, neuroprotective trials would require about 8000 patients. These are painful numbers indeed, and perhaps it has simply been more soothing for investigators and industry to delude themselves into thinking that much smaller numbers will suffice. Consider that 2 of the largest neuroprotective trials to date, CLASS and GAIN I, contained only 1360 and See article on page 1545