Why Are CASTA and CARS Results Different? Analysis of CASTA Data from Korea and Hong Kong

permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Cerebrolysin is a neuropeptide preparation, which mimics the action of endogenous neurotrophic factors. 1 In animal models, Cerebrolysin stabilizes the structural integrity of cells by inhibiting calpain, reduces the number of apoptotic cells and decreases infarct volume and edema formation. Furthermore, Cerebrolysin promotes neurogenesis and supports the self-repair mechanism of the brain, 2,3 resulting in improved functional recovery. The Cerebrolysin Acute Stroke Treatment in Asia (CASTA) trial was a multicenter, randomized, double-blind, placebo-controlled study that examined the efficacy of Cerebrolysin on the recovery of stroke patients. 4 Patients were recruited from 51 centers located in China (1,024 patients), Hong Kong (4 patients), South Korea (16 patients), and Myanmar (26 patients). The confirmatory endpoint showed no significant difference between the patients treated with Cerebrolysin and those receiving placebo. More recently , however, investigators from the Cerebrolysin And Recovery after Stroke (CARS) study reported that Cerebrolysin significantly improved neurologic recovery in ischemic stroke patients. 5 The aim of our present research was to investigate possible reasons for the different outcome of the CASTA and CARS trials on the basis of (1) the study designs and (2) a re-analysis of CASTA data. As summarized in Table 1, there are several notable differences in the study design of the two studies. First, while the CASTA trial focused on the National Institutes of Health Stroke Scale (NIHSS) and enrolled patients with various levels of functional disability, the CARS study defined patients by their motor deficits and included patients with more severe disturbances. Most likely, the design took the post-hoc data of the CASTA study into consideration as the more severe subgroup with a baseline NIHSS score > 12 showed significant improvement in their NIHSS scores (P= 0.04) at day 90. This may be one reason why the CARS study avoided the ceiling effect observed in CAS-TA. Second, in the CARS study treatment was started 24-72 hours post-stroke as compared to 12 hours in the CASTA trial, which allowed to exclude patients with progressive or fluctuating stroke. Third, while Cerebrolysin was given over 10 days in the CASTA trial, it was administered over 21 days in the CARS trial. This allowed the recovering patients to benefit longer from the neurorestorative action of Cerebrolysin. Finally, a standardized rehabilitation program was strictly applied to CARS patients whereas this was not mandatory …