The search for novel therapies to manage acute cardiovascular disease faces severe challenges. Relatively low event rates, diverse patient populations and small treatment effects have made clinical drug development in this setting enormously expensive with sample sizes in the thousands. Population enrichment designs explicitly factor-in the possibility that the experimental compound might differentially benefit different subgroup. In such a design one would prospectively specify the subgroups that the new therapy is expected to benefit. Enrollment would initially be open to a broad patient population with the option to restrict future enrollment, following an interim analysis, to only those subgroups that appeared to be benefiting from the experimental therapy. Our experience with the design of one such large multinational trial of acute coronary syndromes will be presented.