BACKGROUND: To assess concomitant simultaneous effects on multiple end points using global statistical methods in phase II acute heart failure studies. METHODS AND RESULTS: Using simulations we have assessed different statistical methods to evaluate concomitant effects of a new intervention on dyspnea relief (using 2 measures), length of hospital stay, worsening heart failure to 5 days, mortality, and heart failure readmission to 30 days. Treatment effect scenarios included large (20% to 28% relative improvements) and very large (30% to 43% relative improvements) effects among others. Placebo responses and correlations among end points typical in recent acute heart failure clinical trials were used. Powers for the average Z score exceeded 70% with ≥75 patients per group for 35% relative improvement across all 6 end points. Assessing dyspnea alone generally provides lower power than the average Z score approach, with power deducted ≈50% under most of scenarios. Other approaches generally provide lower power than the average Z score method. CONCLUSIONS: Assessing the effects of new therapies on multiple clinical end points using the average Z score enables detection of therapeutic efficacy using sample sizes of 100 to 150 patients per group, approximately double the power achievable assessing the effects on dyspnea alone.