Advanced heart failure (HF) is a progressive disease characterized by recurrent hospitalizations and high risk of mortality. Indeed, outcomes in late stages of HF approximate those seen in patients with various aggressive malignancies. Clinical trials assessing beneficial outcomes of new treatments in patients with cancer have used innovative approaches to measure impact on total disease burden or surrogates to assess treatment efficacy. Although most cardiovascular outcomes trials continue to use time-to-first event analyses to assess the primary efficacy end point, such analyses do not adequately reflect the impact of new treatments on the totality of the chronic disease burden. Consequently, patient enrichment and other strategies for ongoing clinical trial design, as well as new statistical methodologies, are important considerations, particularly when studying a population with advanced chronic HF. The DREAM-HF trial (Double-Blind Randomized Assessment of Clinical Events With Allogeneic Mesenchymal Precursor Cells in Advanced Heart Failure) is an ongoing, randomized, sham-controlled phase 3 study of the efficacy and safety of mesenchymal precursor cells as immunotherapy in patients with advanced chronic HF with reduced ejection fraction. Mesenchymal precursor cells have a unique multimodal mechanism of action that is believed to result in polarization of proinflammatory type 1 macrophages in the heart to an anti-inflammatory type 2 macrophage state, inhibition of maladaptive adverse left ventricular remodeling, reversal of cardiac and peripheral endothelial dysfunction, and recovery of deranged vasculature. The objective of DREAM-HF is to confirm earlier phase 2 results and evaluate whether mesenchymal precursor cells will reduce the rate of nonfatal recurrent HF-related major adverse cardiac events while delaying or preventing progression of HF to terminal cardiac events. DREAM-HF is an example of an ongoing contemporary events-driven cardiovascular cell-based immunotherapy study that has utilized the concepts of baseline disease enrichment, prognostic enrichment, and predictive enrichment to improve its efficiency by using accumulating data from within as well as external to the trial. Adaptive enrichment designs and strategies are important components of a rational approach to achieve clinical research objectives in shorter clinical trial timelines and with increased cost-effectiveness without compromising ethical standards or the overall statistical integrity of the study. The DREAM-HF trial also presents an alternative approach to traditional composite time-to-first event primary efficacy end points. Statistical methodologies such as the joint frailty model provide opportunities to expand the scope of events-driven HF with reduced ejection fraction clinical trials to utilize time to recurrent nonfatal HF-related major adverse cardiac events as the primary efficacy end point without compromising the integrity of the statistical analyses for terminal cardiac events. In advanced chronic HF with reduced ejection fraction studies, the joint frailty model is utilized to reflect characteristics of the high-risk patient population with important unmet therapeutic needs. In some cases, use of the joint frailty model may substantially reduce sample size requirements. In addition, using an end point that is acceptable to the Food and Drug Administration and the European Medicines Agency, such as recurrent nonfatal HF-related major adverse cardiac events, enables generation of clinically relevant pharmacoeconomic data while providing comprehensive views of the patient's overall cardiovascular disease burden. The major goal of this review is to provide lessons learned from the ongoing DREAM-HF trial that relate to biologic plausibility and flexible clinical trial design and are potentially applicable to other development programs of innovative therapies for patients with advanced cardiovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02032004.