Fig. 1.

Alternative clinical trial designs for older adult subjects with heart failure with preserved ejection fraction (HFPEF). a Flow chart of traditional randomized placebo-controlled clinical trial (R). b Trial in which several interventions (numbered in the example as 1, 2, and 3) are instituted sequentially with assessment of outcome of interest in comparison to control. Interventions could include diet and lifestyle modifications (eg, salt restriction or cardiac rehabilitation), pharmacologic therapy (eg, treatment aimed at cardiovascular target or non-cardiac target, such as chronic pain) and/or treatment of extra-cardiac factors (eg, mood disorders, sleep-disordered breathing, diabetes). c Trial design in which cohort of interest is randomized to various interventions (indicated by 1, 2 and 3) and the order of interventions is varied in order to evaluate the efficacy of multiple interventions, which are likely to be required in complex clinical conditions such as heart failure with a preserved ejection fraction and to determine if the order of treatment intervention has an effect on outcomes