Abstract 11375: Clinical Trial Design for Management of Heart Failure Using a Nested Veteran Cohort to Determine Cardiovascular Mortality Linked to Prior Combat Exposure

IntroductionHeart failure (HF) risk is greater in U.S. veterans who self-report combat exposure (CE) than those who do not (RR of 4.99, 95% CI, 1.29, 19.38; Roy, Am J Pub Health, 2015). Whether cardiovascular mortalities (CVMs) differ for CE and non-CE HF veterans is not known. This knowledge gap, and the use of confounding self-reports, gives impetus to design a randomized clinical trial (RCT) to reveal veteran HF related CVM disparity, and to determine new drug efficacy when combined with sacubitril/valsartan (S/V). For this RCT template, a nested veteran cohort within the placebo group is constructed to assess HF CVMs. Non-veterans and U.S. veterans are recruited with reduced ejection fraction, and with either NYHA II or III HF. CE is determined by a veteran’s military-verified combat award, rather than self-report.MethodsLog regression determined RCT feasibility based on RR target and sample size. The CVM of 5.4% per year for HF patients on S/V was obtained from published PARADIGM-HF data. A study time of 5 years, plus 4 for follow-up, was allotted. Type I error was 0.05. Test to control ratio was 1:1.ResultsSee Figure. The RCT requires 5400 subjects to detect an RR of 0.87 for test drug efficacy. Of the 3040 veterans, 1520 are needed for placebo to detect a CE CVM target RR of 1.28.ConclusionsA RCT with a nested cohort is feasible to permit RR determination of HF CVM for CE and non-CE veterans when testing a new drug. SGLT2 inhibitors are possible test candidates. Combat award verification eliminates self-report confounding factors. There are more than 100,000 combat awardees over the past 14 years. A RCT result that reveals elevated HF CVM in CE veterans has implications for government policies and HF guidelines. Further analyses may detect whether the test drug mitigates any CE-related CVM risk. A successful RCT will show how trials can leverage HF improvement for veterans and non-veterans alike, as well as shed light on the nature of a CE-related cardiac or neurocardiac injury.