University of Groningen Identifying Subpopulations with Distinct Response to Treatment Using Plasma Biomarkers in Acute Heart Failure

Background Over the last 50 years, clinical trials of novel interventions for acute heart failure (AHF) have, with few exceptions, been neutral or shown harm. We hypothesize that this might be related to a differential response to pharmacological therapy. Methods We studied the magnitude of treatment effect of rolofylline across clinical characteristics and plasma biomarkers in 2033 AHF patients and derived a biomarkerbased responder sum score model. Treatment response was survival from all-cause mortality through day 180. Results In the overall study population, rolofylline had no effect on mortality (HR 1.03, 95% CI 0.82–1.28, p = 0.808). We found no treatment interaction across clinical characteristics, but we found interactions between several biomarkers and rolofylline. The biomarker-based sum scoremodel included TNF-R1α, ST2, WAP four-disulfide core domain protein HE4 (WAP-4C), and total cholesterol, and the score ranged between 0 and 4. In patients with score 4 (those with increased TNF-R1α, ST2, WAP-4C, and low total cholesterol), treatment with rolofylline was beneficial (HR 0.61, 95% CI 0.40–0.92, p = 0.019). In patients with score 0, treatment with rolofylline was harmful (HR 5.52, 95% CI 1.68–18.13, p = 0.005; treatment by score interaction p < 0.001). Internal validation estimated similar hazard ratio estimates (0 points: HR 5.56, 95% CI 5.27–7–5.87; 1 point: HR 1.31, 95% CI 1.25–1.33; 2 points: HR 0.75, 95% CI 0.74–0.76; 3 points: HR 1.13, 95% CI 1.11–1.15; 4 points, HR 0.61, 95% CI 0.61– 0.62) compared to the original data. Electronic supplementary material The online version of this article (doi:10.1007/s10557-017-6726-1) contains supplementary material, which is available to authorized users. * Adriaan A. Voors A.A.Voors@umcg.nl 1 Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 2 Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 3 Inova Heart and Vascular Institute, Falls Church, VA, USA 4 University of Brescia, Brescia, Italy 5 Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, USA Cardiovasc Drugs Ther (2017) 31:281–293 DOI 10.1007/s10557-017-6726-1 6 Medical University, Clinical Military Hospital, Wroclaw, Poland 7 University of California at San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA 8 Momentum Research, Durham, NC, USA 9 Imperial College, London, UK 10 Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA 11 Merck Research Laboratories, Rahway, NJ, USA Conclusion Biomarkers are superior to clinical characteristics to study treatment heterogeneity in acute heart failure.