Identifying Subpopulations with Distinct Response to Treatment Using Plasma Biomarkers in Acute Heart Failure: Results from the PROTECT Trial

Liu, L. C. Y., Valente, M. A. E., Postmus, D., O'Connor, C. M., Metra, M., Dittrich, H. C., Ponikowski, P., Teerlink, J. R., Cotter, G., Davison, B., Cleland, J. G. F., Givertz, M. M., Bloomfield, D. M., van Veldhuisen, D. J., Hillege, H. L., van der Meer, P. & Voors, A. A., Jun-2017, In : Cardiovascular Drugs and Therapy. 31, 3, p. 281-293 13 p.

Research output: Contribution to journalArticleAcademicpeer-review

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 biomarker-based 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 score model included TNF-R1 alpha, 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-R1a, 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 0.610.62) compared to the original data.

Conclusion: Biomarkers are superior to clinical characteristics to study treatment heterogeneity in acute heart failure.

Original languageEnglish
Pages (from-to)281-293
Number of pages13
JournalCardiovascular Drugs and Therapy
Issue number3
Publication statusPublished - Jun-2017


  • Acute heart failure, Treatment heterogeneity, Biomarkers, Subpopulation treatment effect pattern plot, Rolofylline, RECEPTOR ANTAGONIST ROLOFYLLINE, PERSONALIZED MEDICINE, RANDOMIZED-TRIALS, SUBGROUP ANALYSES, CLINICAL-USE, PREDICTORS, OUTCOMES, SUBSETS

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