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27.06.2017 | ORIGINAL ARTICLE | Ausgabe 3/2017 Open Access

Cardiovascular Drugs and Therapy 3/2017

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

Differential Response in Acute Heart Failure

Zeitschrift:
Cardiovascular Drugs and Therapy > Ausgabe 3/2017
Autoren:
Licette C. Y. Liu, Mattia A. E. Valente, Douwe Postmus, Christopher M. O’Connor, Marco Metra, Howard C. Dittrich, Piotr Ponikowski, John R. Teerlink, Gad Cotter, Beth Davison, John G. F. Cleland, Michael M. Givertz, Daniel M. Bloomfield, Dirk J. van Veldhuisen, Hans L. Hillege, Peter van der Meer, Adriaan A. Voors
Wichtige Hinweise

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.

Abstract

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-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.

Conclusion

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

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