TY - JOUR
T1 - Identifying Subpopulations with Distinct Response to Treatment Using Plasma Biomarkers in Acute Heart Failure
T2 - Results from the PROTECT Trial
AU - Liu, Licette C. Y.
AU - Valente, Mattia A. E.
AU - Postmus, Douwe
AU - O'Connor, Christopher M.
AU - Metra, Marco
AU - Dittrich, Howard C.
AU - Ponikowski, Piotr
AU - Teerlink, John R.
AU - Cotter, Gad
AU - Davison, Beth
AU - Cleland, John G. F.
AU - Givertz, Michael M.
AU - Bloomfield, Daniel M.
AU - van Veldhuisen, Dirk J.
AU - Hillege, Hans L.
AU - van der Meer, Peter
AU - Voors, Adriaan A.
PY - 2017/6
Y1 - 2017/6
N2 - 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.
AB - 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.
KW - Acute heart failure
KW - Treatment heterogeneity
KW - Biomarkers
KW - Subpopulation treatment effect pattern plot
KW - Rolofylline
KW - RECEPTOR ANTAGONIST ROLOFYLLINE
KW - PERSONALIZED MEDICINE
KW - RANDOMIZED-TRIALS
KW - SUBGROUP ANALYSES
KW - CLINICAL-USE
KW - PREDICTORS
KW - OUTCOMES
KW - SUBSETS
U2 - 10.1007/s10557-017-6726-1
DO - 10.1007/s10557-017-6726-1
M3 - Article
SN - 0920-3206
VL - 31
SP - 281
EP - 293
JO - Cardiovascular Drugs and Therapy
JF - Cardiovascular Drugs and Therapy
IS - 3
ER -