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Piotr Ponikowski - One of the best experts on this subject based on the ideXlab platform.
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plasma biomarkers to determine individual response to Rolofylline in acute heart failure results from the protect trial
2017Co-Authors: Licette C Y Liu, Mattia A E Valente, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, Gad Cotter, Howard C Dittrich, Douwe Postmus, Beth A DavisonAbstract: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 interactions 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 0-4. 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 points: 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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Plasma Neutrophil Gelatinase-Associated Lipocalin and Predicting Clinically Relevant Worsening Renal Function in Acute Heart Failure
2017Co-Authors: Kevin Damman, Mattia A E Valente, Marco Metra, Piotr Ponikowski, John G F Cleland, Gad Cotter, Dirk J. Van Veldhuisen, Christopher M. O’connor, Beth Davison, Michael M GivertzAbstract:The aim of this study was to evaluate the ability of Neutrophil Gelatinase-Associated Lipocalin (NGAL) to predict clinically relevant worsening renal function (WRF) in acute heart failure (AHF). Plasma NGAL and serum creatinine changes during the first 4 days of admission were investigated in 1447 patients hospitalized for AHF and enrolled in the Placebo-Controlled Randomized Study of the Selective A1Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) study. WRF was defined as serum creatinine rise ≥ 0.3 mg/dL through day 4. Biomarker patterns were described using linear mixed models. WRF developed in 325 patients (22%). Plasma NGAL did not rise earlier than creatinine in patients with WRF. After multivariable adjustment, baseline plasma NGAL, but not creatinine, predicted WRF. AUCs for WRF prediction were modest (<0.60) for all models. NGAL did not independently predict death or rehospitalization (p = n.s.). Patients with WRF and high baseline plasma NGAL had a greater risk of death, and renal or cardiovascular rehospitalization by 60 days than patients with WRF and a low baseline plasma NGAL (p for interaction = 0.024). A rise in plasma NGAL after baseline was associated with a worse outcome in patients with WRF, but not in patients without WRF (p = 0.007). On the basis of these results, plasma NGAL does not provide additional, clinically relevant information about the occurrence of WRF in patients with AHF
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risk based evaluation of efficacy of Rolofylline in patients hospitalized with acute heart failure post hoc analysis of the protect trial
2016Co-Authors: Biniyam G Demissei, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, John G F Cleland, Gad Cotter, Douwe Postmus, Licette C Y Liu, Beth A DavisonAbstract:Abstract Background The selective adenosine A1 receptor antagonist Rolofylline showed a neutral overall result on clinical outcomes in the PROTECT trial. However, we hypothesized that response to Rolofylline treatment could be influenced by underlying clinical risk. Methods We performed a post-hoc analysis of the PROTECT trial — a large, double-blind, randomized, placebo-controlled trial that enrolled 2033 patients. Baseline risk of 180-day all-cause mortality was estimated using a previously published 8-item model. Evaluation of efficacy of Rolofylline across subpopulations defined based on estimated risk of mortality was performed using subpopulation treatment effect pattern plot (STEPP) analysis. Findings were validated in an independent cohort of acute heart failure patients. Results Median estimated risk of mortality was 13.0%, IQR [8.0%–23.0%] and was comparable between the Rolofylline and placebo arms. In low to intermediate risk subgroups of patients, Rolofylline was associated with a higher rate of 180-day all-cause mortality (11.9% in the Rolofylline versus 8.4% in the placebo arms, p =0.050). In the high risk subgroup of patients, particularly those with estimated risk of mortality between 20% and 30%, 180-day all-cause mortality rate was markedly lower in the Rolofylline arm (18.4% in the Rolofylline versus 34.0% in the placebo arms, p =0.003). The trend towards potential harm with Rolofylline treatment in the low to intermediate risk subpopulations and significant benefit in high risk patients was also observed in the validation cohort. Conclusion Our findings suggest that selective adenosine A1 receptor antagonism could be harmful in low risk acute heart failure patients, while it might significantly benefit higher risk patients.
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combining diuretic response and hemoconcentration to predict rehospitalization after admission for acute heart failure
2016Co-Authors: Jozine M. Ter Maaten, Mattia A E Valente, Kevin Damman, Michael M Givertz, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, John G F Cleland, Daniel M. BloomfieldAbstract:Background— Both diuretic response and hemoconcentration are indicators of decongestion and have individually been found to predict rehospitalization after admission for acute heart failure (HF). This study examines the value of combining diuretic response and hemoconcentration to better predict patients at low risk for rehospitalization after admission for acute HF. Methods and Results— Diuretic response (defined as weight change per 40 mg of furosemide on day 4 after admission) and hemoconcentration (change in hemoglobin at discharge or day 7) were tested both individually and combined to predict the risk of HF and cardiovascular rehospitalization 60 days after hospitalization for acute HF. Analyses were performed in 1180 patients enrolled in the Placebo-Controlled Randomized Study of the Selective Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial and validated in 1776 patients enrolled in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial. Poor diuretic response was associated with low systolic blood pressure, high blood urea nitrogen, and history of coronary revascularization in both data sets (all P <0.05). Hemoconcentration was mainly associated with better renal function ( P <0.05). Patients who displayed both favorable diuretic response and hemoconcentration had a markedly lower risk of rehospitalization for HF in PROTECT (multivariable HR, 0.41; 95% CI, 0.24 to 0.70; P <0.001) compared with all other patients. This finding was confirmed in EVEREST (multivariable HR, 0.52; 95% CI, 0.33 to 0.82; P =0.004) for patients with favorable diuretic response and hemoconcentration compared with all other patients. Conclusions— Combining 2 indicators of decongestion, hemoconcentration and diuretic response improves risk prediction for early rehospitalization after an admission for acute HF and may provide clinicians with an easily accessible tool to identify low-risk patients. Clinical Trial Registration— URL: . Unique identifiers: [NCT00354458][1] and [NCT00071331][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00354458&atom=%2Fcirchf%2F9%2F6%2Fe002845.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00071331&atom=%2Fcirchf%2F9%2F6%2Fe002845.atom
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heterogeneity in efficacy of Rolofylline using a risk based evaluation in patients hospitalized with acute heart failure
2016Co-Authors: Biniyam G Demissei, Marco Metra, Piotr Ponikowski, Christopher M Oconnor, Gad Cotter, Douwe Postmus, Licette C Y Liu, John Cleland, John Teerlink, B DavisonAbstract:There is substantial variation in the etiology, clinical presentation and pathophysiology of patients hospitalized for acute heart failure (AHF) that may influence their natural history and response to therapy. We performed a post-hoc analysis of the PROTECT trial that compared Rolofylline, a
Marco Metra - One of the best experts on this subject based on the ideXlab platform.
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plasma biomarkers to determine individual response to Rolofylline in acute heart failure results from the protect trial
2017Co-Authors: Licette C Y Liu, Mattia A E Valente, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, Gad Cotter, Howard C Dittrich, Douwe Postmus, Beth A DavisonAbstract: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 interactions 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 0-4. 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 points: 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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Plasma Neutrophil Gelatinase-Associated Lipocalin and Predicting Clinically Relevant Worsening Renal Function in Acute Heart Failure
2017Co-Authors: Kevin Damman, Mattia A E Valente, Marco Metra, Piotr Ponikowski, John G F Cleland, Gad Cotter, Dirk J. Van Veldhuisen, Christopher M. O’connor, Beth Davison, Michael M GivertzAbstract:The aim of this study was to evaluate the ability of Neutrophil Gelatinase-Associated Lipocalin (NGAL) to predict clinically relevant worsening renal function (WRF) in acute heart failure (AHF). Plasma NGAL and serum creatinine changes during the first 4 days of admission were investigated in 1447 patients hospitalized for AHF and enrolled in the Placebo-Controlled Randomized Study of the Selective A1Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) study. WRF was defined as serum creatinine rise ≥ 0.3 mg/dL through day 4. Biomarker patterns were described using linear mixed models. WRF developed in 325 patients (22%). Plasma NGAL did not rise earlier than creatinine in patients with WRF. After multivariable adjustment, baseline plasma NGAL, but not creatinine, predicted WRF. AUCs for WRF prediction were modest (<0.60) for all models. NGAL did not independently predict death or rehospitalization (p = n.s.). Patients with WRF and high baseline plasma NGAL had a greater risk of death, and renal or cardiovascular rehospitalization by 60 days than patients with WRF and a low baseline plasma NGAL (p for interaction = 0.024). A rise in plasma NGAL after baseline was associated with a worse outcome in patients with WRF, but not in patients without WRF (p = 0.007). On the basis of these results, plasma NGAL does not provide additional, clinically relevant information about the occurrence of WRF in patients with AHF
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risk based evaluation of efficacy of Rolofylline in patients hospitalized with acute heart failure post hoc analysis of the protect trial
2016Co-Authors: Biniyam G Demissei, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, John G F Cleland, Gad Cotter, Douwe Postmus, Licette C Y Liu, Beth A DavisonAbstract:Abstract Background The selective adenosine A1 receptor antagonist Rolofylline showed a neutral overall result on clinical outcomes in the PROTECT trial. However, we hypothesized that response to Rolofylline treatment could be influenced by underlying clinical risk. Methods We performed a post-hoc analysis of the PROTECT trial — a large, double-blind, randomized, placebo-controlled trial that enrolled 2033 patients. Baseline risk of 180-day all-cause mortality was estimated using a previously published 8-item model. Evaluation of efficacy of Rolofylline across subpopulations defined based on estimated risk of mortality was performed using subpopulation treatment effect pattern plot (STEPP) analysis. Findings were validated in an independent cohort of acute heart failure patients. Results Median estimated risk of mortality was 13.0%, IQR [8.0%–23.0%] and was comparable between the Rolofylline and placebo arms. In low to intermediate risk subgroups of patients, Rolofylline was associated with a higher rate of 180-day all-cause mortality (11.9% in the Rolofylline versus 8.4% in the placebo arms, p =0.050). In the high risk subgroup of patients, particularly those with estimated risk of mortality between 20% and 30%, 180-day all-cause mortality rate was markedly lower in the Rolofylline arm (18.4% in the Rolofylline versus 34.0% in the placebo arms, p =0.003). The trend towards potential harm with Rolofylline treatment in the low to intermediate risk subpopulations and significant benefit in high risk patients was also observed in the validation cohort. Conclusion Our findings suggest that selective adenosine A1 receptor antagonism could be harmful in low risk acute heart failure patients, while it might significantly benefit higher risk patients.
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combining diuretic response and hemoconcentration to predict rehospitalization after admission for acute heart failure
2016Co-Authors: Jozine M. Ter Maaten, Mattia A E Valente, Kevin Damman, Michael M Givertz, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, John G F Cleland, Daniel M. BloomfieldAbstract:Background— Both diuretic response and hemoconcentration are indicators of decongestion and have individually been found to predict rehospitalization after admission for acute heart failure (HF). This study examines the value of combining diuretic response and hemoconcentration to better predict patients at low risk for rehospitalization after admission for acute HF. Methods and Results— Diuretic response (defined as weight change per 40 mg of furosemide on day 4 after admission) and hemoconcentration (change in hemoglobin at discharge or day 7) were tested both individually and combined to predict the risk of HF and cardiovascular rehospitalization 60 days after hospitalization for acute HF. Analyses were performed in 1180 patients enrolled in the Placebo-Controlled Randomized Study of the Selective Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial and validated in 1776 patients enrolled in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial. Poor diuretic response was associated with low systolic blood pressure, high blood urea nitrogen, and history of coronary revascularization in both data sets (all P <0.05). Hemoconcentration was mainly associated with better renal function ( P <0.05). Patients who displayed both favorable diuretic response and hemoconcentration had a markedly lower risk of rehospitalization for HF in PROTECT (multivariable HR, 0.41; 95% CI, 0.24 to 0.70; P <0.001) compared with all other patients. This finding was confirmed in EVEREST (multivariable HR, 0.52; 95% CI, 0.33 to 0.82; P =0.004) for patients with favorable diuretic response and hemoconcentration compared with all other patients. Conclusions— Combining 2 indicators of decongestion, hemoconcentration and diuretic response improves risk prediction for early rehospitalization after an admission for acute HF and may provide clinicians with an easily accessible tool to identify low-risk patients. Clinical Trial Registration— URL: . Unique identifiers: [NCT00354458][1] and [NCT00071331][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00354458&atom=%2Fcirchf%2F9%2F6%2Fe002845.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00071331&atom=%2Fcirchf%2F9%2F6%2Fe002845.atom
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heterogeneity in efficacy of Rolofylline using a risk based evaluation in patients hospitalized with acute heart failure
2016Co-Authors: Biniyam G Demissei, Marco Metra, Piotr Ponikowski, Christopher M Oconnor, Gad Cotter, Douwe Postmus, Licette C Y Liu, John Cleland, John Teerlink, B DavisonAbstract:There is substantial variation in the etiology, clinical presentation and pathophysiology of patients hospitalized for acute heart failure (AHF) that may influence their natural history and response to therapy. We performed a post-hoc analysis of the PROTECT trial that compared Rolofylline, a
John R Teerlink - One of the best experts on this subject based on the ideXlab platform.
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plasma biomarkers to determine individual response to Rolofylline in acute heart failure results from the protect trial
2017Co-Authors: Licette C Y Liu, Mattia A E Valente, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, Gad Cotter, Howard C Dittrich, Douwe Postmus, Beth A DavisonAbstract: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 interactions 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 0-4. 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 points: 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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risk based evaluation of efficacy of Rolofylline in patients hospitalized with acute heart failure post hoc analysis of the protect trial
2016Co-Authors: Biniyam G Demissei, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, John G F Cleland, Gad Cotter, Douwe Postmus, Licette C Y Liu, Beth A DavisonAbstract:Abstract Background The selective adenosine A1 receptor antagonist Rolofylline showed a neutral overall result on clinical outcomes in the PROTECT trial. However, we hypothesized that response to Rolofylline treatment could be influenced by underlying clinical risk. Methods We performed a post-hoc analysis of the PROTECT trial — a large, double-blind, randomized, placebo-controlled trial that enrolled 2033 patients. Baseline risk of 180-day all-cause mortality was estimated using a previously published 8-item model. Evaluation of efficacy of Rolofylline across subpopulations defined based on estimated risk of mortality was performed using subpopulation treatment effect pattern plot (STEPP) analysis. Findings were validated in an independent cohort of acute heart failure patients. Results Median estimated risk of mortality was 13.0%, IQR [8.0%–23.0%] and was comparable between the Rolofylline and placebo arms. In low to intermediate risk subgroups of patients, Rolofylline was associated with a higher rate of 180-day all-cause mortality (11.9% in the Rolofylline versus 8.4% in the placebo arms, p =0.050). In the high risk subgroup of patients, particularly those with estimated risk of mortality between 20% and 30%, 180-day all-cause mortality rate was markedly lower in the Rolofylline arm (18.4% in the Rolofylline versus 34.0% in the placebo arms, p =0.003). The trend towards potential harm with Rolofylline treatment in the low to intermediate risk subpopulations and significant benefit in high risk patients was also observed in the validation cohort. Conclusion Our findings suggest that selective adenosine A1 receptor antagonism could be harmful in low risk acute heart failure patients, while it might significantly benefit higher risk patients.
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combining diuretic response and hemoconcentration to predict rehospitalization after admission for acute heart failure
2016Co-Authors: Jozine M. Ter Maaten, Mattia A E Valente, Kevin Damman, Michael M Givertz, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, John G F Cleland, Daniel M. BloomfieldAbstract:Background— Both diuretic response and hemoconcentration are indicators of decongestion and have individually been found to predict rehospitalization after admission for acute heart failure (HF). This study examines the value of combining diuretic response and hemoconcentration to better predict patients at low risk for rehospitalization after admission for acute HF. Methods and Results— Diuretic response (defined as weight change per 40 mg of furosemide on day 4 after admission) and hemoconcentration (change in hemoglobin at discharge or day 7) were tested both individually and combined to predict the risk of HF and cardiovascular rehospitalization 60 days after hospitalization for acute HF. Analyses were performed in 1180 patients enrolled in the Placebo-Controlled Randomized Study of the Selective Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial and validated in 1776 patients enrolled in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial. Poor diuretic response was associated with low systolic blood pressure, high blood urea nitrogen, and history of coronary revascularization in both data sets (all P <0.05). Hemoconcentration was mainly associated with better renal function ( P <0.05). Patients who displayed both favorable diuretic response and hemoconcentration had a markedly lower risk of rehospitalization for HF in PROTECT (multivariable HR, 0.41; 95% CI, 0.24 to 0.70; P <0.001) compared with all other patients. This finding was confirmed in EVEREST (multivariable HR, 0.52; 95% CI, 0.33 to 0.82; P =0.004) for patients with favorable diuretic response and hemoconcentration compared with all other patients. Conclusions— Combining 2 indicators of decongestion, hemoconcentration and diuretic response improves risk prediction for early rehospitalization after an admission for acute HF and may provide clinicians with an easily accessible tool to identify low-risk patients. Clinical Trial Registration— URL: . Unique identifiers: [NCT00354458][1] and [NCT00071331][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00354458&atom=%2Fcirchf%2F9%2F6%2Fe002845.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00071331&atom=%2Fcirchf%2F9%2F6%2Fe002845.atom
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predictors of postdischarge outcomes from information acquired shortly after admission for acute heart failure a report from the placebo controlled randomized study of the selective a1 adenosine receptor antagonist Rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function protect study
2014Co-Authors: Michael M Givertz, John R Teerlink, John G F Cleland, Beth A Davison, Karen Chiswell, Susanna R Stevens, Mona Fiuzat, George A MansoorAbstract:Background— Acute heart failure is a common reason for admission, and outcome is often poor. Improved prognostic risk stratification may assist in the design of future trials and in patient management. Using data from a large randomized trial, we explored the prognostic value of clinical variables, measured at hospital admission for acute heart failure, to determine whether a few selected variables were inferior to an extended data set. Methods and Results— The prognostic model included 37 clinical characteristics collected at baseline in PROTECT, a study comparing Rolofylline and placebo in 2033 patients admitted with acute heart failure. Prespecified outcomes at 30 days were death or rehospitalization for any reason; death or rehospitalization for cardiovascular or renal reasons; and, at both 30 and 180 days, all-cause mortality. No variable had a c-index >0.70, and few had values >0.60; c-indices were lower for composite outcomes than for mortality. Blood urea was generally the strongest single predictor. Eighteen variables contributed independent prognostic information, but a reduced model using only 8 items (age, previous heart failure hospitalization, peripheral edema, systolic blood pressure, serum sodium, urea, creatinine, and albumin) performed similarly. For prediction of all-cause mortality at 180 days, the model c-index using all variables was 0.72 and for the simplified model, also 0.72. Conclusions— A few simple clinical variables measured on admission in patients with acute heart failure predict a variety of adverse outcomes with accuracy similar to more complex models. However, predictive models were of only moderate accuracy, especially for outcomes that included nonfatal events. Better methods of risk stratification are required. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458.
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predictors of postdischarge outcomes from information acquired shortly after admission for acute heart failure a report from the placebo controlled randomized study of the selective a1 adenosine receptor antagonist Rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function protect study
2014Co-Authors: John G F Cleland, Michael M Givertz, John R Teerlink, Piotr Ponikowski, George A Mansoor, Beth A Davison, Karen Chiswell, Susanna R Stevens, Mona Fiuzat, Adriaan A. VoorsAbstract:Background— Acute heart failure is a common reason for admission, and outcome is often poor. Improved prognostic risk stratification may assist in the design of future trials and in patient management. Using data from a large randomized trial, we explored the prognostic value of clinical variables, measured at hospital admission for acute heart failure, to determine whether a few selected variables were inferior to an extended data set. Methods and Results— The prognostic model included 37 clinical characteristics collected at baseline in PROTECT, a study comparing Rolofylline and placebo in 2033 patients admitted with acute heart failure. Prespecified outcomes at 30 days were death or rehospitalization for any reason; death or rehospitalization for cardiovascular or renal reasons; and, at both 30 and 180 days, all-cause mortality. No variable had a c-index >0.70, and few had values >0.60; c-indices were lower for composite outcomes than for mortality. Blood urea was generally the strongest single predictor. Eighteen variables contributed independent prognostic information, but a reduced model using only 8 items (age, previous heart failure hospitalization, peripheral edema, systolic blood pressure, serum sodium, urea, creatinine, and albumin) performed similarly. For prediction of all-cause mortality at 180 days, the model c-index using all variables was 0.72 and for the simplified model, also 0.72. Conclusions— A few simple clinical variables measured on admission in patients with acute heart failure predict a variety of adverse outcomes with accuracy similar to more complex models. However, predictive models were of only moderate accuracy, especially for outcomes that included nonfatal events. Better methods of risk stratification are required. Clinical Trial Registration— URL: . Unique identifiers: [NCT00328692][1] and [NCT00354458][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00328692&atom=%2Fcirchf%2F7%2F1%2F76.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00354458&atom=%2Fcirchf%2F7%2F1%2F76.atom
Gad Cotter - One of the best experts on this subject based on the ideXlab platform.
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plasma biomarkers to determine individual response to Rolofylline in acute heart failure results from the protect trial
2017Co-Authors: Licette C Y Liu, Mattia A E Valente, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, Gad Cotter, Howard C Dittrich, Douwe Postmus, Beth A DavisonAbstract: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 interactions 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 0-4. 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 points: 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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Plasma Neutrophil Gelatinase-Associated Lipocalin and Predicting Clinically Relevant Worsening Renal Function in Acute Heart Failure
2017Co-Authors: Kevin Damman, Mattia A E Valente, Marco Metra, Piotr Ponikowski, John G F Cleland, Gad Cotter, Dirk J. Van Veldhuisen, Christopher M. O’connor, Beth Davison, Michael M GivertzAbstract:The aim of this study was to evaluate the ability of Neutrophil Gelatinase-Associated Lipocalin (NGAL) to predict clinically relevant worsening renal function (WRF) in acute heart failure (AHF). Plasma NGAL and serum creatinine changes during the first 4 days of admission were investigated in 1447 patients hospitalized for AHF and enrolled in the Placebo-Controlled Randomized Study of the Selective A1Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) study. WRF was defined as serum creatinine rise ≥ 0.3 mg/dL through day 4. Biomarker patterns were described using linear mixed models. WRF developed in 325 patients (22%). Plasma NGAL did not rise earlier than creatinine in patients with WRF. After multivariable adjustment, baseline plasma NGAL, but not creatinine, predicted WRF. AUCs for WRF prediction were modest (<0.60) for all models. NGAL did not independently predict death or rehospitalization (p = n.s.). Patients with WRF and high baseline plasma NGAL had a greater risk of death, and renal or cardiovascular rehospitalization by 60 days than patients with WRF and a low baseline plasma NGAL (p for interaction = 0.024). A rise in plasma NGAL after baseline was associated with a worse outcome in patients with WRF, but not in patients without WRF (p = 0.007). On the basis of these results, plasma NGAL does not provide additional, clinically relevant information about the occurrence of WRF in patients with AHF
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risk based evaluation of efficacy of Rolofylline in patients hospitalized with acute heart failure post hoc analysis of the protect trial
2016Co-Authors: Biniyam G Demissei, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, John G F Cleland, Gad Cotter, Douwe Postmus, Licette C Y Liu, Beth A DavisonAbstract:Abstract Background The selective adenosine A1 receptor antagonist Rolofylline showed a neutral overall result on clinical outcomes in the PROTECT trial. However, we hypothesized that response to Rolofylline treatment could be influenced by underlying clinical risk. Methods We performed a post-hoc analysis of the PROTECT trial — a large, double-blind, randomized, placebo-controlled trial that enrolled 2033 patients. Baseline risk of 180-day all-cause mortality was estimated using a previously published 8-item model. Evaluation of efficacy of Rolofylline across subpopulations defined based on estimated risk of mortality was performed using subpopulation treatment effect pattern plot (STEPP) analysis. Findings were validated in an independent cohort of acute heart failure patients. Results Median estimated risk of mortality was 13.0%, IQR [8.0%–23.0%] and was comparable between the Rolofylline and placebo arms. In low to intermediate risk subgroups of patients, Rolofylline was associated with a higher rate of 180-day all-cause mortality (11.9% in the Rolofylline versus 8.4% in the placebo arms, p =0.050). In the high risk subgroup of patients, particularly those with estimated risk of mortality between 20% and 30%, 180-day all-cause mortality rate was markedly lower in the Rolofylline arm (18.4% in the Rolofylline versus 34.0% in the placebo arms, p =0.003). The trend towards potential harm with Rolofylline treatment in the low to intermediate risk subpopulations and significant benefit in high risk patients was also observed in the validation cohort. Conclusion Our findings suggest that selective adenosine A1 receptor antagonism could be harmful in low risk acute heart failure patients, while it might significantly benefit higher risk patients.
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heterogeneity in efficacy of Rolofylline using a risk based evaluation in patients hospitalized with acute heart failure
2016Co-Authors: Biniyam G Demissei, Marco Metra, Piotr Ponikowski, Christopher M Oconnor, Gad Cotter, Douwe Postmus, Licette C Y Liu, John Cleland, John Teerlink, B DavisonAbstract:There is substantial variation in the etiology, clinical presentation and pathophysiology of patients hospitalized for acute heart failure (AHF) that may influence their natural history and response to therapy. We performed a post-hoc analysis of the PROTECT trial that compared Rolofylline, a
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the predictive value of short term changes in hemoglobin concentration in patients presenting with acute decompensated heart failure
2013Co-Authors: Peter Van Der Meer, Michael M Givertz, Marco Metra, Piotr Ponikowski, Christopher M Oconnor, John G F Cleland, Gad Cotter, Douwe Postmus, Beth A Davison, George A MansoorAbstract:Objectives The study sought to investigate the clinical correlates and prognostic role of anemia and changes in hemoglobin in patients hospitalized for acute decompensated heart failure (AHF). Background Anemia is related to a poor outcome in patients with heart failure. In addition, an increase in hemoglobin during hospitalization might be a sign of effective decongestion and therefore related to improved outcome. Methods This is a post hoc analysis of the PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study in 1,969 patients with AHF and mild to moderate impaired renal function. Hemoglobin levels were measured daily for the first 4 days and at day 7. The endpoint was 180-day all-cause mortality. Results Anemia at baseline was observed in 50.3% of the patients. During follow-up, 359 patients (18.2%) died. Hemoglobin increased in 69.1% and was associated with a better renal function at baseline and more weight loss, but was associated with a deterioration of renal function (p = 0.01), whereas total dose diuretics was lower in patients with hemoconcentration (p Conclusions Patients with AHF and preserved renal function are decongested better, as shown by an increase in hemoglobin. A rapid increase in hemoglobin during the first week is independently associated with a favorable outcome, despite a slight decrease in renal function.
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effects of the adenosine a1 receptor antagonist Rolofylline on renal function in patients with acute heart failure and renal dysfunction results from protect placebo controlled randomized study of the selective a1 adenosine receptor antagonist rolofy
2011Co-Authors: Adriaan A. Voors, Marco Metra, Piotr Ponikowski, Gad Cotter, Barry M Massie, Beth Davison Weatherley, Howard C Dittrich, Paul Delucca, George A Mansoor, John R TeerlinkAbstract:Objectives This study sought to assess the effects of Rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Randomized Study of the Selective A(1) Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Background Small studies have indicated that adenosine A(1) receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF. Methods A total of 2,033 patients with AHF, volume overload, estimated creatinine clearance between 20 and 80 ml/min, and elevated natriuretic peptide levels were randomized (2: 1) within 24 h of hospital presentation to Rolofylline 30 mg/day or intravenous placebo for up to 3 days. Creatinine was measured daily until discharge or day 7 and on day 14. Persistent worsening renal function was defined as an increase in serum creatinine >= 0.3 mg/dl at both days 7 and 14, or initiation of hemofiltration or dialysis or death by day 7. Results At baseline, mean +/- SD estimated creatinine clearance was 51.0 +/- 20.5 ml/min in the placebo group and 50.4 +/- 20.0 ml/min in the Rolofylline group. Changes in creatinine and estimated creatinine clearance were similar between placebo-and Rolofylline-treated patients during hospitalization and at day 14. After 4 days, mean body weight was reduced by 2.6 and 3.0 kg in placebo and Rolofylline patients, respectively (p = 0.005). Persistent worsening renal function occurred in 13.7% of the placebo group and 15.0% of the Rolofylline group (odds ratio vs. placebo: 1.11 [95% confidence interval: 0.85 to 1.46]; p = 0.44). Conclusions In this large, phase III clinical trial, the adenosine A(1) receptor antagonist Rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction. (A Study of the Selective A(1) Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function [PROTECT-1], NCT00328692; and [PROTECT-2], NCT00354458) (J Am Coll Cardiol 2011;57:1899-907) (C) 2011 by the American College of Cardiology Foundation
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effects of the adenosine a1 receptor antagonist Rolofylline on renal function in patients with acute heart failure and renal dysfunction results from protect placebo controlled randomized study of the selective adenosine a1 receptor antagonist rolofy
2011Co-Authors: Adriaan A. Voors, Marco Metra, Piotr Ponikowski, Gad Cotter, Barry M Massie, Beth Davison Weatherley, Howard C Dittrich, Paul Delucca, George A Mansoor, John G ClelandAbstract:OBJECTIVES: This study sought to assess the effects of Rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Randomized Study of the Selective A(1) Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). BACKGROUND: Small studies have indicated that adenosine A(1) receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF. METHODS: A total of 2,033 patients with AHF, volume overload, estimated creatinine clearance between 20 and 80 ml/min, and elevated natriuretic peptide levels were randomized (2:1) within 24 h of hospital presentation to Rolofylline 30 mg/day or intravenous placebo for up to 3 days. Creatinine was measured daily until discharge or day 7 and on day 14. Persistent worsening renal function was defined as an increase in serum creatinine ≥0.3 mg/dl at both days 7 and 14, or initiation of hemofiltration or dialysis or death by day 7. RESULTS: At baseline, mean ± SD estimated creatinine clearance was 51.0 ± 20.5 ml/min in the placebo group and 50.4 ± 20.0 ml/min in the Rolofylline group. Changes in creatinine and estimated creatinine clearance were similar between placebo- and Rolofylline-treated patients during hospitalization and at day 14. After 4 days, mean body weight was reduced by 2.6 and 3.0 kg in placebo and Rolofylline patients, respectively (p = 0.005). Persistent worsening renal function occurred in 13.7% of the placebo group and 15.0% of the Rolofylline group (odds ratio vs. placebo: 1.11 [95% confidence interval: 0.85 to 1.46]; p = 0.44). CONCLUSIONS: In this large, phase III clinical trial, the adenosine A(1) receptor antagonist Rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction. (A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function [PROTECT-1], NCT00328692; and [PROTECT-2], NCT00354458).
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effects of the adenosine a1 receptor antagonist Rolofylline on renal function in patients with acute heart failure and renal dysfunction
2011Co-Authors: Adriaan A. Voors, Marco Metra, Piotr Ponikowski, Gad Cotter, Barry M Massie, Beth Davison Weatherley, Howard C Dittrich, Paul Delucca, George A Mansoor, John R TeerlinkAbstract:Objectives: This study sought to assess the effects of Rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Rando...
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haemodynamic effects of Rolofylline in the treatment of patients with heart failure and impaired renal function
2010Co-Authors: Piotr Ponikowski, Michael M Givertz, Christopher M Oconnor, Gad Cotter, Barry M Massie, Howard C Dittrich, Veselin Mitrovic, Erluo Chen, Meredith Murray, Beth Davison WeatherleyAbstract:Aims The direct effects of adenosine A1 receptor antagonists on haemodynamic parameters in patients with acute heart failure (HF) remain largely unknown. Methods and results We evaluated the haemodynamic effects of the AA1RA Rolofylline in 59 HF patients with concomitant renal impairment (estimated creatinine clearance 20–80 mL/min). Placebo or Rolofylline 30 mg was administered as a 4 h infusion followed by intravenous (i.v.) loop diuretic administration. Haemodynamic measurements were carried out hourly up to 8 h post-dosing by pulmonary artery catheterization. Urine output, fractional excretion of sodium, potassium, urea, and uric acid, and blood urea nitrogen (BUN) and creatinine levels were also measured. In both groups, the changes from baseline in all haemodynamic indices except mean pulmonary artery pressure (PAP) were not clinically significant. Mean [95% confidence interval (CI)] PAP showed a placebo-adjusted decrease with Rolofylline of −1.5 (−4.1, 1.1)mmHg at Hour 4 and −3.5 mmHg (95% CI: −6.2, −0.2) at Hour 8. There was a significant increase with Rolofylline in diuresis [placebo-corrected mean (95% CI) change of 68 (20, 116)mL/h at Hour 2–4 and 103 (21, 185)mL/h at Hour 4–8] and in fractional excretion of sodium, potassium, and uric acid. Placebo-corrected changes in plasma levels of creatinine and BUN with Rolofylline were non-significant. Conclusion Single administration of Rolofylline in patients with HF and impaired renal function produced a slight decrease in mean PAP and consistently increased diuresis and natriuresis without compromising renal function, both before and after administration of i.v. loop diuretics.
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Rolofylline an adenosine a1 receptor antagonist in acute heart failure
2010Co-Authors: Barry M Massie, Michael M Givertz, Marco Metra, John R Teerlink, Piotr Ponikowski, Christopher M Oconnor, John G F Cleland, Gad Cotter, Beth Davison Weatherley, Adriaan A. VoorsAbstract:Background Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of Rolofylline, an adenosine A1−receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure. Methods We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous Rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in r...
