Model-based meta-analysis of changes in circulatory system physiology in patients with chronic heart failure

Abstract

To characterize and compare various medicines for chronic heart failure (CHF), changes in circulatory physiological parameter during pharmacotherapy were investigated by a model-based meta-analysis (MBMA) of circulatory physiology. The clinical data from 61 studies mostly in patients with heart failure with reduced ejection fraction (HFrEF), reporting changes in heart rate, blood pressure, or ventricular volumes after treatment with carvedilol, metoprolol, bisoprolol, bucindolol, enalapril, aliskiren, or felodipine, were analyzed. Seven cardiac and vasculature function indices were estimated without invasive measurements using models based on appropriate assumptions, and their correlations with the mortality were assessed. Estimated myocardial oxygen consumption, a cardiac load index, correlated excellently with the mortality at 3, 6, and 12 months after treatment initiation, and it explained differences in mortality across the different medications. The analysis based on the present models were reasonably consistent with the hypothesis that the treatment of HFrEF with various medications is due to effectively reducing the cardiac load. Assessment of circulatory physiological parameters by using MBMA would be insightful for quantitative understanding of CHF treatment.

FIGURE 1

Overview of this study (a) and pressure‐volume relationship in left ventricle (b). CO, cardiac output; E_a, effective arterial elastance; EDV, end‐diastolic volume; E_es, end‐systolic elastance; EF, ejection fraction; ESPVR, end systolic pressure‐volume relationship; ESV, end‐systolic volume; EW, extra work (energy required to pump blood); HR, heart rate; MAP, mean blood pressure; MVO₂, myocardial oxygen consumption; PE, potential energy (energy required for the basic metabolism and contraction of the heart); P_es, end‐systolic pressure; PVA, pressure‐volume area (consumption energy consumed per heartbeat); SAP, systolic arterial blood pressure; TAC, total arterial compliance; TPR, total peripheral vascular resistance

FIGURE 2

Estimated time‐course changes of circulatory physiological parameter after treatment initiation. Data represent mean change ratio and relative standard error of the change. By multiple regression analysis, the variable factors for the baseline and the change ratio (in β‐blocker group) were identified and corrected. The corrected results of 61 trials were integrated by meta‐analysis based on the random effects model (DerSimonian Laird method). The mean change ratio of function indices (CO, EF, E_es), cardiac load indices (MVO₂, E_a), and vasculature indices (TPR, TAC) were estimated by hemodynamic mathematical model. The standard error was calculated based on the error propagation. CO, cardiac output; E_a, effective arterial elastance; EDV, end‐diastolic volume; E_es, end‐systolic elastance; EF, ejection fraction; ESPVR, end systolic pressure‐volume relationship; ESV, end‐systolic volume; EW, extra work (energy required to pump blood); HR, heart rate; MAP, mean blood pressure; MVO₂, myocardial oxygen consumption; PE, potential energy (energy required for the basic metabolism and contraction of the heart); P_es, end‐systolic pressure; PVA, pressure‐volume area (consumption energy consumed per heartbeat); SAP, systolic arterial blood pressure; TAC, total arterial compliance; TPR, total peripheral vascular resistance

FIGURE 3

Correlations between change of circulatory physiological parameter and odds ratio of mortality after 3 months from treatment initiation. The horizontal axis represents mean change percent and relative standard error from the baseline, and the vertical axis represents mean and standard error of odds ratio. The correlation between mean change ratios of clinical parameters (SAP, MAP, HR, ESV, and EDV) and estimated indices (CO, EF, E_es, MVO₂, E_a, TPR, and TAC) integrated by meta‐analysis from 61 trials, and the mean odds ratios of mortality obtained from 21 large‐scale clinical trials was represented. CO, cardiac output; E_a, effective arterial elastance; EDV, end‐diastolic volume; E_es, end‐systolic elastance; EF, ejection fraction; ESPVR, end systolic pressure‐volume relationship; ESV, end‐systolic volume; EW, extra work (energy required to pump blood); HR, heart rate; MAP, mean blood pressure; MVO₂, myocardial oxygen consumption; PE, potential energy (energy required for the basic metabolism and contraction of the heart); P_es, end‐systolic pressure; PVA, pressure‐volume area (consumption energy consumed per heartbeat); SAP, systolic arterial blood pressure; TAC, total arterial compliance; TPR, total peripheral vascular resistance

FIGURE 4

Determination coefficients between circulatory physiological parameters and odds ratio of mortality after 3, 6, and 12 months from treatment initiation. Determination coefficients (R ²) between clinical parameters (SAP, MAP, HR, ESV, EDV) and estimated indices (CO, EF, E_es, MVO₂, E_a, TPR, TAC), and odds ratio of mortality at 3, 6, and 12 months were represented. Blue, orange and red bars represent R ² at 3, 6, and 12 months, respectively. CO, cardiac output; E_a, effective arterial elastance; EDV, end‐diastolic volume; E_es, end‐systolic elastance; EF, ejection fraction; ESPVR, end systolic pressure‐volume relationship; ESV, end‐systolic volume; EW, extra work (energy required to pump blood); HR, heart rate; MAP, mean blood pressure; MVO₂, myocardial oxygen consumption; PE, potential energy (energy required for the basic metabolism and contraction of the heart); P_es, end‐systolic pressure; PVA, pressure‐volume area (consumption energy consumed per heartbeat); SAP, systolic arterial blood pressure; TAC, total arterial compliance; TPR, total peripheral vascular resistance