Efficacy of azilsartan on left ventricular diastolic dysfunction compared with candesartan: J-TASTE randomized controlled trial

Abstract

Characterized by ventricular and vascular stiffness, heart failure with preserved ejection fraction (HFpEF) has led to high morbidity and mortality. As azilsartan is an angiotensin receptor blocker with the highest myocardial and vascular affinities, azilsartan may improve the left ventricular (LV) diastolic function in patients with hypertension and either HFpEF or HF with mildly reduced ejection fraction (HFmrEF) more than candesartan. In this randomized, open-label trial, we randomly assigned 193 hypertensive patients with HF and LV ejection fraction ≥ 45% to 20 mg of azilsartan (n = 95) or 8 mg of candesartan (n = 98), once daily for 48 weeks. After the initiation of treatment, changes in the doses of the study drugs were permitted based on the patient's conditions, including blood pressure (median dose at 48 weeks: azilsartan 20.0 mg/day, candesartan 8.0 mg/day). The primary endpoint was the baseline-adjusted change in the ratio of peak early diastolic transmitral flow velocity (E) to early diastolic mitral annular velocity (e') (E/e'). Adjusted least-squares mean (LSM) change in E/e' was - 0.8 (95% confidence interval [CI] - 1.49 to - 0.04) in the azilsartan group and 0.2 (95% CI - 0.49 to 0.94) in the candesartan group, providing the LSM differences of - 1.0 (95% CI - 2.01 to 0.03, P = 0.057). The median change in left atrial volume index was - 2.7 mL/m² with azilsartan vs 1.4 mL/m² with candesartan (P = 0.091). The frequency of adverse events related to hypotension and hyperkalemia did not differ between the groups. The current study did not provide strong evidence that azilsartan improves LV diastolic dysfunction, and further confirmatory study is required.

Figure 1

The study flow chart for the enrollment, randomization, and follow-up. The participants who did not receive a dose of either azilsartan or candesartan were excluded from the primary and safety analyses. Both FAS and SAF denotes full analysis set and safety analysis set, respectively.

Figure 2

The changes in the parameters of left ventricular diastolic function with echocardiography from baseline to 48 weeks. (A) E/e′ ratio obtained from the averaged the values of septal and lateral e′, (B) e′ velocity obtained from the averaged values of septal and lateral e′, (C) E/A ratio and (D) the deceleration time of early diastolic mitral annular velocity. The statistical analyses of absolute changes in E/e′ from baseline to 48 weeks were performed using analysis of covariance adjusted for the baseline data. The absolute change in e′, E/A ratio and deceleration time from baseline to 48 weeks between the groups were compared using Student’s t test. Data are expressed as mean ± 95% confidence interval. E/e′ the ratio of peak early diastolic transmitral flow velocity (E) to early diastolic mitral annular velocity (e′), E/A ratio the ratio of peak early diastolic transmitral flow velocity (E) to atrial systolic transmitral flow velocity (A).

Figure 3

The changes in E/e′ from baseline to 48 weeks stratified by the potential influential factors. The statistical analyses of absolute changes in each parameter from baseline to 48 weeks were performed using analysis of covariance adjusted for the baseline data. LSM, 95% CI and p values were calculated from the analysis of covariance model. The LSM difference (3.0 ± 0.5, 95% CI − 8.34 to 14.21) in the patients with LVEF < 50% was omitted because the 95% CI was large due to small sample size. BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, E/e′ ratio the peak early diastolic transmitral flow velocity (E) to peak early diastolic mitral annulus velocity (e′), eGFR estimated glomerular filtration rate, NYHA New York Heart Association, LVEF left ventricular ejection fraction, LSM least-squares mean, CI confidence interval.

Figure 4

The changes in systolic (A) and diastolic (B) blood pressure at each study visit. Data are expressed as mean ± standard deviation. SBP systolic blood pressure, DBP diastolic blood pressure.