Discussion
LV diastolic dysfunction, HFpEF, LV dysfunction, hyperkalemia, hypotension, hypertension, LVEF ≤
ADVERSE EVENTS, PATHOPHYSIOLOGY, ADVERSE EVENT, EVENTS, HYPERTENSION, ADVERSE DRUG REACTIONS
In the present study, azilsartan showed a trend toward improvement in LV diastolic dysfunction in patients with either HFmrEF or HFpEF compared with candesartan, although the difference was not statistically significant (P = 0.057); azilsartan decreased LV E/e′ by 0.8, whereas candesartan increased it by 0.2 for 48 weeks, despite no significant differences in the time course of BP during 48 weeks between both groups. This result supports the hypothesis that the potential of azilsartan to improve LV diastolic dysfunction is superior to candesartan. Furthermore, the present study provided the potential evidence of the following: 1) e′, an index of LV relaxation speed increased by 0.1 cm/s in the azilsartan group and decreased by 0.2 m/s in the candesartan group (P = 0.080) and 2) azilsartan/candesartan decreased/increased LVDd (median 1.4 mm vs. 0.8 mm, p = 0.034), respectively. The most important implication of the present study is that azilsartan has the potential for improvement of LV dysfunction on the pathophysiology of HFmrEF or HFpEF.The tissue Doppler index E/e′ is a routine parameter to assess LV diastolic function in patients with HFpEF in the 2021 European Society of CardiologyHowever, recent studies suggest the limitation of E/e′ for assessing diastolic function in patients with HFpEF for (1) low sensitivity with LV filling pressure and (2) unreliability under certain situations. Further, global longitudinal strain and strain rate by speckle tracking correlates well with LV relaxation and filling pressure compared with E/e′The major issue in the present result is whether an improvement of E/e′ by − 1.0 in the azilsartan group compared with the candesartan group can provide a meaningful impact on cardiovascular events. Several reports showed the tight linkages between the changes in E/e′ and cardiovascular events. In HFmrEF or HFpEF patients with hypertension and patients with characteristics comparable to the present study, Zhou et al. showed that a unit rise of E/e′ is significantly associated with a 26% increase in cardiovascular eventsThe previous studies suggest that the pathophysiology of HFpEF is characterized by high ventricular and vascular stiffnessThere are several clinical trials using ARB in patients with HFpEF. The I-PRESERVEThe CHARM-Preserved study titrated to a target dose of candesartan as 32 mg (mean dose: 25.0 mg), but the J-TASTE trial administered 2 to 12 mg of candesartan (median dose at 48 weeks: 8.0 mg). The dose reactivity of candesartan in BP was observed up to 12 mg in Japanese patients, thus the approved maximum dose of candesartan is 12 mg in Japan. The ARCH-J study showed that 8 mg of candesartan reduced the worsening of HF by 14.8% in Japanese HF patients with LVEF ≤ 45%One may argue that the present study enrolled the patients with LVEF ≥ 45% because we were concerned that the patients with LVEF > 50% are not very numerous in Japan. Contrary to our expectation, only 5% of patients had LVEF < 50%, and the tendency of the superiority of azilsartan to candesartan is exhibited in Fig. The incidence of total adverse events was higher in the azilsartan group than the candesartan group, but there were no differences in incidences of each adverse event, including hypotension and hyperkalemia, adverse drug reactions, severe adverse events and adverse events related to the study drugs. Therefore, azilsartan was generally tolerated but should be prescribed, considering the benefits and disadvantages obtained from the results of this study.There are other limitations, including a small sample size and a relatively short follow-up, resulting in low statistical power. The J-TASTE trial was designed as an open-label trial, wherein participants and researchers were aware of their group allocation. To minimize the potential biases, the core lab sonographers performed the echocardiographic measurements, including the primary endpoint, in a blinded manner. Moreover, the judgment of the events was carried out by an independent committee according to prespecified criteria; therefore, we believe that our data provide clinically important implications. Although eGFR in the azilsartan group was slightly higher than that in the candesartan group, we did not consider the eGFR as a confounding factor because the effect of eGFR on the primary endpoint is small. We found no statistical significance regarding the additional drugs administered between the groups during the study period. Only a few patients received the additional drugs; therefore, this bias has little impact on our results. Finally, the sample size was set at 87 subjects per group without dropouts; however, E/e′ was obtained from 67 subjects in the azilsartan group and 69 in the candesartan group. This smaller number was mainly because septal and/or lateral e′ were not obtained by the core laboratory, as the images were not appropriate for analysis. Therefore, it is necessary to register the subjects whose images of echocardiogram are appropriate for measuring septal and lateral e′.The strengths of the J-TASTE trial design include the multicenter design, central assessment system for echocardiography, suitable guidelines for control of BP by physicians, and assessments for novel biomarkers. In this study, the primary endpoint of the change in E/e′ from the baseline to 48 weeks was not statistically different between the azilsartan and candesartan groups. The current study did not provide the strong evidence that azilsartan improves LV diastolic dysfunction, and further confirmatory study is required.