While data from randomized, controlled trials are the gold standard in evaluating the efficacy and safety of a treatment, real-world evaluation of the performance of such treatment can provide useful information and expand our understanding of the benefit-risk of such treatment in real clinical practice. To the best of our knowledge, this study represents the first real-world evidence evaluating ARNI in the Southeast Asia region. Our pilot study confirmed the benefit of ARNI in reducing morbidity and mortality in the HFrEF population living in this region compared to the standard treatment. This study also supports the favorable tolerability profile of ARNI in a more diverse population compared to those in the RCT.
As expected, there were both similarities and differences in the baseline characteristics of our study population compared to that of the PARADIGM-HF study. Compared to the Western population, the average BMI in our study was only 22.8–24.6 kg/m2 versus 28.1–28.2 kg/m2 in the PARADIGM-HF trial. In terms of the specific baseline prognosis of HF, the NYHA functional class was mainly class II. The baseline rates of GDMT use, including beta-blockers and MRA, were generally high and comparable between the two groups. The rate of intracardiac devices (AICD and CRT) was even higher than that of the PARADIGM-HF trial (the rates of AICD and CRT usage in the PARADIGM-HF trial were approximately 15% and 7%, respectively) . This reflects an acceptable quality of HF care in Thailand.
Since the introduction of ARNI, studies assessing the benefit and risk of ARNI in real-world situation have increased . For Asian population, there are currently 6 published studies. Among these studies, four studies compared pre- and post-treatment changes in surrogate markers or described safety and tolerability of ARNI initiation, without a control group [13,14,15,16]. Two studies from Taiwan compared the effectiveness and safety of ARNI versus standard treatment. Chang et al. compared clinical outcomes of 466 ARNI users to 466 patients receiving standard treatment in a single center study . Another study compared 502 ARNI users to 489 patients receiving angiotensin receptor blockers based standard regimen. Patient selections was performed using propensity score matching, and the two groups were compared using inverse probability of treatment weighting (IPTW) . Compared to the Taiwanese studies, patient characteristics such as age, sex, BMI, and comorbidities of this present study are relatively similar. However, the baseline rate of GDMT use and intracardiac devices in our population were higher than that of the Taiwanese studies. (beta blockers: 92% vs 80%, intracardiac devices; 25% vs 10%, respectively) [17, 18]. Despite such difference, it is reassuring to see that positive findings of our study are in concordance with Taiwanese studies along with other real-world ARNI studies in other population.
Due to the nonrandomized nature of our study, there were differences in the baseline characteristics between the two groups. Most patients in the ARNI group had dilated cardiomyopathy (DCM). The prognosis of DCM is known to be poor, especially when the LVEF is ≤ 35% and the NYHA functional class is III-IV . Therefore, the prognosis of the ARNI group might be worse than that of the standard treatment group. Moreover, patients in the ARNI group had a higher rate of ivabradine and CRT use. This may indicate more symptomatic patients in the ARNI group. In contrast, more patients in the standard group had CKD, which worsens the HF prognosis . Although ACEIs and ARBs have been widely used in patients with CKD, clinical evidence of ARNI use in CKD patients is still limited. This may lead to an imbalance in CKD between these 2 groups. However, we attempted to adjust for these confounding factors by using Cox regression analysis for the primary outcome.
In our pilot study, ARNI treatment was associated with a significant reduction in the composite of all-cause mortality and heart failure hospitalization compared to the standard treatment. However, this favorable outcome was primarily driven by a reduction in hospitalization. The effect size found in our study appeared to be even larger than that of the PARADIGM-HF trial . Based on the Kaplan–Meier curve of the primary outcome, the effectiveness of ARNI was observed within 3 months of drug initiation. Unlike the PARADIGM-HF and other high-quality real-world evidence, our pilot study was unable to demonstrate a clear mortality benefit of ARNI due to the small sample size and short follow-up time (12 months) [6, 17, 18]. However, there was a trend toward lower mortality in patients using ARNI despite the very small number of events.
Consistent with the RCT, a significant reduction in HF signs and symptoms was also found in the ARNI group compared to the standard treatment group. While there was a trend toward a greater reduction in NT-proBNP, this did not reach statistical significance. This was partly due to significant missing data in our cohort since the measurement of NT-proBNP was sporadically implemented, which represented a variation in practice among clinicians. The changes in biochemical markers were all consistent with the known effects of ARNI. We observed that the increase in serum creatinine was significantly lower in the ARNI group. This renal outcome parallels the results from PARADIGM-HF and PARAGON-HF, which was conducted in HF patients with a preserved EF [6, 21]. ARNI has been shown to effectively preserve renal function in several studies, with possible mechanisms of antioxidant, anti-inflammatory, and antifibrotic effects through NP activation in the kidneys . However, the higher incidence of CKD in the standard treatment group at baseline might partly contribute to this difference. Therefore, readers should be cautioned when interpreting this finding. As expected, hypotension was significantly higher in ARNI, especially symptomatic orthostatic hypotension. Despite the lack of a run-in period in real-world practice, angioedema was not found in any case in either arm. In terms of drug titration, patients in both groups were equally titrated to the maximum dose. These findings confirm the safety and tolerability profile of ARNI in patients with HFrEF in Thailand.
Although our pilot study revealed positive results of ARNI in real-world practice, several limitations need to be addressed. First, this was a small, real-world study with a nonrandomized design and a small number of patients. Additional large, multicenter, real-world studies should be conducted. Second, the short duration of follow-up in this study may lead to an underestimation of the mortality benefit. Therefore, future studies should have longer follow-up times to capture the mortality benefit of ARNI in real-world practice. Third, sodium-glucose cotransporter-2 (SGLT-2) inhibitors had not been approved for the treatment of HFrEF at the time of the study. Therefore, the usage of SGLT-2 inhibitors was not included in our analysis. Fourth, missing data for some secondary efficacy outcomes were significant due to the retrospective nature of the analysis. However, significant missing data occurred only among some secondary outcomes that were not strongly associated with the primary outcome. Fifth, all patients who were diagnosed with HF and followed-up at the study site during January 2015 to December 2019 were included based on the inclusion criteria. As a result, our study population contained both newly diagnosed cases and those with established disease. Finally, due to the characteristics of this observational study, our findings were susceptible to confounding factors despite our efforts to perform statistical adjustments.