Hypotension prevents boosting of sacubitril/valsartan doses for Asians with ACHD-related HF

The angiotensin receptor-neprilysin inhibitors (ARNI) sacubitril/valsartan does not appear to help manage heart failure (HF) in Asian patients with adult congenital heart disease (ACHD), with a small study from Singapore showing that the drug can only be tolerated at suboptimal doses and that hypotension prevents uptitration.

In a group of 16 patients with ACHD of moderate to severe complexity who were treated at a tertiary centre in Singapore, the overall mean tolerated daily dose of ARNI was 128 mg. Only six patients were able to tolerate a dose of 100 mg twice daily. [Int J Cardiol Congenit Heart Dis 2021;6:100268]

“Uptitration of ARNI was largely limited by symptomatic hypotension with higher doses,” the investigators said. “Renal function remained within normal limits, and there were no episodes of hyperkalaemia.”

Of note, ARNI was well tolerated at suboptimal doses for a median follow-up of 708 days. ARNI was discontinued due to financial concerns in one patient while two others were lost to follow up due to travel restrictions with the COVID-19 pandemic. None of the patients withdrew ARNI use due to adverse reactions.

“From an efficacy standpoint, the New York Heart Association (NYHA) class status largely remained unchanged after initiation of ARNI, whereas it typically improves symptoms markedly in contemporary HF studies,” the investigators pointed out.

While none of the patients were hospitalized for HF during the follow-up, only four patients reported improvement in their symptoms, they added.

Role of ARNI in ACHD-HF unclear

“Data regarding the safety and tolerability of ARNI comes predominantly from the PARADIGM-HF trial,” according to the investigators.

In PARADIGM-HF, which involved patients (18 percent Asians) with heart failure with reduced ejection fraction (HFrEF), ARNI was superior to and better tolerated than enalapril, with few patients discontinuing the medication due to an adverse event (10.7 percent vs 12.3 percent) or renal impairment (0.7 percent vs 1.4 percent). The most common adverse events were symptomatic hypotension (14 percent), hyperkalaemia (20 percent), and cough (11 percent). [N Engl J Med 2014;371:993-1004]

The mean tolerated daily dose of ARNI was markedly higher in PARADIGM-HF than in the local study (375 vs 128 mg). This difference, according to the investigators, is likely due to PARADIGM-HF recruiting only patients who could tolerate ACE inhibitors and ARNI therapy during the run-in phase of the trial.  

The mean age of the recruited population in PARADIGM HF was 63.8 years, with 60 percent of patients having ischaemic heart disease as the main aetiology of HFrEF. In contrast, the mean age of the 16 Asian ACHD HF patients in the current study was 37 years old, with the youngest being 21 years old at the time of ARNI initiation. The mean systolic blood pressure of the latter was 124 mm Hg, while that of the former was 122 mm Hg.

“Seventy-one percent of patients had concomitant hypertension in the PARADIGM-HF trial, while none of our patients had hypertension. This could perhaps explain the limitation in the uptitration of sacubitril/valsartan in our population, as it was largely limited by symptomatic hypotension despite a similar systolic blood pressure prior to the initiation of [treatment],” the investigators noted.

Nevertheless, the investigators acknowledged that the results of the current study might be overestimated due to the small study population. Furthermore, the accuracy and completeness of documentation and biomarkers limited the interpretation of findings, given the retrospective and nonrandomized nature of the study.