In the present study, we demonstrated that patients with HFrEF initiated on a VLD of SV were characterized by lower SBP, BMI, and LVEF at baseline. Use of VLD SV was associated with an improvement in dyspnea, an increase in LVEF and a decrease in NT-proBNP and LVEDD, similar to that seen with the currently recommended SD of SV, and without any significant differences in adverse events, treatment discontinuation or clinical outcomes, when compared with SD of SV.
Based on the clinical benefits demonstrated in the PARADIGM-HF trial, both the ACC/AHA and ESC guidelines recommend SV treatment in patients with HFrEF.2,3 However, according to a recent report about GDMT in HFrEF (CHAMP-HF, Change and Management of Patients with Heart Failure), 27% of patients did not receive an ACEi/ARB or SV despite absence of contraindications and only 13% of patients received SV.8 Another analysis of the CHAMP-HF registry showed that only 10.8% patients took the target dose of ACEi/ARB, recommended by current guidelines.18 These results suggest that initiation and up-titration of GDMT to target doses is often a clinical challenge in ordinary clinical practice.
The greatest challenge is in patients with a low BP (e.g. SBP < 100 mmHg) who are also those at highest risk of poor outcomes and who, potentially, have much to gain from effective therapies. A post-hoc analysis of the Systolic Heart Failure Treatment with the If Inhibitors Ivabradine (SHIFT) showed that the risk of all-cause mortality increased by 12% as baseline SBP decreased every 10 mmHg in chronic HFrEF patients.19 The significance of low BP is further highlighted by the definition of “advanced heart failure” which includes patients with a SBP < 90 mmHg, and in whom treatments such as a left ventricular assist device or even heart transplantation may need to be considered.3,20 In the real-world practice, it is easy to find patients with HFrEF with a low SBP, as shown in our study. Interestingly, in this study, the patients that physicians elected to start on VLD SV had other features of advanced heart failure. For example, they had a lower BMI which is known to identify higher-risk individuals, some of whom have cardiac cachexia, which is also part of the definition of advanced heart failure.21 Finally, they had a lower LVEF (LVEF < 30%) and this too is also a recognized indicator of advanced HF.20
These high-risk HF patients have a poor tolerance of GDMT, and so it is inevitable that lower doses of guideline-recommended medications are prescribed in clinical practice (or these may not be prescribed at all). However, there have been few clinical studies that have examined the possibility of using lower than usual initial doses of GDMT in patients with HFrEF. We found that a VLD of SV was associated with similar improvements in symptoms, laboratory, echocardiographic parameters, and clinical outcomes, and had a similar adverse event profile in these vulnerable patients, compared to the SD group. Although our patients were not randomized, it is useful to compare our results with those from the PIONEER-HF trial in which hospitalized HFrEF patients with a systolic BP ≥ 100 mmHg were randomized to SV 50 mg bid (titrated, if possible, to 200 mg bid) or enalapril 2.5 mg bid (titrated to 10 mg bid).22 In PIONEER-HF, the lowest dose-level of SV (50 mg bid) led to a greater reduction in NT-proBNP than the equivalent randomized dose-level of enalapril (2.5 mg bid). Compared with enalapril, SV also reduced heart failure re-hospitalization, consistently, across all three dose-levels of study drug (50, 100 and 200 mg bid of SV versus 2.5, 5 and 10 mg bid of enalapril). While we cannot prove that those individuals who remained on VLD SV (i.e. 25 mg bid) obtained benefit from that dose, we can conclude from PIONEER-HF that the 49% who were successfully titrated to 50 mg bid or above likely did. It is also important to note that 94% of patients in the VLD group remained on SV. In the SD group, 78% of patients achieved a dose of SV of 50 mg bid or above and 93% remained on treatment. For comparison, 88% of patients in PIONEER-HF remained on SV of 50 mg bid or above at 12 weeks but 12% were off study drug (there was no 25mg bid option in PIONEER-HF). Arguably, the availability of VLD SV resulted on more patients remaining on treatment in the present study and possibly some patients receiving treatment at all i.e. if it had not been for the availability of VLD SV, some patients might never have been started on treatment or would have been started on SD and had to discontinue treatment. Conversely, a forced-titration strategy, such as that used in randomized trials, might have led to achievement of higher doses that observed in our study, although other “real world” data are consistent with our experience, e.g. in the CHAMP-HF Registry, only 14% of patients received maximal target doses of SV.8
Our findings may be particularly relevant to Asian patients. In the PARADIGM-HF trial, the 1,487 (18%) patients enrolled from the Asia-Pacific region had a lower BMI, lower SBP and lower prevalence of hypertension, findings comparable with our baseline data.23,24 Clinical practice data from Taiwan demonstrated that only 15.8% patients could achieve the target SV dose (97/103mg twice daily) after a 1-year titration pattern.25 In addition, this study showed that very low doses of SV (25 − 24/26 mg daily) were prescribed. Therefore, future prospective studies to demonstrate the clinical role of a very low SV dose should be warranted, especially in the Asian population.
Our study had some limitations. First, it had the inherent limitations of an observational study in a single center. Second, we used a very low dose of SV that is not generally available and had to be prepared locally by splitting a 50mg SV tablet. Third, we analyzed a relatively small number of patients in a specific (Korean) population with a relatively short-term follow-up. A larger prospective, larger, longer term, randomized trial would be useful.
In conclusion, our study suggests that the initiation of VLD of SV (25 mg twice daily), in patients taking a low dose of an ACEi/ARBs, or with a low SBP, or both, is well tolerated and may be associated with similar outcomes an initial standard dose of 50mg twice daily. This may be a useful clinical strategy in the many HFrEF patients who are currently denied SV and other therapies because of concerns about hypotension or who are unable to tolerate standard dose SV.