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Abstract
Background Heart failure (HF) remains a major public health problem with a high mortality and morbidity worldwide. Currently, there is no optimal revascularisation strategy for patients with ischaemic cardiomyopathy despite suggestions that coronary artery bypass graft (CABG) may be superior to medical therapy in improving survival. However, CABG may be associated with substantial risk in HF subjects. We therefore aimed to evaluate the safety and efficacy of the early initiation of sacubitril/valsartan in haemodynamically stabilised patients with HF with reduced ejection fraction (HFrEF) after early CABG.
Methods This was an open-label study in which ~80 patients after CABG were randomised either to the early or late initiation of the sacubitril-valsartan. The study included patients >40 years with left ventricular ejection fraction <45% and New York Heart Association (NYHA) class II–IV at the early stage after CABG. Patients underwent intervention, the starting dose of sacubitril/valsartan (24/26 mg or 49/51 mg two times per day). The follow-up took place every 4 weeks except the first visit, which took place in 2 weeks after initiation. The primary endpoint assessed the key safety outcomes, the secondary endpoints were: the quality of life measured, the N-terminal pro-B-type natriuretic peptide (NT-proBNP) changes and 6 min walk test (6MWT).
Results In total, 83 patients were screened and 77 patients were enrolled. The majority of patients (84.4%) were in the NYHA class III at randomisation. The number of patients who discontinued the study was low in both groups (2.5%, 5.2%), and renal function, hyperkalaemia and symptomatic hypotension rarely seen in both groups did not differ significantly. The improvement in quality of life and distance at the 6MWT in both groups was significant (p<0.001). The NT-proBNP concentration decreased in both groups, the significant reduction was in the early group (p<0.001) versus the postdischarge group.
Conclusions The early initiation of sacubitril/valsartan in patients after CABG with HFrEF is safe and effective. Adverse events and permanent discontinuation were low. The NT-proBNP concentration reduced significantly with the early in-hospital initiation.
- Coronary Artery Bypass
- Heart Failure
- Pharmacology, Clinical
- Coronary Artery Disease
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
In patients with ischaemic heart failure, coronary revascularisation is superior in improving survival (STICH (surgical treatment for ischemic heart failure) trial for coronary artery bypass graft (CABG)) compared with medical therapy. One analysis from that trial showed an increased mortality rate within 30 days (5.1%) among patients who underwent revascularisation.
WHAT THIS STUDY ADDS
This study shows the early initiation of the sacubitril/valsartan in patients after CABG with reduced ejection fraction is safe and effective.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study shows that it is feasible to initiate sacubitril/valsartan in stabilised patients early after CABG and that there is an opportunity to improve outcomes in patients early after CABG.
Introduction
Heart failure (HF) remains a major public health problem with a high mortality and morbidity worldwide.1 2 Its prevalence in developed countries is about 1–2% and steadily increases with age up to 10% in people older than 80 years old.3 The average life expectancy of patients with HF does not exceed 5 years.4 The main cause of HF is coronary artery disease.5
Currently, the optimal revascularisation strategy for patients with ischaemic cardiomyopathy is uncertain. The only study comparing the coronary artery bypass graft (CABG) strategy combined with medical therapy versus optimal medical therapy alone was the STICH (surgical treatment for ischemic heart failure) trial.6 The mortality rate within 30 days was higher among patients who underwent the procedure and amounted to 5.1%.7–9 Although CABG did not reduce early postoperative left ventricle (LV) volumes, increase ejection fraction (EF), it was suggested that CABG may prevent late LV remodelling or fibrosis. There was no significant difference between medical therapy alone and medical therapy plus CABG with respect to the primary endpoint of death from any cause. Patients assigned to CABG, as compared with those assigned to medical therapy alone, had lower rates of death from cardiovascular causes and of death from any cause or hospitalisation for cardiovascular causes. 10-year follow-up of the STICH trial showed the cost-benefit of effectiveness associated with CABG similar to other one-time interventions such as implantable cardioverter-defibrillator therapy.10
At present, optimal medical therapy remains the cornerstone for improving outcomes among patients with HF. Therefore, the current HF guidelines recommend four pillars including beta blockers, mineralocorticoid receptor antagonists, SGLT2-I and ACE inhibitor (ACEi)/angiotensin receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor.11 12 Two studies were conducted at approximately the same time for patients with acute decompensated heart failure (ADHF). The PIONEER-HF (the comparison of sacubitril/valsartan versus enalapril on effect on nt-pro-bnp in patients stabilized from an acute heart failure episode) trial was designed to evaluate the efficacy measured by changes of N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration and safety of the sacubitril-valsartan uses after haemodynamic stabilisation among patients who were hospitalised for ADHF.13 As a result, such treatment showed a benefit in NT-proBNP reduction and worsening renal function, hyperkalaemia, symptomatic hypotension and angioedema did not differ significantly between the two groups. Another study, TRANSITION (comparison of pre- and post-discharge initiation of sacubitril/valsartan therapy in HFrEF patients after an acute decompensation event), aimed to show the safety and tolerability of sacubitril/valsartan initiated early after decompensation requiring hospitalisation in patients with HF with reduced ejection fraction (HFrEF).14 The findings from TRANSITION study complement those from the PIONEER-HF study showing that early administration of sacubitril/valsartan to a wide range of patients with HFrEF who have recently been admitted for ADHF is possible either in hospital or shortly after discharge.15 16
CABG is associated with an early risk of death from any cause among all patients who underwent the procedure. The safety and efficacy of the initiation of sacubitril/valsartan early after CABG is uncertain. We therefore undertook a randomised controlled trial of sacubitril/valsartan initiated early (after haemodynamic stabilisation) or late (from 2 to 4 weeks) after CABG.
Methods
Study population
We conducted an open-label study in which ~80 patients after CABG were randomised either to early (after haemodynamic stabilisation) or late (from 2 to 4 weeks) initiation of the sacubitril-valsartan at the Scientific Institute of Cardiology and Internal Medicine (Almaty, Kazakhstan). The study included male and female patients >40 years with left ventricular ejection fraction <45% and New York Heart Association (NYHA) class II–IV in the early stage after CABG. Haemodynamic stabilisation, as in the TRANSITION trial, meant the absence of need for intravenous diuretics and/or inotropic support in the 24 hours prior to randomisation, and a systolic blood pressure (SBP) ≥110 mm Hg for ≥6 hours prior to randomisation. The main exclusion criteria were hypersensitivity to sacubitril, ACEi, ARB or any component of sacubitril/valsartan, SBP <100 mm Hg, glomerular filtration rate <30 mL/min/1.73 m2 (MDRD (modification of diet in renal disease study), potassium level >5.4 mmol/L, known history of angioedema, severe lung disease, a history of peripartum cardiomyopathy or cancer therapy-related cardiomyopathy, severe liver disease, cirrhosis, cholestasis, bilateral renal artery stenosis or haemodynamically significant congenital heart diseases except secondary mitral regurgitation.
The starting dose of sacubitril/valsartan (24/26 mg or 49/51 mg two times per day) and the uptitration up to maximal tolerated doses were based on the manufacturer’s recommendations. Discontinuation (temporary or constant) and downtitration were also undertaken in line with the recommendations.
Follow-up
Follow-up took place at 2 weeks after the initiation of therapy and four weekly thereafter. Primary endpoints were the key safety outcomes, including the rates of worsening renal function (a decrease in the estimated glomerular filtration rate of ≥25%), hyperkalaemia (a serum potassium concentration of ≥5.5 mmol/L), symptomatic hypotension (SBP <100 mm Hg) and angioedema or any other adverse event (AE) judged to be associated with sacubitril/valsartan.
The secondary endpoints were: the quality of life measured by Minnesota Living with Heart Failure Questionnaire (MLHFQ), the NT-proBNP changes and 6 min walk test (6MWT). The MLHFQ was used as the health-related quality of life instrument. MLHFQ was administered at the time of randomisation and as the baseline measure. In addition, MLHFQ was measured at 6 months. The 6MWT is a simple test to evaluate the physical functional capacity in patients with HF. Similarly, 6MWT was performed at the baseline visit and after 6 months of therapy.
Statistical analysis
The obtained research results were entered into the MS Excel program, their processing and analysis were carried out in the Stata V.15 analysis package on a personal computer. Descriptive statistics methods were used for statistical processing of data. Normally distributed data are presented as mean±SD (M±SD), otherwise they are median, minimum and maximum (or IQR) and discrete variables are presented as frequencies with percentages. To assess the significance of differences in mean values when comparing between groups, an unpaired Student’s t-test was used for variables with a normal distribution; in non-parametric cases, the Mann-Whitney U test was used. Risks were expressed as relative risk with CI (the association was assessed using the relative risk with CI). Differences were considered statistically significant at p<0.05. ORs are considered statistically significant if the 95% CI for the OR in its interval does not include 1.
Results
Within a year from January to December 2022, in total, 83 patients were screened and 77 patients were randomised. Four patients withdrew during the screening and two discontinued prior randomisation, thus 39 patients were randomly assigned to the early initiation group and 38 patients to postdischarge group (figure 1).
Screening, randomisation and follow-up.
Baseline characteristics of the patients are shown in table 1. The mean (±SD) age of the patients was 63±7 years; 58 patients were male (75.3%). The majority of patients (84.4%) were in the NYHA class III at randomisation, and at admission more than half of them were ACEi/ARB naïve (58.4%), and 49.4% were receiving diuretics. The mean (±SD) SBP at randomisation was 118±14, and one-third (31.1%) of the patients had an SBP less than 110 mm Hg, which explains the initial low dose of sacubitril/valsartan (24/26 mg) in 36 (46.7%); the remaining patients were given the higher dose (49/51 mm Hg). At admission, the median NT-proBNP concentration was 1074 (IQR: 531–1530).
Patient characteristics at the baseline
Primary safety outcome
The number of patients who discontinued the study was low in both treatment groups. Thus, with exclusion of the single patient who died, in the early group there was one discontinuation (2.5%) caused by rash, whereas in the postdischarge group both patients (5.2%) discontinued due to AEs such as dizziness. Therefore, the discontinuation did not show a major difference between groups, although the most frequent AE in the postdischarge group was dizziness (5.2%).
Table 2 shows that the rates of worsening renal function, hyperkalaemia and symptomatic hypotension in both groups did not differ significantly.
Primary safety outcomes
Secondary efficacy outcome
Although the NT-proBNP concentration decreased in both groups (figure 2), the significant reduction was in the early group (p<0.001) compared with the postdischarge group (p=0.7). The baseline score of MLHFQ in the two-treatment group did not differ significantly. At 6 months (figure 3), the patients noted meaningful improvement in the quality of life, and the difference in change scores was greater in the early group (−16, p<0.001) versus the postdischarge group (−9, p<0.026). The mean distance walked on the baseline in the early and postdischarge groups was 245 and 259 m, respectively (figure 4). The value increased to 369 m (p<0.001) in the early group compared with 367 m (p<0.001) in the postdischarge group after 6 months of therapy.
Change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level.
Change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score.
Change in 6 min walk test (6MWT) distance.
Discussion
The risk of death during the first 30 days after CABG was three times higher than with the use of drug therapy alone.7–9 We aimed to evaluate the safety and efficacy of early initiation of sacubitril/valsartan to improve the 30-day outcome as a vulnerable period for patients after CABG. Two trials, PIONEER-HF and TRANSITION, compared early initiation of sacubitril/valsartan in stabilised patients after acute decompensation of HF.13 14 These trials were without run-in period, patients were with severe clinical profile. While the PIONEER-HF study compared two different drugs, sacubitril/valsartan versus enalapril, the main principle of TRANSITION was to evaluate the tolerability and safety of the early initiation compared with later initiation. The results of PIONEER-HF and TRANSITION may not be applicable to the post-CABG situation.15 16 In our study, we compared two treatment modalities of sacubitril/valsartan initiation in patients with reduced EF after CABG in the early stages after haemodynamic stabilisation and postdischarge.
The incidence of the discontinuation due to AEs was similar and low in both trials, TRANSITION and PIONEER-HF,15 16 and compared well with the rate of discontinuations in our study. One patient (2.5%) in the early group permanently discontinued due to rash and two patients in the postdischarge arm (5.2%) discontinued because of dizziness. There were no events of hyperkalaemia or renal function worsening that could cause the permanent discontinuation.
In PIONEER-HF study, the time-averaged reduction in the NT-proBNP concentration was significantly greater in the sacubitril-valsartan group compared with the enalapril group and was accompanied by the high-sensitive cardiac troponin concentration reduction, which is associated with the myocardial injury and worse prognosis among patients with HF. Therefore, such findings show that early in-hospital initiation of sacubitril/valsartan should be superior in terms of the reduction of the serious clinical outcomes.13 Similarly, in our study, early initiation of sacubitril/valsartan allowed to significantly reduce the NT-proBNP concentration (p<0.001), a biomarker of neurohormonal activation, haemodynamic stress and subsequent cardiovascular events, compared with the postdischarge initiation (p=0.7).
Another important key target of therapy in the management of patients with HF is health-related quality of life, which is more impaired than patients without illness and with other comorbidities. There were statistically significant reductions in both treatment groups after 6 months of therapy compared with the baseline scores which was accompanied by the improvements of the 6MWT (±124 m in the early group and ±108 m in the postdischarge group). It is established that the 6MWT improvement >50 m is associated with reduction of the mortality in patients with HF.
The main limitation of the current study may be the modest sample size which may make it difficult to detect significant differences. For example, the (insignificant) HR of 2.8 for hyperkalaemia in the early treatment group looks impressive but is based on a total of four cases. It is not clinically likely, however, that such a difference would persist in a larger study.
In summary, the early initiation of sacubitril/valsartan in patients after CABG with reduced EF is safe and effective. AEs and permanent discontinuation were low. The improvement in quality of life and distance at the 6MWT was significant in both groups, meanwhile, the NT-proBNP concentration reduced significantly with the early in-hospital initiation.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
This study was reviewed and approved by the Ethics Committee of Kazakh National Medical University named after S Asfendiyarov (No 1121 on 28 April 2021). The study was conducted in accordance with the principles established by the Declaration of Helsinki (2013). As this was an interventional cohort study all patients provided written informed consent.
References
Footnotes
Twitter @arakisheva
Contributors MN and AR conceived and designed the study. AR and AM requested funding for the study. AR, MN, DS and RZ contributed to patient inclusion and data collection. MN, AR and AM analysed the data. MN and AR wrote the draft version of the manuscript. All authors provided input on the study design, data analysis and interpretation of the results; revised the paper critically for important intellectual content; and approved the final version. AR is responsible for the overall content as guarantor.
Funding The work was supported by the scientific grant of the Ministry of Health of the Republic of Kazakhstan (BR 11065383) and dissertation work of the first author
Competing interests AR received a speaker honorarium from AstraZeneca, Novartis and Roche.
Provenance and peer review Not commissioned; externally peer reviewed.