2Department of Pharmacy, Ruijin Hospital School of Medicine, Shanghai Jiaotong University, Shanghai, China
3Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
Abstract
Background: The aim of this study was to investigate the influence of aging on the effectiveness and tolerance of sacubitril/valsartan (sac/val) among hypertensive patients complicated with heart failure in a real-world setting.
Methods: This multicenter, retrospective study included patients (≥18 years old) admitted with a diagnosis of hypertension and heart failure, starting sac/val therapy between January 2020 and December 2021 from 3 medical centers. Patients were grouped by the cutoff age of 65 years. Outcomes were collected 31-365 days after the initiation of sac/val and were compared in a matched cohort after 1: 1 propensity score matching (PSM).
Results: A total of 794 patients were finally analyzed. Blood pressure and cardiac functions improved significantly compared with values at baseline. There were 269 patients in each cohort (<65 years and ≥65 years) after PSM. After PSM, the incidence of hyperuricemia and hypotension in the elderly patients (≥65 years) was significantly higher than in those <65 years of age. Kaplan–Meier estimate suggested that the cumulative incidence of new or recurrent cardiovascular events increased significantly at the age of ≥65 years after the point of 3 months (log-rank P =.00087).
Conclusion: Sac/val benefited patients in both cohorts by improving blood pressure and cardiac function. Elderly patients (≥65 years) were susceptible to hypotension, low diastolic blood pressure, hyperuricemia, and underwent cardiac-related readmissions more frequently.
Highlights
- Elderly patients were susceptible to hypotension after sacubitril/valsartan therapy.
- Laboratory indicators should be monitored when taking sacubitril/valsartan.
- Intolerance made the elderly patients easily undergo rehospitalization for cardiac events.
- Dosage of sacubitril/valsartan should be up-titrated cautiously for the elderly patients.
- Prompt treatments for adverse events are in need to improve tolerance.
Introduction
The prevalence of hypertension and heart failure (HF) is increasing worldwide, contributing to an increasing incidence of unexpected cardiovascular events and mortality, thereby placing a heavy medical burden on the society. The majority of patients diagnosed with HF in Asia are accompanied by hypertension.1 The link between hypertension and HF could be mainly attributed to hypertrophy, changes in the renin–angiotensin–aldosterone system (RAAS) and myocardial insult. Hypertension is strongly associated with HF, especially in the elderly,2 which could be attributed to myocardial stiffness and multiple comorbidities with aging.3 Elderly HF patients are more susceptible to treatment-resistant hypertension. Hence, it seems necessary to control resistant hypertension among the elderly to improve clinical outcomes.4
As an angiotensin receptor–neprilysin inhibitor, sacubitril/valsartan (sac/val) is superior to other types of antihypertensive agents because its mechanism covers both the natriuretic peptide system and RAAS,5 showing a promising role in improving cardiovascular outcomes.6 Sac/val has been found to be efficacious in the treatment of resistant hypertension, renal hypertension, and systolic hypertension in elderly Asian patients.7-
Approximately 20% of patients discontinued sac/val in the run-in phase because of adverse events, and hypotension occurred most frequently.11 In addition, a single-center retrospective study focusing on patients with hypertension and HF in China found that a history of atrial fibrillation or chronic kidney disease, and high baseline levels of serum creatinine, uric acid, and N-terminal pro B-type natriuretic peptide (NT-proBNP) might lead to the discontinuation of sac/val due to intolerance.12 However, there is limited evidence on these populations, especially the elderly. Hence, we conducted a multicenter study to explore the influence of aging on the clinical outcomes of sac/val in hypertensive patients combined with HF.
Methods
Study Design and Patient Selection
In this multicenter, observational, retrospective real-world study, clinical information was obtained from the electronic medical record (EMR) systems. The study population comprised patients (≥18 years old) admitted with a diagnosis of hypertension and HF (or cardiac insufficiency, with the New York Heart Association (NYHA class II-IV, NT-proBNP >300 pg/mL), newly receiving sac/val therapy between January 2020 and December 2021 from 3 medical centers. Individuals were excluded if their systolic blood pressure (SBP) was <110 mm Hg or >180 mm Hg on admission, information after initiating sac/val during a 12-month follow-up period was not attainable, they discontinued sac/val therapy within 31 days, or they took angiotensin-converting enzyme inhibitors (ACEI) within 36 hours or angiotensin-receptor blockers (ARB) within 24 hours before starting sac/val. To investigate the impact of aging, the study population was divided into 2 cohorts: patients aged <65 years and patients aged ≥65 years. The date of data collection was 31 January 2022.
Data Collection
All information on the medical history of patients was collected from the EMR. Demographic data included gender, age, history of smoking, and alcohol. Clinical data included blood pressure, diagnosis on admission, dosage of sac/val (maximum tolerated dosage), concomitant medication use, and results of laboratory tests as well as echocardiographic parameters. Baseline SBP and diastolic blood pressure (DBP) referred to the values obtained on admission. Laboratory indicators included electrolytes, liver function (alanine aminotransferase (ALT), aspartate aminotransferase (AST), kidney function (estimated glomerular filtration rate (eGFR) serum creatinine, and uric acid), and myocardial markers (NT-proBNP). Laboratory results were obtained at baseline and after initiation of sac/val. Echocardiographic parameters were obtained by echocardiography 31-365 days after receiving sac/val. The maximum tolerated dosage of sac/val was adjusted from the initial levels by senior physicians according to the effectiveness and tolerance of each patient.
Definitions of Outcomes
The primary outcomes measured were data on the improvement of blood pressure, laboratory indicators, and cardiac biomarkers, as well as the proportion of participants achieving the target threshold of echocardiographic parameters 31-365 days after the initiation of sac/val. Secondary outcomes included the frequencies of adverse events, the proportion of patients discontinuing sac/val due to intolerable adverse events, and the incidence of first or recurrent cardiovascular events within 12 months. Cardiovascular events were defined as emergency admissions, unplanned visits, or hospitalizations due to acute HF, myocardial infarction, or stroke.
In terms of adverse events, hypotension and dizziness were self-reported by patients; abnormal serum creatinine referred to values above the upper limit of normal or those increasing up to 20% from baseline; hyperuricemia was defined as values of serum uric acid above the upper limit of normal laboratory reference values (female: 357 µmol/L; male: 428 µmol/L), and hyperkalemia referred to serum potassium concentration exceeding 5.5 mmol/L.
Statistical Analysis
Statistical analysis was performed using SPSS software (version 19.0; IBM, Armonk, NY, USA). Comparisons of normally distributed values between the 2 groups were analyzed by
To eliminate confounding factors and control for consistent baseline levels between the 2 cohorts, the patients were matched by age-stratified analysis using propensity score matching (PSM). Each patient aged <65 years was matched with a patient aged ≥65 years. Control variables were SBP and DBP on admission, gender, renal insufficiency, number of hypertensive drug classes, and the maximum tolerated dosage. Frequencies of cardiovascular events between the 2 age groups (<65 years vs. ≥65 years) were estimated by the Kaplan–Meier (K-M) curve.
Results
Participants
A total of 1150 patients diagnosed with hypertension and HF (or cardiac insufficiency, with the NYHA class II-IV), receiving sac/val from the 3 centers were collected. The inclusion process of the 794 patients who were finally analyzed is presented in
Effectiveness Outcomes
Compared with the median values at baseline, the blood pressure, and NT-proBNP values decreased significantly after treatment in the 2 cohorts (
After PSM, the Kaplan–Meier analysis illustrated that the cumulative incidence of new or recurrent cardiovascular events increased significantly in the ≥65 years age group after 3 months (log-rank
Safety Outcomes
In terms of safety concerns, adverse events reported during the follow-up period mainly included dizziness, hypotension, elevated creatinine, hyperuricemia, and hyperkalemia. As shown in
Discussion
The impact of aging on the effectiveness and tolerance of sac/val in patients with hypertension and HF in the real world has been rarely studied. The novelty of our study lies in assessing the differences in effectiveness and safety outcomes between subgroups of patients stratified by the cutoff point of 65 years of age, and reminding physicians to increase the dose cautiously and to prevent and manage adverse reactions promptly.
The main finding of this multicenter retrospective study is that a greater decline in DBP, higher incidence of hyperuricemia and hypotension, and more cardiovascular events were reported among the elderly patients (≥ 65 years) when compared with those aged <65 years.
A retrospective study by Umehara et al13 suggested that the high frailty severity and low LVEF might act synergistically to cause physical deterioration and an increase in readmissions among HF patients.13 Advancing age was associated with frailty.14,
Another published study found that the benefits of sac/val for the elderly increase with age, even considering the discontinuation and switching rates observed in the real world.19 Nevertheless, it is necessary to clarify the factors leading to intolerance. It had been previously reported that the median age of the intolerance group was higher than those reaching the maximum tolerated dose (73.4 years vs. 69.1 years).20 In this study, the proportion of elderly patients discontinuing sac/val due to intolerance in the ≥65 years age group was not significantly different from those aged <65 years. The exclusion of patients who discontinued sac/val within 31 days might result in no difference in the tolerance between the 2 subgroups. Moreover, starting with a lower dose and prolonging the period to reach the standard dose is favorable for improving patient tolerance.21
Previous studies identified a high prevalence of isolated systolic hypertension and isolated diastolic hypotension in older adults due to the stiffening of large arteries with aging.22,
Though evidence showed the benefit of sac/val in reducing uric acid due to its role in increasing urinary uric acid excretion,29 this study found that elderly patients ≥65 years were more susceptible to hyperuricemia after receiving sac/val, potentially contributing to worse cardiovascular outcomes in the subgroup.30 Urate-lowering therapy was recommended in elderly patients with hyperuricemia after antihypertensive therapy.30 An epidemiological research confirmed older age as a significant factor for the prevalence of hyperuricemia in China, increasing from 60 years of age and peaking after 70 years of age.31 Another survey conducted in the United States also identified the increasing prevalence of hyperuricemia with age, among those aged ≥65 years.32
Study Limitations
The study has some limitations. First, the results might be biased by selecting 65 years of age as the cutoff point between the 2 age-stratified groups and the retrospective nature of the study. Secondly, clinical events among patients lacking follow-up information were not analyzed, thus data on adverse events and cardiovascular events might have been underestimated. Thirdly, this study did not perform a frailty assessment and failed to confirm the association of frailty with effectiveness and safety of sac/val in the age-stratified subgroups. Fourthly, data on right ventricular function were not available in this study, which might also affect the tolerability of sac/val therapy in HF patients.33 Further prospective studies with larger sample sizes and longer follow-up periods are required to examine the impact of frailty on clinical outcomes of sac/val in Chinese patients with hypertension and HF.
Conclusion
Sac/val benefited patients from both cohorts in improving blood pressure and cardiac function. However, older patients (≥65 years) were found to be susceptible to hypotension, low DBP, and hyperuricemia, and were more likely to undergo readmissions due to new or recurrent cardiovascular events. Therefore, it is necessary to up-titrate the dosage cautiously for elderly patients, closely monitor the laboratory indicators, and promptly administer treatment for the corresponding adverse reactions.
Footnotes
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