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Abstract
Background Studies comparing the safety of orexin receptor antagonists and other hypnotic types for older patients with heart failure (HF) remain lacking. This study aimed to compare orexin receptor antagonists (suvorexant) with benzodiazepines or Z-drugs for sleep treatment and investigate the risk of acute HF-related rehospitalisation in older patients with HF.
Methods This study used a cohort design to analyse data from an administrative claims database from April 2008 to December 2020. The study population was determined based on inclusion and exclusion criteria from a cohort of 1 159 937 patients aged ≥65 years, selected through random sampling. The follow-up period was censored based on multiple criteria, including outcome occurrences and hypnotic classification changes. Kaplan-Meier survival analysis and Cox proportional hazards models were conducted for risk assessment.
Results The analysis included 1858 patients, aged ≥65 years and experiencing their first HF-related hospitalisation. These patients were categorised based on the initially prescribed hypnotic classification, including suvorexant, benzodiazepines and Z-drugs in 490, 606 and 762 patients, respectively. The average age and SD were similar across all hypnotic classes at 82.7±7.6 years. Kaplan-Meier curves indicated a higher trend of rehospitalisation risk for benzodiazepines and Z-drugs than for suvorexant. The adjusted HRs were 2.77 (95% CI 1.17 to 6.52) for benzodiazepines and 2.98 (95% CI 1.33 to 6.68) for Z-drugs.
Conclusions Suvorexant administration for sleep treatment in older patients with HF shows a potentially reduced risk of acute HF-related rehospitalisation compared with benzodiazepines and Z-drugs. The results of this study provide valuable information for selecting hypnotics in older patients with HF having concurrent sleep disorders.
- HEART FAILURE
- Pharmacology, Clinical
- EPIDEMIOLOGY
Data availability statement
The original data used for this survey were purchased from a medical information database handling company and, therefore, could not be shared.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
In previous research, the prescription of benzodiazepines to patients with heart failure (HF) was associated with a marginally elevated risk of rehospitalisation due to HF, compared with the use of Z-drugs.
WHAT THIS STUDY ADDS
In our study, there was no noticeable distinction between benzodiazepines and Z-drugs of medications.
The study suggests that benzodiazepines and Z-drugs may increase the risk of rehospitalisation due to acute HF in older patients with HF compared with treatment with suvorexant, an orexin receptor antagonist.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Patients diagnosed with HF exhibit a higher prevalence of insomnia compared with the general populace. Findings from this investigation indicate the feasibility of selecting an optimal medication for sleep treatment in HF patients, without exacerbating the risk of hospital readmission attributable to acute HF exacerbations.
Introduction
Epidemiological surveys that target the general population in Japan reported that 12.2% and 14.6% of males and females suffer from insomnia, respectively.1 In contrast, patients with heart failure (HF) demonstrated a higher prevalence of insomnia, at 23%–73%, compared with the general population.2 Insomnia generally reduces the quality of life as well as promotes the incidence of certain cancers and the risk of developing dementia.3 Furthermore, insomnia activates the renin–angiotensin–aldosterone system, interleukin 6 and tumour necrosis factor-alpha, which may contribute to the onset of cardiovascular diseases.4–8
Suvorexant, an orexin receptor antagonist, is a new class of hypnotics and is attracting attention due to its favourable side effect profile, including a low risk of dependence and respiratory depression. Suvorexant is approved solely for treating insomnia and is not prescribed for any other conditions. Orexin, which is a neuropeptide that is involved in sleep–wake cycle regulation, energy balance, autonomic control and emotional behaviour,9 is gaining attention as a potential therapeutic agent in cardiovascular treatment.10 Research has demonstrated that those with genetic mutations in the orexin receptor 2 in patients with HF with reduced ejection fraction (HFrEF) demonstrate less improvement in cardiac function, indicating a potential role for orexin in facilitating cardiac recovery.10 Therefore, careful monitoring of disease progression is crucial when administering orexin receptor antagonists to patients with HF. Conversely, orexin receptor antagonists with no muscle-relaxing properties may be beneficial in treating sleep apnoea, which is a prevalent comorbidity in patients with HF. Benzodiazepines should be avoided by patients with sleep apnoea because they induce pharyngeal muscle relaxation and cause respiratory depression.11 Clinical studies that investigate the efficacy of suvorexant in patients with HF coexisting with sleep apnoea are currently ongoing.12
At present, definitive research evidence regarding the cardiovascular risks associated with the use of orexin receptor antagonists in patients with HF remains unavailable. However, investigating the safety of orexin receptor antagonists in real clinical settings is necessary, particularly because of HF and sleep disorder prevalence in older patients.
Therefore, this study aimed to assess the difference in the risk of acute HF-related rehospitalisation among older inpatients with HF treated with orexin receptor antagonists compared with benzodiazepines or Z-drugs.
Methods
Data source
This study used a data subset from April 2008 to December 2020 provided by Medical Data Vision Co (MDV), a medical information database operator based in Tokyo, Japan. MDV is an administrative claims database that includes data collected from approximately 24% of acute care hospitals in Japan that have adopted the Diagnosis Procedure Combination (DPC) system. MDV serves as a source of real-world data in the field of pharmacoepidemiology in Japan and can be used for post-marketing surveillance and research.13 14 The MDV database includes inpatient and outpatient data, health insurance claim codes, prescriptions, diagnoses, DPC data, the International Classification of Diseases 10th Revision (ICD-10) codes and Anatomical Therapeutic Chemical (ATC) codes of the European Pharmaceutical Market Research Association Anatomical Classification.15 Data from medical institutions that participate in this database is anonymised before being transferred to MDV.
The DPC system, which was introduced in Japan in 2003, was developed as a measurement tool for increasing the transparency of acute inpatient care to standardise and improve medical care quality in Japan. Attending physicians must record diagnoses based on medical records to improve diagnosis accuracy in DPC data. Additionally, medical clerks must accurately input records of procedures, surgeries, medications, and other treatments. Submission of DPC data to the Ministry of Health, Labour and Welfare is mandatory, and the ministry uses these data to deliberate healthcare policies. Therefore, DPC data are considered reliable and suitable for research.
Study design
In this study, we selected a cohort design to evaluate the effects of exposure to different hypnotic classes, including orexin receptor antagonists, benzodiazepines and Z-drugs, on the risk of acute HF-related rehospitalisation.
Study population
In our study, we used a dataset containing 1 159 937 patients aged ≥65 years admitted to DPC hospitals purchased from MDV. Subsequently, we determined study participants who met all the inclusion criteria and none of the exclusion criteria. The inclusion criteria were (1) patients who had their first HF-related hospitalisation after January 2016 and (2) those whose initial hypnotic prescription occurred between the first hospital admission and discharge. New drugs in Japan are subject to a 2-week prescription limit for the first year after their release, thereby constraining the availability of new medications until removing this restriction. This would predominantly include patients who take the drug on an as needed basis, considering that the intervals between visits for patients with HF are not brief, and that Suvorexant was prescribed only for a 2-week supply. Therefore, the study included patients from the period after the prescription restrictions were lifted to avoid selection bias. The definition of HF-related hospitalisation was based on patients whose DPC diagnosis category was ‘most resource-consuming diagnosis’, ‘main diagnosis’ or ‘admission-precipitating diagnosis’ and had one of the ICD-10 codes ‘I500’, ‘I501’ or ‘I509’. This definition was used following the validation of previous research.16 We selected definitions with high sensitivity from the outcome definitions available in the study’s database to more comprehensively identify patients experiencing their first episode of HF. The exclusion criteria were (1) patients prescribed hypnotics from multiple drug classes during their hospital stay, (2) patients with <180 days of data before starting the follow-up, (3) patients with a follow-up period of <1 day and (4) patients prescribed cardiotonic glycosides in 180 days before starting the follow-up.
Exposure
This study identified the exposure based on the drug classes of orexin receptor antagonists, benzodiazepines and Z-drugs. The exposure period for each drug class was calculated considering the prescription period (the day subtracted by one from the date obtained by adding the number of prescribed days to the prescription initiation date) within the drug class, as well as intervals between consultations and prescriptions, to identify prescription continuity. The exposure period end date was calculated by adding a grace period to account for factors, including leftover medication and drug carry-over effects. In this study, the prescription interval and grace period were set at 60 days. Typically, hypnotics are administered as needed for treating insomnia, which may not require daily intake. Additionally, acknowledging the practice of patients taking higher doses in halved quantities is warranted due to prescription day limitations. Moreover, this study will conduct a sensitivity analysis concerning prescription interval and grace period changes. Refer to online supplemental data for sensitivity analysis results when the prescription interval and grace period setting were changed to 30 days, 90 days and 120 days.
Supplemental material
Definition of the follow-up period
The start date of follow-up in this study was defined as the discharge date following inclusion criterion.1 The end date of the follow-up was identified as the earliest of the following: (1) the date of outcome occurrence, (2) the end date of the exposure period, (3) the end date of the data period, (4) the day before the hypnotic prescription from a different pharmacological class than the one initiated at follow-up, (5) the last date of medical information occurrence within the data period and (6) the date 365 days after initiating the follow-up. These criteria were used to define the follow-up period.
Outcome
The study outcome was defined as acute HF-related rehospitalisation after initiating follow-up. The outcome was defined based on patients with the ICD-10 code ‘I50.x’ attributed to the most resource-consuming diagnosis, as well as the additional diagnosis codes ‘30101’ or ‘30 102’. This outcome definition was validated in previous study.16 We selected the outcome definition with the highest positive predictive value to more accurately identify hospitalisations for acute HF.
Covariates
The covariates collected for this study included age and gender, in addition to HF-associated factors and those prominently observed in older patients, which were selected based on a clinical perspective and the availability of information from the database. Data on comorbidities were collected as covariates if the ICD-10 codes for the diseases were assigned within 180 days before initiating the follow-up. Information on surgeries and cardiac rehabilitation was collected for the entire period before starting the follow-up and included as covariates if the relevant medical procedure codes were assigned. Information on comedications was collected as a covariate if ATC codes for the drugs were assigned within 180 days before initiating the follow-up. See online supplemental table S1 for details on the aggregated factors. Factors that were considered to be particularly clinically relevant to HF are listed in table 1, and the rest are listed in online supplemental table S2.
Patient characteristics by class of hypnotics
Patient and public involvement
Patients and the public were not involved in the study design or the conduct of the study.
Statistical analysis
The study conducted a risk assessment for acute HF-related hospitalisation across different pharmacological classes of hypnotics. One-way analysis of variance for continuous variables and the χ2 test for categorical variables were used to determine p values for patient characteristics. Non-normal distribution of the follow-up period was expressed using the median and IQR. Kaplan-Meier survival analysis using the log-rank test was conducted to compare survival times across pharmacological classes. Additionally, the number and incidence rate of outcomes were calculated for each pharmacological class. Furthermore, crude and adjusted HRs, along with their 95% CIs, were estimated using the Cox proportional hazards model to evaluate the risk of benzodiazepines and Z-drugs relative to orexin receptor antagonists. Propensity scores were calculated from the collected covariates and incorporated as a continuous variable when calculating the adjusted HRs because of the anticipated low number of outcomes in this study. In propensity score matching with a 1:1 ratio, there is a possibility that the number of subjects will be reduced to match the smaller group. Considering the possibility that the number of outcomes in this study might be small, a method adjusting for covariates was chosen. Statistical Analysis Software V.9.4 (SAS Institute, Cary, North Carolina, USA) was used for all statistical analyses.
Results
Study population
Out of 1 159 937 hospitalised patients aged ≥65 years, 4283 met all the inclusion criteria for this study. Of these, the analysis target population included 1858 patients who did not meet any exclusion criteria. The patients were categorised following the pharmacological classification of the initially prescribed hypnotics into benzodiazepine (606 patients), Z-drugs (762 patients) and orexin receptor antagonist (490 patients) (figure 1). Notably, the drug class of orexin receptor antagonists initially included both suvorexant and lemborexant as targets for extraction, whereas lemborexant, as newly released, was not extracted. Therefore, this study referred to orexin receptor antagonists as ‘suvorexants’.
Flowchart subject selection in this study. DPC, Diagnosis Procedure Combination; HF, heart failure.
Baseline characteristics
This study categorised patients based on the pharmacological classification of hypnotics and revealed no significant differences across many characteristics among the three groups. However, significant differences were identified in certain factors, particularly in the use of comedications including antiarrhythmics and beta-blockers. Furthermore, a significant difference was observed in the proportion of patients undergoing cardiac rehabilitation across the three groups. The average age of all three groups was >80 years. The factors for comorbidities and comedications were broadly similar to those observed in previous studies.17 18 Table 1 and online supplemental table S2 show the details.
Acute HF outcomes
Figure 2 presents the Kaplan-Meier curves for the three groups. Until the end of the maximum follow-up period of 1 year, 4 (0.8%) patients were observed for suvorexant, 16 (2.6%) for benzodiazepines and 19 (2.5%) for Z-drugs. The median and IQR of the follow-up period for each group were as follows: suvorexant with 54 (37–63), benzodiazepines with 57 (40–72) and Z-drugs with 55 (39–67) (figure 2). Sensitivity analysis when changing the prescription interval and grace period showed no significant difference at 30 days, but a significant difference at 90 and 120 days. Refer to online supplemental figures S1–S3 for the results.
Survival curves for the three groups.
Outcomes occurred in 9 (1.8%) patients treated with suvorexant, 31 (5.1%) with benzodiazepines and 38 (5.0%) with Z-drugs. The risk assessment of benzodiazepines or Z-drugs relative to suvorexant revealed that the adjusted HR for benzodiazepines was 2.77 (95% CI 1.17 to 6.52) and for Z-drugs was 2.98 (95% CI 1.33 to 6.68). Both benzodiazepines and Z-drugs appeared to increase the risk of acute HF-related rehospitalisation compared with suvorexant (figure 3). The sensitivity analysis, where the prescription interval and grace period were adjusted to 30 days, indicated no significant risk, as the CI encompassed zero. Conversely, altering these periods to 90 and 120 days revealed a risk, with the lower confidence limit surpassing zero. Refer to online supplemental figures S4–S6 for the results.
Adjusted HRs and Forest plots of benzodiazepines or Z-drugs for suvorexant. Adjusted for propensity scores calculated from all covariates shown in table 1 and online supplemental table S2.
Discussion
This study used real-world data reflective of actual clinical practice in Japan to investigate the effect of hypnotics prescribed to older patients with HF. We revealed that benzodiazepines and Z-drugs increase the risk of acute HF-related rehospitalisation compared with suvorexant. To the best of our knowledge, this is the first study to compare the risk of rehospitalisation in patients with HF receiving suvorexant, which is a type of orexin receptor antagonist, and those receiving benzodiazepines or Z-drugs. The results of this study were congruent across sensitivity analyses with prescription intervals and grace periods adjusted to 90 and 120 days. However, sensitivity analyses, where these periods were shortened to 30 days, indicated no significant differences. Hence, differences appeared over the medium to long term, whereas the short-term effects may be negligible.
Insomnia is considered a result of increased sympathetic nervous activity,19 which is associated with elevated blood pressure and heart rate. Symptoms of insomnia are prevalently observed in patients with HF20 and are associated with cardiovascular function deterioration21 and increased HF incidence.22 Suvorexant suppresses the action of orexin in the central nervous system, which is associated with the wakefulness system, thereby inhibiting blood pressure and sympathetic nerve activity increase.23 Furthermore, insomnia has been a risk factor for the onset of HF.4 Suvorexant is known to improve overall sleep duration, reduce sleep latency and enhance subjective sleep quality24 25 without affecting the sleep profile. Therefore, suvorexant may reduce the risk of acute HF-related rehospitalisation by comprehensively improving the negative effects on the cardiovascular system, compared with benzodiazepines and Z-drugs. However, our observational study cannot adequately evaluate the comprehensive beneficial effects on the cardiovascular system. Furthermore, doses higher than the appropriate prescription levels for sleep medications may be administered in the case of receiving benzodiazepines and Z-drugs,26 thereby warranting further detailed research.
Previous studies that compared the risk of HF-related rehospitalisation between benzodiazepines and Z-drugs have revealed that benzodiazepine increases the risk in patients with HF with both preserved ejection fraction and HFrEF.27 28 However, our study revealed that the survival curves (figure 2) demonstrated no marked differences between benzodiazepines and Z-drugs. Furthermore, the incidence rates for benzodiazepines and Z-drugs compared with those for suvorexant were observed at similar levels (figure 3). This difference may be because our study participants were older and had first-time HF-related hospitalisation, which may have affected the acute HF exacerbation compared with the participants in previous studies.
Our results do not recommend suvorexant as the first choice for treating insomnia in patients with HF and concurrent sleep disorders. A cognitive-behavioural therapy for insomnia (CBTI) is the gold standard for treating insomnia.29 Pharmacological treatment with hypnotics only provides temporary relief from insomnia. In contrast, CBTI persists in reducing sleep latency, decreasing wake after sleep onset time and extending total sleep duration, thereby improving sleep quality, despite treatment discontinuation.30 Generally, CBTI, in addition to removing factors that adversely affect sleep before prescribing hypnotics, should be considered when initiating insomnia treatment. Additionally, the interaction between hypnotics and drugs used for treating HF should be considered. Suvorexant is a P-glycoprotein inhibitor. Particular caution is necessary when prescribing suvorexant to patients with HF, because they may be prescribed cardiotonic glycosides, which is a P-glycoprotein substrate. This study excluded the prescription of cardiotonic glycosides as a potential confounder in selecting hypnotics.
The strength of our study lies in being the first to elucidate the differences in risks between suvorexant, which is an orexin receptor antagonist previously unexplored, and benzodiazepines and Z-drugs, in association with acute HF exacerbation in older patients and their respective hypnotic classes. Our results provide new evidence for selecting sleep treatment in patients with HF and concurrent sleep disorders. This study has several limitations that should be considered when interpreting the results. First, the accuracy of information regarding diagnoses and treatments entirely depends on the records in the database because this study is a secondary analysis of claim data. The analysis results indicate inadequacies or inaccuracies in these records. Additionally, the available information is based on what is recorded in the database. The presence or absence of diagnoses can be ascertained from the database records, but accounting for the severity or classification of HF and comorbidities is impossible. Moreover, the effect of hospital-specific factors on insomnia cannot be considered. Further, smoking history and alcohol consumption information are unknown. These unconsidered factors could have affected the risk assessment in this study. Second, the MDV database used in this study cannot correlate data from different medical institutions. Therefore, no drug exposure in a patient at a different medical institution may reflect the exposure by the same patient, thereby potentially affecting the analysis results. Furthermore, an HF-related hospitalisation of a patient at another medical institution before the first HF-related hospitalisation determined in this study may not be accurately identified as the first hospitalisation. These informational biases may have impacted follow-up period. Third, we conducted no detailed analysis of hypnotic dosages or action duration of benzodiazepines, as our study was primarily focused on comparisons between drug classes. Consequently, their potential effect on the risk of acute HF rehospitalisation remains unclear. Moreover, the information obtained from the database does not allow for medication adherence verification. Fourth, the MDV data include clinical laboratory values and mortality information, but these details are limited to only a portion of the patients. Therefore, this study did not use them from the perspective of comprehensiveness. Finally, as our study subjects were limited to those aged 65 or older, we were unable to examine the effects on younger patients with HF. Additionally, as this was an observational study, prospective studies involving all age groups are needed to verify the findings.
Conclusion
This observational study used a medical information database and revealed that prescribing benzodiazepines and Z-drugs to older patients with HF may promote the risk of acute HF-related rehospitalisation compared with suvorexant, which is an orexin receptor antagonist. The results of this study reveal valuable information for selecting hypnotics in older patients with HF and concurrent sleep disorders.
Data availability statement
The original data used for this survey were purchased from a medical information database handling company and, therefore, could not be shared.
Ethics statements
Patient consent for publication
Ethics approval
The Ethics Committee of Juntendo University approved our research protocol (approval number: E21-0264). However, the need for informed consent was waived because this study used anonymised medical data.
References
Footnotes
Contributors TS and SN: study design; TS and SN: data collection and analysis; TS, SN, RN and TK: interpretation of results; TS, SN, RN and TK: drafting of the manuscript; and TS, SN, RN and TK: revision of the manuscript. All authors read and approved the final submitted manuscript and agree to be accountable for the work. TK is the guarantor.
Funding This work was supported by a Grant-in-Aid for Scientific Research (grant number: 26507010); JSPS KAKENHI (grant number: JP17K09527, JP18K15904, JP19K12870, JP21K08116, JP21K16034); Intractable Respiratory Diseases and Pulmonary Hypertension Research Group, from the Ministry of Health, Labor and Welfare, Japan, Grant/Award Number: 20FC1027, 23FC1031; a research grant from the Japanese Center for Research on Women in Sport, Juntendo University. The funding agency has no role other than funding this study, and the results reported here are independent of the funding source.
Competing interests None declared.
Patient and public involvement statement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; internally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.