Relationship Between Medical Therapy, Long-Term Care Insurance, and Comorbidity in Elderly Patients With Heart Failure With Systolic Dysfunction

Abstract

Background: Although guideline-directed medical therapy (GDMT), including β-blockers, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), improves survival and quality of life, most patients with heart failure with reduced (HFrEF) and mildly reduced (HFmrEF) ejection fraction are treated with inadequate medications. We investigated the prescription patterns of GDMT in elderly patients with HFrEF and HFmrEF and their characteristics, including the certification of long-term care insurance (LTCI), which represents frailty and disability.

Methods and Results: This retrospective cross-sectional study analyzed 1,296 elderly patients with symptomatic HFrEF and HFmrEF with diuretic use (median age 78 years; 63.8% male; median left ventricular ejection fraction 40%). Prescription rates of GDMT were inadequate (ACEi, ARBs, β-blockers, and MRAs: 27.0%, 30.1%, 54.1%, and 41.9%, respectively). LTCI certification was independently associated with reduced prescription of all medications (ACEi/ARB: odds ratio [OR] 0.591, 95% confidence interval [CI] 0.449–0.778, P=0.001; β-blockers: OR 0.698, 95% CI 0.529–0.920, P<0.001; MRAs: OR 0.743, 95% CI 0.560–0.985, P=0.052). Patients with LTCI certification also had a high prevalence of polypharmacy and prescription of diuretics.

Conclusions: Vulnerable patients with LTCI may be an explanation for the challenges in implementing GDMT, and communicating is required for favorable heart failure care in this population.

Current management guidelines for patients with heart failure with reduced ejection fraction (HFrEF) strongly support the use of multiple medications that are proven to improve survival and quality of life.^1,2 Moreover, evidence that the standard therapy for HFrEF may be effective in and extended to select patients with heart failure with mildly reduced ejection fraction (HFmrEF) has grown.^3–6 In daily clinical practice in Japan, the medication regimen in patients with HFmrEF is similar to that in patients with HFrEF.⁷ Nonetheless, most patients have been treated inadequately and have had no changes in the use or dose of the medication suggested; thus, there remain significant gaps in the guidelines’ recommendations.^8,9 In implementing guideline-directed medical therapy (GDMT), patient-related factors (comorbidities, advanced age, frailty, cognitive impairment, poor adherence, low socioeconomic status), treatment-related factors (intolerance, side effects), and healthcare-related factors influence the availability and accessibility of heart failure care.¹⁰ Concerns about intolerance and side effects are particularly important in elderly patients with frailty and disability, in whom comorbidities, cognitive impairment, polypharmacy, and limited social support impose significant obstacles to adequate heart failure therapy.^11,12 However, the prescription patterns of GDMT in Japanese elderly patients with HFrEF and HFmrEF and the characteristics related to lower rates of GDMT prescriptions remain unclear. In this study, we surveyed prescription records using our database of patients with echocardiographic left ventricular systolic dysfunction and examined the factors leading to inadequate GDMT prescription.

Methods

Study Design and Patient Enrolment

This retrospective cross-sectional multicenter echocardiography based study involved elderly patients with symptomatic HFrEF and HFmrEF with diuretic use. Details concerning the study design and baseline clinical data have been reported elsewhere.¹³ Briefly, patients aged ≥65 years with an echocardiographic left ventricular ejection fraction (LVEF) <50% were enrolled. Echocardiography was performed between January 2011 and December 2016. Available baseline clinical data, including comorbidities, therapies, and long-term care insurance (LTCI) data were reviewed and extracted from patients’ medical records. LTCI data were used as an indicator of frailty and disability. Patients with LTCI were considered to be frail with disability.^14,15

The study was approved by the ethics committee of Niigata University and was conducted in accordance with the guidelines of the Declaration of Helsinki and in compliance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects. Information concerning the implementation of the research, including the handling of existing specimens or information, and research implementation was made public, with opportunities provided for patients to withdraw from the study. Eethics committee of Niigata University considered that these activities met the criteria for ensuring patient consent, and waived the need for written informed consent. We used the opt-out method because of the retrospective nature of the study. This study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry in Japan (Registration no. UMIN-000043255).

LTCI System in Japan

The LTCI system was implemented in Japan in 2000 to support the independence of elderly patients with frailty and disability. Every elderly person who needs public nursing and financial support must register with the LTCI system. Therefore, the use of LTCI is considered an indicator of frailty and disability in Japan. Elderly patients aged ≥65 years are eligible for benefits based on physical and cognitive dysfunction. Eligibility is assessed using a 74-item questionnaire based on activities of daily living, a home visit report, and a medical doctor’s opinion, and is finally decided by a Care Need Certification Committee. There are 7 levels of support and care: support levels 1 and 2 and care need levels 1 (least disabled) to 5 (most disabled). Services are provided to insured persons who have certified long-term care requirements according to their support and care needs levels.¹⁶

Non-Cardiac Comorbidity

The severity of comorbidities was evaluated using the Charlson comorbidity index (CCI).¹⁷ This index includes 19 pathologies with different scores, and patients are classified into 4 groups according to their CCI score: low (CCI 0); medium (CCI 1–2); high (CCI 3–4), and very high (CCI ≥5). In this study, we defined patients with high and very high CCI scores as having severe comorbidities. Based on the characteristics of the study population, all enrolled patients were considered to have heart failure during the CCI evaluation. However, in the present study we excluded chronic heart failure (CHF) scores when assessing comorbidities in patients with CHF because, using only the patients’ medical records, it was challenging to fully determine the severity of diabetes and hepatic diseases. Therefore, we considered all diagnoses of diabetes as “diabetes without end-organ damage” and hepatic diseases as “mild liver diseases” in the index. In the present study, stroke included brain infarction, brain hemorrhage, and subarachnoid hemorrhage. Connective tissue diseases included rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and other collagen vascular diseases.

Medications

Based on the design of a previous clinical study, we identified and categorized prescribed drugs as follows. The amount of loop diuretics was converted to the corresponding amount of furosemide using the formula 40 mg/day furosemide=60 mg/day azosemide=8 mg/day torsemide.¹⁸ Using the World Health Organization-defined daily dose, we defined a polypharmacy episode as overlapping treatment with ≥5 medications occurring for at least 1 day.¹⁹ Previous systematic reviews have reported that the common definition of polypharmacy is ≥5 medications,^20,21 and we used the same cut-off in the present study.

In the present study, GDMT was defined as the introduction of medication therapy that was expected to improve prognosis, including β-blockers, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs). Sacubitril/valsartan inhibitors and sodium-glucose cotransporter 2 inhibitors (SGLT2i) were excluded because during the period included in this study, sacubitril/valsartan inhibitors were not approved for the treatment of heart failure and SGLT2i were not yet recommended in many countries, including Japan.^22,23

Statistical Analysis

Comparative statistical analysis in the groups was performed using a Mann-Whitney U test for non-parametric data. Fisher’s exact test was used to assess differences in the distribution of categorical variables between groups. Comparison of the 4 groups differentiated by severe comorbidities and LTCI was performed by Bonferroni’s multiple comparison test. Multiple logistic regression analysis was used to identify factors associated with ACEi/ARB and/or β-blocker use among patients with CHF. Statistical significance was set at P<0.05 (two-tailed).

All statistical analyses were performed using EZR version 1.54 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria),²⁴ involving a modified version of the R commander designed to add statistical functions frequently used in biostatistics.

Results

Patient Characteristics

The median age for the 1,269 patients with HFrEF and HFmrEF was 78 years (interquartile range [IQR] 72.0–84.0 years), 63.1% of patients were aged ≥75 years, 63.8% were male, and median LVEF was 40.0%. Patients with LTCI, who were considered to have frailty and disability, were older and a higher proportion of these patients were female. Patients with LTCI had higher CCI scores than those without LTCI. Baseline characteristics of the study cohort, as well as according to LTCI status, are presented in Table 1.

Table 1. Baseline Patient Characteristics

	Total (n=1,269)	LTCI certification		P value
		No (n=971)	Yes (n=298)
Age (years)	78.00 [72.00–84.00]	76.00 [70.00–82.00]	84.00 [77.00–88.00]	<0.001
Age ≥75 years	801 (63.1)	550 (56.6)	251 (84.2)	<0.001
Male sex	809 (63.8)	659 (67.9)	150 (50.3)	<0.001
Comorbidity
Hypertension	42 (3.3)	34 (3.5)	8 (2.7)	0.582
Diabetes	820 (36.0)	367 (37.8)	108 (36.2)	0.681
Dyslipidemia	565 (44.5)	452 (46.5)	113 (37.9)	0.009
Stroke	283 (22.3)	174 (17.9)	109 (36.6)	<0.001
Dementia	145 (11.4)	71 (7.3)	74 (24.8)	<0.001
Creatinine ≥3 (mg/dL)	76 (6.0)	51 (5.3)	25 (8.4)	0.051
Dialysis renal failure	58 (4.6)	40 (4.1)	18 (6.0)	0.203
Malignant tumor	285 (22.5)	201 (20.7)	84 (28.2)	0.009
CCI
Low	270 (21.3)	191 (19.7)	79 (26.5)	<0.001
Medium	242 (19.1)	211 (21.7)	31 (10.4)
High	609 (48.0)	474 (48.8)	135 (45.3)
Very high	148 (11.7)	95 (9.8)	53 (17.8)
LVEF (%)	40.00 [33.00–46.00]	40.00 [32.00–46.00]	40.00 [33.00–45.00]	0.835
IHD	587 (46.3)	461 (47.5)	126 (42.3)	0.127
Cardiomyopathy	219 (17.3)	188 (19.4)	31 (10.4)	<0.001
Valvular heart disease	483 (38.1)	373 (38.4)	110 (36.9)	0.683
Medication
ACEi	343 (27.0)	286 (29.5)	57 (19.1)	<0.001
ARB	382 (30.1)	305 (31.4)	77 (25.8)	0.071
β-blockers	689 (54.3)	558 (57.5)	131 (44.0)	<0.001
MRA	532 (41.9)	422 (43.5)	110 (36.9)	0.052
Furosemide conversion (mg)	20.00 [20.00–40.00]	20.00 [20.00–40.00]	20.00 [20.00–40.00]	0.007
Total no. medications	8 [6–10]	8 [6–10]	8 [7–11]	0.001
Polypharmacy	1,120 (88.3)	843 (86.8)	277 (93.0)	0.006

Unless indicated otherwise, data are given as the median [interquartile range] or n (%). ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCI, Charlson comorbidity index; IHD, ischemic heart disease; LTCI, long-term care insurance; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist.

Medications

Among the elderly patients with HFrEF and HFmrEF, 343 (27.0%) were on ACEi, 382 (30.1%) were on ARBs, 689 (54.3%) were on β-blockers, and 532 (41.9%) were on MRAs. The median amount of furosemide was 20.0 mg (IQR 20.0–40.0 mg). The median number of medications was 8 (IQR 6.0–10.0; Table 1). Figure 1 shows the distribution of medications. Overall, 88.3% of patients required polypharmacy. Regardless of age, most prescriptions consisted of non-GDMT drugs (Figure 2; Supplementary Figure). As indicated in Table 2, factors associated with polypharmacy were age ≥75 years (odds ratio [OR] 0.564; 95% confidence interval [CI] 0.382–0.831), LTCI certification (OR 2.300; 95% CI 1.400–3.780), and severe CCI (OR 1.750; 95% CI 1.150–2.660).

Figure 1.

Distribution of the number of medications.

Figure 2.

Medication regimen by age. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MRA, mineralocorticoid receptor antagonist.

Table 2. Factors Associated With Polypharmacy

	OR (95% CI)	P value
Intercept	7.410 (4.770–11.500)	<0.001
Age ≥75 years	0.564 (0.382–0.831)	0.004
Female sex	1.330 (0.926–1.910)	0.122
LTCI	2.300 (1.400–3.780)	0.001
Severe CCI	1.750 (1.150–2.660)	0.009
LVEF <40%	0.828 (0.585–1.170)	0.290

CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Factors Associated With GDMT

The factors associated with ACEi and ARB prescriptions were LTCI certification (OR 0.591; 95% CI 0.449–0.778; Table 3). Factors associated with β-blocker prescriptions were age (OR 0.693; 95% CI 0.543–0.884), LTCI certification (OR 0.698; 95% CI 0.529–0.920), severe CCI (OR 0.677; 95% CI 0.530–0.865), and LVEF <40% (OR 1.380; 95% CI 1.100–1.730; Table 4). Only LTCI certification was associated with MRA prescriptions (OR 0.743; 95% CI 0.560–0.985; Table 5). LTCI certification was also associated with a lower rate of GDMT prescriptions and a higher rate of furosemide prescriptions (Figure 3).

Table 3. Factors Associated With ACEi and ARB Prescriptions

	OR (95% CI)	P value
Intercept	1.600 (1.210–2.120)	0.001
Age ≥75 years	0.793 (0.622–1.010)	0.061
Female sex	1.020 (0.798–1.290)	0.897
LTCI	0.591 (0.449–0.778)	<0.001
Severe CCI	0.847 (0.664–1.080)	0.184
LVEF <40%	1.240 (0.989–1.560)	0.062

Abbreviations as in Tables 1,2.

Table 4. Factors Associated With β-Blocker Prescriptions

	OR (95% CI)	P value
Intercept	1.410 (1.060–1.870)	0.017
Age ≥75 years	0.693 (0.543–0.884)	0.003
Female sex	1.230 (0.962–1.560)	0.100
LTCI	0.698 (0.529–0.920)	0.011
Severe CCI	0.677 (0.530–0.865)	0.002
LVEF <40%	1.380 (1.100–1.730)	0.005

Abbreviations as in Tables 1,2.

Table 5. Factors Associated With MRA Prescriptions

	OR (95% CI)	P value
Intercept	0.838 (0.634–1.110)	0.215
Age ≥75 years	1.070 (0.839–1.360)	0.590
Female sex	0.800 (0.628–1.020)	0.069
LTCI	0.743 (0.560–0.985)	0.039
Severe CCI	0.787 (0.614–1.010)	0.057
LVEF <40%	1.230 (0.979–1.540)	0.076

Abbreviations as in Tables 1,2.

Figure 3.

Impact of the Charlson comorbidity index (CCI) score and long-term care insurance (LTCI) certification on polypharmacy and the prescription of different medications. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MRA, mineralocorticoid receptor antagonist.

Discussion

Frailty and disability, represented by LTCI, were independently associated with lower ACEi/ARB, β-blocker, and MRA prescription rates in elderly patients with HFrEF and HFmrEF. Their characteristics partially explained the success of GDMT in clinical trials, which includes younger, more active patients with fewer comorbidities. A relatively high prevalence of polypharmacy in such vulnerable elderly patients suggested the seriousness of their health condition. From our findings, there is a need for enhanced discussions regarding prognosis and goals of care between patients and physicians.

GDMT in Vulnerable Elderly Patients With Heart Failure

Generally, medications must be carefully prescribed in elderly patients taking into consideration physiological age-related pharmacodynamic changes, risks of medication side effects, patient disability, and caregiver burden.²⁵ Recent large studies demonstrated an age-related decline in recommended heart failure therapy,^26–28 and a higher rate of comorbidities was one explanation for the age-associated decline in drug prescriptions.^29,30 In contrast to these earlier studies, the severity of non-cardiac comorbidities was accurately assessed by CCI in the present study. Among elderly people aged ≥80 years, multimorbidity is more common than any single disease, with over 80% of this age group having ≥2 chronic conditions, and 54% of those aged ≥85 years having ≥4 chronic conditions.^31,32 Depending on the type and combination of comorbidities, adequate treatment of underlying diseases becomes even more challenging.

Frailty and disability in elderly patients are highly prevalent and are associated with a worse prognosis;^13,33 this may explain, in part, the lower prescription rate in elderly patients.³⁴ In the present study we surveyed LTCI as a marker of frailty and disability,^14,15 because it assesses patients’ physical dysfunction, cognitive impairment, and social isolation using relevant public and social medical teams in Japan. A possible explanation for the underutilization of GDMT in patients with frailty and disability is the perception among physicians that these patients are prone to adverse effects or intolerance to medication.³⁵ Frequent reasons given for inadequate GDMT in these patients are that they are considered “clinically stable” and “already at maximally tolerated therapy”.³⁶ Clinical inertia for vulnerable elderly patients may lead to a decline in prescription rates of ACEi/ARBs, β-blockers, and MRAs.

Although chronological aging is immutable, age does not reliably predict health and mental problems in patients. The characteristics of vulnerable populations predict the need for attentive follow-up and efforts to optimize treatment. Importantly, our study revealed that LTCI was independently associated with lower prescription rates of ACEi/ARBs, β-blockers, and MRAs. Recognizing these characteristics may contribute to improved clinical care for heart failure, including appropriate GDMT medications, and prospective studies are needed to address how to treat vulnerable elderly patients.

Polypharmacy in Vulnerable Elderly Patients With Heart Failure

Polypharmacy is very common among patients with heart failure due to medications for both heart failure and non-cardiac comorbidities.³⁷ Because of clinical practice guidelines for multidrug regimens, which improve outcomes and symptoms, patients with heart failure tend to be prescribed many drugs.³⁸ However, older patients with multiple morbidities, who are more likely to receive polypharmacy, have been excluded from many evidence-generating clinical trials. Definitions of polypharmacy were not developed specifically for elderly patients with heart failure and may need to be modified to meaningfully describe medication burden and promote appropriate medical therapy. As shown in the present study, multiple medications and polypharmacy are almost inevitable for patients with severe comorbidities. Interestingly, patients with LTCI were prescribed many drugs, despite their lower prescription rate of GDMT. This can be explained, in part, by varying health priorities in vulnerable elderly patients.³⁹ If patients prefer to control symptoms and maintain activities of daily living and quality of life rather than simply prolonging life, physicians may not necessarily always choose to focus on improving prognosis and emphasize a “healthy life expectancy” rather than solely “life expectancy”.⁴⁰ High utilization of diuretics in patients with LTCI was observed, potentially signaling the prioritization of symptom relief. This is not an unexpected finding in an aging society, and the findings suggest that a multidisciplinary intervention with frequent patient–physician communication may be valuable.

Study Limitations

This study had several limitations. First, data collection, including medications, was performed at the time of echocardiography, and patient conditions at that time were varied.

Second, this study data were derived retrospectively from medical records, which limits the generalisability of our findings. Moreover, this cross-sectional study could not explain the direction of causality, although it is clear that LTCI certification and a decline in GDMT prescriptions were related.

Third, for the CCI used for evaluating comorbidity, the items “diabetes with end-organ damage (2 points)” and “moderate or severe liver disease (3 points)” could not be evaluated based on their description in the medical records. We considered these as “diabetes (1 point)” and “mild liver disease (1 point)”, respectively, which may have led to an underestimation of the severity of the comorbidity.

Fourth, the subjects in this study were patients using diuretics. Because identifying the degree of patients’ symptoms at enrolment was difficult, we considered diuretic use as an indicator of symptomatic patients with heart failure who should be treated with GDMT, regardless of the degree of symptoms. Diuretics are usually used for decongestion and have been frequently used in patients with symptomatic HFrEF in previous studies examining the effectiveness of GDMT.^41–44 We believe that the study population was not significantly different from patients who should be receiving GDMT, although by requiring that patients were using diuretics, we may have excluded patients with symptoms other than congestion.

Fifth, it is necessary to discuss whether frailty and disability should be determined based only on the presence of certification of LTCI. There have been many studies that treat a presence of LTCI certification as an indicator of frailty and disability, regardless of support or care needs levels.⁴⁵ Further research is needed into the relationship between LTCI certification and frailty and disability.

Finally, the severity of cognitive impairment was not included in this analysis, which is likely to have influenced the medication regimen.

Conclusions

There was a decline in GDMT, such as ACEi/ARB, β-blocker, and MRA prescriptions, in elderly patients with HFrEF and HFmrEF with LTCI certification. These patients also had a high prevalence of polypharmacy and high diuretic doses. LTCI certification is a possible marker for identifying vulnerable populations for GDMT prescriptions. In such a vulnerable population, communication is required for favorable heart failure care.

Acknowledgment

The Niigata City Welfare Department Nursing Care Insurance Division contributed to the data extraction for community-dwelling older people.

Sources of Funding

This work was supported in part by Grants-in-Aid for Community Health from the Medical Association of Niigata City (GC02520183). The funder had no role in the design of the study, in the collection, analysis, and interpretation of data, or in writing the manuscript.

Disclosures

T.M. and T.I. are members of Circulation Journal’s Editorial Team. All other authors declare no conflicts of interests.

IRB Information

This study was approved by the Ethics Committee of Niigata University (Approval no.: Niigata University 1788).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-22-0830

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