Guideline-directed medical therapy use in unfunded patients with heart failure with reduced ejection fraction within an academic health system

INTRODUCTION

Heart failure (HF) is a major public health issue, affecting over 6 million adults in the United States. Every year there are more than 1 million HF hospitalizations. Among patients hospitalized for HF, approximately 20% of them are readmitted within 30 days.^[1] Goals for these patients include a reduction in hospitalizations and mortality by optimizing guideline-directed medical therapy (GDMT).

To date, there is an abundance of evidence that has demonstrated improved clinical outcomes from GDMT in patients with HF with reduced ejection fraction (HFrEF) taking contemporary therapy. The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) Guidelines for the Management of HF recommend initiating GDMT therapy consisting of four agents: (1) ACEI, ARB, or ARNI; (2) Beta-blocker (BB); (3) MRA; and (4) SGLT2i.^[2] Titration of quadruple therapy to target dosing is associated with a significant reduction in morbidity and all-cause mortality among other GDMT therapy combinations, with an estimated cumulative effect of 73% relative reduction in all-cause mortality over two years.^[3]

In 2018, the Change the Management of Patients with HF (CHAMP-HF) registry study found significant gaps in the utilization and titration of GDMT in HFrEF outpatients. Greene et al. noted that nearly half of their study population was receiving GDMT at recommended doses.^[4] The common reasons for not receiving optimal GDMT were older age, female sex, African-American race, lack of provider awareness of GDMT guidelines, concerns about side effects, lack of access to care, and financial constraints.^[4] To better identify gaps in care at University Health in San Antonio, TX, we aimed to evaluate outpatient prescribing patterns of GDMT and its clinical impact specifically in unfunded patients with HFrEF.

MATERIALS AND METHODS

RESULTS

Baseline cohort characteristics

Between July 1, 2020, and March 31, 2022, a total of 3219 patients presented to outpatient provider visits within the institution’s clinics. Of these, 232 patients met inclusion criteria (7.2%) [Figure 1]. The most common reason for exclusion was active insurance status (n = 2,655).

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Figure 1:

Sample selection and attrition criteria.

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Patients in the study were predominantly Hispanic/Latino (62.9%) middle-aged men (83%). Most patients were under the county’s financial assistance program (61.6%) and had a median age of 63 years (interquartile range [IQR] 58–69 years) [Table 1]. Patients had a median LVEF of 27% (standard deviation [SD] 8%), BNP of 401 pg/mL (IQR 117–808 pg/mL), SCr of 1.18 mg/dL (IQR 0.98–1.5 mg/dL), and a potassium level of 4.1 mmol/L (IQR 3.8–4.6 mmol/L). Vitals included a median SBP of 125 mmHg (110–139 mmHg), DBP of 74 mmHg (65–83 mmHg), HR of 80 beats/min (SD 14 beats/min), and BMI of 30.4 kg/m² (IQR 25.2–36.4 kg/m²).

Table 1: Baseline cohort characteristics.

Characteristic	All patients (n=232)	On triple GDMT (n=144)	Not on triple GDMT (n=88)	P-value
Age (years), median (IQR)	56 (49–61)	56 (49–61)	56 (49–60)	0.630
Male, n (%)	191 (82)	117 (81)	74 (84)	0.582
Race, n (%)
Caucasian	150 (65)	95 (66)	55 (63)	0.647
African-American	27 (12)	14 (10)	13 (15)
Multiracial	9 (4)	5 (3)	4 (5)
Other	46 (20)	30 (21)	16 (18)
Ethnicity – Hispanic/Latino, n (%)	146 (63)	87 (60)	59 (67)	0.310
Other HF medications, n (%)
Loop diuretic	191 (82)	126 (88)	65 (74)	0.008
Hydralazine/dinitrate	10 (4)	2 (1)	8 (9)	0.007
Ivabradine	4 (2)	3 (2)	1 (1)	1.00
Digoxin	21 (9)	15 (10)	6 (7)	0.354
Vericiguat	0 (0)	0 (0)	0 (0)	1.00
SBP (mmHg), mean (SD)	126 (21)	125 (20)	127 (22)	0.374
DBP (mmHg), mean (SD)	75 (14)	75 (12)	75 (16)	0.906
HR (bpm), mean (SD)	80 (14)	81 (14)	77 (12)	0.131
LVEF, mean (SD)	30 (11)	30 (11)	31 (11)	0.213
BNP (pg/mL), median (IQR)	401 (117–830)	417 (124–881)	253 (103–756)	0.431
SCr (mg/dL), median (IQR)	1.18 (0.98–1.5)	1.15 (0.97–1.36)	1.31 (1–2.06)	0.005
eGFR (mL/min/1.73m2)
Rate of >60 – n/total, n (%)	100 (61)	76/118 (64)	24/47 (51)	0.154
Rate of 30–60 – n/total, n (%)	55 (33)	37/118 (31)	18/47 (38)
Rate <30 – n/total, n (%)	10 (6)	5/118 (4)	5/47 (11)
Potassium (mmol/L), median (IQR)	4.1 (3.8–4.6)	4.2 (3.9–4.5)	4.1 (3.8–4.6)	0.352
BMI (kg/m2), median (IQR)	30.4 (25.2–36.5)	30.7 (26.9–37.1)	29.8 (24.4–34.9)	0.044

BMI (kg/m²), median (IQR) 30.4 (25.2–36.5) 30.7 (26.9–37.1) 29.8 (24.4–34.9) 0.044 BMI: Body mass index, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, HR: Heart rate, LVEF: Left ventricular ejection fraction, BNP: B-type natriuretic peptide, SCr: Serum creatinine, eGFR: Estimated glomerular filtration rate, IQR: Interquartile range, GDMT: Guideline-directed medical therapy

By the end of the study period, triple GDMT was prescribed in 60.3% of patients, while 36.2% of patients were prescribed quadruple GDMT therapy. Among the study population, 48.3% were on an ACEI or ARB, 31% on an ARNI, 87.1% on a BB, 72.4% on an MRA, and 52.2% on a SGLT2i. Prescribing rates for target doses of ACEI/ARB, ARNI, BB, MRAs, and SGLT2i were 29.5%, 13.9%, 23.3%, 81.5%, and 90.1%, respectively [Table 2].

Table 2: Primary outcomes.

GDMT agents	Rates of treatment	Rates of target dosing
ACEI/ARB/ARNI	ACEI/ARB: 48.3% ARNI: 31%	ACEI/ARB: 29.5% ARNI: 13.9%
BB	87.1%	23.3%
MRA	72.4%	81.5%
SGLT2i	52.2%	90.1%
Patients on triple therapy (ACEI/ARB/ARNI+BB+MRA), no. (%)		140 (60.3)
Patients on quadruple therapy (triple+SGLT2i), no. (%)		84 (36.2)

ACEI: Angiotensin-converting enzyme inhibitors, ARB: Angiotensin receptor blockers, ARNI: Angiotensin receptor/neprilysin inhibitor, BB: beta-blocker, MRA: Mineralocorticoid receptor antagonist, SGLT2i: Sodium-glucose cotransporter 2 inhibitor, GDMT: Guideline-directed medical therapy

DISCUSSION

While other studies have examined rates of GDMT prescribing in the outpatient setting, this study is one of the few to evaluate GDMT prescribing patterns solely in unfunded patients. Our results suggest that overall rates of GDMT prescribing and dose optimization in unfunded patients are low at our institution. These results are alarming given that our county’s financial assistance program offers medications at more affordable prices, which begs the question of why many patients still go without proper GDMT. The severity of suboptimal GDMT prescribing is highlighted in a study that evaluated the impact of GDMT in commercially insured people and found that inadequate GDMT confers a higher mortality rate.^[6] These findings emphasize the need to identify other barriers to GDMT besides medication cost.

Many patient-specific factors can affect prescribing patterns, such as tolerability, lack of health literacy, and insurance status. Compared to our findings, among patients eligible for all classes of GDMT from the CHAMP-HF registry, 755 patients (22.1%) were simultaneously prescribed some dose of ACEI/ARB/ARNI, evidence-based BB, and MRA therapy, and 37 patients (1.1%) were simultaneously prescribed target doses of all three therapies. Our findings show that prescribing patterns and target dosing rates at our institution are much higher than the national average. These results were not something expected considering that most of our cohort fell in a lower healthy literacy category and all were uninsured. A population-based, retrospective study of newly diagnosed HFrEF patients in Olmsted County, Minnesota found that being seen in an HF clinic was independently associated with initiation of new GDMT across all classes.^[7] This finding suggests that patients who seek care are more likely to be on GDMT than those who are resistant to seeking care. Moreover, this also may justify why our study found higher rates of hospitalization in patients on GDMT than those who were not.

Given the rising prevalence of HF and the fact that approximately 27 million Americans are uninsured, treatment of HF in unfunded patients needs further investigation.^[8] Our study has several strengths that contribute to new findings in GDMT optimization literature. First, we had access to medication dispensing data from our institution’s system-based pharmacies. As a result, an accurate calculation of the PDC was used to assess medication adherence, similar to other HF GDMT utilization studies.^[9] Although the study’s generalizability is limited to a low-income minority population, using patients from multiple clinics in San Antonio, TX increased the sample size and decreased the likelihood that provider- or clinic-specific practice biases could impact our findings.

The limitations of our study included a transition from one EHR system to another during the study period, which could have caused variability in data collection results and potentially underestimated the GDMT prescribing rates or achievement of target doses. In addition, the study period did not allow for a full assessment of GDMT quadruple therapy per the recent 2022 ACC/AHA/HFSA HF Guideline updates. During our study period, current guidelines (2017 ACC/AHA/FSA) only recommended triple therapy for GDMT. However, in the years between guideline updates, the use of quadruple therapy was increasingly becoming the standard of care due to the blooming evidence supporting the use of SGLT2i in HFrEF management. It is important to note that some patients in the study may have been receiving sacubitril/valsartan through a drug manufacturer’s patient assistance program (PAP) or may have filled GDMT prescriptions at an outside pharmacy. In either case, these patients’ medication adherence could not be accurately assessed due to PAP delivering medication directly from manufacturer to patient, or PDC was not available in our EMR. Moreover, 21.1% of patients initially identified for inclusion were lost to follow-up and were not included in the clinical outcomes analysis, which may result in an underestimation of our prescribing rates. Another limitation of this study is that dose titration information may not reflect changes made if patients were seen outside of our health system. While we are unable to quantify the number of patients affected by this, it is unlikely to be significant due to the discounted cost of medications offered to patients on the county’s financial assistance program.

The role of pharmacists in the management of HF is becoming increasingly important. As the population ages and the prevalence of HF increases, pharmacists will play a key role in helping patients achieve GDMT and improve clinical outcomes. Clinical pharmacists practicing under a collaborative practice agreement have the capability to titrate GDMT with closer follow-up than a PCP or cardiologist. According to Shah and colleagues, integrating clinical pharmacists into an HF clinic may be a workable approach at safety-net hospitals when a lack of medical staff and resources prevents prompt introduction and titration of GDMT.^[10] For example, involving pharmacists within interdisciplinary teams increased GDMT use and optimization compared to teams without pharmacist involvement.^[11] More so, Patil and colleagues found that pharmacist-led HF clinics significantly increased the proportion of patients who achieved triple and quadruple GDMT at 90 days, reduced hospitalization and ER visits related to HF, and improved quality of life.^[12] Pharmacists can play a role in better understanding current prescribing patterns to help identify areas for improvement in HFrEF management. With this information, pharmacists can help improve patient outcomes, develop safer prescribing practices, and increase quality of care.

CONCLUSION

While our institution’s GDMT prescribing rates were higher than the national average, our findings illustrated significant gaps in proper GDMT utilization and dose titration for patients with HFrEF. Pharmacist involvement in GDMT dose titration within our institution was seldom, highlighting pharmacists’ potential to fill in these gaps of care for unfunded patients. Further research is warranted to explore the positive impact pharmacists can make on GDMT prescribing rates and achieving target dosing for quadruple therapy.