Abstract
Background
Contemporary use of sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) and angiotensin receptor‐neprilysin inhibitors (ARNi) in patients with atrial fibrillation (AF) and heart failure (HF) has not been described.
Methods and Results
We analyzed the MarketScan databases for the period January 1, 2021 to July 30, 2022. Validated algorithms were used to identify patients with AF and HF, and to classify patients into HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). We assessed the prevalence of SGLT2i and ARNi use overall and by HF type. Additionally, we explored correlates of lower use, including demographics and comorbidities. The study population included 60 927 patients (mean age, 75 years; 43% women) diagnosed with AF and HF (85% with HFpEF, 15% with HFrEF). Prevalence of ARNi use was 11% overall (30% in HFrEF, 8% in HFpEF), whereas the corresponding figure was 6% for SGLT2i (13% in HFrEF, 5% in HFpEF). Use of both medications increased over the study period: ARNi from 9% to 12% (22%–29% in HFrEF, 6%–8% in HFpEF), and SGLT2i from 3% to 9% (6%–16% in HFrEF, 2%–7% in HFpEF). Female sex, older age, and specific comorbidities were associated with lower use of these 2 medication types overall and by HF type.
Conclusions
Use of ARNi and SGLT2i in patients with AF and HF is suboptimal, particularly among women and older individuals, though use is increasing. These results underscore the need for understanding reasons for these disparities and developing interventions to improve adoption of evidence‐based therapies among patients with comorbid AF and HF.
Keywords: angiotensin receptor‐neprilysin inhibitors, atrial fibrillation, heart failure, sodium‐glucose cotransporter‐2 inhibitors
Subject Categories: Heart Failure, Atrial Fibrillation
Nonstandard Abbreviations and Acronyms
- ARNi
angiotensin receptor‐neprilysin inhibitors
- HFpEF
heart failure with preserved ejection fraction
- HFrEF
heart failure with reduced ejection fraction
- MRA
mineralocorticoid receptor antagonist
- SGLT2i
sodium‐glucose cotransporter‐2 inhibitors
Clinical Perspective.
What Is New?
Information on prescription of angiotensin receptor‐neprilysin inhibitors and sodium‐glucose cotransporter‐2 inhibitors is not available in contemporary cohorts of patients with heart failure (HF), particularly those with comorbidities like atrial fibrillation.
Analyzing of a health care claims database, including 60 927 patients with HF and atrial fibrillation from 2021 to 2022, we report low use of angiotensin receptor‐neprilysin inhibitors and sodium‐glucose cotransporter‐2 inhibitors in patients with HF with preserved or reduced ejection fraction.
Older age, female sex, and specific comorbidities were associated with lower use of these 2 medication types overall and by HF type.
What Are the Clinical Implications?
Future research should identify barriers to use of angiotensin receptor‐neprilysin inhibitors and sodium‐glucose cotransporter‐2 inhibitors in patients with comorbid HF and atrial fibrillation.
Specific efforts are required to reduce age and sex disparities in prescription for angiotensin receptor neprilysin‐inhibitors and sodium‐glucose cotransporter‐2 inhibitors.
Atrial fibrillation (AF) and heart failure (HF) are 2 commonly occurring cardiovascular conditions that frequently coexist and interact with each other. 1 More than 30% of patients with AF present with HF, 2 and >25% of HF patients with New York Heart Association functional class III to IV also have AF. 3 Moreover, the coexistence of HF and AF often worsen the patient's symptoms and disease progression, leading to increased morbidity and mortality. 4 Comorbid AF and HF can also contribute to challenges in clinical management given the high burden of multimorbidity and polypharmacy in these patients. 5 , 6 , 7 , 8 Despite the large burden of co‐occurring HF and AF, treatment guidelines offer insufficient guidance about best approaches to manage this group of patients. 9 , 10
Based on results from landmark randomized trials testing the efficacy of sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) and angiotensin receptor‐neprilysin inhibitors (ARNi) in the treatment of HF, current treatment guidelines strongly recommend the use of SGLT2i and ARNi in the management of patients with HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction, and HF with preserved ejection fraction (HFpEF). 9 , 11 Secondary analyses of large SGLT2i and ARNi trials showed no difference in efficacy between patients with AF and those without AF. 12 , 13 However, these trials were not powered to detect such differences. Also, it is unclear whether findings accurately generalize to real‐world patient populations given the restrictive inclusion criteria of many clinical trials. These knowledge gaps could potentially hinder the appropriate use of SGLT2i and ARNi in patients with comorbid AF and HF. 14 To gain a better understanding of the use of SGLT2i and ARNi in this patient group, we examined the frequency of prescription and the demographic and clinical factors associated with SGLT2i and ARNi use in a large contemporary cohort of patients with comorbid AF and HF identified from a health care claims database in the United States.
METHODS
Data Sources: MarketScan Databases
We identified patients with AF and HF included in the Merative MarketScan Commercial and Medicare databases (Merative, Ann Arbor, MI). The MarketScan databases include patient‐level information on clinical use in inpatient and outpatient settings, as well as enrollment and prescription data, from individuals enrolled in a selection of large employers, health governments, and government and public health organizations in the United States. The MarketScan Commercial database contains data from individuals insured through employer‐sponsored plans, whereas the MarketScan Medicare database includes Medicare‐eligible individuals with Medicare Supplemental or Medicare Advantage plans. For the current study, we considered the period January 1, 2021 to June 30, 2022 to evaluate contemporary use after approval by the US Food and Drug Administration in 2020 of SGLT2i for HFrEF treatment in patients with and without type 2 diabetes (approval of SGLT2i for HFpEF treatment occurred in early 2022; off‐label use may have occurred before), and the approval of the ARNi sacubitril/valsartan to patients with chronic HF independently of their ejection fraction in 2021.
The institutional review board of Emory University determined that this study did not require institutional review board review because it does not meet the definition of research with human subjects or clinical investigation, because the database provides researchers with deidentified information. Given the nature of the data, this study was exempt from obtaining informed consent. These are commercial data, available for purchase from Merative. Because of the licensing agreement, the authors cannot make these data available. Requests to access the data can be made directly to Merative.
Identification of Patients With Comorbid AF and HF
Ascertainment of AF was done following previously described algorithms. 15 Briefly, AF diagnosis required the presence of International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM) code I48.xx in 2 outpatient claims >7 days and <365 days apart or in 1 inpatient claim. A systematic review of algorithms for AF ascertainment using claims data reported a median positive predictive value of 89% and a median sensitivity of 79%. 16 Diagnosis of HF required 1 inpatient claim with HF as primary discharge diagnoses or 2 inpatient claims with HF diagnoses in any position or 2 outpatient claims with HF diagnoses in any position >7 days and <365 days apart (ICD‐10‐CM codes I09.81, I11.0, I13.0, I13.2, I50.xx). 17 We further categorized HF cases at the time of first diagnosis as HFrEF or HFpEF using a validated algorithm. 18 , 19 This algorithm considers demographic variables and inpatient, outpatient, and pharmacy claims in the period 6 months before and 1 month after the diagnosis of HF, and in the MarketScan databases has a positive predictive value of 73% and 81% for HFrEF and HFpEF, respectively. 19 Date of comorbid AF/HF diagnosis was defined as the latest of the diagnosis of AF or the diagnosis of HF.
Medication Use
The primary end point variable was the use of SGLT2i and ARNi. Filled outpatient prescriptions for sacubitril/valsartan (ARNi) and dapagliflozin and empaglifozin (SGLT2i approved for HF treatment) during the study period were identified. Information on the following medications was also ascertained: β‐blockers, mineralocorticoid receptor antagonists (MRAs), angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), antiarrhythmic agents, and oral anticoagulants. We determined use of a specific medication at the time of AF/HF diagnosis if a filled prescription for a specific medication was active 90 days before or after the diagnosis date. We defined triple therapy if a patient was receiving a β‐blocker, an MRA, and an ACE inhibitor, ARB, or ARNi, and quadruple therapy if the patient also received an SGLT2i.
Comorbidities
Presence of comorbidities at the time of AF/HF diagnosis was determined from ICD‐10‐CM diagnosis codes in outpatient and inpatient claims. Conditions were defined using algorithms proposed by the Chronic Conditions Data Warehouse from the Center for Medicare and Medicaid Services (https://www2.ccwdata.org/web/guest/condition‐categories‐chronic), when available. Hypotension was also included as a relevant comorbidity and defined based on the presence of ICD‐10‐CM codes I95.x. These comorbidities were selected based on being potential predictors of ARNi or SGLT2i use. Prior history of dialysis use (ICD‐10‐CM codes Y84.1, Z49.01, Z49.02, Z49.31, Z49.32; Current Procedural Terminology (CPT) codes 90 935, 90 937, 90 940, 90 945, 90 947), catheter ablation (CPT codes 93 656, 93 657), and cardioversion (CPT codes 92 960, 92 961) were added as a covariate, because it could affect decisions about ARNi or SGLT2i prescribing.
Statistical Analysis
We evaluated patient characteristics at time of AF/HF diagnosis, overall and by HF type (HFrEF and HFpEF). Using the eligible patient population as reference, age‐ and sex‐standardized quarterly prevalence of use of ARNi and SGLT2i over the study period was calculated as the proportion of patients with prevalent AF/HF in that quarter who had at least 1 active prescription for that medication during that time period. We calculated proportions of patients using ARNi and SGLT2i around the time of AF/HF diagnosis across demographic and clinical variables. Finally, we evaluated independent demographic and clinical predictors of ARNi and SGLT2i use by calculating relative risks from log‐binomial models (or Poisson models with robust variance estimation if the log‐binomial model did not converge). These analyses included the following covariates simultaneously in the models: age, sex, HF type, hypertension, diabetes, hyperlipidemia, coronary artery disease, ischemic stroke, hemorrhagic stroke, chronic kidney disease, dialysis, hypotension, chronic obstructive pulmonary disease, use of oral anticoagulants, use of antiarrhythmic drugs, ACE inhibitor/ARB, β‐blocker, MRA, and, when corresponding, ARNi and SGLT2i. These variables were selected because they may directly influence use of ARNi and SGLT2i, or be correlates of other independent factors affecting ARNi or SGLT2i use. Analyses were conducted in the overall AF/HF population, by HF type and, for SGLT2i, by diabetes status.
RESULTS
We identified 60 927 patients diagnosed with comorbid AF and HF enrolled in the MarketScan databases during the period January 1, 2021 to June 30, 2022. Of these, 9335 (15%) were categorized as HFrEF, and 51 592 (85%) as HFpEF. Patient characteristics overall and by HF type are presented in Table 1. Mean age was 75 years in the overall sample, and 68 and 76 years among patients with HFrEF and HFpEF, respectively. Over three‐quarters of patients with HFrEF were men, whereas numbers of men and women were similar in HFpEF. Prevalence of comorbidities was high overall and in both HF types.
Table 1.
Characteristics of Patients With Atrial Fibrillation and Heart Failure at the Time of Codiagnosis, MarketScan 2021 to 2022
| Characteristic | Overall | HFrEF | HFpEF |
|---|---|---|---|
| N | 60 927 | 9335 | 51 592 |
| Age, y | 75±13 | 68±14 | 76±12 |
| Sex | |||
| Women | 26 291 (43%) | 2281 (24%) | 24 010 (47%) |
| Men | 34 636 (57%) | 7054 (76%) | 27 582 (53%) |
| Hypertension | 57 122 (94%) | 8310 (89%) | 48 812 (95%) |
| Diabetes | 27 573 (45%) | 3811 (41%) | 23 762 (46%) |
| Hyperlipidemia | 46 580 (76%) | 6704 (72%) | 39 876 (77%) |
| Coronary artery disease | 37 308 (61%) | 6129 (66%) | 31 179 (60%) |
| Ischemic stroke | 6041 (10%) | 763 (8%) | 5278 (10%) |
| Intracranial bleeding | 1072 (2%) | 136 (1%) | 936 (2%) |
| Chronic kidney disease | 28 550 (47%) | 3833 (41%) | 24 717 (48%) |
| Dialysis | 1554 (3%) | 157 (2%) | 1397 (3%) |
| Hypotension | 7840 (13%) | 1259 (13%) | 6581 (13%) |
| COPD | 19 121 (31%) | 2192 (23%) | 16 929 (33%) |
| Oral anticoagulant use | 45 262 (74%) | 7184 (77%) | 38 078 (74%) |
| Antiarrhythmic drug use | 13 899 (23%) | 3145 (34%) | 10 754 (21%) |
| Cardioversion | 5788 (10%) | 1387 (15%) | 4401 (9%) |
| Catheter ablation | 1409 (2%) | 311 (3%) | 1098 (2%) |
Values correspond to n (%) or mean±SD. COPD indicates chronic obstructive pulmonary disease; HFpEF, heart failure with preserved ejection fraction; and HFrEF, heart failure with reduced ejection fraction.
Prevalence of ARNi use around the time of AF/HF diagnosis was 11% (95% CI, 11%–12%), 30% (95% CI, 29%–31%) in HFrEF, and 8% (95% CI, 8%–8%) in HFpEF. Corresponding figures for SGLT2i were 6% (95% CI, 6%–6%) overall, 13% (95% CI, 12%–13%) in HFrEF, and 5% (95% CI, 5%–5%) in HFpEF. Only 31% (95% CI, 30%–31%) of patients with HFrEF were receiving triple therapy (β‐blocker plus ACE inhibitor/ARB/ARNi plus MRA). Prevalence of quadruple therapy was 7% (95% CI, 7%–8%) in HFrEF (Table 2). SGLT2i use was higher in patients with diabetes (11% [95% CI, 10%–11%]) than in those without diabetes (3% [95% CI, 3%–3%]) (Figure S1).
Table 2.
Prevalence of Active Prescriptions for Guideline‐Directed Medical Therapy in Patients With Comorbid AF and HF at the Time of Codiagnosis (±90 days), MarketScan 2021 to 2022
| Therapy | Overall (N=60 927) | HFrEF (N=9335) | HfpEF (N=51 592) |
|---|---|---|---|
| β‐Blocker | 48 330 (79% [95% CI, 79%–80%]) | 8312 (89% [95% CI, 88%–90%]) | 40 018 (78% [95% CI, 77%–78%]) |
| ACE inhibitor/ARB | 30 013 (49% [95% CI, 49%–50%]) | 5055 (54% [95% CI, 53%–55%]) | 24 958 (48% [95% CI, 48%–49%]) |
| ARNi | 6856 (11% [95% CI, 11%–12%]) | 2773 (30% [95% CI, 29%–31%]) | 4083 (8% [95% CI, 8%–8%]) |
| ACE inhibitor/ARB/ARNi | 34 896 (57% [95% CI, 57%–58%]) | 6948 (74% [95% CI, 74%–75%]) | 27 948 (54% [95% CI, 54%–55%]) |
| MRA | 13 167 (22% [95% CI, 21%–22%]) | 3505 (38% [95% CI, 37%–39%]) | 9662 (19% [95% CI, 18%–19%]) |
| SGLT2i | 3828 (6% [95% CI, 6%–6%]) | 1178 (13% [95% CI, 12%–13%]) | 2650 (5% [95% CI, 5%–5%]) |
| Triple therapy | 8279 (14% [95% CI, 13%–14%]) | 2851 (31% [95% CI, 30%–31%]) | 5428 (11% [95% CI, 10%–11%]) |
| Quadruple therapy | 1446 (2% [95% CI, 2%–2%]) | 663 (7% [95% CI, 7%–8%]) | 783 (2% [95% CI, 1%–2%]) |
Triple therapy: use of ACE inhibitor, ARB, or ARNi plus β‐blocker plus MRA. Quadruple therapy: triple therapy plus use of SGLT2i. ACE indicates angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor‐neprilysin inhibitors; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; and SGLT2i, sodium‐glucose cotransporter‐2 inhibitors.
During the study period, use of ARNi slightly increased from 9% (95% CI, 9%–9%) in the first quarter of 2021 to 11% (95% CI, 11%–11%) in the second quarter of 2022 (Figure 1). Trends showing increased use were similar for HFrEF and HFpEF, with increases from 22% (95% CI, 21%–23%) to 28% (95% CI, 27%–29%) in HFrEF and from 6% (95% CI, 6%–7%) to 8% (95% CI, 8%–8%) in HFpEF. In contrast, use of SGLT2i experienced a large relative increase, with prevalence almost tripling, from 3% (95% CI, 3%–4%) to 8% (95% CI, 8%–9%) for all HF, and from 7% (95% CI, 6%–7%) to 16% (95% CI, 15%–17%) in HFrEF and 3% (95% CI, 2%–3%) to 7% (95% CI, 7%–7%) in HFpEF (Figure 1; Table S1). Tests of time trend for both ARNi and SGLT2i, overall, and by HF type had P values <0.001.
Figure 1. Age‐ and sex‐standardized prevalence of SGLT2i and ARNi use among patients with atrial fibrillation and heart failure by quarter, MarketScan databases 2021 to 2022.
Error bars correspond to 95% CIs. ARNi indicates angiotensin receptor‐neprilysin inhibitors; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; and SGLT2i, sodium‐glucose cotransporter‐2 inhibitors.
Figure 2 shows the use of ARNi and SGLT2i by age, sex, and HF type. Women and older patients had lower prevalence of use of both medication types. Similarly, we calculated prevalence of use of ARNi and SGLT2i by presence of comorbidities and use of selected medications, finding lower use of ARNi and SGLT2i in patients with some comorbidities and higher use in those receiving other medications for AF or HF (Figure 3). The pattern was similar by HF type (HFrEF and HFpEF), with overall lower frequency of use in patients with HFpEF than in those with HFrEF (Figure S2). In multivariable analyses, several demographic and clinical factors were strong predictors of ARNi and SGLT2i use in the overall HF population (Table 3). Older age and female sex were associated with lower probability of being prescribed these medications. Compared with patients <65 years old, patients ≥85 years old had a 58% and 76% lower probability of being prescribed ARNi or SGLT2i, respectively. Quadruple therapy was 91% less likely in patients ≥85 years old than those <65 years old. Women were 32% and 27% less likely than their male counterparts to receive ARNi or SGLT2i, respectively. Patients with prior history of some comorbidities, including diabetes, ischemic and hemorrhagic stroke, chronic kidney disease, and chronic obstructive pulmonary disease, were less likely to be prescribed ARNi. Hypertension, ischemic and hemorrhagic stroke, and chronic obstructive pulmonary disease were also associated with lower likelihood of SGLT2i prescription. Dialysis was a strong predictor of lower likelihood of being prescribed ARNi, SGLT2i, triple therapy, or quadruple therapy, and cardioversion and catheter ablation were associated with lower likelihood of triple therapy. Patterns were similar for prescriptions of ARNi and SGLT2i in HFrEF and HFpEF separately (Table S2) and for prescriptions of SGLT2i by diabetes status (Table S3).
Figure 2. Prevalence of ARNi and SGLT2i use among patients with atrial fibrillation and heart failure by age and sex, MarketScan databases 2021 to 2022.
Error bars correspond to 95% CIs. ARNi indicates angiotensin receptor‐neprilysin inhibitors; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; and SGLT2i, sodium‐glucose cotransporter‐2 inhibitors.
Figure 3. Prevalence of ARNi and SGLT2i use among patients with atrial fibrillation and heart failure by presence of comorbidities and use of other relevant medications, MarketScan databases 2021 to 2022.
ACEi indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi indicates angiotensin receptor‐neprilysin inhibitors; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; MRA, mineralocorticoid receptor antagonist; and SGLT2i, sodium‐glucose cotransporter‐2 inhibitors.
Table 3.
Predictors of Use of ARNi, SGLT2i, Triple Therapy, and Quadruple Therapy in Patients With AF and HF at Time of Codiagnosis (±90 Days)
| Predictor | ARNi | SGLT2i | Triple therapy | Quadruple therapy |
|---|---|---|---|---|
| Age, y | ||||
| <65 | 1 (reference) | 1 (reference) | 1 (reference) | 1 (reference) |
| 65 to <75 | 0.84 (0.79–0.89) | 0.68 (0.63–0.74) | 0.80 (0.76–0.84) | 0.51 (0.44–0.58) |
| 75 to <85 | 0.64 (0.61–0.68) | 0.51 (0.47–0.55) | 0.59 (0.56–0.62) | 0.30 (0.26–0.34) |
| ≥85 | 0.40 (0.37–0.44) | 0.23 (0.20–0.27) | 0.37 (0.35–0.40) | 0.09 (0.06–0.12) |
| Sex | ||||
| Men | 1 (reference) | 1 (reference) | 1 (reference.) | 1 (reference) |
| Women | 0.68 (0.65–0.72) | 0.73 (0.68–0.78) | 0.96 (0.92–1.00) | 0.69 (0.60–0.78) |
| HF type | ||||
| HFpEF | 1 (reference) | 1 (reference) | 1 (reference) | 1 (reference) |
| HfrEF | 2.14 (2.05–2.24) | 1.16 (1.09–1.24) | 2.22 (2.13–2.31) | 2.78 (2.50–3.09) |
| Hypertension | 1.00 (0.93–1.07) | 0.77 (0.68–0.86) | 1.07 (1.00–1.15) | 0.95 (0.79–1.14) |
| Diabetes | 0.93 (0.89–0.98) | 3.69 (3.44–3.97) | 1.12 (1.08–1.17) | 2.40 (2.15–2.68) |
| Hyperlipidemia | 1.07 (1.02–1.12) | 1.24 (1.14–1.34) | 1.06 (1.02–1.12) | 1.07 (0.94–1.21) |
| CAD | 1.34 (1.28–1.40) | 1.07 (1.00–1.14) | 1.18 (1.13–1.23) | 1.36 (1.22–1.52) |
| Ischemic stroke | 0.82 (0.75–0.89) | 0.88 (0.78–0.98) | 0.80 (0.74–0.86) | 0.75 (0.61–0.92) |
| Hemorrhagic stroke | 0.89 (0.73–1.08) | 0.78 (0.58–1.05) | 1.05 (0.89–1.24) | 0.51 (0.27–0.98) |
| CKD | 0.84 (0.80–0.87) | 1.07 (1.01–1.14) | 0.88 (0.84–0.91) | 0.89 (0.80–0.99) |
| Dialysis | 0.29 (0.22–0.40) | 0.15 (0.09–0.25) | 0.19 (0.14–0.26) | 0.02 (0.003–0.15) |
| Hypotension | 0.96 (0.90–1.02) | 1.00 (0.91–1.10) | 0.99 (0.94–1.05) | 1.00 (0.85–1.17) |
| COPD | 0.80 (0.76–0.85) | 0.78 (0.73–0.84) | 0.85 (0.81–0.89) | 0.67 (0.58–0.76) |
| Oral anticoagulant use | 1.35 (1.28–1.43) | 1.14 (1.06–1.24) | 1.56 (1.48–1.65) | 1.59 (1.38–1.83) |
| Antiarrhythmic drug use | 1.23 (1.18–1.29) | 1.06 (0.99–1.13) | 1.13 (1.09–1.18) | 1.32 (1.18–1.47) |
| Cardioversion | 0.91 (0.86–0.97) | 1.00 (0.91–1.09) | 0.94 (0.88–0.99) | 0.93 (0.80–1.08) |
| Catheter ablation | 0.94 (0.85–1.05) | 1.03 (0.88–1.20) | 0.83 (0.74–0.94) | 0.86 (0.67–1.12) |
| ACE inhibitor/ARBh | 0.33 (0.32–0.35) | 1.32 (1.24–1.40) | … | … |
| β‐Blocker | 3.03 (2.75–3.34) | 1.33 (1.19–1.48) | … | … |
| MRA | 1.70 (1.62–1.77) | 1.90 (1.79–2.03) | … | … |
| ARNi | … | 2.83 (2.63–3.03) | … | … |
| SGLT2i | 1.93 (1.84–2.04) | … | … | … |
Triple therapy: use of ACE inhibitor, ARB, or ARNi plus β‐blocker plus MRA. Quadruple therapy: triple therapy plus use of SGLT2i. Results correspond to relative risks and 95% CIs from log‐linear model (or Poisson regression when model not converging) including all variables in the table. MarketScan, 2021 to 2022. ACE indicates angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor‐neprilysin inhibitors; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; and SGLT2i, sodium‐glucose cotransporter‐2 inhibitors.
DISCUSSION
In a large contemporary sample of patients with AF and HF, we found that frequency of ARNi and SGLT2i use is low, even among patients with HFrEF, but increasing. We identified potential age and sex differences in the use of these medications, with women and older patients being less likely to fill prescriptions for ARNi or SGLT2i, in unadjusted analyses and also independently of clinical variables. Low use of SGLT2i in patients with HFpEF is likely influenced by this indication not being approved until early 2022.
Our results in the MarketScan databases are consistent with reports from other sources. A recent analysis of the Get With The Guidelines (GWTG)‐HF registry reported that only 20% of patients hospitalized for HFrEF were prescribed an SGLT2i at discharge, with lower proportions among women and people >75 years old. 14 Important differences with our analysis include the inclusion of HFpEF in our sample, the restriction to patients with comorbid AF, and the use of information from filled outpatient prescriptions, a better marker of use than prescriptions at hospital discharge, because not all patients with HF fill their prescriptions after discharge. 20 For example, in a different analysis of the GWTG‐HF registry, more than one‐third of patients with HFrEF discharged from the hospital with a new prescription for ARNi did not have any evidence of ARNi use in the 90‐day period after discharge. 21
The low frequency of ARNi and SGLT2i use in our study population underscores existing gaps in the use of guideline‐directed medical therapy in patients with HF. In the Change the Management of Patients with Heart Failure registry, including 3518 patients with HFrEF enrolled between 2015 and 2017, <25% of patients were receiving triple therapy (ACE inhibitor/ARB/ARNI, β‐blocker, and MRA), and only 1% of eligible patients were receiving target doses of all 3 medications. 22 Older age and comorbidities were associated with lower use. Given the impact of suboptimal HF medical therapy on negative outcomes, including HF admissions, the high prevalence of HF, and the known efficacy of guideline‐recommended therapies, identifying and implementing interventions that improve use and adherence of these medications, including increasing affordability, should be a priority. How these interventions can be adapted to patients with comorbid HF and AF requires additional attention.
The present analysis has important strengths, including the large sample size, the focus on an understudied population, the use of real‐world data, and the contemporary relevance of the data. These strengths should be tempered by relevant limitations, including the lack of information on race, ethnicity, or socioeconomic status in the MarketScan databases and, therefore, the inability to evaluate the impact of these variables on ARNi and SGLT2i prescriptions. Furthermore, misclassification imposed by the use of health care claims to define the study population, predictors, and end points, and the lack of objective information on vital signs (eg, blood pressure), laboratory values (eg, creatinine to calculate estimated glomerular filtration rate), ejection fraction, and other HF‐specific relevant variables to characterize the type and severity of disease can result in misclassification and biased results. Moreover, claims data do not allow a valid categorization of patients with AF into subtypes (paroxysmal, permanent, persistent), which may influence HF treatments. Generalizability of these findings to patient populations not represented in MarketScan databases (eg, Medicaid enrollees, uninsured) may be inadequate. Additionally, the unavailability of data after June 2022 limits our ability to properly evaluate use of SGLT2i in patients with HFpEF. Moreover, data reflect a specific time period in which the COVID‐19 pandemic still had a major impact on health care delivery, which likely affected care of patients with HF.
In conclusion, our analysis shows an important gap in the use of ARNi and SGLT2i in patients with comorbid HF and AF, identifies correlates of lower use, and reports on recent trends in prescriptions of these medications by HF type. This information could be used to develop targeted interventions to improve the management of patients with AF and HF. Future studies with more contemporary data should evaluate the intake of SGLT2i in patients with HFpEF, as well as the comparative effectiveness of these medications in real‐world populations.
Sources of Funding
This work was supported by the Stephen D. Clements Jr Chair in Cardiovascular Disease Prevention at the Rollins School of Public Health, Emory University. Dr Alvaro Alonso was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number K24HL148521, and Dr Pamela Lutsey under the National Heart, Lung, and Blood Institute/National Institutes of Health award number K24HL159246. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Disclosures
None.
Supporting information
Tables S1–S3
Figures S1–S2
Preprint posted on MedRxiv September 10, 2023. doi: https://doi.org/10.1101/2023.09.08.23295280.
This article was sent to Sula Mazimba, MD, MPH, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.123.032783
For Sources of Funding and Disclosures, see page 9.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Tables S1–S3
Figures S1–S2