Background
Comorbidities are common in patients with atrial fibrillation (AF) and affect prognosis, yet are often undertreated. However, contemporary rates of use of guideline-directed therapies (GDT) for non-AF comorbidities and their association with outcomes are not well described.
Methods
We used the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) to test the association between GDT for non-AF comorbidities and major adverse cardiac or neurovascular events (MACNE; cardiovascular death, myocardial infarction, stroke/thromboembolism, or new-onset heart failure), all-cause mortality, new-onset heart failure, and AF progression. Adjustment was performed using Cox proportional hazards models and logistic regression.
Results
Only 6,782 (33%) of the 20,434 patients eligible for 1 or more GDT for non-AF comorbidities received all indicated therapies. Use of all comorbidity-specific GDT was highest for patients with hyperlipidemia (75.6%) and lowest for those with diabetes mellitus (43.1%). Use of “all eligible” GDT was associated with a nonsignificant trend toward lower rates of MACNE (HR 0.90 [0.79-1.02]) and all-cause mortality (HR 0.90 [0.80-1.01]). Use of GDT for heart failure was associated with a lower risk of all-cause mortality (HR 0.77 [0.67-0.89]), and treatment of obstructive sleep apnea was associated with a lower risk of AF progression (OR 0.75 [0.62-0.90]).
Conclusions
In AF patients, there is underuse of GDT for non-AF comorbidities. The association between GDT use and outcomes was strongest in heart failure and obstructive sleep apnea patients where use of GDT was associated with lower mortality and less AF progression.
Atrial fibrillation (AF) is an increasingly prevalent condition, which carries a substantial risk of stroke, heart failure, cognitive impairment, and mortality. , Comorbid conditions that carry additional cardiovascular risk are common among AF patients and are associated with higher rates of adverse outcomes. Many of these conditions have been associated with overall worsening of cardiac function and progression of AF from paroxysmal to persistent forms. , Prior work has shown that the treatment of risk factors can improve outcomes in patients with AF, and use of guideline-directed therapies (GDT) for comorbid conditions can help reduce risk associated with these comorbidities. Yet, the majority of patients with AF do not receive all GDT for comorbid cardiovascular conditions for which they are eligible, and the impact of receiving all eligible GDT on clinical outcomes in AF patients is not well studied. We hypothesized that the use of all eligible GDT for comorbidities is associated with lower rates of adverse events among AF patients, as well as less progression of AF (from paroxysmal to persistent/permanent).
Methods
Study population
The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure. Patients from the Outcomes for Better Informed Treatment of AF (ORBIT-AF and ORBIT-AF II) registries were considered for inclusion in this study. The details of these registries have been previously published. , Briefly, the ORBIT-AF and ORBIT-AF II registries enrolled ambulatory, adult patients with electrocardiographically documented AF from outpatient US practices and followed them semiannually tracking clinical outcomes and events for a minimum of 2 years. ORBIT-AF enrolled 10,137 patients from 176 sites from June 29, 2010, through August 9, 2011. ORBIT-AF II enrolled 13,394 patients from 244 US sites from February 20, 2013, through July 12, 2016. The study protocol was reviewed and approved by the Duke University Medical Center Institutional Review Board and the Institutional Review Board at each enrolling center. Primary funding was provided by Ortho-McNeil Janssen Scientific Affairs , LLC. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.
For the purpose of this study, only patients with at least 1 of the following GDT-eligible conditions (coronary artery disease [CAD], diabetes mellitus [DM], heart failure [HF], hyperlipidemia [HL], hypertension [HTN], peripheral vascular disease [PVD], or obstructive sleep apnea [OSA]) at baseline were included in this analysis. Additionally, patients were excluded if they did not have any available follow-up data.
GDT assessment
GDT eligibility was defined according to current professional guidelines published by the American College of Cardiology and American Heart Association and related professional societies for the management of CAD, DM, , HF, HL, HTN, PVD, and OSA. Specifically, GDT for CAD included use of a β-blocker, statin, angiotensin-converting enzyme inhibitor (ACEi), or angiotensin receptor blocker (ARB) in the presence of DM or left ventricular ejection fraction (LVEF) ≤ 40%, and an antiplatelet agent if the patient had a myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery within the preceding 12 months. DM GDT included use of a statin and use of ACEi or ARB in the presence of CAD or LVEF ≤40%. Although glycemic control agents (eg, insulin, metformin) are an important component of DM GDT, their use was not captured in the ORBIT registry and thus not included in the assessment of GDT for DM in this study. GDT for HF included use of a B[HYPHEN]blocker, ACEi/ARB (in the setting of LVEF ≤40% or DM), aldosterone antagonist in the presence of New York Heart Association (NYHA) class II-IV symptoms and suitable creatinine level (≤2.5 mg/dL in men, ≤2.0 mg/dL in women), and implantable cardioverter-defibrillator (ICD) in the presence of LVEF ≤35% and NYHA class II-III symptoms. GDT for HL included use of a statin in the presence of CAD, DM, or PVD. GDT for HTN included use of an aldosterone antagonist, ACEi/ARB, calcium channel blocker, diuretic, or β-blocker in the presence of previously diagnosed HTN or documented blood pressure ≥140/90 (≥130/80 in patients with DM or chronic kidney disease). GDT for PVD required use of a statin. Although antiplatelet agents are also indicated in patients with PVD, given the high use of anticoagulants in the ORBIT-AF cohorts which may influence antiplatelet use, we did not require use of antiplatelet therapy in our assessment of GDT for PVD in this study. Patients with OSA were considered to be on GDT if they reported use of a continuous positive airway pressure (CPAP) machine.
Because the number of therapies included in the GDT estimate varied by disease state (and consequently between patients), GDT use was analyzed across several different levels. The primary analysis was performed at the individual level with GDT as a binary variable (“All eligible” vs “Not all eligible”). GDT were evaluated as a binary variable because there was variance in both the number of comorbidities each patient had as well as the number of therapies considered as GDT for each comorbidity in this study (4 of the 7 evaluated had only one therapy included as GDT). In addition, comorbidity-specific GDT use (also binary) was also assessed at an individual level to better understand how treatment of each comorbidity was associated with outcomes. Finally, GDT use was evaluated as a continuous variable (%GDT defined by [number of eligible therapies used] / [total number of eligible therapies]) at the site level to evaluate whether site-level treatment patterns had similar effects on outcomes as individual treatment effects.
Clinical outcomes
The primary outcome of interest for this study was major adverse cardiac/neurovascular events (MACNE) including cardiovascular (CV) death, myocardial infarction, embolic event (central nervous system or systemic), and new-onset HF. Secondary outcomes included all-cause mortality, new-onset HF, and AF progression from paroxysmal to persistent or from persistent to permanent (excluding patients with new-onset or permanent AF at baseline).
Statistical analyses
Demographic and patient baseline characteristics were compared between patients who received “all eligible” GDT and those who received some or none of the GDT for which they were eligible (“not all eligible”). Variables following a Gaussian distribution were presented as mean ± SD; variables following non-Gaussian distributions were presented as median (interquartile range). Variables were compared using χ 2 tests for categorical variables and the Wilcoxon rank sum test for continuous variables.
The relationship between all eligible GDT use and clinical outcomes was assessed with adjusted and unadjusted Cox proportional hazard models for clinical outcomes and pooled logistic regression for AF progression (with site included as a random effect). Covariates included in the adjusted model are listed in the Appendix (Supplemental material) with analyses stratified across 128 combinations of comorbidities to account for number and type of comorbidity. All continuous variables were tested for linearity, and any nonlinear associations were accounted for using linear splines. A nonlinear association was noted between the site-level %GDT use and outcomes, so a linear spline with a knot at 60% was used for site-level analyses. At the patient level, a robust covariance estimate was included to account for within-site correlation. Missingness was handled by 5-fold multiple imputation. Analyses were performed using SAS software version 9.4 (SAS Institute, Cary, NC).
Results
Study population
Of the 23,531 patients included in the combined ORBIT-AF and ORBIT-AF II registries, 2,446 patients were excluded for not having any of the conditions eligible for the GDT evaluated in this study, and an additional 651 patients did not have follow-up data, resulting in a final study cohort of 20,434 patients. Table I shows the distribution of demographics, medical history, baseline laboratory data, and enrolling provider specialty stratified by patients being on all eligible GDT (“all eligible”) versus some or none of the GDT for which they were eligible (“not all eligible”). The mean age was 72.3 ± 10.8 years, 41.7% were female, and 87.1% were white. A total of 6,782 (33.2%) patients were on all GDT for which they were eligible, whereas 13,652 (66.8%) were on some or none of their eligible GDT. Patients in the “not all eligible” group were more frequently black (5.8% vs 4.0%, P < .001) and/or Hispanic (5.0% vs 4.5%, P < .001) and were more commonly insured by Medicare or Medicaid (57.3% vs 53.4%, P < .001). Of the cardiovascular comorbidities with treatments included in our assessment of GDT, patients in the “not all eligible” group more frequently had 5 of the 7 studied comorbidities: CAD (38.8% vs 25.0%), DM (40.0% vs 12.3%), HF (33.4% vs 21.2%), PVD (13.3% vs 8.0%), and OSA (23.1% vs 13.2%) ( P < .001 for all). Evaluating total number of GDT-eligible comorbidities, patients in the “not all eligible” group had a median of 3 (2-4) GDT-eligible comorbidities compared to 2 (2-3) in patients on “all eligible” therapies ( P < .001). Patients in the “not all eligible” group also more commonly had a medical history of non–GDT-related conditions including thyroid disease, COPD, anemia, prior stroke or transient ischemic attack, GI bleed, liver disease, and dialysis. More patients in the “not all eligible” group had frailty (defined as 3 or more of the following: unintentional weight loss, self-reported exhaustion, weakness, slow walking speed, or low physical activity) compared to the “all eligible” group (5.3% vs 3.4%, P < .001). CHA 2 DS 2 VASC scores were higher in patients in the “not all eligible” group (4 [3-5] vs 3 [2-4], P < .001), yet these patients had slightly lower rates of oral anticoagulation use (84.1% vs 85.5%, P = .01).
| Overall | “Receiving all eligible” | “Not receiving all eligible” | P Value | |
|---|---|---|---|---|
| n | 20,434 | 6782 | 13,652 | |
| Age, y | 72.3 ± 10.8 | 71.8 ± 10.8 | 72.6 ± 10.7 | <.001 |
| Sex (n, % female) | 8523 (41.7%) | 2782 (41.0%) | 5741 (42.0%) | .16 |
| Race | <.001 | |||
| White | 17,794 (87.1%) | 6022 (88.8%) | 11,772 (86.3%) | |
| Black/African American | 1071 (5.3%) | 274 (4.0%) | 797 (5.8%) | |
| Asian | 256 (1.3%) | 80 (1.2%) | 176 (1.3%) | |
| American Indian/Alaska Native | 57 (0.3%) | 17 (0.2%) | 40 (0.3%) | |
| Hispanic | 987 (4.8%) | 308 (4.5%) | 679 (5.0%) | |
| Native Hawaiian/Pacific Islander | 20 (0.1%) | 10 (0.2%) | 10 (0.1%) | |
| Other | 234 (1.2%) | 69 (1.0%) | 165 (1.2%) | |
| Missing | 15 (0.1%) | 2 (<0.1%) | 13 (0.1%) | |
| Insurance | <.001 | |||
| Medicare or Medicaid | 11,454 (56.0%) | 3624 (53.4%) | 7830 (57.3%) | |
| Private | 7941 (38.9%) | 2804 (41.4%) | 5137 (37.6%) | |
| Cardiovascular comorbidities and risk factors | ||||
| Total number of GDT-eligible comorbidities | 3 (2-4) | 2 (2-3) | 3 (2-4) | <.001 |
| Coronary artery disease | 6990 (34.2%) | 1692 (25.0%) | 5298 (38.8%) | <.001 |
| Diabetes mellitus | 6294 (30.8%) | 835 (12.3%) | 5459 (40.0%) | <.001 |
| Heart failure | 6001 (29.4%) | 1438 (21.2%) | 4563 (33.4%) | <.001 |
| Hyperlipidemia | 14,601 (74.4%) | 4863 (71.7%) | 9738 (71.3%) | .58 |
| Hypertension | 18,474 (90.4%) | 6123 (90.3%) | 12,351 (90.5%) | .67 |
| Peripheral vascular disease | 2358 (11.5%) | 543 (8.0%) | 1815 (13.3%) | <.001 |
| Obstructive sleep apnea | 4045 (19.8%) | 894 (13.2%) | 3151 (23.1%) | <.001 |
| Other medical history | ||||
| Cancer | 4437 (21.7%) | 1455 (21.4%) | 2982 (21.8%) | .52 |
| Thyroid disease | 4051 (19.8%) | 1233 (18.2%) | 2818 (20.6%) | <.001 |
| COPD | 2930 (14.3% | 768 (11.3%) | 2162 (15.8%) | <.001 |
| Anemia | 2921 (14.3%) | 788 (11.6%) | 2133 (15.6%) | <.001 |
| Prior stroke or transient ischemic attack | 2697 (13.2%) | 771 (11.4%) | 1926 (14.1%) | <.001 |
| Frailty | 949 (4.7%) | 229 (3.4%) | 720 (5.3%) | <.001 |
| GI bleed | 1391 (6.8%) | 387 (5.7%) | 1004 (7.4%) | <.001 |
| Cognitive impairment/dementia | 468 (2.3%) | 146 (2.2%) | 322 (2.4%) | .35 |
| Liver disease | 442 (2.2%) | 123 (1.8%) | 319 (2.3%) | .02 |
| Dialysis | 237 (1.2%) | 46 (0.7%) | 191 (1.4%) | <.001 |
| CHA 2 DS 2 VASC score | 4 (3-5) | 3 (2-4) | 4 (3-5) | <.001 |
| On oral anticoagulation | 17,285 (84.6%) | 5799 (85.5%) | 11,486 (84.1%) | .01 |
| Laboratory data, median (IQR) | ||||
| eGFR (mL/min/1.73 m 2 ) | 69.7 (55.4-85.3) | 73.6 (61.6-87.0) | 67.1 (52.3-84.0) | <.001 |
| Hemoglobin (g/dL) | 13.5 (12.2-14.7) | 13.7 (12.5-14.8) | 13.4 (12.1-14.6) | <.001 |
| Provider specialty | <.001 | |||
| Cardiology | 13,929 (68.2%) | 4625 (68.2%) | 9304 (68.2%) | |
| Electrophysiology | 3775 (18.5%) | 1318 (19.4%) | 2457 (18.0%) | |
| Internal medicine/family practice | 2646 (13.0%) | 802 (11.8%) | 1844 (13.5%) |
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