Impact of Multimorbidity and Polypharmacy on Clinical Outcomes of Elderly Chinese Patients with Atrial Fibrillation

Background: The co-incidence of multiple morbidities and polypharmacy is common amongst patients with atrial fibrillation (AF); however, data on their impact on clinical outcomes are scarce in Asian cohorts. Objective: To evaluate the impact of multimorbidity and polypharmacy on clinical outcomes and AF management among elderly Chinese patients. Methods: The ChiOTEAF registry is a prospective, multicenter nationwide study conducted from October 2014 to December 2018. Endpoints of interest were the composite outcome of all-cause death/any thromboembolism (TE), all-cause death, cardiovascular death, TE events, major bleeding, as well as AF management. Results: The eligible cohort included 6341 individuals (mean age 74.7 ± 10.7; 39.1% female), of whom 4644 (73.2%) had multimorbidity (defined as two or more chronic diseases), and 2262 (35.7%) were treated with five or more medications. There were 2775 (43.8%) patients on anticoagulant (OAC) use. On multivariate analysis, (i) multimorbidity was associated with a higher odds ratio of the composite outcome (OR: 2.04; 95% CI: 1.49–2.79), all-cause death (OR: 1.82; 95% CI: 1.31–2.54), cardiovascular death (OR: 2.05; 95% CI: 1.13–3.69), any TE (OR: 2.69; 95% CI: 1.29–5.62), and major bleeding (OR: 2.61; 95% CI: 1.25–5.45); (ii) polypharmacy was associated with a lower odds ratio of all-cause death (OR: 0.78; 95% CI: 0.63–0.96). The use of OAC was safe and was associated with a lower odds ratio of the composite outcome and all-cause death in all subgroups of patients. Conclusions: Multimorbidity and polypharmacy were common among elderly AF Chinese patients. Multimorbidity was an independent predictor of adverse clinical outcomes. The use of OAC was safe and significantly improved survival amongst AF patients with multimorbidity and polypharmacy.

Previous studies confirmed that multimorbidity is associated with worse clinical outcomes among AF patients [8]; the all-cause death rate is six-fold higher than in AF patients without concomitant health problems [9]. Moreover, the diagnosis of heart failure, chronic obstructive pulmonary disease, and osteoporosis were attributed to a higher risk of all-cause death in AF patients with multimorbidity [10]. However, data on multimorbidity and polypharmacy among Asian patients with AF are scarce, especially among elderly individuals.
This analysis evaluates the prognosis and impact of multimorbidity and polypharmacy on clinical outcomes and AF management among elderly Chinese patients included in a prospective nationwide registry.

Materials and Methods
The Optimal Thromboprophylaxis in Elderly Chinese Patients with Atrial Fibrillation (ChiOTEAF) registry is a prospective cohort study conducted between October 2014 and December 2018 in 44 sites from 20 Chinese provinces. The study protocol has been previously published [11]. Consecutive AF patients presenting to cardiologists, neurologists, or surgeons were enrolled. Data were gathered by local investigators at enrollment and follow-up visits and reported into an electronic form. Follow-up visits were performed at 6 and 12 months, and then annually for the following 2 years. The present analysis was focused on the primary endpoint at the 1 year follow-up of the initial cohort.

Ethics Statement
The registry was approved by the Central Medical Ethics Committee of Chinese PLA General Hospital, Beijing, China (approval no S2014-065-01) and local institutional review boards. Written informed consent was obtained from all individual participants included in the study.

Objectives
The principal objectives were as follows: (i) to describe the baseline characteristics of patients with multimorbidity and polypharmacy; (ii) to evaluate the impact of multimorbidity and polypharmacy on clinical outcomes, including the composite outcome of all-cause death/any thromboembolism (TE; ischemic stroke, transient ischemic attack, or peripheral embolism), as well as individual endpoints of all-cause death, cardiovascular death, TE events, and major bleeding; (iii) to identify potential predictors of the composite outcome in patients with multimorbidity; (iv) to assess the impact of multimorbidity and polypharmacy on AF management; and (v) to assess the efficacy and safety of oral anticoagulation (OAC) among these subgroups.

Definitions
'Multimorbidity' was defined as the co-incidence of two or more morbidities (in addition to AF) at enrolment among patients with AF [12,13]. For our analysis, we included diabetes mellitus, lipid disorder, prior ischemic stroke, chronic kidney disease, heart failure, coronary artery disease, hypertension, chronic liver disease, chronic obstructive pulmonary disease, and sleep apnea.
The CHA 2 DS 2 -VASc score [15] and the HAS-BLED bleeding score [16] were used to assess the thromboembolic (TE) and bleeding risks. Bleeding events were categorized according to the ISTH definition [17]. AF management was described by OAC-use (including 12-month persistence) and the use of rate or rhythm control procedures (i.e., electrical or pharmacological cardioversion, AF ablation, and cardiac implantable electronic device implantation). The effectiveness of OACs was assessed by the odds of the composite outcome, all-cause death, cardiovascular death, TE events, and safety by the odds of major bleeding at 1-year follow-up amongst study subgroups. Other variables included in the registry and their definitions were designed to match the EORP-AF Long-term General Registry [18] (see Supplementary Data, Methods).
Major bleeding was defined as clinically overt bleeding accompanied by one or more of the following: a decrease in the blood hemoglobin level of more than 2.0 g/dL or more over 24 h, the need for a transfusion of 2 or more units of packed red cells, the need for corrective surgery, or the bleeding at a critical site (extracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal).
All-cause death included cardiac death, vascular death, and non-cardiovascular death. Cardiac death included death caused by STEMI/NSTEMI, heart failure (HF), arrhythmia, cardiac perforation/tamponade, and other deaths of cardiac origin. Vascular death included death ascribed to ischemic stroke, hemorrhagic stroke, systemic bleeding, peripheral embolism, and pulmonary embolism.

Statistical Analysis
Continuous variables were reported as mean ± standard deviation (SD); betweengroup comparisons were made using the Student's t-test or the Mann-Whitney U test (based on distribution). Categorical variables were reported as counts and percentages; between-group comparisons were made by χ 2 test. Patient-reported quality of life was assessed by the EuroQol five dimensions questionnaire (EQ-5D-5L) [19]. The quality of life was assessed based on the EQ summary index (ranged from 0 to 1; the score of 1 indicates the best health state) estimated from the EQ-5D-5L value set for China [20]. A logistic univariate regression analysis was used to assess the predictors of the composite outcome in the multimorbidity group. The significant variables of relevant clinical interests were subsequently included in a multivariate regression model. Finally, logistic regression analysis assessed the age-adjusted association between the (i) multimorbidity, (ii) polypharmacy and clinical outcomes, as well as AF management. We provided additional analyses for AF patients multimorbidity and polypharmacy (combined); as well as for the notanticoagulated subgroup.
In all analyses, a p value < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS ® version 24 (IBM Corp, Armonk, NY, USA).

Mortality and Morbidity
Of the overall study cohort, 435 (6.8%) patients died between the enrolment and the 1-year follow-up visit; and 390 (89.6%) deaths occurred in the multimorbidity group; whilst 151 (34.7%) died in the polypharmacy group. Rates of adverse events at 1 year follow-up are reported in Supplementary Data Table S1.
Patients with multimorbidity had higher rates of the composite outcome ( In patients with polypharmacy (vs. non-polypharmacy group), no statistically significant differences were found in the rates of these clinical outcomes. However, polypharmacy was associated with a lower (age-adjusted) odds ratio of all-cause death (OR: 0.78; 95% CI: 0.63-0.96)- Table 2.

Multivariate Analysis
During multivariate analysis (

Impact of Oral Anticoagulation
In the overall cohort, OAC use was associated with a lower odds ratio of the composite outcome and all-cause death, regardless of the number of comorbidities (Supplementary  Data Table S4). In patients with polypharmacy, the use of OAC was related to a lower odds ratio of the composite outcome (polypharmacy: OR: 0.32; 95% CI: 0.23-0.45) and all-cause death (OR: 0.33; 95% CI: 0.23-0.48); see Supplementary Data Table S5.

Discussion
The ChiOTEAF registry provides contemporary management among elderly Chinese AF patients, along with 1 year follow-up data [21]. This analysis focused on multimorbidity and polypharmacy, evaluating their impact on clinical outcomes and AF management. To our knowledge, this is the first large-cohort study assessing these issues in Asian patients.
The primary findings of the present study are as follows: (i) 73.2% of elderly AF patients had multimorbidity, while polypharmacy was present in 35.7% of patients; (ii) multimorbidity was associated with higher rates of the composite outcome, all-cause death, cardiovascular death, any TE, and major bleeding; and was an independent predictor of the adverse clinical outcomes; (iii) the independent predictors of the composite outcome among multimorbidity patients were the non-use of OAC, age, heart failure, prior ischemic stroke, chronic kidney disease, chronic obstructive pulmonary disease, and non-polypharmacy; (iv) multimorbidity was associated with a higher odds ratio of antiplatelet use and rate control strategy; and (v) OAC use was safe and improved survival in AF patients with multimorbidity, as well as polypharmacy.
Multimorbidity and polypharmacy are commonly associated with older patients and impairment of their clinical status [5,22,23]. It is challenging for clinicians to prescribe OACs to elderly patients with comorbidities and increased polypharmacy because of unclear clinical net benefit. The present study shows how OAC has reduced the composite outcome of all-cause death and any thromboembolism in this complex AF population with multimorbidity, re-emphasizing the importance of optimal thromboprophylaxis. Given that our study cohort was comprised of elderly AF patients, the vast majority (73.2%) had multimorbidity, and a third had polypharmacy. Previous studies have confirmed that various risk factors and comorbidities concomitant with AF (such as older age, heart failure, coronary artery disease, and diabetes) are associated with the risk of hospitalization and death [24]. In our analysis, the independent predictors of the composite outcome (all-cause death/any TE) among multimorbidity patients were the non-use of OAC, age, heart failure, prior ischemic stroke, chronic kidney disease, chronic obstructive pulmonary disease, and non-polypharmacy. Furthermore, we found that multimorbidity (but not polypharmacy) was associated with higher rates of the composite outcome, all-cause death, cardiovascular death, any TE, and major bleeding, and was an independent predictor of the adverse clinical outcomes.
Instead, polypharmacy was protective against the composite outcome of all-cause death/any TE. These may reflect the adequate care provided to these complex patients, including a higher number of patients persistent to OAC at 12 months compared with the non-polypharmacy group. Our previous analysis showed a slightly better persistence among patients prescribed with a NOAC (than warfarin); in particular among those treated with rivaroxaban (the once-daily dosing regimen), compared with dabigatran (twice-daily regimen) [25].
Furthermore, the differences in AF management were evident across the study cohort. Of note, the rhythm control strategy was limited, and AF ablation was performed only in 11.9% of the overall study cohort. Consistent with previous data [26], patients with multimorbidity were more often treated with digoxin; while amiodarone and propafenone were used in non-multimorbidity patients. Multimorbidity and polypharmacy were associated with a lower odds ratio of AF ablation.
Another aspect is the low number of anticoagulated patients (42% of patients in the multimorbidity group), despite a high risk of TE events. In our previous study, guideline adherent OAC use was found to be safe among elderly Chinese AF patients [25]. Notably, in this analysis, the efficacy and safety of OACs were sustained regardless of the number of comorbidities or the presence of polypharmacy. Interestingly, we found that patients with multimorbidity were less likely to be prescribed with a NOAC; instead, these patients had a three-fold higher odds ratio of antiplatelet use. This may reflect the 'real-life' clinical practice, in which elderly with multimorbidity or polypharmacy are not prescribed with OAC due to a fear of bleeding and drug-drug interactions [27]. Of note, among nonanticoagulated patients, multimorbidity was significantly attributed to the composite outcome, as well as all-cause death and TE events.
Previous studies showed that NOACs were more effective than warfarin, and (at least) just as safe in patients with polypharmacy [28,29]. In the recent analysis, efficacy and safety of apixaban were preserved in AF patients with multimorbidity, extending trial results to the most complex individuals [30]. Of note, the ARISTOPHANES subgroup analysis evaluated the effectiveness and safety of OAC in AF patients with multimorbidity (defined as six or more comorbidities) [31]. Apixaban and rivaroxaban were associated with a lower risk of TE, while apixaban and dabigatran had a lower risk of major bleeding than warfarin [31].
Multimorbidity and polypharmacy are highly prevalent in AF patients, but it should not be a reason to withhold OAC therapy. Instead, these patients should be involved into an integrated holistic care model to improve their clinical outcomes and quality of life [32,33]. Due to fewer drug-drug interactions (compared with VKA), NOACs should be preferred in AF patients with polypharmacy and multimorbidity [34].

Limitations
The primary limitation of the ChiOTEAF registry is its observational character. Patients were enrolled in 44 centers for a relatively long recruitment period, implying a potential bias and variability in the local AF management. We found that a moderate proportion of patients were lost to follow-up (9.3%), and the causes of 67 deaths (15.4%) were unknown. The number of adverse clinical events, as well as AF-related procedures, may be underreported. Data on anticoagulation control, the use of traditional Chinese medicines, and management of comorbidities/cardiovascular risk factors were not available and could not be considered in the analysis.

Conclusions
Multimorbidity and polypharmacy were common among elderly AF Chinese patients. Multimorbidity was an independent predictor of adverse clinical outcomes. The use of OAC was safe and significantly improved survival amongst AF patients with multimorbidity and polypharmacy.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm11051370/s1, Methods: Definitions; Table S1: Rates of the clinical outcomes: composite outcome; all-cause death; cardiovascular death; any thromboembolism; and major bleeding among patients with multimorbidity (A), polypharmacy (B), and multimorbidity and polypharmacy (C); Table S2: The effects of multimorbidity and polypharmacy on the AF management; Table S3: The number of comorbidities and their effect on OAC prescription among AF patients; Table S4: Efficacy and safety of OAC in AF patients regarding the number of comorbidities, in AF patients with polypharmacy, and in AF patients with multimorbidity and polypharmacy; Table S5: The effects of multimorbidity and polypharmacy on clinical outcomes (composite outcome; all-cause death; cardiovascular death; any thromboembolism; major bleeding) among non-anticoagulated patients; Figure S1: Proportion of patients with atrial fibrillation according to number of comorbidities; List of ChiOTEAF registry investigators.
Author Contributions: A.K. and Y.G. contributed equally to design the study, interpret data, and draft the manuscript (joint first authors); Y.W. and G.Y.H.L. contributed in the interpretation of data, and revised the manuscript critically for important intellectual content (joint senior authors). All authors have read and agreed to the published version of the manuscript.

Funding:
The study was supported by Beijing Natural Science Foundation, China (Z141100002114050), and Chinese Military Health Care (17BJZ08).

Institutional Review Board Statement:
This study was performed in line with the principles of the Declaration of Helsinki. Ethics approval was granted by the Central Medical Ethic Committee of Chinese PLA General Hospital (approval no S2014-065-01).
Informed Consent Statement: Written informed consent was obtained from all individual participants included in the study.

Data Availability Statement:
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.