Combination of Oral Anticoagulant with Antiplatelet and All-cause Mortality in Elderly Patients with Atrial Fibrillation and Ischemic Heart Disease

Aim: Clinicians are often face the dilemma of choosing more appropriate antithrombotic regimen, since there is no evidence regarding the role of antiplatelets, 58.6% for OAC and 42.9% for combination of both, respectively. OAC and /or antiplatelet use were associated with risk of mortality (chi-square=11.03, log rank p = 0.004) using unadjusted Kaplan-Meier analysis. In overall cohort, the adjusted hazard ratios for mortality for combination of OAC and antiplatelet was 0.41 (95% CI 0.19-0.87, p = 0.019) as compared to antiplatelet use, 0.80 (95% CI 0.39-1.64, p = 0.541) as compared to OAC use. In subgroup age ≥ 75 years, the adjusted hazard ratios for mortality were 0.40 (95% CI 0.16-1.02, p = 0.054) for combination of OAC and antiplatelet as compared to antiplatelet use, 0.79 (95% CI 0.31-1.96, p = 0.605) for combination of OAC and antiplatelet as compared to OAC use, and compared to antiplatelet use, the adjusted hazard ratio for mortality were 0.51 (95% CI 0.32-0.81, p = 0.005) for OAC use. Conclusions: Combination of OAC with antiplatelet is associated with reduced all-cause mortality and OAC is better on outcome as compared to antiplatelet agents, but OAC plus antiplatelet is not superior to OAC in elderly patients with AF and IHD and in subgroup aged ≥ 75 years.


INTRODUCTION
Atrial Fibrillation (AF) and Ischemic Heart Disease (IHD) are prevalent with increasing age, particularly among those older than age 60 [1]. Previous evidence showed that Oral Anticoagulant (OAC) is superior to antiplatelets for stroke protection in AF [2], and OAC is more effective than antiplatelet drugs in reducing the risk of thromboembolic events associated with AF [3]. Antiplatelet agents are preferred in patients with IHD as well as those receiving percutaneous coronary intervention (PCI) [4][5][6]. However, clinicians are often face the dilemma of choosing more appropriate antithrombotic regimen for elderly patients with both AF and IHD. The PIONEER AF-PCI study is the first randomized comparison of VKA vs novel oral anticoagulant therapy in patients with NVAF receiving antiplatelet therapy after PCI to assess the relative risks of bleeding complications in patients at least 18 years of age who have AF and have undergone a PCI procedure [7]. There is no evidence regarding the role of combination of OAC and antiplatelet which played in elderly patients with AF and IHD. We therefore investigated the effect of combination of OAC and antiplatelet on all-cause mortality in elderly patients with AF and IHD.

Study Design
This was a retrospective analytical study.

Setting
The study conducted in Chinese PLA General Hospital, Beijing, China.

Study Population
Selected patients' data available for the period between 2008 and 2014 were included in this study. A total of 699 older patients (≥ 60 years) with AF and IHD were eligible for this study. Diagnosis of AF is based on electrocardiography (ECG) (12-lead ECG), or 24-hour Holter ECG, and medical history at enrolment. IHD included myocardial infarction, unstable and stable angina, which was diagnosed according to recent cardiovascular guideline. Demographics, other medical diagnoses, OAC or antiplatelet agents, and laboratory data were also collected from the patients discharged. Exclusion criteria included any one of the following conditions: rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, mitral valve repair, and death in hospital. CHADS 2 score (cardiac failure or dysfunction, hypertension, age ≥75 years, diabetes, stroke/transient ischemic attack (doubled) was used for stroke risk stratification.

Outcome Measure
The outcome measure was all-cause mortality. Survival status was ascertained on 31 December 2014 from an electronic clinical information system in our hospital.

Ethical Considerations
The registry and analysis of data were approved by ethics committee of our hospital. Individual patient consent was not required, but patients or his/her relatives were informed of entry into our study.

Statistical Analysis
For baseline characteristics, categorical variables are presented as frequencies with percentages and continuous variables as means with SDs. All continuous variables were first tested for normality and homogeneity of variance. The continuous variables with normal distribution were analysed using student's t-tests and Mann-Whitney U rank-sum tests were used for these continuous variables with non-normality. Pearson chi-square tests for categorical variables. We compared mortality outcomes with Kaplan-Meier analysis and log-rank tests. Furthermore, Cox proportional hazards models were used to calculate and test hazard ratios. Differences were considered statistically significant at p < 0.05. Statistical analyses were performed with IBM SPSS Statistic 21.0 (IBM Corporation, Armonk, NY, USA).

Outcomes in Relation to OAC and /or Antiplatelet Use
In the unadjusted analysis, OAC and /or antiplatelet use was associated with risk of mortality (chi-square=11.03, log rank p = 0.004), and OAC or combination of OAC and antiplatelets was associated with reduced mortality as compared with antipaltelet using Kaplan-Meier analysis (Fig. 1).
Compared to antiplatelet use, the adjusted hazard ratio for mortality were 0.51 (

DISCUSSION
In this study, we report an association of combination of OAC and antiplatelet with allcause mortality in elderly patients with AF and IHD. We show that combination of OAC and antiplatelet is associated with reduced all-cause mortality and OAC are better on outcome as compared to antiplatelet, but OAC plus antiplatelet is not superior to OAC in elderly patients with AF and IHD and in subgroup aged ≥ 75 years.
Clinicians often meet a dilemma for antithrombotic therapy, where risk of stroke or stent thrombosis must be balanced with bleeding risk in elderly patients with AF and IHD. As we known, the cornerstone of AF treatment should include OACs if 1 or more stroke risk factors (such as vascular disease) are present [8], whereas initial preventive treatment after myocardial infarction or PCI consists of drugs for platelet antiaggregation [9]. Both single-and dual-antiplatelet therapy are valuable after an MI and after a PCI procedure [10,11]. Benefit of long-term OAC therapy in selected patients with AF is also demonstrated by a randomized trial [2]. Use of clopiogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention [12]. The WOEST (What Is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) study showed that a composite secondary end point of death, myocardial infarction and stent thrombosis was significantly lower in the dual-therapy group compared with the triple-therapy group [12]. Oral anticoagulant plus aspirin were associated with a significant increased risk of all-cause death, and OAC and clopidogrel was equal or better on both benefit and safety outcomes compared to triple therapy in AF patients after myocardial infarction and PCI [13]. Addition of antiplatelet to OAC is not associated with a reduction in risk of recurrent coronary events or thromboembolism, whereas risk of bleeding is increased significantly in atrial fibrillation patients with stable coronary artery disease [14]. However, the evidence for an optimal long-term antithrombotic treatment strategy in elderly patients with AF coexisting IHD is little. As we known, only one study demonstrated that among older patients aged ≥ 65years with AF and IHD, antithrombotic strategy was not associated with improved 1-year adjusted outcomes [15]. Therefore, further investigation into optimizing antithrombotic strategies in this population is warranted. In our study, only 9.0% patients received the combination of antiplatelet and OAC, and the mean CHADS 2 scores were 4.22 in patients with both antiplatelet and OAC. We showed that combination of OAC and antiplatelet was associated with reduced all-cause mortality as compared with antiplatelets, however the antithrombotic combination was not superior to OAC in elderly patients with AF and IHD, and OAC use was better on outcome as compared with antiplatelets.
Prior findings of an annual stroke risk of 23.5% in patients with AF 80 to 89 years old [16], however, bleeding with warfarin is more common in the first year of treatment in very old patients with [17], and older patients are at higher risk for bleeding after falls, physicians may favour platelet inhibitors over oral anticoagulation in older patients due to a perceived lower bleeding risk [18], although data from clinical trials show similar bleeding rates for aspirin plus clopidogrel versus warfarin alone [19]. Our study showed that among older patients with AF and IHD, OAC use was low, and only 8.0% patients took antiplatelet plus OAC in subgroup aged ≥ 75 years. Moreover, the optimal antithrombotic   Our study has some limitations. In elderly patients with AF and IHD, we investigated the relationships between anticoagulant and/or antiplatelet and all-cause mortality; however we didn't further observed the prognostic significance of triple antithrombotic therapy (OAC plus dual antiplatelet therapy). Patients without medication records were excluded, and a proxy for discharge medications was used. We also lacked data regarding both bleeding events, which precluded a net clinical benefit analysis, and AF and treatment duration; medication changes could have confounded our results. There were significantly statistical differences of some variables such as statin usage, eGFR, etc. among the three groups, so multivariate Cox regression was used to balance the effects of the confounders on outcome. Finally, the time point when AF was defined at enrollment, so we were unable to differentiate between persistent and permanent AF.

CONCLUSIONS
Combination of OAC with antiplatelet is associated with reduced all-cause mortality and OAC is better on outcome as compared to antiplatelets, but OAC plus antiplatelet is not superior to OAC in elderly patients with AF and IHD and in subgroup aged ≥ 75 years.