Choice of antithrombotic therapy for patients with atrial fibrillation undergoing carotid angioplasty and stenting: a nationwide population-based study

Nonvalvular atrial fibrillation (NVAF) and carotid stenosis are important risk factors for stroke. Carotid angioplasty and stent placement (CAS) is recommended for patients with symptomatic high-grade carotid stenosis. The optimal medical management for patients with NVAF after CAS remains unclear. We aimed to clarify this issue using real-world data from the Taiwanese National Health Insurance Research Database (NHIRD). In total, 2116 consecutive NVAF patients who received CAS between January 1, 2010, and December 31, 2016, from NHIRD were divided into groups based on post-procedure medication as follows: only antiplatelet agent (OAP, n = 587); only anticoagulation agent (OAC, n = 477); dual antiplatelet agents (DAP, n = 49); and a combination of antiplatelet and anticoagulation agents (CAPAC, n = 304). Mortality, vascular events, and major bleeding episodes were compared after matching with the Charlson comorbidity index and CHA2DS2-VASc score. The CAPAC and the OAC groups had lower mortality rates than the OAP group (P = 0.0219), with no statistical differences in major bleeding, ischemic stroke, or vascular events. Conclusively, OAC therapy after CAS appears suitable for NVAF patients. CAPAC therapy might be considered as initial therapy or when there is concern about vascular events.

www.nature.com/scientificreports/ restenosis and vascular events after CAS is antiplatelet drugs or even dual antiplatelet drugs plus statins, with improved risk factor control. Antiplatelet and anticoagulation agents seem equally necessary for patients with AF and severe carotid stenosis after vascular intervention. A combination of anticoagulation and dual antiplatelet agents appears to be a reasonable choice; however, there are concerns about a high bleeding risk 18 . There is recent preliminary evidence concerning a similar dilemma in the choice of medical therapy after acute coronary syndrome or percutaneous coronary intervention (PCI) in patients with AF [19][20][21][22][23] . Combination therapy with one NOAC and a P2Y12 inhibitor provided adequate protection with few bleeding events in these patients 19 . However, there are few studies focusing on antithrombotic agents after CAS, especially in NVAF patients. We aimed to conduct a preliminary evaluation of the effects of different medical therapies for this situation in real-world data.

Methods
Data source. This retrospective cohort study used claims data from the NHIRD in Taiwan. The National Health Insurance (NHI) program, which commenced on March 1, 1995, has reimbursed the health care costs of 99.9% of Taiwan's population since 2014. The NHI program stores detailed health data, including demographic data on the insured population, consultations, diagnostic codes, and drug prescriptions. The International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) was used for recording diagnoses in NHIRD until 2016, and the Tenth Edition (ICD-10) has been used after that. Several scientific studies have used this database with high reliability. NHIRD provides a variety of personal medical information and comprehensive long-term follow-up.

Ethics statement. This research was approved by a full ethical review from Fu Jen Catholic University
Institutional Review Board in Taiwan (Approval number: C104016), and all methods were carried out in accordance with relevant guidelines and regulations. The requirement for informed consent was waived by the Fu Jen Catholic University Institutional Review Board in Taiwan because of the retrospective nature of the study and all NHIRD data had been de-identified.
Study population. We enrolled consecutive patients diagnosed with AF (ICD-9-CM code 427.31, between January 1, 2010, and December 31, 2015, or ICD-10-CM code I48, between January 1 and December 31, 2016), who received a carotid stent (operation code 33074B and 33128B) and were discharged without complications (in the absence of ICD-9-CM: 996.4 or ICD-10-CM: T82), according to medical records. Patients with the history of prosthetic valve (ICD-9-CM code V43.3, or ICD-10-CM codes Z95.2), venous thrombosis (ICD-9-CM code 453 or ICD-10-CM code I82), mitral valve stenosis (ICD-9-CM code 396 or ICD-10-CM codes I08) were excluded. Further exclusions included patients who did not take any antithrombotic agent or with missing data. Secondary prevention therapy was required for at least 3 months in the 6 months following the vascular intervention; otherwise, patients with poor adherence were excluded. The patients were divided into four groups according to prescribed medicines: only antiplatelet agent (OAP) group, treated with aspirin or clopidogrel; only anticoagulation agent (OAC) group, treated with Warfarin or a NOAC, dual antiplatelet agent (DAP) group, who had aspirin plus clopidogrel and combined antiplatelet and anticoagulation agent (CAPAC) group, who were prescribed an antiplatelet agent plus an anticoagulation agent. The index date was defined as the day they received the first dose of prescribed medicines. (Fig. 1).
Comorbidities and variable definitions. The baseline characteristics included sex, age, Charlson comorbidity index, and CHA2DS2-VASc scores (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus (DM), previous stroke or transient ischemic attack (TIA), vascular disease, age 65-74 years, female sex), and comorbidities including peripheral vascular disease (PVD), ischemic stroke or systemic embolism, hypertension (HTN), hyperlipidemia, DM, chronic liver disease, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF) and TIA. The Charlson comorbidity index score (CCIs) is the classic index in the literature 24 . The comorbidities are weighted from 1 to 6, and a score that reflects long-term outcomes is calculated for patients. Patients with a myocardial infarction (MI), CHF, cerebrovascular disease, connective tissue disease, PVD, dementia, COPD, DM, ulcer disease, or mild liver disease are assigned one point. Hemiplegia, moderate-to-severe renal disease, diabetes-with-end-organ-damage, and any malignancy, including lymphoma and leukemia, except malignant neoplasm of the skin get two points. Three points are given for moderate or severe liver disease, while metastatic solid tumors and acquired immune deficiency syndrome are given six points.

Definition of outcomes.
The primary outcome was all-cause mortality at the 1-year, 2-year, and 3-year follow-up. The secondary outcomes were vascular events, including ischemic stroke and acute MI happening within one year. We also evaluated the incidence of symptomatic hemorrhage within one year and the mortality rate over the whole follow-up period. Patients were followed up until death, vascular event, major bleeding, or the end of the study, whichever came earliest. ICD codes used to define comorbidities and clinical outcomes in our study are listed in Table 1.

Statistical analysis.
This research used the Chi-square test for categorical variables (shown as numbers and percentages; N %) and analysis of variance for continuous variables (shown as mean and standardized differences; mean ± SD) to analyze three different medication groups according to baseline demographics. We used 1:1 ratio propensity score matching to reduce the effect of confounding factors. www.nature.com/scientificreports/ sex, CHA2DS2-VASc scores, and history of disease ( Table 1). The Kaplan-Meier method was used to evaluate time-to-death outcomes from the index date and the Cox proportional hazard regression model to estimate the hazard ratios (HR), 95% confidence interval (CIs) for mortality rates up to 3 years. We used SAS 9.4 software (SAS Institute, Cary, NC, USA). In the two-tailed tests, P < 0.05 indicated statistical significance.
Ethics approval. The requirement for informed consent was waived by the Fu Jen Catholic University Institutional Review Board (C108121) in Taiwan because due to the retrospective nature of the study and all NHIRD data had been de-identified.

Results
After exclusions, we enrolled 2116 consecutive NVAF patients who received successful CAS with regular followup between January 1, 2010, and December 31, 2016. All patients received bare-metal stents due to the health insurance regulations of Taiwan. A total of 587, 477, 49, and 304 patients took OAP, OAC, DAP, and CAPAC with persistent drug adherence. The data showed a diversity of drug choice, which suggested difficulty in drug selection. Moreover, around one-third of all patients (n = 733) had inconsistent treatment records. The leading causes of mortality were vascular events, accounting for more than one-third of all deaths. Patients who took OAP or OAC were older and had relatively higher CHA2DS2-VASc scores than patients who took CAPAC (Table 2). Moreover, there was a higher proportion of comorbidities like DM, CKD, and COPD in the OAP group patients. The final analysis was based on cross-comparison after matching between groups except the DAP group because there were not enough patients who took dual antiplatelet agents consistently after CAS to match with other groups. For limited sample size, we could not balance all variables equally in these subgroups. Our final selection is matching different therapy groups mainly according to age, sex, and CHA2DS2-VASc scores to compare www.nature.com/scientificreports/ primary outcomes. The CHA2DS2-VASc score that includes most comorbidities is an excellent evaluation tool for the risk of stroke in patients with NVAF 25 . It is also effective in predicting mortality rate of patients with AF or heart failure, mortality rate after episodes of ischemic stroke, and the clinical outcomes of patients undergoing CAS [26][27][28][29][30] . The OAP group showed a higher mortality rate in the acute stage and at the end of follow-up compared with the CAPAC and OAC groups (Table 3 and Fig. 2). Administration of an anticoagulation agent seemed to be an essential protective factor influencing 3-year mortality with a hazard ratio of 0.624 (Table 4). There was no significant difference between these three groups in major bleeding, ischemic stroke, or vascular events in the acute stage. However, there was a trend toward fewer vascular events, especially ischemic stroke, but more bleedings, observed in the CAPAC group.

Discussion
In-stent restenosis and cardioembolic stroke should be prevented in patients with NVAF who receive CAS for symptomatic high-grade carotid stenosis. Even after CAS, patients with a history of severe carotid atherosclerosis have a high risk of composite vascular events such as MI and vascular death. The combination of antiplatelet and anticoagulation agents might be a reasonable choice for these patients after intervention for the coexisting risks of atherosclerotic and cardioembolic events in these patients. There has been much discussion about combining antiplatelet and anticoagulation agents for AF and thrombotic events in cardiovascular disease [20][21][22][23]31 . According to recent cohort studies, for patients with AF after acute coronary syndrome or PCI, triple therapy with dual antiplatelet and one anticoagulation agent should be used briefly, with caution. Then changing to treatment with one NOAC and P2Y12 inhibitor is recommended 19 . Cardiovascular and cerebrovascular diseases have a similar etiology and pathophysiology. However, a recent study investigating combination therapy for stable peripheral or carotid artery disease showed the benefit of reducing major adverse limb events at the cost of increasing major www.nature.com/scientificreports/ bleeding 32 . There are no guidelines or extensive cohort studies providing evidence on whether to follow the same track in managing patients with coexisting AF and carotid artery stenosis. To our knowledge, there is no large randomized trial focusing on antiplatelet and anticoagulation agents after CAS in patients with underlying NVAF. Although there are several articles debating this issue, we are the first retrospective national study with convincible sample size. According to our NHIRD 2008-2017 data, Taiwanese patients with coexisting AF and symptomatic carotid stenosis had a high mortality rate after CAS, and less than half were alive after five years. Vascular events were the primary cause of death even with intensive regular medical prevention. The lack of a standard treatment is shown by the divergent drug selection in our data.
Several periprocedural complications, such as hyperperfusion syndrome, gastrointestinal hemorrhage, MI, systemic embolism, stroke, and TIA, occurred frequently within 30 days of CAS with an incidence of around 4% 33 . These events during admission for CAS may be difficult to determine from our data and might have influenced drug choice. Our study focused on the drug choice for patients with NVAF within half year after CAS. In comparing primary outcomes, a combination of antiplatelet and anticoagulation agents or only anticoagulation agents in the acute stage seemed more helpful for these patients than only an antiplatelet agent. A lower incidence of vascular events, especially ischemic stroke, was observed in the combination group. There was an increased risk of bleeding, which was not statistically significant. A strategy focusing on anticoagulation effects plays a vital role in this situation. Compared to the previous study focusing on antithrombotic agents after acute coronary syndrome or PCI in AF, our analysis showed fewer vascular events but more bleeding 22 . As we previously mentioned, most in-stent restenosis and vascular events happened within the first month in patients without NVAF receiving CAS who would not be included in our study. Further, our study was based on observational data according to the admission ICD codes, therefore, some minor strokes or vascular events without admission might have been missed. However, overall mortality rates may reflect the sum of these physical problems. Treatments containing anticoagulation agents must be implemented in clinical practice in patients with NVAF receiving CAS. A combination of a single antiplatelet and an anticoagulation agent might be indicated when there are concerns about possible vascular events. It might be beneficial to initially prescribe combination therapy during the high-risk period. Kouhei also suggested administering one NOAC plus a single antiplatelet agent in a published case series 34 . Clopidogrel may be a good choice of antiplatelet agent according to studies of PCI 22,35 . Our study did not separate patients taking aspirin and warfarin or clopidogrel and NOACs, which might be the reason more bleeding was recorded.
Current European guidelines recommend lifelong OAC with no antiplatelet agent beyond one year after coronary stenting in patients with NVAF 36 . Anticoagulation monotherapy was superior to aspirin or clopidogrel www.nature.com/scientificreports/ alone in preventing ischemic events. An anticoagulant plus a single antiplatelet agent did not improve protection but increased the risk of bleeding after the acute stage of MI. Our study showed that a single anticoagulation agent provided better prevention than a single antiplatelet agent and had a lower bleeding risk than combination therapy. Prevention of vascular events and bleeding risk resulted in low mortality during follow-up, and most hazard ratio reduction was recorded in the only anticoagulation therapy group. One anticoagulant seemed to be enough for most cases with NVAf after CAS. Based on the experience of previous clinical trials, the use of dual antiplatelet drugs for a short period is the consensus for medical management after CAS 37 . But these trials were non-blinded and had small numbers 38 . The appropriate duration of dual antiplatelet therapy after CAS is unknown. In line with the existing guidelines for the period covered by our study, dual antiplatelet agents were prescribed for one month after intervention. Therefore, in our study, most physicians stopped dual antiplatelet agents after 1 month, and there were only 49 cases that were prescribed dual antiplatelet agents consistently in the half-year following carotid stenting. According to experience from studies focusing on acute coronary syndrome or PCI in AF, triple therapy with dual antiplatelet agents and one anticoagulation agent is unnecessary. It increases bleeding risk one month after the intervention for most cases. These two kinds of medicine selection were not considered in our study.
This study has several limitations. It is only a retrospective observational study based on NHIRD data. The identification of comorbidities and complications is based on diagnostic codes listed in the database; some coding errors may have occurred. A diagnostic bias concerning the endpoints can be ruled out due to specific operation codes and ICD codes for significant events being checked carefully during admission according to health insurance requirements. The disease severity and any underlying diseases may affect the physician's drug choice. To Table 3. Clinical outcomes of different therapeutic groups after matching by age, sex, CHA2DS2-VASc score and baseline comorbidities. NOAC, Non-vitamin K antagonist oral anticoagulant; NT$, New Taiwan dollar; SD, standard deviation; CHA2DS2-VASc, congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, female; PVD, peripheral vascular disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CHF, congestive heart failure; TIA, transient ischemic attack; PCI, percutaneous coronary intervention.  The OAP group showed a higher mortality rate than the CAPAC and the OAC groups in the acute stage and after the follow-up. www.nature.com/scientificreports/ In summary, this study may offer preliminary evidence for clinical practice and insights for further investigation. One anticoagulation agent had a lower mortality rate and relatively low bleeding risk. The Cox proportional model estimate of the HR showed that drug choice of one anticoagulation agent might be the critical factor influencing mortality at 3-year follow-up. One anticoagulation agent may be standard medical therapy after CAS in patients with NVAF. Combination therapy with one antiplatelet and one anticoagulation agent may be considered as initial therapy when there are concerns about possible vascular events. NOACs might be a better choice than warfarin, according to some studies in Asian populations [39][40][41] . Clopidogrel may be a good choice of antiplatelet agent.
Prompt intervention followed by intensive medical control with anticoagulation therapy is the most reasonable choice for patients with NVAF and high-grade carotid stenosis. Further large-scale randomized trials are needed to confirm this.