RESEARCH ARTICLE Impact of Triple Therapy in Elderly Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention Antonia Sambola1*, Maria Mutuberría1, Bruno García del Blanco1, Albert Alonso1, José A. Barrabés1, Héctor Bueno2, Fernando Alfonso3, Angel Cequier4, Javier Zueco5, Oriol Rodríguez-Leor6, Pilar Tornos1, David García-Dorado1 1 Cardiology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain, 2 Cardiology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain, 3 Cardiology Department, Hospital Universitario Clínico San Carlos, Madrid, Spain, 4 Cardiology Department, Hospital Universitari de Bellvitge, L’Hospitalet del Llobregat, Barcelona, Spain, 5 Cardiology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain, 6 Cardiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain * asambola@vhebron.net Abstract OPEN ACCESS Citation: Sambola A, Mutuberría M, García del Background and Purpose Blanco B, Alonso A, Barrabés JA, Bueno H, et al. (2016) Impact of Triple Therapy in Elderly Patients Selecting an ideal antithrombotic therapy for elderly patients with atrial fibrillation (AF) with Atrial Fibrillation Undergoing Percutaneous undergoing percutaneous coronary intervention (PCI) can be challenging since they have a Coronary Intervention. PLoS ONE 11(1): e0147245. higher thromboembolic and bleeding risk than younger patients. The current study aimed to doi:10.1371/journal.pone.0147245 assess the efficacy and safety of triple therapy (TT: oral anticoagulation plus dual antiplate- Editor: Michael J Lipinski, Medstar Washington let therapy: aspirin plus clopidogrel) in patients 75 years of age with atrial fibrillation (AF) Hospital Center, UNITED STATES undergoing percutaneous coronary intervention (PCI). Received: September 19, 2015 Accepted: January 3, 2016 Methods Published: January 25, 2016 A prospective multicenter study was conducted from 2003 to 2012 at 6 Spanish teaching Copyright: © 2016 Sambola et al. This is an open hospitals. A cohort study of consecutive patients with AF undergoing PCI and treated with access article distributed under the terms of the TT or dual antiplatelet therapy (DAPT) was analyzed. All outcomes were evaluated at 1- Creative Commons Attribution License, which permits year of follow-up. unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Results Data Availability Statement: All relevant data are Five hundred and eighty-five patients, 289 (49%) of whom were 75 years of age (79.6±3.4 within the paper and its Supporting Information files. years; 33% women) were identified. TT was prescribed in 55.9% of patients at discharge Funding: This study was supported by a research who had a higher thromboembolic risk (CHA2DS2VASc score: 4.23±1.51 vs 3.76±1.40, p = grant from the Spanish Government (Fondo de 0.007 and a higher bleeding risk (HAS-BLED 3: 88.6% vs 79.2%, p = 0.02) than those on Investigación Sanitaria; References TRA-200; EC11- 473). No additional external funding was received for DAPT. Therefore, patients on TT had a lower rate of thromboembolism than those on DAPT this study. AS was the author who received the Grant. (0.6% vs 6.9%, p = 0.004; HR 0.08, 95% CI: 0.01–0.70, p = 0.004). Major bleeding events Competing Interests: The authors have declared occurred more frequently in patients on TT than in those on DAPT (11.7% vs 2.4%, p = that no competing interests exist. 0.002; HR 5.2, 95% CI: 1.53–17.57, p = 0.008). The overall mortality rate was similar in both PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 1 / 12 Triple Therapy and Elderly Patients treatment groups (11.9% vs 13.9%, p = 0.38); however, after adjustment for confounding variables, TT was associated with a reduced mortality rate (HR 0.33, 95% CI: 0.12–0.86, p = 0.02). Conclusions In elderly patients with AF undergoing PCI, the use of TT compared to DAPT was associ- ated with reduced thromboembolism and mortality rates, although a higher rate of major bleeding. Introduction Atrial fibrillation (AF) is the most common sustained arrhythmia and is a major independent risk factor for stroke and systemic embolism, particularly in elderly patients in whom it is more disabling [1]. The Screening for Atrial Fibrillation in the Elderly (SAFE) trial showed a 12% prevalence of atrial fibrillation in people aged 75–84, and 16% in people aged 85 or over [2]. In addition, the AF rate is the highest among older people (in the United Kingdom, 56% of the population with AF are aged over 75) and the risks of stroke are also the greatest [3,4]. The clinical scenario in which percutaneous coronary intervention (PCI) is necessary in patients with coronary artery disease (CAD) and concomitant AF poses a common treatment dilemma concerning the selection of an effective and safe antithrombotic strategy. Few observations from clinical trials or observational studies have specifically assessed this high-risk group [5– 17]. Nevertheless, guidelines and recent expert consensus reports [18–20] recommend “triple therapy” (TT), i.e., the combination of oral anticoagulation (OAC) plus dual antiplatelet ther- apy (DAPT) for the prevention of recurrent thromboembolic events in high-risk patients with AF undergoing PCI. The selection of a therapeutic regimen in elderly patients is particularly challenging since they are not only at significantly higher risk for thromboembolic events but also for a higher bleeding risk with aggressive antithrombotic therapies [2,3]. We sought to assess the efficacy and safety of TT in patients 75 years old with AF undergoing PCI. Methods A prospective cohort study of consecutive patients with AF undergoing PCI and treated with TT or DAPT was analyzed. The population consisted of two distinct prospective cohorts: the first enrolled patients from January 2003 to December 2006 at 6 Spanish teaching centers [7] and the second cohort was recruited at a single center (University Hospital Vall d'Hebron) between 2007 and 2012. In the latter, 325 (55.6%) patients were included from 2003–2006 and the remaining 260 (44.5%) patients from 2007–2012. Patients with a pre-existing diagnosis of permanent, persistent or paroxysmal AF and those who developed new-onset AF during their index admission were included. The risk of stroke or systemic embolism in patients with AF was assessed using the CHA2DS2-VASc score [1,2,5]. Bleeding risk in patients with AF was estimated by the HAS-BLED score [1,2,5]. At each participating hospital, demographic and clinical data, CHA2DS2-VASc score, bleeding risk estimated by the HAS-BLED score [1,2,5] as low (<3) or high (3), percutaneous coronary intervention details, therapeutic regimen prescribed and its recommended duration after stent implantation were recorded by the local investigator. PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 2 / 12 Triple Therapy and Elderly Patients Since this was an observational study, decisions as to the type of revascularization per- formed, type of stent used or choice of antithrombotic therapies at discharge were left to the discretion of the attending cardiologists. In patients discharged with DAPT (aspirin 100 mg once a day and clopidogrel 75 mg once a day), one antiplatelet agent was usually stopped at least 1 month following PCI when a BMS was used, and between 3 and 12 months when a DES was used (64.2% paclitaxel and 35.8% of new generation). All patients treated with OAC received vitamin K antagonists plus DAPT or plus clopidogrel alone following the regimen described previously. Thereafter, patients were followed up as part of the routine clinical prac- tice of each hospital. Clinical and demographic characteristics, risk factors for thromboembolism, and the use of antithrombotic therapy before PCI and at discharge were collected. Clinical follow-up was car- ried out by telephone interviews and review of clinical records of patients with hospital read- missions and/or outpatient clinic visits to confirm the ongoing antithrombotic regimen followed after discharge, and ascertain the occurrence of any of those adverse events. Bleeding and thromboembolic events were collected by a predefined questionnaire, and all adverse events with their antithrombotic therapy at the timing of occurrence. The patterns of antithrombotic strategies chosen in patients 75 years according to the CHA2DS2-VASC and HAS-BLED scores and the benefits and risks of the use of TT vs DAPT in patients 75 years old were analyzed. End-point definitions The primary end-point was defined as the occurrence of any thromboembolism event. Second- ary end-points were: 1) development of any major bleeding episode (BARC 3a) and 2) any cause of death. The composite end-points of major adverse cardiac events (MACEs: death, acute myocardial infarction, stent thrombosis or target vessel failure), and major adverse events (MAEs; MACE, major bleeding, or thromboembolism) were also analyzed. Definitions of adverse events Stroke was defined as the sudden onset of a neurologic deficit in an area consistent with the ter- ritory of a major cerebral artery, and was categorized as ischemic, hemorrhagic or unspecified. Hemorrhagic transformation was not considered as a hemorrhagic stroke. Intracranial hemor- rhage was defined as a hemorrhagic stroke or a subarachnoid or subdural hemorrhage. Stroke was diagnosed by techniques such as brain CT or MRI [21]. Systemic embolism was acute vas- cular occlusion of the limbs or any organ (kidneys, mesenteric arteries, spleen, retina or grafts) and was documented by angiography, surgery, scintigraphy or autopsy. Any degree of bleeding (major and minor) was defined according to the classification scheme of TIMI and BARC [22,23]. Acute myocardial infarction was defined according to the following the criteria of the ESC/ACCF/AHA/WHF [24] and stent thrombosis according to the criteria of The Academic Research Consortium [25]. The two cohort studies comply with the Declaration of Helsinki and were approved by the Institutional Review Boards of all hospitals involved [7]. The current study was approved by the Vall d’Hebron University Institutional Review Board. Prior to participating in this study, each investigator obtained local Ethics Committee approval and patients gave their written informed consent. Statistical analysis Descriptive analysis was made using mean ± standard deviation (SD) and range for continuous variables. Absolute and relative frequencies of patients in each category were analyzed for PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 3 / 12 Triple Therapy and Elderly Patients categorical variables. Comparison of continuous variables between the two treatment groups was made by Student's t-test and by chi-square test for categorical variables. The probability of adverse events during follow-up for each therapeutic group was calcu- lated by Kaplan-Meier analysis and compared by the Mantel-Cox log-rank test in a multivari- ate model. In this model, we also included variables that showed a probability value <0.15 in the univariate analysis when patients with and without oral anticoagulation at discharge were compared, as well as all demographic, clinical or procedural variables that were potentially not well balanced. A Cox proportional hazards model was used to assess the association between the therapeutic regimen at discharge and cardiovascular events. A 2-tailed p value <0.05 was considered significant. Statistical analysis was performed using the statistical package SPSS 20.0. Results Characteristics of patients with AF undergoing PCI in relation to age Five hundred and eighty-five patients with AF undergoing PCI treated with TT or DAPT were identified, 289 of whom (49.4%) were aged 75 years or older. Elderly patients had a higher prevalence of risk factors and thromboembolic and bleeding risk than younger patients. By def- inition, all elderly patients had a CHA2DS2VASc score2. Despite the differences in score results, the use of both antithrombotic strategies was similar between age groups (Table 1). An acute coronary syndrome was the index event in 76% of elderly patients. A DES was implanted in 38.5% of patients. In those who received TT, 35.8% of DES were new generation. Table 1. Characteristics of patients with atrial fibrillation undergoing percutaneous intervention with regard to age. Total patients (N = 585) Age <75 year (N = 296) Age 75 years (N = 289) p value Women, No. (%) 24.4 16.2 32.9 0.0001 Age, years, mean±SD 66.8±6.2 66.9±6.1 79.6±3.4 0.0001 Smoking, (%) 50.1 57.4 42.9 0.0001 Hypertension, (%) 74.7 70.6 78.9 0.01 Diabetes, (%) 37.6 40.5 34.6 0.08 History of heart failure, (%) 24.9 22.8 27 0.13 History of stroke or embolism, (%) 14.5 10.8 18.3 0.007 Renal failure, (%) 16.2 12.6 19.7 0.01 Peripheral arterial disease, (%) 13.6 12.6 14.6 0.27 COPD, (%) 19 16.5 21.5 0.07 Previous PCI, (%) 32.7 32.7 33.6 0.52 History of CABG, (%) 11.1 10.6 11.6 0.40 Previous MI, (%) 33.6 30.7 36.6 0.07 Acute coronary syndrome, (%) 73.2 70.0 76.5 0.039 CHADS2VASC2, mean±SD 2.4±1.4 2.4±1.4 4.0±1.4 0.0001 CHADS2VASC22, (%) 73.2 52.7 100 0.0001 HAS-BLED3, (%) 69.8 15.6 84.4 0.02 Patient with DES, (%) 40.2 41.8 38.5 0.22 TT: Coumarin+ Aspirin + Clopidogrel, (%) 45.5 45.9 45 0.44 CHA2DS2VAS-c score indicates: congestive heart failure, hypertension, age 75 years, diabetes, history of previous stroke, vascular disease, age 65 to 74 years and sex (female). HAS-BLED indicates: hypertension, renal/liver failure, stroke, bleeding history of predisposition, INR lability, age > 65 years, concomitant drugs or alcohol. COPD: chronic obstructive pulmonary disease; PCI: Percutaneous coronary intervention; MI: myocardial infarction; DES: Drug- eluting stent; TT: Triple therapy. doi:10.1371/journal.pone.0147245.t001 PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 4 / 12 Triple Therapy and Elderly Patients Overall, 159 (55.9%) patients received TT at discharge. The Time in Therapeutic Range (TTR) could only be obtained in patients from our center, and was analyzed in 53.5% of patients  75 years of age and 48.1% of patients under 75. In those cases, TTR was 68% in patients 75 year and 67% of those < 75 years. Among patients treated with DES, the duration of treatment was significantly shorter in those who received TT than in those receiving DAPT (5.7 ± 3.8 vs 7.8 ± 4.2 months, p = 0.007), while for patients who received BMS, the recommended duration of treatment was slightly longer for patients on TT than for those on DAPT (2.9 ± 1.1 vs 1.5 ± 0.5 months, p = 0.04). Relationship between of CHA2DS2VASc and HAS-BLED Scores with choice of triple therapy in elderly patients Baseline characteristics according to treatment group are shown in Table 2. Among 289 elderly patients, the absence of renal failure, previous PCI and ACS as the reason for index admission were associated with a higher use of TT, while age, gender or use of DES had no influence. Patients who received TT had a higher CHA2DS2-VASc score (4.23 ± 1.51 vs 3.76 ± 1.40, p = 0.007) and more frequently a high bleeding risk (HAS-BLED score 3: 88.6% vs 79.2%, p = 0.02) than those who received DAPT. Triple therapy and 1-year outcomes in elderly patients Outcomes during follow-up in both groups are shown in Table 2. One-hundred and six adverse events occurred. On average, TT was used in patients who received BMS and DES for 94.8 ± 71.33 and 188 ± 100 days, respectively (p = 0.0001). Table 2. Characteristics of patients with atrial fibrillation 75 years of age undergoing coronary stenting in relation to treatment. Total patients (N = 289) Triple therapy (N = 159) Dual antiplatelet therapy (N = 130) p value Women, No. (%) 32.9 34.6 30.8 0.28 Age, years, mean±SD 79.6±3.4 79.4±3.3 79.8±3.6 0.34 Smoking, (%) 42.9 39.9 46.5 0.15 Hypertension, (%) 78.9 84.3 72.3 0.08 Diabetes, (%) 34.6 34.6 34.6 0.54 History of heart failure, (%) 26.6 26.8 26.3 0.51 History of stroke or embolism, (%) 18.3 21.4 14.6 0.09 Renal failure, (%) 19.7 15.7 24.6 0.04 Peripheral arterial disease, (%) 14.6 11.9 18.0 0.10 COPD, (%) 21.5 18.6 25.0 0.12 Previous PCI, (%) 32.6 42.0 21.1 0.0001 History of CABG, (%) 11.6 12.1 10.9 0.45 Previous MI, (%) 36.6 38.6 34.1 0.25 Acute coronary syndrome, (%) 76.5 72.3 81.5 0.04 CHADS2VASc2, mean±SD 4.02±1.4 4.23±1.5 3.76±1.4 0.007 CHADS2VASc2> = 2, (%) 94.1 93.7 94.6 0.47 HAS-BLED3, (%) 88.4 88.6 79.2 0.02 Patients with DES, (%) 38.5 36.1 41.4 0.21 CHA2DS2-VASc score indicates: congestive heart failure, hypertension, age 75 years, diabetes, history of previous stroke, vascular disease, age 65 to 74 years and sex (female); HAS-BLED indicates: hypertension, renal/liver failure, stroke, bleeding history of predisposition, INR lability, age > 65 years, concomitant drugs or alcohol; COPD: chronic obstructive pulmonary disease; PCI: Percutaneous coronary intervention; MI: myocardial infarction; ACS: acute coronary syndrome; DES: Drug- eluting stent; TT: Triple therapy. doi:10.1371/journal.pone.0147245.t002 PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 5 / 12 Triple Therapy and Elderly Patients However, in patients 75 years old who were on TT, no significant differences were found between those patients who received BMS or DES regarding the incidence of stroke or systemic embolism (1% vs 0%, p = 0.63) or bleeding events (total bleeding: 23.8% vs 24.6%, p = 0.52). However, overall, the incidence of thromboembolic events was lower in patients receiving TT compared with those treated with DAPT (0.6% vs 6.9%, p = 0.03). By contrast, patients who received TT tended a trend to have a higher bleeding rate than those treated with DAPT (23.9% vs 16.2%, p = 0.06) owing to an excess of major bleeding (11.7% vs 2.4%, p = 0.002). Eight of the 21 patients who presented major bleeding had an intracraneal hemorrhage and 3 died from this cause. However, no significant differences were found in any cause of death, car- diovascular mortality, MACE and MAE between TT and DAPT (Table 3). Survival free of thromboembolic events was significantly higher in patients treated with TT than in those with DAPT (Fig 1, log-rank p = 0.004), but did show a trend towards a higher incidence of major bleeding than patients treated with DAPT (Fig 2, log rank p = 0.08). Sur- vival curves for thromboembolic events diverged very early (before 30 days), but remained quite parallel afterwards, while the curves for bleeding events showed a continuous drop in of events over time (Figs 1 and 2). CHA2DS2-VASc score was not associated with any adverse event in univariate analysis (thromboembolic events, total bleeding, major bleeding, death from all causes, MACE or MAE). Cox regression analysis selected TT as a protective factor against thromboembolism (HR 0.08, 95% CI 0.01–0.70; p = 0.004) as well as of death from all causes (HR 0.33; 95% CI 0.12–0.86, p = 0.02). In contrast, TT and HAS-BLED score 3 were associated with a higher risk of major bleeding events, while renal failure, peripheral vascular disease and heart failure were associated with death from all causes. Finally, number of vessels and renal failure were associated with occurrence of MACE, while TT was not (S1 Table). Discussion This is the first prospective study to specifically show that TT reduced thromboembolic events and all-cause mortality in elderly patients with AF undergoing PCI, despite of the increased rate of bleeding events. In contrast to previous studies, we observed that the choice of antithrombotic therapeutic strategies, in this particular setting, seems be guided by thromboembolic risk. In our cohort, patients who received TT at discharge had a higher thromboembolic risk than those who Table 3. Comparison of outcomes during 1-year follow-up in patients  75 years according to treatment. Total patients (N = 289) Triple therapy (N = 159) Dual antiplatelet (N = 130) p value Stroke, (%) 2.4 0.6 4.6 0.03 Stroke or embolism, (%) 3.5 0.6 6.9 0.004 Stent thrombosis, (%) 1.4 1.3 1.6 0.59 Ischemic events, (%) 10.4 9.4 11.5 0.34 BARC <3, (%) 20.4 23.9 16.2 0.06 BARC  3a, (%) 6.6 11.7 2.4 0.002 Death, (%) 12.8 11.9 13.8 0.38 Cardiovascular death, (%) 8.7 7.5 10.1 0.29 MACE, (%) 19.9 18.2 21.9 0.26 MAE, (%) 36.8 37.1 36.4 0.50 MACE: major adverse cardiovascular event; MAE: major adverse events; BARC 3a: overt bleeding plus hemoglobin drop of 3 to 5 g/dL* (provided hemoglobin drop is related to bleed). Any transfusion with overt bleeding. doi:10.1371/journal.pone.0147245.t003 PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 6 / 12 Triple Therapy and Elderly Patients Fig 1. Influence of triple therapy (TT) at discharge in patients 75 years. Kaplan-Meier survival curves. Red line, TT used at discharge. Blue line, DAPT used at discharge. Probability of embolic events in patients 75 years. doi:10.1371/journal.pone.0147245.g001 Fig 2. Influence of triple therapy (TT) at discharge in patients 75 years. Kaplan-Meier survival curves. Red line, TT used at discharge. Blue line, DAPT used at discharge. Probability of bleeding events in patients 75 years. doi:10.1371/journal.pone.0147245.g002 PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 7 / 12 Triple Therapy and Elderly Patients received DAPT, in contrast to other authors who found no relationship between the antith- rombotic strategy chosen and thromboembolic risk [26–28]. In this regard, Mennuni et al found the choice of the intensity of antithrombotic therapy to be correlated with the risk of ischemic rather than bleeding events in this cohort of patients with AF who underwent PCI [28]. In our cohort, both thromboembolic and bleeding risks were higher in patients who received TT. Since both risks overlap when the CHADS2VASC2 score is used to estimate the thromboembolic risk instead of the CHAD2S risk. Moreover, on the one hand, the use of TT was significantly higher than observed by other authors. Fosbol et al found a very low rate of TT use (27%) in AF patients 65 years of age with non-ST segment elevation myocardial infarction undergoing PCI [26,27], and Shireman et al, observed that, in patients with AF, the use of concomitant warfarin—antiplatelet therapy declined with advancing age [29]. On the other hand, Fosbol et al, surprisingly, found no differences in the bleeding readmis- sion rate between TT compared with DAPT treatment, maybe reflecting a degree of selection bias for warfarin use in patients with low comorbidity [26,27]. However, in agreement with our data, Shireman et al found an increased rate of major bleeding in patients on TT [29]. Our results differ from those reported by Hess et al in that we found a reduction in the inci- dence of stroke and systemic embolism in elderly patients treated with TT compared with those receiving DAPT. Overall, patients aged 75 years have an estimated thromboembolic risk far higher than patients <75 years, and this risk is intrinsically linked to their higher age that by itself counts 2 points on the CHAD2SVAS2C score. Thus, the reasons why elderly patients treated with DAPT had the same embolic incidence as those on TT in Hess’s study are difficult to understand. A possible explanation, perhaps related to the time of enrollment, is that the currently recommended CHAD2SVAS2C and HAS-BLED scores were not used in that study [30]. On the other hand, it is surprising lower prescription of TT (27.1%) in these patients with high thromboembolic risk, when since ever, clinical practice guidelines have rec- ommended the use of TT in patients with AF undergoing PCI regardless of their age. More- over, that study, despite the large number of data collected, was retrospective, with all the limitations of a study of this nature [30]. Although there is robust evidence supporting the efficacy of OAC in AF, with vitamin K antagonists reducing the stroke risk by up to 3-fold, in routine practice, less than half of elderly patients with AF deemed eligible for warfarin are actually receiving it.[28–31]. Furthermore, new anticoagulants (NOACs) may have contributed to improving the use of anticoagulants in this population; however, until recently their use had not been recommended in patients with AF undergoing PCI [19]. In our study, survival curves for thromboembolic events diverged very early (before 30 days), but remained quite parallel afterwards, while the curves for bleeding events showed a continuous drop in events over time. The different timings of thromboembolic events mostly occurring soon after PCI and bleeding events being more evenly distributed over time suggests a differential time-dependent risk/benefit benefit/risk ratio of antithrombotic therapy. This finding is consistent with the notion that a more intensive antithrombotic therapy, namely TT, may be justified early after PCI even in older patients who have a higher bleeding risk, while longer TT duration of more than 4 weeks may not be justified, as pointed out in guidelines [19,32]. The impact of the warfarin-DAPT combination on bleeding risk remains unclear owing to the inconsistencies between randomized trial designs and clinical practice. These include the exclusion from randomized trials of many elderly patients and those with a higher bleeding risk. Thus, current evidence is insufficient to support clinical decision-making for AF patients requiring both OAC and DAPT. PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 8 / 12 Triple Therapy and Elderly Patients A recent clinical trial, The Woest, showed that the combination of OAC and clopidogrel might be an option in elderly patients with AF undergoing PCI, since this combination reduces the incidence of bleeding events and does not increase the rate of thrombotic events [17]. How- ever, we believe that the omission of aspirin could trigger thrombotic events in patients at high risk for ischemic events (prevalence of ACS: 73.2%) as other authors have pointed out [33]. Specifically, in our cohort, the therapeutic strategy consisting of oral anticoagulation (OAC) plus clopidogrel was chosen in few patients (50 patients, 7.9%, of whom 23 [54%] were 75 years). These small numbers may be explained by the fact that during the study period, this strategy was not accepted after stenting, because of the notion that the omission of DAPT could determine a greater incidence of early and late stent thrombosis [33]. In contrast, dual antiplatelet therapy (DAPT) seemed an attractive alternative to triple therapy (TT), especially in elderly patients or those with difficulties in OAC control, despite the lack of evidence in sup- port of this strategy. In the present study, we found a trend towards higher rates of stent throm- bosis in patients on OAC plus clopidogrel compared with those treated with DAPT or TT (7.4% vs 1.3% vs 1.6%, p = 0.94); however the sample size was too small to draw any conclusions. It is currently impossible to extrapolate the results of the ACS trials in no AF patients to patients with AF and ACS, and an improved assessment of the role of new oral anticoagulants (NOACs: Non-vitamin K-antagonist oral anticoagulants) in AF patients with ACS and PCI will be obtained from ongoing prospective trials. In summary, our results showed that the use of TT in elderly patients with AF undergoing PCI was guided by the assessment of thromboembolic risk. Furthermore, TT was associated with an early reduction in thromboembolic and mortality risks in patients 75 years at the cost of a progressive increase in major bleeding risk. Our findings have important public health implications. The use of TT in elderly patients with AF undergoing PCI may be recommended, despite increasing the rate of bleeding events. Controlled randomized trials are required to define the best strategy and timing of antithrombotic therapy, specifically in elderly patients with AF undergoing PCI. Limitations This study has some limitations. Although it is one of the largest prospective studies in this population group, the number of patients was small. Despite the lack of statistical adjustment for baseline differences, we did not consider making a propensity-score analysis owing to the small size of the sample. A further limitation is the lack of information on the existence and fre- quency of switching from one therapy to the other in the follow-up. On the other hand, the use of an antithrombotic therapy regimen was at the discretion of the attending physician and was non-randomized. Supporting Information S1 Table. Multivariate Cox regression analyses for prediction of adverse outcomes. (DOC) Acknowledgments We are indebted to Christine O0 Hara for help with the English version of the manuscript and to Dr. Ignacio Ferreira-González for assistance in some aspects of statistical analysis. PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 9 / 12 Triple Therapy and Elderly Patients Disclosures None. The authors are solely responsible for the design and conduct of this study, all study analyses, drafting and editing of the paper and its final contents. Author Contributions Conceived and designed the experiments: AS BGB PT. Performed the experiments: MM AA AS HB FA AC JZ OR. Analyzed the data: AS BGB. Wrote the paper: AS HB JAB DGD PT. References 1. Miyasaka Y, Barnes ME, Bailey KR, Cha SS, Gersh BJ, Seward JB, et al. Mortality trends in patients diagnosed with first atrial fibrillation—a 21-year community study. J Am Coll Cardiol 2007; 49:986–92. PMID: 17336723 2. Fitzmaurice DA, Hobbs FDR, Jowett S, Mant J, Murray ET, Holder R, et al. Screening versus routine practice for detection of atrial fibrillation in people aged 65 or over: cluster randomised controlled trial. BMJ 2007; 335:383–6. PMID: 17673732 3. Van Walraven C, Hart RG, Connolly S, Austin PC, Mant J, Hobbs FDR, et al. The influence of patient age on the effect of stroke prevention therapy in atrial fibrillation: a secondary analysis of data from ran- domized trials. Stroke 2009: 40:1410–6. 4. Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, et al. Validation of risk stratifi- cation schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011; 342:d124. doi: 10.1136/bmj.d124 PMID: 21282258 5. Karjalainen PP, Porela P, Ylitalo A, Vikman S, Nyman K, Vaittinen MA et al. Safety and efficacy of com- bined antiplatelet warfarin therapy after coronary stenting. Eur Heart J 2007; 28:726–732. PMID: 17267456 6. Nguyen M, Lim YL, Walton A, Lefkovits J, Agnelli G, Goodman SG, et al. GRACE investigators. Com- bining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events: is it safe and effective to use just one antiplatelet agent? Eur Heart J 2007; 28:1717–1722. 7. Sambola A, Ferreira-Gonzalez I, Angel J, Alfonso F, Maristany J, Rodríguez O et al. Therapeutic strate- gies after coronary stenting in chronically anticoagulated patients: the MUSICA study. Heart 2009; 95:1483–1488. doi: 10.1136/hrt.2009.167064 PMID: 19451141 8. Hansen ML, Sorensen R, Clausen MT, Fog-Petersen ML, Raunsø J, Gadsbøll N et al. Risk of bleeding with single, dual or triple therapy with warfarin, aspirin and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010; 170:1433–1441. doi: 10.1001/archinternmed.2010.271 PMID: 20837828 9. Zhao HJ, Zheng ZT, Wang ZH, Li SH, Zhang Y, Zhong M, et al. "Triple therapy" rather than "triple threat": a meta-analysis of the two antithrombotic regimens after stent implantation in patients receiving long-term oral anticoagulant treatment. Chest 2011; 139:260–270. doi: 10.1378/chest.09-3083 PMID: 21285053 10. Lamberts M, Olesen JB, Ruwald MH, Hansen CM, Karasoy D, Kristensen S et al. Bleeding after initia- tion of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myo- cardial infarction and coronary intervention: a nation-wide cohort study. Circulation 2012; 126:1185– 1193. doi: 10.1161/CIRCULATIONAHA.112.114967 PMID: 22869839 11. Denas G, Padayattil Jose S, Gresele P, Erba N, Testa S, De Micheli V et al. Major bleeding in patients undergoing PCI and triple or dual antithrombotic therapy: a parallel-cohort study. J Thromb Thromboly- sis 2013; 35:178–84. doi: 10.1007/s11239-012-0790-y PMID: 22833198 12. Nikolsky E, Mehran R, Dangas GD, Yu J, Parise H, Xu K, et al. Outcomes of patients treated with triple antithrombotic therapy after primary percutaneous coronary intervention for ST-elevation myocardial infarction (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trial). Am J Cardiol 2012; 109:831–838. doi: 10.1016/j.amjcard.2011.10. 046 PMID: 22196778 13. Chan W, Ajani AE, Clark DJ, Stub D, Andrianopoulos N, Brennan AL et al. Melbourne impact of peripro- cedural atrial fibrillation on short-term clinical outcomes following percutaneous coronary intervention. Interventional Group Investigators. Am J Cardiol 2012; 109:471–477. 14. Smith JG, Wieloch M, Koul S, Braun OO, Lumsden J, Rydell E et al. Triple antithrombotic therapy fol- lowing an acute coronary syndrome: prevalence, outcomes and prognostic utility of the HAS-BLED score. EuroIntervention 2012; 8:672–678. doi: 10.4244/EIJV8I6A105 PMID: 23086784 PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 10 / 12 Triple Therapy and Elderly Patients 15. Ho KW, Ivanov J, Freixa X, Overgaard CB, Ostem MD, Ing D et al. Antithrombotic therapy after coro- nary stenting in patients with nonvalvular atrial fibrillation. Can J Cardiol 2013; 29:213–8 doi: 10.1016/j. cjca.2012.08.008 PMID: 23089528 16. Annala AP, Karjalainen PP, Biancari F, Niemelä M, Ylitalo A, Vikman S et al. Long-term safety of drug- eluting stents in patients on warfarin treatment. Ann Med 2012; 44:271–278. doi: 10.3109/07853890. 2010.543919 PMID: 21208149 17. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP et al. for the WOEST study investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381:1107–15. 18. Faxon DP, Eikelboom JW, Berger PB, Olmes DR Jr, Bhatt DL, Moliterno DJ, et al. Antithrombotic ther- apy in patients with atrial fibrillation undergoing coronary stenting: a North American perspective: exec- utive summary. Circ Cardiovasc Interv 2011; 4:522–34. doi: 10.1161/CIRCINTERVENTIONS.111. 965186 PMID: 22010191 19. Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific. Heart Rhythm Society (APHRS). Task Force Members: Lip GY, Windecker S, Huber K et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percu- taneous coronary or valve interventions: a joint consensus document of the European Society of Cardi- ology. Eur Heart J 2014; 35: 3155–3179 doi: 10.1093/eurheartj/ehu298 PMID: 25154388 20. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1–76. PMID: 24685669 21. Whiteley WN, Slot KB, Fernandes P, Sandercock P, Wardlaw J. Risk factors for intracranial hemor- rhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a sys- tematic review and meta-analysis of 55 studies. Stroke 2012; 43:2904–2909. doi: 10.1161/ STROKEAHA.112.665331 PMID: 22996959 22. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, et al. Thrombolysis in Myocardial Infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987; 76:142–154. PMID: 3109764 23. Mehran R, Rao S, Bhatt DL, Gibson MC, Caixeta A, Eikelboom J, et al. Standardized Bleeding Defini- tions for Cardiovascular Clinical Trials A Consensus Report From the Bleeding Academic Research Consortium. Circulation. 2011; 123:2736–2747. doi: 10.1161/CIRCULATIONAHA.110.009449 PMID: 21670242 24. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD et al. Third universal definition of myocardial infarction. Circulation 2012; 126:2020–35. doi: 10.1161/CIR.0b013e31826e1058 PMID: 22923432 25. Cutlip DE, Windecker S, Mehran R. Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115:2344–2351. 26. Fosbol E, Wang TY, Li S, Piccini JP, Lopes RD, Shah B et al. Safety and effectiveness of antithrombotic strategies in older adult patients with atrial fibrillation and non—ST elevation myocardial infarction. Am Heart J 2012; 163:720–8. doi: 10.1016/j.ahj.2012.01.017 PMID: 22520540 27. Fosbol EL, Wang TY, Li S, Piccini J, Lopes RD, Mills RM, et al. Warfarin use among older atrial fibrilla- tion patients with non-ST-segment elevation myocardial infarction managed with coronary stenting and dual antiplatelet therapy. Am Heart J. 2013; 166:864–70. doi: 10.1016/j.ahj.2013.08.005 PMID: 24176442 28. Mennuni MG, Halperin JL, Bansilal S, Schoos MM, Theodoropoulos KN, Meelu OA et al. Balancing the Risk of Bleeding and Stroke in Patients With Atrial Fibrillation After Percutaneous Coronary Intervention (from the AVIATOR Registry). Am J Cardiol. 2015; 116:37–42. doi: 10.1016/j.amjcard.2015.03.033 PMID: 25956624 29. Shireman I, Howard PA, Kresowik TF, Ellerbeck EF. Fibrillation Patients Combined Anticoagulant Anti- platelet Use and Major Bleeding Events in Elderly Atrial Fibrillation. Stroke. 2004; 35:2362–2367. 30. Hess C, Peterson ED, Peng A, De lemos JA, Fosbol EL, Thomas L et al. Use and outcomes of triple therapy among older patients with acute myocardial infarction and atrial fibrillation. J Am Coll Cardiol 2015; 66:616–27 doi: 10.1016/j.jacc.2015.05.062 PMID: 26248987 31. Hobbs FD, Roalfe AK, Lip GY, Fletcher K, Fitzmaurice DA, Mant J; Birmingham Atrial Fibrillation in the Aged Investigators and Midland Research Practices Consortium Network. Performance of stroke risk PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 11 / 12 Triple Therapy and Elderly Patients scores in older people with atrial fibrillation not taking warfarin: comparative cohort study from BAFTA trial. BMJ. 2011; 342:d3653. 32. Fauchier L, Greenlaw N, Ferrari R, Ford I, Fox KM, Tardif JC, et al;CLARIFY Investigators. Use of Anti- coagulants and Antiplatelet Agents in Stable Outpatients with Coronary Artery Disease and Atrial Fibril- lation. International CLARIFY Registry. PloS One. 2015 Apr 27; 10(4):e0125164. doi: 10.1371/journal. pone.0125164 eCollection 2015. PMID: 25915904 33. Fox KA. Dual or single antiplatelet therapy with anticoagulation? Lancet 2013 30; 381:1080–1. doi: 10. 1016/S0140-6736(13)60054-9 PMID: 23415014 PLOS ONE | DOI:10.1371/journal.pone.0147245 January 25, 2016 12 / 12