Thrombosis Research 131 (2013) 502507

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Thrombosis Research
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Regular Article

Major bleeding risk in anticoagulated patients receiving concomitant antiplatelet therapy: A prospective study
Jacques Donz a,, Nicolas Rodondi b, Grard Waeber c, Jacques Cornuz d, Drahomir Aujesky b
a

Division of General Internal Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, USA Department of General Internal Medicine, Bern University Hospital, Bern, Switzerland Division of General Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland d Department of Ambulatory Care and Community Medicine, Lausanne University Hospital, Lausanne, Switzerland
b c

a r t i c l e

i n f o

a b s t r a c t
Introduction: Current literature suggesting a higher bleeding risk during combination therapy compared to oral anticoagulation alone is primarily based on retrospective studies or specic populations. We aimed to prospectively evaluate whether unselected medical patients on oral anticoagulation have an increased risk of bleeding when on concomitant antiplatelet therapy. Material and Methods: We prospectively studied consecutive adult medical patients who were discharged on oral anticoagulants between 01/2008 and 03/2009 from a Swiss university hospital. The primary outcome was the time to a rst major bleed on oral anticoagulation within 12 months, adjusted for age, international normalized ratio target, number of medications, and history of myocardial infarction and major bleeding. Results: Among the 515 included anticoagulated patients, the incidence rate of a rst major bleed was 8.2 per 100 patient-years. Overall, 161 patients (31.3%) were on both anticoagulant and antiplatelet therapy, and these patients had a similar incidence rate of major bleeding compared to patients on oral anticoagulation alone (7.6 vs. 8.4 per 100 patient-years, P = 0.81). In a multivariate analysis, the association of concomitant antiplatelet therapy with the risk of major bleeding was not statistically signicant (hazard ratio 0.89, 95% condence interval, 0.37-2.10). Conclusions: The risk of bleeding in patients receiving oral anticoagulants combined with antiplatelet therapy was similar to patients receiving oral anticoagulants alone, suggesting that the incremental bleeding risk of combination therapy might not be clinically signicant. 2013 Elsevier Ltd. All rights reserved.

Article history: Received 9 January 2013 Received in revised form 15 March 2013 Accepted 30 April 2013 Available online 30 May 2013 Keywords: Anticoagulants Platelet aggregation inhibitors Hemorrhage Risk factor

Introduction The decision to combine antiplatelet therapy with oral anticoagulants or to discontinue one of the two is a frequent dilemma in daily practice, as both therapies are specically indicated for diseases that commonly co-exist. Atrial brillation and coronary artery disease represent the typical duo. Approximately 70% of the patients with atrial brillation have an indication for long-term oral anticoagulation [1], and 20-30% of them would also require at least one antiplatelet agent for coronary artery disease [2]. This is also true for: patients having both an acute coronary syndrome and an articial heart valve; patients with both recent acute coronary syndrome and venous thromboembolism event; and patients with anterior myocardial infarction and risk of left ventricular thrombus [3]. The assessment of such concomitant treatment is of high importance in the prevention of bleeding events.
Corresponding author at: 1620 Tremont Street, OBC-3-2U, Division of General Internal Medicine, Brigham and Womens Hospital, Boston, MA 02120-1613, USA. Tel.: +1 617 525 6660; fax: +1 617 732 7072. E-mail address: jdonze@partners.org (J. Donz). 0049-3848/$ see front matter 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.04.033

There is strong evidence that patients on both oral anticoagulant and antiplatelet therapy have a higher risk of bleeding than patients on antiplatelet therapy alone [4,5]. However, there are few data comparing the risk between a combination of oral anticoagulant plus antiplatelet therapy, and oral anticoagulant alone. In a meta-analysis of ten randomized trials including mainly patients with mechanical heart valves, the risk of major bleeding was increased in patients receiving aspirin and oral anticoagulants compared to oral anticoagulants alone (odds ratio [OR] 1.43; 95% condence interval [CI] 1.002.02), but failed to achieve statistical signicance (P = 0.05) [6]. Since then, two other post-hoc analyses from randomized trials that have compared the combination of oral anticoagulants and aspirin showed a signicantly increased risk of major bleeding (hazard ratio [HR] 1.58 (95%CI 1.01-2.49) and 2.47 (95%CI 2.07-2.96), respectively) [7,8]. Although these trials suggest an increased risk of major bleeding when adding antiplatelet to oral anticoagulants, they were mainly restricted to patients with mechanical heart valves, or with atrial brillation and a CHADS2 score 1, limiting the generalizability of their ndings [68]. Moreover, retrospective studies have shown conicting results [917]. Thus, the evidence for an increased risk of major bleeding in unselected medical patients who receive a

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combination of oral anticoagulants and antiplatelet treatment is relatively weak. We aimed to prospectively evaluate in a real-life medical population whether patients on oral anticoagulant plus antiplatelet agent have an increased risk of major bleeds compared to patients on oral anticoagulant alone. Materials and Methods This study prospectively collected data from January 1, 2008 to March 31, 2009 at a Swiss university hospital [18]. During the rst 15 months, all consecutive adult inpatients discharged on oral anticoagulants from the internal medicine department were identied with the computerized physician order entry system and included in the study. In the same period, outpatients of the ambulatory care department who were treated with an oral anticoagulant were also included based on physician notication of study staff. Patients were excluded if they refused or were unable to provide informed consent due to severe cognitive impairment. After inclusion, patients had their anticoagulation treatment monitored by their own primary care physician in most instances. The study protocol was approved by the local ethics committee. Data Collection At study enrollment (time of hospital discharge for inpatients and time of consultation for outpatients), a trained research nurse used a standardized form to collect patient demographics and medical information at baseline, including the indication and duration of oral anticoagulation, the international normalized ratio (INR) target level, and the use of concomitant antiplatelet therapy at the time of enrollment. Doses of antiplatelet agent were not gathered since almost all prescriptions in Switzerland are for aspirin 100 mg per day and clopidogrel 75 mg per day. Other data collected included age, sex, total number of medications, comorbid conditions (history of stroke, major bleeding event, arterial hypertension, diabetes mellitus, angina pectoris, myocardial infarction, heart failure, peripheral artery disease, cancer [active or in remission b 1 year], liver cirrhosis and alcohol or drug abuse), and laboratory parameters (hemoglobin, hematocrit, creatinine, platelet count, and INR). We assessed the risk of falls using two validated screening questions [19]. Each medical condition was considered present if documented in the medical chart. Based on all INR collected during the follow-up, we calculated the percentage of time in therapeutic INR range (TTR), dened as the number of days with an INR between 2.0 and 3.0 divided by the total days of observation, after exclusion of intervals greater than 56 days [20,21]. Study Outcome The study outcome was time to the rst major bleed within 12 months of follow-up. A rst major bleed was dened as a fatal bleed, a symptomatic bleed in a critical area or organ (intracranial, intraspinal, intraocular with threat to vision, retroperitoneal, intraarticular, pericardial, or intra-muscular with compartment syndrome), or a bleed causing a fall in hemoglobin level of 20 g/l or leading to a transfusion of two or more units of whole blood or red cells [22,23]. A fatal bleed was dened as any death occurring within seven days of a major bleed in the absence of an alternative cause of death [24]. Death was considered of cardiovascular origin if patients died from cardiac arrest, cardiogenic shock, heart failure, or myocardial infarction. To ascertain outcomes during follow-up, the study nurse contacted patients or caregivers via telephone at 4, 8, and 12 months after enrollment. Primary care physicians were also contacted and hospital records reviewed for all outcomes. We collected the following information at each follow-up interview: occurrence of bleeding

event or death (with date and cause), anticoagulant therapy and antiplatelet therapy at time of event, and all INR values. Based on the best available evidence from patient and physician interviews and medical records, three independent consultant general physicians adjudicated major bleeding events and deaths. The adjudicators were blinded to comorbidities, patients demographics (age, gender), habits, medical treatment, and other bleeding risk factors. Final assignments were based on the full consensus of this panel [25]. Statistical Analyses Baseline characteristics were presented according to the concomitant use or not of antiplatelet agents along with oral anticoagulation. The study outcome was time to a rst major bleed. Patients were censored at the time they stopped their anticoagulation therapy, if they died from a cause other than bleeding, or if they did not experience the outcome by the end of the follow-up period of 12 months. The unadjusted rate of major bleeding event was compared between patients with and without a concomitant antiplatelet agent using a Kaplan-Meier curve and log-rank test. Multivariable analyses were performed using the Cox proportional hazards method with the rst major bleeding event as the dependent variable and antiplatelet therapy (no one vs. at least one antiplatelet agent) as the independent variable. All important confounders based on a priori knowledge were included in the model: age, target INR at the time of enrollment, total number of medications, history of major bleeding event, and history of myocardial infarction. The proportional hazards assumption was tested using Schoenfeld residuals and was found to be valid. All tests were conducted as two-sided at a 0.05 level of signicance. Analyses were performed using SAS (version 9.2 for Windows; SAS Institute Inc, Cary, North Carolina, USA). Results During the enrollment period, 650 consecutive patients were discharged on oral anticoagulants. Of these, 132 (20.8%) were excluded because of refusal or inability to give informed consent, and 3 (0.5%) because they withdrew consent during follow-up, leaving 515 patients for analysis. The one-year follow-up was complete for all 515 included patients, with a mean follow-up time before censoring of 269 days (379 patient-years). The mean age was 69.0 years (SD 13.4) and 186 (36.1%) were female. Most of the patients were enrolled at the time of discharge from the hospital (96%). All patients had acenocoumarol as anticoagulant therapy, except 8 (1.6%) patients who received phenprocoumon. Among the 515 enrolled patients, 131 (25.4%) were starting with a new oral anticoagulation. At inclusion, 161 (31.3%) of the anticoagulated patients were on concomitant antiplatelet therapy. Most of them (n = 105, 65.2%) were on acetylsalicylic acid, 11 (6.8%) were on clopidogrel, 42 (26.1%) were on both acetylsalicylic acid and clopidogrel, and nally only 3 (1.9%) were on a triple antiaggregation with acetylsalicylic acid, clopidogrel, and dipyridamole. The percentage of TTR was 48% (95%CI 46-50%) in the entire cohort, and did not differ between patients with and without concomitant antiplatelet therapy (47% [95%CI 44-50%] vs. 48% [95%CI 46-50%], respectively). Patients on both anticoagulation and antiplatelet therapy were signicantly more likely to be male, to have a lower platelet count at enrollment, and to have hypertension, diabetes, and a history of angina pectoris or myocardial infarction (Table 1). Patients on both treatments also had a higher number of medications and were less likely to be anticoagulated for venous thromboembolism. Major Bleeds Overall, 31 out of 515 patients (6.0%) had a rst major bleed, resulting in an incidence rate of 8.2 major bleeds per 100 patient-years. A similar

504 Table 1 Baseline Characteristics. OAC only (n = 354) Female, n (%) Age, mean (SD) Serum creatinine (mcmol/l), median (IQR) Hemoglobin (g/l), mean (SD) Platelet count (G/l), median (IQR) Comorbid diseases, n (%) Alcohol abuse Stroke or transitory ischemic attack History of gastro-intestinal bleed History of major bleed History of myocardial infarction Angina pectoris Diabetes Hypertension Active cancer Heart failure Liver cirrhosis High risk of fall Number of drugs, median (IQR) Concomitant NSAID treatment, n (%) Indications for anticoagulation , n (%) Atrial brillation Thromboembolism Articial heart valve Other Anticoagulation started > 3 months before inclusion Target INR, n (%) 2.0-3.0 2.5-3.5 3.0-4.0

J. Donz et al. / Thrombosis Research 131 (2013) 502507 Table 3 Locations of the First Major Bleeding Events, n (%). OAC + antiplatelet P-Value (n = 161) 0.001 0.19 b 0.001 0.23 b 0.001 0.59 0.34 0.36 0.52 b 0.001 b 0.001 b 0.001 b 0.001 0.09 0.86 0.91 0.27 b 0.001 0.32 0.03 b 0.001 0.22 b 0.001 0.53 0.55 331 (93.5) 18 (5.1) 5 (1.4) 149 (92.6) 11 (6.8) 1 (0.6) Events Location Gastrointestinal Intracerebral Urogenital Ear, nose & throat Other Total OAC only 8 (36) 4 (18) 4 (18) 1 (5) 5 (23) 22 (71) OAC + antiplatelet 3 (33) 1 (11) 1 (11) 3 (33) 1 (11) 9 (29) Total 11 5 5 4 6 31 (35) (16) (16) (13) (19) (100)

144 (40.7) 42 (26.1) 68.5 (14.3) 70.0 (11.2) 83 (35) 97 (40) 128 (21) 215 (102) 28 (7.9) 42 (11.9) 20 (5.7) 29 (8.2) 29 (8.2) 2 (0.6) 73 (20.6) 194 (54.8) 24 (6.8) 106 (29.9) 4 (1.1) 206 (58.2) 6 (4) 3 (0.9) 227 94 26 47 230 (64.1) (26.6) (7.3) (13.3) (65.0) 126 (21) 208 (85) 15 (8.3) 24 (14.9) 6 (3.7) 16 (9.9) 88 (54.7) 12 (7.5) 57 (35.4) 125 (77.6) 5 (3.1) 47 (29.2) 2 (1.2) 102 (63.4) 8 (4) 3 (1.9) 87 (54.0) 15 (9.3) 17 (10.6) 56 (34.8) 100 (62.1)

OAC: oral anticoagulant therapy.

Over-anticoagulation at the time of event, dened as an INR greater than the upper limit of target INR range, was present in 9 (29.0%) of the 31 patients with rst bleeding events. Among the ve fatal bleeding events, all patients were on oral anticoagulation only. The incidence rate of fatal bleeding event was 1.3 per 100 patient-years. Among the 48 (9.3%) patients who were censored for a non-bleeding related death, the proportion of patients on oral anticoagulant only was non statistically different from the proportion of patients on both anticoagulant and antiplatelet therapy (11.6 vs. 6.6%, P = 0.09). The number of cardiovascular deaths that occurred during the follow-up was not statistically signicantly different between the group with oral anticoagulation alone and the group with both oral anticoagulation and antiplatelet therapy (2.3 vs. 3.7%, P = 0.34). Bivariate Associations with Major Bleeding Event The unadjusted survival curves comparing the rst major bleed rates of participants with anticoagulation only and on both anticoagulant and antiplatelet therapy are shown in Fig. 1. The two curves are almost identical, with no statistically signicant difference in major bleeds between patients in the two groups (P = 0.81). In bivariate analysis, the concomitant use of oral anticoagulant and antiplatelet therapy had a similar hazard ratio of major bleeding event compared with the use of anticoagulant alone (HR 0.91, 95% condence interval [CI] 0.42-1.98) (Table 4). The number of medications was statistically signicantly associated with a higher rst major bleed rate, with a 13% increase for each additional drug being taken (HR 1.13, 95% CI 1.02-1.24). Also, a high INR target level was associated with a signicantly higher rate of major bleeding events (HR 3.83, 95% CI 1.65-8.89). Multivariable Associations with Major Bleeding Event After adjustment for age, initial INR target, number of medications, history of major bleeding event, and history of myocardial infarction, there was no signicant association between a combination of oral anticoagulation and antiplatelet therapy and major bleeds (HR 0.89, 95% CI: 0.37-2.10) (Table 4). Only the number of medications (HR 1.13, 95%CI 1.02-1.25) and a higher target INR (HR 3.67, 95%CI 1.56-8.62) remained signicantly associated with major bleeding event.

g/l: gram per liter, G/l: Giga per liter, INR: International Normalized Ratio, IQR: interquartile range, mcmol/l: micromole per liter, OAC: oral anticoagulant therapy, NSAID: non steroidal anti-inammatory drug, SD: standard deviation. Dened as present if listed in the medical chart. Active cancer or cancer with less than 1-year remission. Patients could have more than one reason for oral anticoagulation therapy. Other anticoagulation indications: akinetic myocardium (n = 44), peripheral or coronary artery disease/bypass (n = 18), pulmonary arterial hypertension (n = 13), intramyocardial thrombus or cardioembolism (n = 7), other thrombus localizations (n = 6), other indications (n = 15).

proportion of bleeding events occurred on oral anticoagulation only (n = 22, 6.2%), as compared to 5.6% (n = 9) of the events on oral anticoagulation combined with at least one antiplatelet agent (Table 2). Patients on a combination of oral anticoagulation and antiplatelet therapy had a similar crude incidence rate of major bleeds than patients on anticoagulant alone (7.6 vs. 8.4 per 100 patient-years, P = 0.81). When dividing the patients in 3 groups (oral anticoagulation alone (n = 354), combination with one antiplatelet agent (n = 116), or combination with 2 or more antiplatelet agents (n = 45), crude incidence rates remained similar (8.4, 8.7 and 3.8 per 100 patient-years, respectively, P = 0.67). Among the patients with major bleeding event, only one patient stopped the antiplatelet agent between the inclusion and the bleeding event and conversely two were on antiplatelet therapy only at the time of bleeding. Locations of bleeding event are shown in Table 3.
Table 2 Antiplatelet Therapy and Major and Fatal Bleeds. OAC only

OAC with 1 antiplatelet agent 1 antiplatelet agent ASA Clopidogrel 11 1 (9.1%) 0 2 antiplatelet agents ASA + clopidogrel 42 1 (2.4%) 0 ASA + clopidogrel + dipyridamole 3 0 0

Number of patients Major bleeds, n (%) Fatal bleeds, n (%)

354 22 (6.2%) 5 (1.4%)

105 7 (6.7%) 0

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Fig. 1. Kaplan-Meier curve for anticoagulated subjects with and without any concomitant antiplatelet therapy.

Discussion In this prospective study in a real-life medical population on oral anticoagulants, we found that patients with both antiplatelet and oral anticoagulant therapies had similar risk of major bleeding event as patients on anticoagulant therapy alone, and that a high target INR and the number of medications were the only signicant predictors for major bleeding events. Our ndings contrast somewhat with two previous retrospective studies on patients anticoagulated for any indication. Schalekamp et al. matched 1,848 major bleeding events in new users of oral anticoagulants with 5,818 controls [14]. Outcomes were identied through ICD9-CM codes over all the study period and the results were adjusted for potential confounders using medications as proxy variables for medical conditions. Users of clopidogrel or aspirin showed a signicantly increased risk of hospitalization because of major bleeding event (OR 2.9, 95%CI 1.2-6.9 and OR 1.6, 95%CI 1.3-1.9, respectively). Another retrospective study looked at 4,183 patients with various anticoagulation indications: a combination of warfarin and any antiplatelet use was independently associated with major hemorrhagic events at 6 months when compared with warfarin only (OR 2.06, 95%CI 1.01-4.36) [13]. Similarly, in patients at high risk for cardiovascular diseases, a meta-analysis found that the risk for major bleeding event was signicantly higher in patients receiving the combination anticoagulant-aspirin compared with anticoagulant therapy alone (OR 1.43, 95%CI 1.00-2.02) [6]. This meta-analysis included 10 relatively old randomized trials published between 1976 and 2002, in which most patients received anticoagulation for mechanical heart valves. In a post-hoc analysis of the SPORTIF III and V trials comparing

Table 4 Cox Bivariate and Multivariable-Adjusted Analyses (n = 515). HR (95%CI) Variable Concomitant antiplatelet therapy Age, per 10 years Target INR ( 3.0 vs. b 3.0) Number of medication(s), per additional drug taken History of major bleed History of myocardial infarction Bivariate Analyses 0.91 (0.42 1.11 (0.84 3.83 (1.65 1.13 (1.02 2.66 (1.09 0.53 (0.19 1.98) 1.47) 8.89) 1.24) 6.48) 1.51) Adjusted Model 0.89 (0.37 1.16 (0.85 3.67 (1.56 1.13 (1.02 2.07 (0.82 0.44 (0.14 2.10) 1.56) 8.62) 1.25) 5.20) 1.41)

INR = international normalized ratio, HR = hazard ratio. Adjusted for age, target INR, number of drugs, history of bleed and history of myocardial infarction.

ximelagatran to warfarin in patients with atrial brillation, Flaker et al. found also a signicant increase in the risk of major bleeding event (HR 1.58, 95%CI 1.01-2.49) when comparing the use of aspirin and warfarin to warfarin alone [7]. In a more recent post-hoc analysis of a subset of the AMADEUS trial [8], Lane et al. found a signicant higher risk of major bleeding event when comparing anticoagulation combined with any antiplatelet agent to anticoagulation only (idraparinux 2.5 mg/week or adjusted-dose warfarin) (HR 2.47, 95%CI 2.07-2.96). There are several possible reasons why our results contrast with previous studies. Firstly, the majority of patients in our study were enrolled at the time of discharge from the hospital and thus, may be at higher risk of bleeding than outpatients included in prior studies [26]. Moreover, we prospectively enrolled unselected patients receiving oral anticoagulants while previous studies were mainly restricted to patients with mechanical heart valves, or a CHADS2 score 1 [7,8,27,28]. Secondly, the bleeding event rate was not adjusted for important confounders (e.g., previous major bleeding event or target INR) in many retrospective studies, which may have misestimated the bleeding risk of patients receiving the combination therapy [12,15,17]. Thirdly, the vast majority of patients in our study had target INR values between 2.0-3.0 and received aspirin at a dose of 100 mg per day, whereas at least four of the trials had a mean INR target above 2.5 [2932], and another four studies used higher aspirin doses ranging from 200 to 1000 mg per day [27,31,33,34]. There is, however, evidence that aspirin doses of 100 mg/day or less are associated with fewer major bleeding events than 200 mg/day [35]. Finally, bleeding denitions varied widely across previous studies and were not always in concordance with the current standard denition used in our study [36]. Many trials used both minor and major bleeding events as an outcome [27,28,31,34,37,38], and outcomes in all retrospective studies were based on ICD9-CM bleeding event codes only [912,14,16,17]. The fact that none of the previous trials except one adjudicated the major bleeding events by a committee unaware of treatment group could also contribute to the difference in the ndings. Our study has several potential limitations. Firstly, it is limited by its single-center design, although we have included all consecutive patients and had a complete follow-up. Secondly, patients who were judged by their physician to be at very high risk of major bleeding event may not have received oral anticoagulation and/or antiplatelet agents and therefore, may not have been enrolled in our study. Thirdly, we did not systematically capture any discontinuation of antiplatelet therapy during the follow-up. Among the patients with major bleeding event, only one patient stopped the antiplatelet agent between the inclusion and the bleeding event. Moreover, we could not assess adherence to antiplatelet therapy because this information was not available in our database. Fourthly, most of the patients included were discharged from a hospital setting, which may reduce the generalizability of the results to outpatients that are not hospitalized. Fifthly, given the observational design of our study, we cannot exclude that unmeasured, residual confounders of bleeding risk were present. Finally, our patients were enrolled at different stages in their course of anticoagulation. Given that the bleeding risk is known to decrease after the early phase of anticoagulation [39], the high proportion of patients (65%) who received oral anticoagulants for more than three months before inclusion has the potential to decrease the overall bleeding risk in our study. Our ndings may have several potential implications. First, our results suggest that the addition of antiplatelet therapy on oral anticoagulants is safer in general medical patients than anticipated from previous studies conducted in specic populations. Therefore, when physicians are considering a combination of oral anticoagulant plus antiplatelet therapy, prescription should be tailored to each patients bleeding risk. Many low-risk patients could indeed still benet from this combination without facing an increased risk of bleeding. Clinicians who meet patients with a high cardiovascular risk in their

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Table 5 Summary Recommendations of Anticoagulation and Antiaggregation Therapies. Stable CAD Low risk AF Intermediate risk AF High risk AF

ACS ASA + clopi (12 months) OAC + ASA (12 months) OAC + ASA (12 months) OAC + ASA (3 months, grade 1B) then DT (to 12th month, grade 1B)

BMS ASA + clopi (12 months) ASA + clopi (12 months) TT (1 months) then OAC + ASA (to 12th month) TT (1 month) then OAC + ASA (to 3rd month) then ASA + clopi (to 12th month, grade 1B)

DES ASA + clopi (12 months) ASA + clopi (12 months) TT (3-6 months) then OAC + ASA (to 12th month) TT (3-6 month) then ASA + clopi (to 12th month, grade 1B)

OAC alone OAC alone OAC alone Not applicable

Anterior MI with LV thrombus, or at risk for LV thrombus

Adapted from Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, CHEST 2012 [3,35]. Recommendations are grade 2C if not otherwise stated. ACS: acute coronary syndrome, AF: atrial brillation, ASA: low-dose aspirin, BMS: bare metal stent, CAD: coronary artery disease, clopi: clopidogrel, DES: drug-eluting stent, DT: dual antiplatelet therapy, LV: left ventricule, MI: myocardial infarction, mo: month, OAC: oral anticoagulant therapy, TT: triple therapy (oral anticoagulation + aspirin + clopidogrel). Score CHADS2 = 0. Score CHADS2 = 1. Score CHADS2 2. Dened as: ejection fraction b 40%, or anteroapical wall motion abnormality.

daily practice may consider a combination therapy in accordance to current recommendations (Table 5) [3,40]. Nonetheless, clear evidence for prescribing both anticoagulants and platelet inhibitors is limited [41,42]. Second, since a high target INR was a signicant predictor of major bleeding event in our cohort, physicians should pay close attention to patients with high target INR levels, such as patients with mechanical heart valves. Given that the number of medications seems to be a potential contributor to bleeding events, the number of co-medications should be limited if possible.

References
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Conclusions In conclusion, in a cohort of unselected patients discharged from the hospital, patients receiving oral anticoagulants who were on concomitant antiplatelet therapy did not have a higher rate of major bleeds compared to patients on oral anticoagulants alone. Our ndings suggest that the additional bleeding risk of combining oral anticoagulants with antiplatelet therapy might not be clinically signicant in such patients.

Role of the Funding Source This study was nancially supported by an intramural grant (CardioMet) from the University Hospital Lausanne, Switzerland. Dr Donz was supported by the Swiss National Science Foundation and the Swiss Foundation for Medical-Biological Scholarships. The funding sources had no role the design and conduct of this study, the analysis or interpretation of the data, or the preparation of this manuscript.

Conict of Interest Statement There is no conict of interest for any of the authors and no relationships with industry.

Acknowledgments We thank our two study nurses Stephanie Witzig and Yolande Bangala for the careful data collection. All authors were involved in the writing, reviewing and approval of this manuscript.

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