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Clinical outcome in patients with venous thromboembolism receiving concomitant anticoagulant and antiplatelet therapy
European Journal of Internal Medicine 25 (2014) 821–825
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Clinical outcome in patients with venous thromboembolism receiving concomitant anticoagulant and antiplatelet therapy Inna Tzoran a,⁎, Benjamin Brenner a,b, Gleb Sakharov a, Javier Trujillo-Santos c, Alicia Lorenzo d, Olga Madridano e, Juan Bosco López-Sáez f, Manuel Monreal g, RIETE investigators a
Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Israel Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel Department of Internal Medicine, Hospital Universitario de Santa Lucía, Cartagena, Spain d Department of Internal Medicine, Hospital Universitario La Paz, Madrid, Spain e Department of Internal Medicine, Hospital Infanta Sofía, Madrid, Spain f Department of Internal Medicine, Hospital Universitario Puerto Real, Cádiz, Spain g Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Spain b c
a r t i c l e
i n f o
Article history: Received 30 June 2014 Received in revised form 11 September 2014 Accepted 12 September 2014 Available online 5 October 2014 Keywords: Antiplatelet Anticoagulant Venous thromboembolism
a b s t r a c t Introduction: Patients with arterial disease receiving antiplatelet agents may develop venous thromboembolism (VTE) and need anticoagulant therapy, although concomitant use of these drugs may increase bleeding risk. We analyzed RIETE data and compared clinical outcomes depending on decision to discontinue or maintain antiplatelet therapy at VTE diagnosis. Methods: Consecutive patients with acute VTE were enrolled in RIETE. Only patients receiving antiplatelet therapy at baseline were included in this analysis. Primary outcomes were: rate of subsequent ischemic events, major bleeding or death during anticoagulation course. Results: 1178 patients who received antiplatelet drugs at VTE diagnosis were included. Antiplatelet therapy was discontinued in 62% of patients. During anticoagulation course, patients also receiving antiplatelet therapy had higher rates of lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p b 0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p b 0.05) or death (23.6 vs. 13.9 deaths per 100 patientsyears; p b 0.01). No differences in the rate of major bleeding or recurrent VTE were revealed. In matched analysis, patients on antiplatelet therapy were found to have a significantly higher rate of limb amputations (odds ratio: 15.3; 95% CI: 1.02–229) and an increased number of composite outcomes including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03–2.06), with no differences in major bleeding rate. Conclusion: Concomitant anticoagulant and antiplatelet therapy in patients with VTE and arterial disease is not associated with increased risk for bleeding, recurrent VTE or death. The worse outcome observed in patients who continued antiplatelet therapy requires further investigations. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Venous thromboembolism (VTE) is a commonly diagnosed condition with significant morbidity and mortality [1]. Current guidelines recommend patients with VTE to be initially treated with low-molecular-weight heparin (LMWH), fondaparinux or unfractionated heparin, followed by long-term anticoagulation, which is usually accomplished with vitamin K antagonists (VKA) [2,3]. However, a number of
⁎ Corresponding author at: Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 8 Ha'Aliya Street, Haifa 31096, Israel. Tel.: +972 4 854 2541; fax: +972 4 854 2343. E-mail address: [email protected] (I. Tzoran).
patients with acute VTE are using antiplatelet therapy for prior myocardial infarction, stroke or other arterial events [4–6]. This is important since concomitant use of anticoagulant and antiplatelet therapy may increase the risk for bleeding [3,4]. The Registro Informatizado de Enfermedad ThromboEmbolica (RIETE) is an ongoing, multicentre, international (Spain, France, Italy, Israel, Switzerland, Greece, Czech Republic and Republic of Macedonia), prospective registry of consecutive patients presenting with symptomatic acute VTE. Data from this registry have been used to evaluate outcome after acute VTE, such as bleeding, recurrent VTE, mortality and risk factors for these outcomes. The current analysis was aimed to evaluate VTE patients who used antiplatelet therapy at baseline, and to compare their clinical outcomes with regard to the decision to discontinue or not antiplatelet agents.
http://dx.doi.org/10.1016/j.ejim.2014.09.010 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
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2. Patients and methods Consecutive patients with acute VTE confirmed by objective tests such as contrast venography or ultrasonography for suspected deep vein thrombosis (DVT); and pulmonary angiography, lung scintigraphy or helical computed tomography scan for pulmonary embolism (PE), were enrolled in RIETE. Patients were excluded if they were participating in a therapeutic clinical trial with blinded therapy. All patients provided written or oral consent for participation in the registry, in accordance with local ethic committee requirements. In the RIETE registry, participating physicians ensure that eligible patients were consecutively enrolled. Data were recorded in a computerbased case report form at each participating hospital and submitted to a centralized coordinating center through a secure website. The study coordinating center assigned patients a unique identification number to maintain patient confidentiality and was responsible for all data management. Data quality was regularly monitored electronically, including checks to detect inconsistencies or errors, which were resolved by contacting the local coordinators. Data quality was also monitored by periodic visits to participating hospitals by contract research organizations that compared medical records with submitted data. 2.1. Study design This analysis was limited to patients who received antiplatelet therapy at baseline. Their clinical characteristics and outcomes were compared according to the doctor's decision of discontinuing or not antiplatelet drugs. The rates of subsequent ischemic events, major bleeding or death during the course of anticoagulation were considered the primary outcome of the study. Ischemic events were defined as myocardial infarction (chest pain, ECG changes, elevation of cardiac biomarkers), ischemic stroke (new neurological changes, brain CT with characteristic pathology), lower limb amputation and mesenteric ischemia (abdominal pain and changes on abdominal CT scan) as diagnosed by physicians in participating hospitals. Major bleeding was defined as an overt bleeding that required a transfusion of two or more units of blood, or was retroperitoneal, spinal, intracranial, or fatal. Fatal bleeding was defined as any death occurring within 10 days of a major bleeding episode, in the absence of an alternative cause of death. Fatal ischemia was defined as any death occurring with 10 days from the event, in absence of an alternative cause of death. 2.2. Baseline variables The following parameters were recorded when the qualifying episode of VTE was diagnosed: patient's sex, age and body weight; presence of arterial disease and its risk factors such as smoking, diabetes, hypertension and hyperlipidemia; presence of coexisting conditions such as chronic heart or lung disease; recent (b30 days prior to VTE) major bleeding; presence of risk factors for VTE, including cancer, immobilization, surgery; and initial presentation of VTE. 2.3. Treatment and follow-up Patients were managed according to the clinical practice of each participating hospital (i.e., treatment was not standardized). The type, dose and duration of anticoagulant therapy were recorded. Patients were followed for up to a year in the outpatient clinics. During each visit, any signs or symptoms suggesting ischemic event (chest pain, neurological deficit, limb or abdominal pain) or bleeding complications were registered. Each episode of clinically suspected ischemic event was investigated using appropriate methods (ECG, laboratory tests, angiography or appropriate CT scan). Most outcomes were classified as reported by the clinical centers. However, if the staff at the coordinating center was uncertain how to
classify a reported outcome, the event in question was reviewed by the central adjudication committee (b10% of events).
2.4. Statistical analysis Student's t test and X2 test (or Fisher's exact test where appropriate) were used to compare continuous and categorical variables (respectively) between patients being treated with antiplatelet drugs at VTE diagnosis that continued with these drugs versus those in whom this therapy was stopped. Incidence rates of ischemic events, major bleeding, recurrent VTE, as well as overall and specific causes of death were calculated and compared between the two groups of patients and expressed as the number of events per 100 patient-years on anticoagulant therapy. Odds ratios and corresponding 95% confidence intervals (CI) were calculated for clinical outcomes during the anticoagulant therapy. A p value b0.05 was considered to be statistically significant for all these comparisons. Because patients were not randomly assigned to continue antiplatelet therapy when VTE index events were diagnosed, we used propensity score matching to adjust for differences in baseline characteristics. Table 1 Clinical characteristics and treatment strategies of patients who continued or stopped antiplatelet therapy. Antiplatelet drugs withdrawn
Antiplatelet drugs continued
729
449
Patients, no. Clinical characteristics Gender (males) Mean age (years ± SD) Body weight (kg ± SD) Inpatients
346 (48%) 76 ± 11 76 ± 16 229 (32%)
‡
260 (58%) 74 ± 11 76 ± 16 129 (30%)
Arterial disease Prior coronary artery disease Prior cerebral ischemia Prior peripheral artery disease Current smoking Diabetes Hypertension
129 (18%)‡ 169 (24%) 87 (12%) 73 (10%) 213 (30%) 531 (75%)
171 (39%) 100 (23%) 62 (14%) 51 (12%) 141 (32%) 332 (76%)
Underlying conditions Chronic heart failure Chronic lung disease Abnormal creatinine levels Creatinine clearance b30 mL/min Anemia Recent major bleeding
180 (25%) 179 (25%)† 199 (28%) 73 (10%) 265 (36%)‡ 23 (3.2%)
100 (22%) 79 (18%) 141 (32%) 60 (13%) 211 (47%) 13 (2.9%)
Risk factors for VTE Postoperative Immobility ≥4 days Cancer None of the above Prior VTE
52 (7.1%)‡ 232 (32%) 76 (10%)† 398 (55%) 144 (20%)
62 (14%) 128 (29%) 70 (16%) 224 (50%) 79 (18%)
VTE presentation at baseline Pulmonary embolism
477 (65%)†
256 (57%)
Initial therapy Low-molecular-weight heparin Mean LMWH dose (IU/kg/day) LMWH dose ≥150 IU/kg/day Unfractionated heparin Fondaparinux Inferior vena cava filter
633 (87%) 177 ± 72⁎ 531 (77%)† 54 (7.4%) 17 (2.3%) 14 (1.9%)
402 (90%) 166 ± 68 302 (69%) 23 (5.2%) 11 (2.5%) 8 (1.8%)
Long-term therapy Vitamin K antagonists Low-molecular-weight heparin Days of treatment (mean, SD) Days of treatment (median, IQR)
523 (75%)‡ 160 (23%)‡ 242 ± 257 169 ± 214⁎
266 (63%) 149 (35%) 213 ± 215 133 ± 163
VTE, venous thromboembolism. ⁎ p b 0.05. † p b 0.01. ‡ p b 0.001.
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Table 2 Clinical outcome during the course of anticoagulation. Findings expressed as events per 100 patient-years and 95% confidence intervals. Antiplatelet drugs withdrawn Events, No Patients, No Years of treatment Myocardial infarction Ischemic stroke Amputation of lower limb Any ischemic event Major bleeding Recurrent VTE Recurrent PE Recurrent DVT Fatal bleeding Fatal PE Fatal myocardial infarction Fatal ischemic stroke Fatal lower limb ischemia Fatal ischemic events Overall death
729 483 1 3 1 11 28 13 5 8 5 3 1 0 0 1 67
Antiplatelet drugs continued Events per 100 patient-years
Events, No
Events per 100 patient-years
0.21 (0.01–1.02) 0.62 (0.16–1.69) 0.21 (0.01–1.02)† 2.28 (1.20–3.96)⁎ 5.80 (3.93–8.27) 2.69 (1.50–4.49) 1.04 (0.38–2.29) 1.66 (0.77–3.15) 1.04 (0.38–2.29) 0.62 (0.16–1.69) 0.21 (0.01–1.02) – – 0.21 (0.01–1.02) 13.9 (10.8–17.5)†
449 263 1 5 6 15 17 11 6 5 1 2 0 2 1 3 62
0.38 (0.02–1.88) 1.90 (0.70–4.21) 2.28 (0.92–4.74) 5.70 (3.31–9.20) 6.46 (3.89–10.1) 4.18 (2.20–7.27) 2.28 (0.93–4.74) 1.90 (0.70–4.21) 0.38 (0.02–1.88) 0.76 (0.13–2.51) – 0.76 (0.13–2.51) 0.38 (0.02–1.88) 1.14 (0.29–3.10) 23.6 (18.2–30.0)
Abbreviations: PE, pulmonary embolism; DVT, deep vein thrombosis; VTE, venous thromboembolism. ⁎ p b 0.05. † p b 0.01. ‡ p b 0.001.
Variables that were considered in the calculation of the propensity score included: gender, age, body weight, inpatient care, prior coronary artery disease, prior cerebral ischemia, prior peripheral artery disease, current smoking, diabetes, hypertension, chronic heart failure, chronic lung disease, creatinine clearance b30 mL/min, anemia, abnormal platelet count, recent major bleeding, postoperative state, immobility ≥4 days, cancer, and pulmonary embolism. We built a logistic regression model in which antiplatelet treatment at baseline was a dependent variable and the variables eventually related to either arterial ischemic events, major bleeding, recurrent VTE or overall death were independent variables. These models made it possible to calculate a propensity score, indicating the likelihood that any individual patient would have received antiplatelet treatment, given all other known covariates. We used the full matching method for the previously calculated propensity scores in order to make comparable patients in whom antiplatelet treatment was continued versus those in whom it was withdrawn. Full matching makes use of all individuals in the dataset by forming a series of matched sets in which each set has either one treated individual and multiple comparison individuals or one comparison individual and multiple treated individuals. Full matching has been shown to be particularly effective at reducing bias related to observed confounding variables [7]. After matching, we estimated covariate balance between patients continuing and withdrawing antiplatelets using absolute standardized differences [8], which directly quantifies the bias in the means and proportions of covariates across the groups, expressed as a percentage of the pooled standard deviations. We employed matched univariate logistic regression analysis to estimate associations of antiplatelet use with various outcomes. Propensity score matching was performed using the optmatch, RItools and MatchIt packages for R program v 2.15.1 and IBM SPSS software for Mac version 20 were used for analysis of the rest of data. 3. Results As of January 2014, 1178 patients in RIETE were receiving antiplatelet drugs at the time of VTE diagnosis. The mean follow-up was 213 days for patients who continued antiplatelet treatment and 242 days for those who discontinued this therapy. Antiplatelet therapy was discontinued in 729 (62%). Discontinuation of antiplatelet therapy was less frequently observed in males, patients initially presenting with PE, or having prior coronary heart disease, anemia, recent surgery or cancer (Table 1).
Most patients in both subgroups received low molecular weight heparin (LMWH) (87% and 90%) as initial therapy for VTE, and significantly more patients who discontinued the antiplatelet agents received higher doses of LMWH (77% vs. 69%; p b 0.01) (Table 1). Of note, more patients continuing with antiplatelet drugs switched to vitamin K antagonists (VKA) (Table 1), while patients discontinuing antiplatelet drugs received a longer course of anticoagulation (169 ± 214 days vs. 133 ± 163; p b 0.05). During anticoagulation, patients on antiplatelet therapy presented a higher rate of major adverse outcomes, including lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p b 0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p b 0.05) or death (23.6 vs. 13.9 deaths per 100 patients-years; p b 0.01), but no differences in the rate of major bleeding or recurrent VTE were observed (Table 2). A higher number of ischemic events (18 vs. 8), recurrent VTE (16 vs. 8) and overall deaths (97 vs. 32) occurred later (≥15 days) in the treatment of patients who received both antiplatelet and anticoagulant therapy (Table 3). Matched analysis showed patients on antiplatelet therapy to have a significantly higher rate of lower limb amputations (odds ratio: 15.3; 95% CI: 1.02–229) and an increased number of composite outcomes, Table 3 Number of adverse events that occurred in first two weeks after VTE diagnosis and later in treatment in patients who continued antiplatelet treatment. Days of treatment
Myocardial infarction Ischemic stroke Amputation of a lower limb Any ischemic event Major bleeding Recurrent VTE Recurrent PE Recurrent DVT Fatal bleeding Fatal PE Fatal myocardial infarction Fatal ischemic stroke Fatal lower limb ischemia Fatal ischemic events Overall death
≤15 days
≥15 days
1 2 3 8 20 8 4 4 2 5 0 1 0 1 32
1 6 4 18 25 16 7 9 4 0 2 1 1 3 97
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Table 4 Odds ratio for clinical outcome during the course of anticoagulation, according to antiplatelet treatment (continued vs. withdrawn), before and after matching.
Outcome Myocardial infarction Ischemic stroke Amputation of lower limb Any ischemic event Major bleeding Recurrent VTE Recurrent PE Recurrent DVT Fatal bleeding Fatal PE Fatal ischemic events Overall death Composite outcome Composite outcome with VTE complications
Pre-matching
Post full matching
1.63 (0.10–26.0) 2.73 (0.65–11.5) 9.86 (1.18–82.2)⁎ 2.07 (0.96–4.45) 0.99 (0.53–1.82) 1.38 (0.61–3.12) 1.96 (0.60–6.46) 1.02 (0.33–3.12) 0.32 (0.04–2.78) 1.08 (0.18–6.50) 4.90 (0.51–47.2) 1.53 (1.06–2.21)⁎
0.43 (0.02–7.69) 1.11 (0.24–5.02) 15.3 (1.02–229)⁎ 1.23 (0.53–2.85) 0.89 (0.45–1.75) 1.06 (0.43–2.61) 1.49 (0.42–5.30) 0.75 (0.21–2.76) 0.38 (0.04–3.65) 0.89 (0.14–5.80) 1.92 (0.19–19.4) 1.35 (0.91–2.00) 1.46 (1.02–2.11)⁎
1.72 (1.21–2.43)† 1.72 (1.23–2.39)†
1.46 (1.03–2.06)⁎
DVT, deep vein thrombosis; PE, pulmonary embolism. Composite outcome = death or ischemic events. Composite outcome with VTE complications = death or ischemic events or recurrent PE or DVT. ⁎ p b 0.05. † p b 0.01. ‡ p b 0.001.
including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03–2.06), with no differences in the rate of major bleeding (Table 4).
4. Discussion Patients receiving antiplatelet therapy due to prior arterial disease may develop VTE [5]. Physicians and patients are facing a challenge, since VTE should be treated with anticoagulants and concomitant antiplatelet therapy may increase the risk for bleeding. Current literature has not thoroughly addressed this question. Our data reveal that in real life one in every 3 such patients continued with both therapies and that this approach was not associated with an increased risk for bleeding, recurrent VTE, ischemic events or death. Our findings differ from those in recent trials demonstrating an increased rate of bleeding complications in patients concomitantly receiving anticoagulant and antiplatelet therapy, which reached 9.1% patients/year [6]. A plausible explanation for this difference could be attributed to a relatively short period of follow-up (up to 8 months) in our study and to the fact that most patients, assumed to be at a higher risk for bleeding in our series, would probably discontinue antiplatelet treatment at baseline. In our study, the rate of bleeding in both groups was similar, despite their high age (76 ± 11 and 74 ± 11), a finding that correlates with recent publications reporting a better outcome in octogenarian patients with atrial fibrillation and coronary events who were discharged with combined anticoagulant and antiplatelet treatment [9]. Recurrent VTE was found to be the same in both groups, despite different treatment regimens, which could be explained by a relatively short follow-up. On the contrary, the higher rate of ischemic events observed in patients that maintained antiplatelet treatment may be explained by the fact that they were sicker and more likely to develop ischemic events. Moreover, some of these patients may be resistant to antiplatelet treatment and therefore could have demonstrated active ischemic disease despite concomitant therapy [10]. In addition, antiplatelet treatment failure can be related to many other reasons, including patients' failure to take their medications appropriately or to drug–drug interactions [11–15]. The number of composite outcomes incorporating all-cause death, arterial events and VTE was higher among patients that continued
antiplatelet treatment. This can be explained by the fact that such patients have a higher rate of thrombotic risk factors, e.g., postoperative state and cancer. Other possible explanations are a longer treatment with anticoagulants in patients who discontinued antiplatelet therapy and higher doses of LMWH (Table 1), and a more potent treatment with VKA [16–18] which could account in part for the observed survival advantage. The limitations of the current study include the retrospective nature of the analysis of consecutively recruited patients, a relatively short follow-up period, lack of information regarding the specific antiplatelet regimen used or the international normalized ratio (INR) values and time in therapeutic range (TTR). 5. Conclusion Based on our results, the combination of antiplatelet drugs with anticoagulants used for a short-term treatment of VTE does not increase the risk for bleeding. Conflict of interest statement The authors have no conflicts to declare. Acknowledgements We express our gratitude to Sanofi Spain for supporting this Registry with an unrestricted educational grant. We also express our gratitude to Bayer Pharma AG for supporting this Registry. Bayer Pharma AG’s support was limited to the part of RIETE outside Spain, which accounts for a 20.9% of the total patients included in the RIETE Registry. We also thank the RIETE Registry Coordinating Center, S & H Medical Science Service, for their quality control data, logistic and administrative support. Appendix A
Coordinator of the RIETE Registry: RIETE Steering Committee Members:
RIETE National Coordinators:
RIETE Registry Coordinating Center:
Dr. Manuel Monreal (Spain) Dr. Hervè Decousus (France) Dr. Paolo Prandoni (Italy) Dr. Benjamin Brenner (Israel) Dr. Raquel Barba (Spain) Dr. Pierpaolo Di Micco (Italy) Dr. Laurent Bertoletti (France) Dr. Sebastian Schellong (Germany) Dr. Manolis Papadakis (Greece) Dr. Inna Tzoran (Israel) Dr. Abilio Reis (Portugal) Dr. Marijan Bosevski (R.Macedonia) Dr. Henri Bounameaux (Switzerland) Dr. Radovan Malý (Czech Republic) S & H Medical Science Service
Appendix B. Members of the RIETE Group SPAIN: Andújar V, Arcelus JI, Auguet T, Barba R, Barrón M, BarrónAndrés B, Bascuñana J, Blanco-Molina A, Bueso T, Casado I, Casillas C, Conget F, del Molino F, del Toro J, Falgá C, Fernández-Capitán C, Font L, Gallego P, García-Bragado F, Gómez V, González J, González-Bachs E, Guijarro R, Guil M, Gutiérrez J, Hernández L, Hernández-Huerta S, JaraPalomares L, Jaras MJ, Jiménez D, Jiménez R, Lobo JL, López-Jiménez L, López-Montes L, López-Reyes R, López-Sáez JB, Lorente MA, Lorenzo A, Luque JM, Llutart J, Madridano O, Marchena PJ, Martín M, MartínAntorán JM, Mellado M, Monreal M, Nauffal D, Nieto JA, Ogea JL, Otero R, Pagán B, Pedrajas JM, Peris ML, Porras JA, Pons I, Riera-Mestre A,
I. Tzoran et al. / European Journal of Internal Medicine 25 (2014) 821–825
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Clinical outcome in patients with venous thromboembolism receiving concomitant anticoagulant and antiplatelet therapy Inna Tzoran a,⁎, Benjamin Brenner a,b, Gleb Sakharov a, Javier Trujillo-Santos c, Alicia Lorenzo d, Olga Madridano e, Juan Bosco López-Sáez f, Manuel Monreal g, RIETE investigators a
Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Israel Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel Department of Internal Medicine, Hospital Universitario de Santa Lucía, Cartagena, Spain d Department of Internal Medicine, Hospital Universitario La Paz, Madrid, Spain e Department of Internal Medicine, Hospital Infanta Sofía, Madrid, Spain f Department of Internal Medicine, Hospital Universitario Puerto Real, Cádiz, Spain g Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Spain b c
a r t i c l e
i n f o
Article history: Received 30 June 2014 Received in revised form 11 September 2014 Accepted 12 September 2014 Available online 5 October 2014 Keywords: Antiplatelet Anticoagulant Venous thromboembolism
a b s t r a c t Introduction: Patients with arterial disease receiving antiplatelet agents may develop venous thromboembolism (VTE) and need anticoagulant therapy, although concomitant use of these drugs may increase bleeding risk. We analyzed RIETE data and compared clinical outcomes depending on decision to discontinue or maintain antiplatelet therapy at VTE diagnosis. Methods: Consecutive patients with acute VTE were enrolled in RIETE. Only patients receiving antiplatelet therapy at baseline were included in this analysis. Primary outcomes were: rate of subsequent ischemic events, major bleeding or death during anticoagulation course. Results: 1178 patients who received antiplatelet drugs at VTE diagnosis were included. Antiplatelet therapy was discontinued in 62% of patients. During anticoagulation course, patients also receiving antiplatelet therapy had higher rates of lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p b 0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p b 0.05) or death (23.6 vs. 13.9 deaths per 100 patientsyears; p b 0.01). No differences in the rate of major bleeding or recurrent VTE were revealed. In matched analysis, patients on antiplatelet therapy were found to have a significantly higher rate of limb amputations (odds ratio: 15.3; 95% CI: 1.02–229) and an increased number of composite outcomes including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03–2.06), with no differences in major bleeding rate. Conclusion: Concomitant anticoagulant and antiplatelet therapy in patients with VTE and arterial disease is not associated with increased risk for bleeding, recurrent VTE or death. The worse outcome observed in patients who continued antiplatelet therapy requires further investigations. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Venous thromboembolism (VTE) is a commonly diagnosed condition with significant morbidity and mortality [1]. Current guidelines recommend patients with VTE to be initially treated with low-molecular-weight heparin (LMWH), fondaparinux or unfractionated heparin, followed by long-term anticoagulation, which is usually accomplished with vitamin K antagonists (VKA) [2,3]. However, a number of
⁎ Corresponding author at: Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 8 Ha'Aliya Street, Haifa 31096, Israel. Tel.: +972 4 854 2541; fax: +972 4 854 2343. E-mail address: [email protected] (I. Tzoran).
patients with acute VTE are using antiplatelet therapy for prior myocardial infarction, stroke or other arterial events [4–6]. This is important since concomitant use of anticoagulant and antiplatelet therapy may increase the risk for bleeding [3,4]. The Registro Informatizado de Enfermedad ThromboEmbolica (RIETE) is an ongoing, multicentre, international (Spain, France, Italy, Israel, Switzerland, Greece, Czech Republic and Republic of Macedonia), prospective registry of consecutive patients presenting with symptomatic acute VTE. Data from this registry have been used to evaluate outcome after acute VTE, such as bleeding, recurrent VTE, mortality and risk factors for these outcomes. The current analysis was aimed to evaluate VTE patients who used antiplatelet therapy at baseline, and to compare their clinical outcomes with regard to the decision to discontinue or not antiplatelet agents.
http://dx.doi.org/10.1016/j.ejim.2014.09.010 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
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2. Patients and methods Consecutive patients with acute VTE confirmed by objective tests such as contrast venography or ultrasonography for suspected deep vein thrombosis (DVT); and pulmonary angiography, lung scintigraphy or helical computed tomography scan for pulmonary embolism (PE), were enrolled in RIETE. Patients were excluded if they were participating in a therapeutic clinical trial with blinded therapy. All patients provided written or oral consent for participation in the registry, in accordance with local ethic committee requirements. In the RIETE registry, participating physicians ensure that eligible patients were consecutively enrolled. Data were recorded in a computerbased case report form at each participating hospital and submitted to a centralized coordinating center through a secure website. The study coordinating center assigned patients a unique identification number to maintain patient confidentiality and was responsible for all data management. Data quality was regularly monitored electronically, including checks to detect inconsistencies or errors, which were resolved by contacting the local coordinators. Data quality was also monitored by periodic visits to participating hospitals by contract research organizations that compared medical records with submitted data. 2.1. Study design This analysis was limited to patients who received antiplatelet therapy at baseline. Their clinical characteristics and outcomes were compared according to the doctor's decision of discontinuing or not antiplatelet drugs. The rates of subsequent ischemic events, major bleeding or death during the course of anticoagulation were considered the primary outcome of the study. Ischemic events were defined as myocardial infarction (chest pain, ECG changes, elevation of cardiac biomarkers), ischemic stroke (new neurological changes, brain CT with characteristic pathology), lower limb amputation and mesenteric ischemia (abdominal pain and changes on abdominal CT scan) as diagnosed by physicians in participating hospitals. Major bleeding was defined as an overt bleeding that required a transfusion of two or more units of blood, or was retroperitoneal, spinal, intracranial, or fatal. Fatal bleeding was defined as any death occurring within 10 days of a major bleeding episode, in the absence of an alternative cause of death. Fatal ischemia was defined as any death occurring with 10 days from the event, in absence of an alternative cause of death. 2.2. Baseline variables The following parameters were recorded when the qualifying episode of VTE was diagnosed: patient's sex, age and body weight; presence of arterial disease and its risk factors such as smoking, diabetes, hypertension and hyperlipidemia; presence of coexisting conditions such as chronic heart or lung disease; recent (b30 days prior to VTE) major bleeding; presence of risk factors for VTE, including cancer, immobilization, surgery; and initial presentation of VTE. 2.3. Treatment and follow-up Patients were managed according to the clinical practice of each participating hospital (i.e., treatment was not standardized). The type, dose and duration of anticoagulant therapy were recorded. Patients were followed for up to a year in the outpatient clinics. During each visit, any signs or symptoms suggesting ischemic event (chest pain, neurological deficit, limb or abdominal pain) or bleeding complications were registered. Each episode of clinically suspected ischemic event was investigated using appropriate methods (ECG, laboratory tests, angiography or appropriate CT scan). Most outcomes were classified as reported by the clinical centers. However, if the staff at the coordinating center was uncertain how to
classify a reported outcome, the event in question was reviewed by the central adjudication committee (b10% of events).
2.4. Statistical analysis Student's t test and X2 test (or Fisher's exact test where appropriate) were used to compare continuous and categorical variables (respectively) between patients being treated with antiplatelet drugs at VTE diagnosis that continued with these drugs versus those in whom this therapy was stopped. Incidence rates of ischemic events, major bleeding, recurrent VTE, as well as overall and specific causes of death were calculated and compared between the two groups of patients and expressed as the number of events per 100 patient-years on anticoagulant therapy. Odds ratios and corresponding 95% confidence intervals (CI) were calculated for clinical outcomes during the anticoagulant therapy. A p value b0.05 was considered to be statistically significant for all these comparisons. Because patients were not randomly assigned to continue antiplatelet therapy when VTE index events were diagnosed, we used propensity score matching to adjust for differences in baseline characteristics. Table 1 Clinical characteristics and treatment strategies of patients who continued or stopped antiplatelet therapy. Antiplatelet drugs withdrawn
Antiplatelet drugs continued
729
449
Patients, no. Clinical characteristics Gender (males) Mean age (years ± SD) Body weight (kg ± SD) Inpatients
346 (48%) 76 ± 11 76 ± 16 229 (32%)
‡
260 (58%) 74 ± 11 76 ± 16 129 (30%)
Arterial disease Prior coronary artery disease Prior cerebral ischemia Prior peripheral artery disease Current smoking Diabetes Hypertension
129 (18%)‡ 169 (24%) 87 (12%) 73 (10%) 213 (30%) 531 (75%)
171 (39%) 100 (23%) 62 (14%) 51 (12%) 141 (32%) 332 (76%)
Underlying conditions Chronic heart failure Chronic lung disease Abnormal creatinine levels Creatinine clearance b30 mL/min Anemia Recent major bleeding
180 (25%) 179 (25%)† 199 (28%) 73 (10%) 265 (36%)‡ 23 (3.2%)
100 (22%) 79 (18%) 141 (32%) 60 (13%) 211 (47%) 13 (2.9%)
Risk factors for VTE Postoperative Immobility ≥4 days Cancer None of the above Prior VTE
52 (7.1%)‡ 232 (32%) 76 (10%)† 398 (55%) 144 (20%)
62 (14%) 128 (29%) 70 (16%) 224 (50%) 79 (18%)
VTE presentation at baseline Pulmonary embolism
477 (65%)†
256 (57%)
Initial therapy Low-molecular-weight heparin Mean LMWH dose (IU/kg/day) LMWH dose ≥150 IU/kg/day Unfractionated heparin Fondaparinux Inferior vena cava filter
633 (87%) 177 ± 72⁎ 531 (77%)† 54 (7.4%) 17 (2.3%) 14 (1.9%)
402 (90%) 166 ± 68 302 (69%) 23 (5.2%) 11 (2.5%) 8 (1.8%)
Long-term therapy Vitamin K antagonists Low-molecular-weight heparin Days of treatment (mean, SD) Days of treatment (median, IQR)
523 (75%)‡ 160 (23%)‡ 242 ± 257 169 ± 214⁎
266 (63%) 149 (35%) 213 ± 215 133 ± 163
VTE, venous thromboembolism. ⁎ p b 0.05. † p b 0.01. ‡ p b 0.001.
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Table 2 Clinical outcome during the course of anticoagulation. Findings expressed as events per 100 patient-years and 95% confidence intervals. Antiplatelet drugs withdrawn Events, No Patients, No Years of treatment Myocardial infarction Ischemic stroke Amputation of lower limb Any ischemic event Major bleeding Recurrent VTE Recurrent PE Recurrent DVT Fatal bleeding Fatal PE Fatal myocardial infarction Fatal ischemic stroke Fatal lower limb ischemia Fatal ischemic events Overall death
729 483 1 3 1 11 28 13 5 8 5 3 1 0 0 1 67
Antiplatelet drugs continued Events per 100 patient-years
Events, No
Events per 100 patient-years
0.21 (0.01–1.02) 0.62 (0.16–1.69) 0.21 (0.01–1.02)† 2.28 (1.20–3.96)⁎ 5.80 (3.93–8.27) 2.69 (1.50–4.49) 1.04 (0.38–2.29) 1.66 (0.77–3.15) 1.04 (0.38–2.29) 0.62 (0.16–1.69) 0.21 (0.01–1.02) – – 0.21 (0.01–1.02) 13.9 (10.8–17.5)†
449 263 1 5 6 15 17 11 6 5 1 2 0 2 1 3 62
0.38 (0.02–1.88) 1.90 (0.70–4.21) 2.28 (0.92–4.74) 5.70 (3.31–9.20) 6.46 (3.89–10.1) 4.18 (2.20–7.27) 2.28 (0.93–4.74) 1.90 (0.70–4.21) 0.38 (0.02–1.88) 0.76 (0.13–2.51) – 0.76 (0.13–2.51) 0.38 (0.02–1.88) 1.14 (0.29–3.10) 23.6 (18.2–30.0)
Abbreviations: PE, pulmonary embolism; DVT, deep vein thrombosis; VTE, venous thromboembolism. ⁎ p b 0.05. † p b 0.01. ‡ p b 0.001.
Variables that were considered in the calculation of the propensity score included: gender, age, body weight, inpatient care, prior coronary artery disease, prior cerebral ischemia, prior peripheral artery disease, current smoking, diabetes, hypertension, chronic heart failure, chronic lung disease, creatinine clearance b30 mL/min, anemia, abnormal platelet count, recent major bleeding, postoperative state, immobility ≥4 days, cancer, and pulmonary embolism. We built a logistic regression model in which antiplatelet treatment at baseline was a dependent variable and the variables eventually related to either arterial ischemic events, major bleeding, recurrent VTE or overall death were independent variables. These models made it possible to calculate a propensity score, indicating the likelihood that any individual patient would have received antiplatelet treatment, given all other known covariates. We used the full matching method for the previously calculated propensity scores in order to make comparable patients in whom antiplatelet treatment was continued versus those in whom it was withdrawn. Full matching makes use of all individuals in the dataset by forming a series of matched sets in which each set has either one treated individual and multiple comparison individuals or one comparison individual and multiple treated individuals. Full matching has been shown to be particularly effective at reducing bias related to observed confounding variables [7]. After matching, we estimated covariate balance between patients continuing and withdrawing antiplatelets using absolute standardized differences [8], which directly quantifies the bias in the means and proportions of covariates across the groups, expressed as a percentage of the pooled standard deviations. We employed matched univariate logistic regression analysis to estimate associations of antiplatelet use with various outcomes. Propensity score matching was performed using the optmatch, RItools and MatchIt packages for R program v 2.15.1 and IBM SPSS software for Mac version 20 were used for analysis of the rest of data. 3. Results As of January 2014, 1178 patients in RIETE were receiving antiplatelet drugs at the time of VTE diagnosis. The mean follow-up was 213 days for patients who continued antiplatelet treatment and 242 days for those who discontinued this therapy. Antiplatelet therapy was discontinued in 729 (62%). Discontinuation of antiplatelet therapy was less frequently observed in males, patients initially presenting with PE, or having prior coronary heart disease, anemia, recent surgery or cancer (Table 1).
Most patients in both subgroups received low molecular weight heparin (LMWH) (87% and 90%) as initial therapy for VTE, and significantly more patients who discontinued the antiplatelet agents received higher doses of LMWH (77% vs. 69%; p b 0.01) (Table 1). Of note, more patients continuing with antiplatelet drugs switched to vitamin K antagonists (VKA) (Table 1), while patients discontinuing antiplatelet drugs received a longer course of anticoagulation (169 ± 214 days vs. 133 ± 163; p b 0.05). During anticoagulation, patients on antiplatelet therapy presented a higher rate of major adverse outcomes, including lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p b 0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p b 0.05) or death (23.6 vs. 13.9 deaths per 100 patients-years; p b 0.01), but no differences in the rate of major bleeding or recurrent VTE were observed (Table 2). A higher number of ischemic events (18 vs. 8), recurrent VTE (16 vs. 8) and overall deaths (97 vs. 32) occurred later (≥15 days) in the treatment of patients who received both antiplatelet and anticoagulant therapy (Table 3). Matched analysis showed patients on antiplatelet therapy to have a significantly higher rate of lower limb amputations (odds ratio: 15.3; 95% CI: 1.02–229) and an increased number of composite outcomes, Table 3 Number of adverse events that occurred in first two weeks after VTE diagnosis and later in treatment in patients who continued antiplatelet treatment. Days of treatment
Myocardial infarction Ischemic stroke Amputation of a lower limb Any ischemic event Major bleeding Recurrent VTE Recurrent PE Recurrent DVT Fatal bleeding Fatal PE Fatal myocardial infarction Fatal ischemic stroke Fatal lower limb ischemia Fatal ischemic events Overall death
≤15 days
≥15 days
1 2 3 8 20 8 4 4 2 5 0 1 0 1 32
1 6 4 18 25 16 7 9 4 0 2 1 1 3 97
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Table 4 Odds ratio for clinical outcome during the course of anticoagulation, according to antiplatelet treatment (continued vs. withdrawn), before and after matching.
Outcome Myocardial infarction Ischemic stroke Amputation of lower limb Any ischemic event Major bleeding Recurrent VTE Recurrent PE Recurrent DVT Fatal bleeding Fatal PE Fatal ischemic events Overall death Composite outcome Composite outcome with VTE complications
Pre-matching
Post full matching
1.63 (0.10–26.0) 2.73 (0.65–11.5) 9.86 (1.18–82.2)⁎ 2.07 (0.96–4.45) 0.99 (0.53–1.82) 1.38 (0.61–3.12) 1.96 (0.60–6.46) 1.02 (0.33–3.12) 0.32 (0.04–2.78) 1.08 (0.18–6.50) 4.90 (0.51–47.2) 1.53 (1.06–2.21)⁎
0.43 (0.02–7.69) 1.11 (0.24–5.02) 15.3 (1.02–229)⁎ 1.23 (0.53–2.85) 0.89 (0.45–1.75) 1.06 (0.43–2.61) 1.49 (0.42–5.30) 0.75 (0.21–2.76) 0.38 (0.04–3.65) 0.89 (0.14–5.80) 1.92 (0.19–19.4) 1.35 (0.91–2.00) 1.46 (1.02–2.11)⁎
1.72 (1.21–2.43)† 1.72 (1.23–2.39)†
1.46 (1.03–2.06)⁎
DVT, deep vein thrombosis; PE, pulmonary embolism. Composite outcome = death or ischemic events. Composite outcome with VTE complications = death or ischemic events or recurrent PE or DVT. ⁎ p b 0.05. † p b 0.01. ‡ p b 0.001.
including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03–2.06), with no differences in the rate of major bleeding (Table 4).
4. Discussion Patients receiving antiplatelet therapy due to prior arterial disease may develop VTE [5]. Physicians and patients are facing a challenge, since VTE should be treated with anticoagulants and concomitant antiplatelet therapy may increase the risk for bleeding. Current literature has not thoroughly addressed this question. Our data reveal that in real life one in every 3 such patients continued with both therapies and that this approach was not associated with an increased risk for bleeding, recurrent VTE, ischemic events or death. Our findings differ from those in recent trials demonstrating an increased rate of bleeding complications in patients concomitantly receiving anticoagulant and antiplatelet therapy, which reached 9.1% patients/year [6]. A plausible explanation for this difference could be attributed to a relatively short period of follow-up (up to 8 months) in our study and to the fact that most patients, assumed to be at a higher risk for bleeding in our series, would probably discontinue antiplatelet treatment at baseline. In our study, the rate of bleeding in both groups was similar, despite their high age (76 ± 11 and 74 ± 11), a finding that correlates with recent publications reporting a better outcome in octogenarian patients with atrial fibrillation and coronary events who were discharged with combined anticoagulant and antiplatelet treatment [9]. Recurrent VTE was found to be the same in both groups, despite different treatment regimens, which could be explained by a relatively short follow-up. On the contrary, the higher rate of ischemic events observed in patients that maintained antiplatelet treatment may be explained by the fact that they were sicker and more likely to develop ischemic events. Moreover, some of these patients may be resistant to antiplatelet treatment and therefore could have demonstrated active ischemic disease despite concomitant therapy [10]. In addition, antiplatelet treatment failure can be related to many other reasons, including patients' failure to take their medications appropriately or to drug–drug interactions [11–15]. The number of composite outcomes incorporating all-cause death, arterial events and VTE was higher among patients that continued
antiplatelet treatment. This can be explained by the fact that such patients have a higher rate of thrombotic risk factors, e.g., postoperative state and cancer. Other possible explanations are a longer treatment with anticoagulants in patients who discontinued antiplatelet therapy and higher doses of LMWH (Table 1), and a more potent treatment with VKA [16–18] which could account in part for the observed survival advantage. The limitations of the current study include the retrospective nature of the analysis of consecutively recruited patients, a relatively short follow-up period, lack of information regarding the specific antiplatelet regimen used or the international normalized ratio (INR) values and time in therapeutic range (TTR). 5. Conclusion Based on our results, the combination of antiplatelet drugs with anticoagulants used for a short-term treatment of VTE does not increase the risk for bleeding. Conflict of interest statement The authors have no conflicts to declare. Acknowledgements We express our gratitude to Sanofi Spain for supporting this Registry with an unrestricted educational grant. We also express our gratitude to Bayer Pharma AG for supporting this Registry. Bayer Pharma AG’s support was limited to the part of RIETE outside Spain, which accounts for a 20.9% of the total patients included in the RIETE Registry. We also thank the RIETE Registry Coordinating Center, S & H Medical Science Service, for their quality control data, logistic and administrative support. Appendix A
Coordinator of the RIETE Registry: RIETE Steering Committee Members:
RIETE National Coordinators:
RIETE Registry Coordinating Center:
Dr. Manuel Monreal (Spain) Dr. Hervè Decousus (France) Dr. Paolo Prandoni (Italy) Dr. Benjamin Brenner (Israel) Dr. Raquel Barba (Spain) Dr. Pierpaolo Di Micco (Italy) Dr. Laurent Bertoletti (France) Dr. Sebastian Schellong (Germany) Dr. Manolis Papadakis (Greece) Dr. Inna Tzoran (Israel) Dr. Abilio Reis (Portugal) Dr. Marijan Bosevski (R.Macedonia) Dr. Henri Bounameaux (Switzerland) Dr. Radovan Malý (Czech Republic) S & H Medical Science Service
Appendix B. Members of the RIETE Group SPAIN: Andújar V, Arcelus JI, Auguet T, Barba R, Barrón M, BarrónAndrés B, Bascuñana J, Blanco-Molina A, Bueso T, Casado I, Casillas C, Conget F, del Molino F, del Toro J, Falgá C, Fernández-Capitán C, Font L, Gallego P, García-Bragado F, Gómez V, González J, González-Bachs E, Guijarro R, Guil M, Gutiérrez J, Hernández L, Hernández-Huerta S, JaraPalomares L, Jaras MJ, Jiménez D, Jiménez R, Lobo JL, López-Jiménez L, López-Montes L, López-Reyes R, López-Sáez JB, Lorente MA, Lorenzo A, Luque JM, Llutart J, Madridano O, Marchena PJ, Martín M, MartínAntorán JM, Mellado M, Monreal M, Nauffal D, Nieto JA, Ogea JL, Otero R, Pagán B, Pedrajas JM, Peris ML, Porras JA, Pons I, Riera-Mestre A,
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