Blood Coagulation, Fibrinolysis and Cellular Haemostasis 1120 Efficacy and safety of early parenteral anticoagulation as a bridge to warfarin after mechanical valve replacement Joseph G. Mathew 1 ; Alex C. Spyropoulos 2 ; Arif Yusuf 1 ; Jessica Vincent 1 ; John Eikelboom 1,7 ; Olga Shestakovska 1 ; Stephen Fremes 3 ; Joseph Noora 4 ; Linrui Guo 5 ; Mark Peterson 6 ; Menaka Pai 7 ; Richard Whitlock 1 1 Population Health Research Institute, McMaster University, Hamilton, Canada; 2 Hofstra, North Shore/LIJ School of Medicine, Manhasset, New York, USA; 3 Sunnybrook Health Sciences Centre, Toronto, Canada; 4 Trillium Health Centre, Mississauga, Canada; 5 London Health Sciences Centre, London, Canada; 6 St. Michael s Hospital, Toronto, Canada; 7 Department of Medicine, McMaster University, Hamilton, Canada Summary Limited evidence exists to guide the use of early parenteral anticoagulation following mechanical heart valve replacement (MVR). The purpose of this study was to compare the 30-day rates of thrombotic and bleeding complications for MVR patients receiving therapeutic versus prophylactic dose bridging regimens. In this retrospective cohort study we reviewed anticoagulation management and outcomes of all patients undergoing MVR at five Canadian hospitals between 2003 and 2010. The primary efficacy outcome was thromboembolism (stroke, transient ischaemic attack, systemic embolism or valve thrombosis) and the primary safety outcome was major bleeding at 30-days. Outcomes were compared using a logistic regression model adjusting for propensity score and in a 1:1 propensity matched sample. A total of 1777 patients underwent mechanical valve replacement, of whom 923 received therapeutic dose bridging anticoagulation and 764 received prophylactic dose bridging postoperatively. Sixteen patients (1.8 %) who received therapeutic dose bridging and fifteen patients (2.1 %) who received prophylactic dose bridging experienced the primary efficacy outcome (odds ratio [OR] 0.90; 95 % confidence interval [CI], 0.37 to 2.18, p=0.81). Forty-eight patients (5.4 %) in the therapeutic group and 14 patients (1.9 %) in the prophylactic group experienced the primary safety outcome of major bleeding (OR 3.23; 95 % CI, 1.58 to 6.62; p=0.001). The direction of the effects, their magnitude and significance were maintained in the propensity matched analysis. In conclusion, we found that early after mechanical valve replacement, therapeutic dose bridging was associated with a similar risk of thromboembolic complications, but a 2.5 to 3-fold increased risk of major bleeding compared with prophylactic dose bridging. Keywords Cardiac surgery, valvular heart diseases, anticoagulants, heparin, thromboembolism Correspondence to: Dr. Richard Whitlock, MD, PhD David Braley Cardiac, Vascular & Stroke Research Institute 237 Barton Street East, Room 1C1 114 Hamilton, Ontario, Canada, L8L 2X2 Tel.: +1 905 521 2100 40306 E-mail: richard.whitlock@phri.ca Received: March 27, 2014 Accepted after major revision: June 24, 2014 Epub ahead of print: August 28, 2014 http://dx.doi.org/10.1160/th14-03-0284 Thromb Haemost 2014; 112: 1120 1128 Introduction Patients with mechanical heart valves require lifelong anticoagulation with a vitamin K antagonist to prevent thromboembolic complications (1, 2). Warfarin treatment is usually initiated within 48 hours (h) of valve replacement surgery but takes 4 5 days to reach therapeutic levels and during this time many cardiac surgeons bridge their patients with a rapidly acting parenteral anticoagulant. Uncertainty remains about the benefits of parenteral bridging anticoagulation after mechanical valve replacement surgery as well as about the choice and intensity of the anticoagulant. This uncertainty is highlighted by conflicting guideline recommendations: the 2005 European Society of Cardiology (ESC) consensus statement from the Valvular Heart Disease Working Groups recommends bridging with therapeutic dose intravenous (IV) unfractionated heparin (UFH) (3), the 2012 American College of Chest Physician (ACCP) guidelines suggest use of low-dose UFH, low-dose low-molecular-weight heparin (LMWH) or therapeutic dose LMWH over therapeutic dose UFH (Grade 2C evidence) (4), while the 2008 American College of Cardiology/ American Heart Association (ACC/AHA) guidelines make no recommendations regarding postoperative bridging anticoagulation (5). Lack of consensus among the guidelines may contribute to widely differing practices among cardiac surgery centres in the use of bridging anticoagulation after mechanical valve replacement (6). The purpose of this study was to describe the use of early postoperative bridging anticoagulation at Canadian cardiac surgery centres for patients undergoing mechanical valve replacement and to compare the rates of thrombotic and bleeding events between patients receiving standard therapeutic doses of bridging anticoagulation and those receiving less intensive (prophylactic dose) bridging anticoagulation.
1121 Mathew et al. Bridging anticoagulation after mechanical heart valve replacement Methods Design Five Canadian cardiac surgical centres participated in this study. Data were collected for every patient undergoing heart valve replacement with a mechanical prosthesis from January 1, 2003 to December 31, 2010 at participating centres. The study was approved by the local research ethics board at each of the five participating centres. Patients Patients were eligible for this study if they were 18 years or older at the time of mechanical valve replacement surgery. Patients with concomitant coronary artery bypass graft (CABG) and aortic procedures were included. Data collection Using standardised case report forms, detailed preoperative and postoperative data were collected from patient charts and clinical databases ( Table 2). Patient demographics and risk factors for thrombosis and bleeding were most commonly obtained from consult notes and pre-operative clinic notes. Valve type and position were obtained from operative reports. Data regarding the type and daily dose of parenteral anticoagulant were collected to 30 days or hospital discharge from medication administration records and physician order sheets. Thrombotic outcomes were identified from progress notes and diagnostic imaging reports. Bleeding outcomes were ascertained from progress notes, and then confirmed with laboratory evidence of a fall in hemoglobin or evidence of blood transfusions from blood bank records. Outcomes The primary efficacy outcome was arterial thromboembolism, defined as the composite of: stroke, transient ischaemic attack (TIA), systemic embolism or valve thrombosis confirmed by imaging. Secondary efficacy outcomes included individual components of the primary outcome as well as venous thromboembolism (VTE), defined as deep-vein thrombosis (DVT) or pulmonary embolism (PE) confirmed by objective diagnostic testing, death, and length of stay. The primary safety outcome was major bleeding, defined as clinically overt bleeding with the additional requirement of a drop in haemoglobin 20 g/l, or necessitating transfusion of 2 units of packed red blood cells (PRBCs), bleeding into a critical organ (intracranial, intraspinal, intraocular, retroperitoneal, or intra-articular), surgical site bleeding requiring re-operation or re-admission to the intensive care unit (ICU), and fatal bleeding. Only bleeding starting after the first dose of post-operative parenteral anticoagulation was recorded. Efficacy and safety outcomes were collected up until hospital discharge or 30 days post valve replacement surgery, whichever came first. and prophylactic dose treatment groups In general, prophylactic bridging anticoagulation was defined by doses typically used for DVT prophylaxis, while therapeutic anticoagulation was defined by doses used for treatment of confirmed thromboembolism ( Table 1). At each site, use of IV UFH was guided by a nomogram-based therapeutic protocol. Patients experiencing an arterial or venous thromboembolic event were categorised based on the agent the patient was exposed to for the longest period of time prior to the event, while patients experiencing no adverse events within 30 days of valve surgery were categorised based on the agent the patient was exposed to for the longest period of time during their hospital stay. If the patient experienced a bleeding event, categorisation was based on the most recent agent used prior to the event. Statistical analysis and sample size Patient baseline characteristics and surgical details were summarised as means and standard deviations for continuous variables and numbers and percentages for categorical variables. Differences in baseline characteristics between therapeutic and prophylactic treatment groups in the entire sample were tested using Wilcoxon two-sample test for continuous variables and Pearson chi-square test for categorical variables. Table 1: Categorisation of parenteral bridging anticoagulation treatment groups. Group dose parenteral anticoagulation dose parenteral anticoagulation No parenteral anticoagulation Description dose UFH dose LMWH dose other Low dose UFH Low dose LMWH Low dose other No parenteral anticoagulant Definition > 15,000 IU sc/day or nomogram-based IV UFH Dalteparin > 10,000 IU QD; and/or Enoxaparin > 75 mg QD; and/or Tinzaparin > 8,750 IU QD Danaparoid > 1,500 units sc BID; and/or Fondaparinux > 5 mg QD 15000 IU sc/day Dalteparin < 5,000 IU QD; and/or Enoxaparin < 60mg QD; and/or Tinzaparin < 3,750 IU QD Danaparoid < 750 units sc BID; and/or Fondaparinux < 2.5 mg QD Patient not given any anticoagulant BID = bis in die (twice daily); IU= international units; IV = intravenous; LMWH= low-molecular-weight heparin; QD= quaque die (once daily); SC=subcutaneous; UFH = unfractionated heparin. Thrombosis and Haemostasis 112.6/2014 Schattauer 2014
Mathew et al. Bridging anticoagulation after mechanical heart valve replacement 1122 A All baseline characteristics as well as study centre and year of surgery were included in a logistic regression model to estimate the propensity score or predicted probability of patients receiving either therapeutic or prophylactic of antithrombotic treatment as a function of their baseline characteristics. Consecutively, patients in the two groups were matched 1:1 on the logit of the propensity score with calipers of width equal to 0.2 of the standard deviation of the logit of the propensity score (7, 8) ( Figure 1). Differences between baseline characteristics in the matched sample were tested using Wilcoxon signed rank sum test for continuous variables and McNemar s test for categorical variables. Standardised differences were calculated before and after propensity matching and the absolute standardised differences (%) were presented in a love plot (9). We used a logistic regression model with propensity score included as a covariate to estimate the effect of therapeutic vs prophylactic of antithrombotic treatment on the risk of study efficacy and safety outcomes. Higher terms of the propensity score were tested and if not significant they were removed from the model. The final model included group and a linear term of the propensity score as explanatory variables. Further, the effect of therapeutic vs prophylactic was estimated in the matched sample using exact conditional logistic regression with matched pairs as strata. The standardised differences of all baseline characteristics in the matched sample were within 10 %, therefore only group was included in the model as an explanatory variable. Because matching resulted in substantial reduction of the sample size (matches were found for only approximately half of the patients), we also performed a stratified analysis by sub-classifying patients in the entire sample according to quintiles of the propensity score, and using exact conditional logistic regression with quintiles as strata. Type I error level was set at 5 % and all tests of significance were two-sided. For sample size calculation, assuming risk of major bleeding of 6 % in the therapeutic group and 3 % in the prophylactic group (10)], it was determined that a total of 1,498 patients (749 per group) would be needed in order to have 80 % power to detect 50 % relative risk reduction in the risk of major bleeding between therapeutic and prophylactic bridging with a two-sided type I error of 5 % using Pearson Chi-square test. Analyses were conducted using SAS software, version 9.2 of the SAS System for SunOS (SAS Institute Inc., Cary, NC, USA). Sensitivity analysis Analyses were repeated with the treatment groups defined based on the first parenteral agent and dose received by a patient. B Figure 1: Distribution of the propensity score in therapeutic and prophylactic groups, before and after propensity matching. Results Characteristics of study patients A total of 1,777 patients underwent mechanical valve replacement at the five study centres between 2003 and 2010, of who 923 received therapeutic of antithrombotic treatment and 764 received prophylactic of antithrombotic treatment during 30 days post-surgery. Thirteen patients received intermediate of LMWH and 77 patients received no bridging therapy; because of small group sizes these patient were excluded from the analysis.
1123 Mathew et al. Bridging anticoagulation after mechanical heart valve replacement Table 2: Baseline characteristics of study patients by group. Table 2: Ba Before propensity matching After propensity matching (N=923) (N=764) (N=393) (N=393) Age, years 59.1 ± 11.3 57.4 ± 10.2 0.0003 58.1 ± 10.7 57.7 ± 10.6 0.34 Male sex 524 (56.8) 491 (64.3) 0.002 257 (65.4) 240 (61.1) 0.22 Valve position 0.22 Aortic 393 (42.6) 546 (71.5) 262 (66.7) 259 (65.9) Mitral 398 (43.1) 177 (23.2) 103 (26.2) 110 (28.0) Aortic + Mitral 112 (12.1) 36 (4.7) 23 (5.9) 19 (4.8) Mitral + Tricuspid 14 (1.5) 4 (0.5) 4 (1.0) 4 (1.0) Aortic + Mitral + Tricuspid 6 (0.7) 1 (0.1) 1 (0.3) 1 (0.3) Concomitant CABG surgery 229 (24.8) 225 (29.5) 0.03 105 (26.7) 105 (26.7) > 0.99 History of atrial fibrillation 398 (43.2) 175 (22.9) 108 (27.5) 109 (27.7) 0.93 Rheumatic heart disease 236 (25.6) 102 (13.4) 63 (16.0) 62 (15.8) 0.92 Previous arterial thromboembolic event 84 (9.1) 41 (5.4) 0.004 24 (6.1) 27 (6.9) 0.66 Peripheral vascular disease 35 (3.8) 22 (2.9) 0.30 13 (3.3) 15 (3.8) 0.69 History of venous thromboembolism 27 (2.9) 16 (2.1) 0.28 > 0.99 Congestive heart failure 370 (40.3) 185 (24.6) 116 (29.5) 112 (28.5) 0.75 Previous myocardial infarction 122 (13.2) 89 (11.6) 0.33 50 (12.7) 46 (11.7) 0.65 Malignancy 41 (4.4) 33 (4.3) 0.90 22 (5.6) 20 (5.1) 0.76 Prior stroke 60 (6.5) 29 (3.8) 0.01 17 (4.3) 19 (4.8) 0.72 Diabetes 172 (18.7) 155 (20.3) 0.40 83 (21.1) 81 (20.6) 0.86 Hypertension 474 (51.4) 388 (50.9) 0.84 215 (54.7) 211 (53.7) 0.77 History of thrombocytopenia 13 (1.4) 8 (1.0) 0.50 2 (0.5) 3 (0.8) 0.65 Previous gastrointestinal bleed 1 17 (2.2) 0.58 8 (2.0) 0.80 Coagulopathy or bleeding disorder 11 (1.2) 15 (2.0) 0.20 5 (1.3) 0.53 Pre-op use of NSAIDs 10 (1.1) 23 (3.0) 0.004 9 (2.3) 0.62 Pre-op use of antiplatelets 176 (19.2) 130 (17.2) 0.29 79 (20.1) 72 (18.3) 0.52 Post-op laboratory values Serum creatinine, µmol/l 102.4 ± 63.2 97.8 ± 86.4 99.8 ± 65.2 103.7 ± 94.7 0.06 Among the 1687 patients in the primary analysis, 939 (56 %) underwent isolated aortic valve replacement, 575 (34 %) underwent isolated mitral valve replacement, and 148 (9 %) underwent combined aortic and mitral valve replacement ( Table 2). Mean age was 58 years and 40 % of the patients were female. Compared with patients receiving prophylactic dose bridging, those receiving therapeutic dose anticoagulation were more likely to have baseline characteristics associated with increased risk of arterial thromboembolism such as mechanical mitral valve (43 % vs 23 %, p), history of atrial fibrillation (43 % vs 23 %, p), previous thromboembolic event (9 % vs 5 %, p=0.004), and congestive heart failure (40 % vs 25 %, p) ( Table 2). Factors significantly affecting propensity to receive therapeutic bridging were isolated mitral valve replacement, combined aortic and mitral valve replacement, history of atrial fibrillation, rheumatic heart disease, initiation of warfarin therapy after greater than two days post-surgery and site (standardised difference > 0.3), while major factors influencing the decision to use non-therapeutic anticoagulation were isolated aortic valve replacement, initiation of oral anticoagulation on day one post-operative and site (standardised difference < 0.3). The absolute standardised differences of all baseline characteristics in the propensity matched sample were within 10 % ( Figure 2), which can be taken to indicate a negligible difference between treatment groups (8). Thrombosis and Haemostasis 112.6/2014 Schattauer 2014
Mathew et al. Bridging anticoagulation after mechanical heart valve replacement 1124 Table 2: Continued Platelet count, 10 9 /l Haemoglobin, g/dl No. of days until OAC started Not given < 24 hours 1 day 2 days > 2 days Study centre Site 1 Site 2 Site 3 Site 4 Site 5 Year of surgery 2003 2004 2005 2006 2007 2008 2009 2010 Before propensity matching (N=923) 173.8 ± 84.7 10.5 ± 3.1 36 (3.9) 115 (12.5) 276 (30.1) 176 (19.2) 315 (34.3) 104 (11.3) 169 (18.3) 147 (15.9) 165 (17.9) 338 (36.6) 74 (8.0) 116 (12.6) 148 (16.0) 105 (11.4) 121 (13.1) 131 (14.2) 159 (17.2) 69 (7.5) (N=764) 162.6 ± 66.7 10.4 ± 5.3 26 (3.4) 72 (9.5) 404 (53.3) 148 (19.5) 108 (14.2) 420 (55.0) 79 (10.3) 107 (14.0) 36 (4.7) 122 (16.0) 34 (4.5) 88 (11.5) 97 (12.7) 98 (12.8) 115 (15.1) 122 (16.0) 112 (14.7) 98 (12.8) Missing data in therapeutic/prophylactic groups: concomitant CABG surgery (1/0), history of atrial fibrillation (1/1), rheumatic heart disease (1/0), previous arterial thromboembolic event (1/0), peripheral vascular disease (1/0), history of venous thromboembolism (1/0), congestive heart failure (4/13), previous myocardial infarction (1/0), malignancy (1/0), prior stroke (1/0), diabetes (1/0), hypertension (0/1), history of thrombocytopenia (1/0), previous gastro - intestinal bleed (1/0), coagulopathy or bleeding disorder (1/0), pre-op use of NSAIDs (4/5), pre-op use of antiplatelets (8/9), serum creatinine (6/3), platelet count (8/2), hemoglobin (4/2), no. of days until OAC started (5/6). 0.04 0.01 0.0002 After propensity matching (N=393) 173.0 ± 81.0 10.7 ± 3.8 16 (4.1) 57 (14.5) 168 (42.7) 77 (19.6) 75 (19.1) 90 (22.9) 83 (21.1) 95 (24.2) 27 (6.9) 98 (24.9) 17 (4.3) 37 (9.4) 56 (14.2) 49 (12.5) 61 (15.5) 64 (16.3) 67 (17.0) 42 (10.7) (N=393) 170.1 ± 74.1 10.8 ± 6.1 17 (4.3) 54 (13.7) 175 (44.5) 68 (17.3) 79 (20.1) 100 (25.4) 71 (18.1) 81 (20.6) 32 (8.1) 109 (27.7) 25 (6.4) 34 (8.7) 57 (14.5) 48 (12.2) 60 (15.3) 55 (14.0) 64 (16.3) 50 (12.7) 0.89 0.26 0.52 0.52 0.52 Primary efficacy and safety outcomes Arterial thromboembolism (stroke, TIA, systemic embolism or valve thrombosis) occurred in 16 patients (1.8 %) who received therapeutic dose bridging and 15 patients (2.1 %) who received prophylactic dose bridging (odds ratio [OR] 0.90; 95 % confidence interval [CI], 0.37 to 2.18; P=0.81) ( Table 3). Forty-eight patients (5.4 %) in the therapeutic group and 14 patients (1.9 %) in the prophylactic group experienced the primary safety outcome of major bleeding (OR 3.23; 95 % CI, 1.58 to 6.62; p=0.001). The direction of the effects, their magnitude, and their significance were all maintained in both the matched propensity analysis and the stratification for propensity score quintiles ( Table 3). Secondary outcomes Risk of death was 3.1 % in patients treated with therapeutic dose anticoagulation and 3.0 % in patients treated with prophylactic dose anticoagulation (OR 1.02; 95 % CI 0.51 to 2.07; p=0.95) ( Table 4). Venous thromboembolism occurred in four patients (0.5 %) receiving therapeutic dose anticoagulation and five patients (0.7 %) receiving prophylactic dose anticoagulation. Finally, 57.3 % of patients receiving therapeutic dose anticoagulation and 19.4 % receiving prophylactic dose anticoagulation had hospital stay 10 days (OR 3.08; 95 % CI 2.36 to 4.01; p).
1125 Mathew et al. Bridging anticoagulation after mechanical heart valve replacement Figure 2: Absolute standardised differences between baseline characteristics of the patients in therapeutic and prophylactic groups, before ( ) and after ( ) propensity matching. Thrombosis and Haemostasis 112.6/2014 Schattauer 2014
Mathew et al. Bridging anticoagulation after mechanical heart valve replacement 1126 Outcome No. of Events/Patients (%) Dosing (N=923) Dosing (N=764) Odds Ratio (95 % CI) Table 3: Primary efficacy and safety outcomes, by group. Adjustment for propensity score Primary efficacy outcome (stroke, TIA, systemic embolism, or valve thrombosis) 16/895 (1.8) 15/729 (2.1) 0.90 (0.37 2.18) 0.81 Primary safety outcome (major bleeding) 48/894 (5.4) 14/729 (1.9) 3.23 (1.58 6.62) 0.001 Matching on propensity score Primary efficacy outcome (stroke, TIA, systemic embolism, or valve thrombosis) 7/393 (1.8) 7/393 (1.8) 1.00 (0.35 2.85) > 0.99 Primary safety outcome (major bleeding) 18/393 (4.6) 7/393 (1.8) 2.57 (1.03 7.28) 0.04 Stratification by propensity score quintiles Primary efficacy outcome (stroke, TIA, systemic embolism, or valve thrombosis) 16/895 (1.8) 15/729 (2.1) 1.01 (0.39 2.60) > 0.99 Primary safety outcome (major bleeding) 48/894 (5.4) 14/729 (1.9) 3.05 (1.43 6.86) 0.003 Outcome No. of Events/Patients (%) Dosing (N=923) Dosing (N=764) Odds Ratio (95 % CI) Table 4: Secondary efficacy outcomes, by group. Adjustment for propensity score Stroke 8/895 (0.9) 7/729 (1.0) 0.67 (0.19 2.37) 0.54 TIA 3/895 (0.3) 3/729 (0.4) Systemic embolism 3/895 (0.3) 2/729 (0.3) Valve thrombosis 4/895 (0.5) 4/729 (0.6) VTE or death 32/895 (3.6) 27/729 (3.7) 0.95 (0.50 1.81) 0.87 VTE 4/895 (0.5) 5/729 (0.7) Death 28/895 (3.1) 22/728 (3.0) 1.02 (0.51 2.07) 0.95 Prolonged hospital stay 10 days 512/893 (57.3) 141/728 (19.4) 3.08 (2.36 4.01) Sensitivity analysis Re-categorising patients based on the first parenteral anticoagulant exposure resulted in 433 group changes. The majority (84.3 %) were patients in the therapeutic group based on duration of treatment in the primary analysis that moved to the prophylactic dose group. These were commonly patients who received a single prophylactic dose of anticoagulant just prior to initialising the therapeutic parenteral anticoagulant regimen. Repeating the analysis with these groups yielded similar results for both the primary efficacy outcome and for major bleeding, although non-significant trends towards an increase in the risk of the primary efficacy outcome was seen in the prophylactic heparin bridging group (3.1 % vs 2.2 %, p=0.07, Suppl. Table 1, available online at www. thrombosis-online.com). Comparison of outcomes with different heparin agents A total of 1,216 patients (68.4 %) received UFH while 445 patients (25.0 %) received LMWH. In a post-hoc analysis comparing outcomes between UFH vs LMWH, there were more thromboem-
1127 Mathew et al. Bridging anticoagulation after mechanical heart valve replacement bolic complications with therapeutic UFH compared to therapeutic LMWH (2.4 % vs 0.9 %; OR 5.57; 95 % CI 1.07 29.1; p=0.04) and a trend towards more major bleeding with therapeutic UFH (7.2 % vs 2.5 %; OR 2.75; 0.94 8.07; p=0.07). There was no difference in outcomes when comparing prophylactic UFH vs prophylactic LMWH (Suppl. Table 2, available online at www.throm bosis-online.com). Discussion We found that therapeutic compared with prophylactic dose parenteral bridging anticoagulation was associated with similar 30-day rates of thromboembolic complications (stroke, TIA, systemic embolism, and valve thrombosis), but a 2.5 to 3-fold excess of major bleeding and prolonged hospital stay following mechanical valve replacement. Previous studies comparing the rates of thromboembolic complications and bleeding associated with different heparin bridging regimens following mechanical valve replacement were limited by small sample sizes and low event rates, although the thromboembolic rate of 2.0 % and major bleed rate of 2 5 % in the present study are in-line with previous experience (11 15). The largest of these studies involved 245 patients and revealed a thromboembolic event rate of 1.5 % and a nearly two-fold increase in major bleeding (8.8 % absolute rate) when comparing mostly treatmentdose UFH vs treatment-dose LMWH as bridging therapy in patients with mechanical heart valves on long-term oral anticoagulants (15). However, none of the previous studies had control groups or enough power to detect differences in prophylactic dose bridging regimens versus therapeutic-dose bridging regimens. A systematic review by Kulik et al. (10) of 30 studies demonstrated that prophylactic dose subcutaneous UFH, IV UFH and therapeutic dose LMWH were associated with similar rates of thromboembolism (0.9 %, 1.1 % and 0.6 %, respectively) whereas prophylactic dose UFH had lower rates of early postoperative bleeding compared to IV UFH and therapeutic dose LMWH (3.3 %, 7.2 % and 4.8 %, respectively). Our study results confirm these findings revealing a low thromboembolic event rate but a 2.5 to 3-fold increased risk of major bleeding using therapeutic-dose heparin bridging. These results are also consistent with a recent large metaanalysis by Siegal et al. demonstrating that therapeutic compared with prophylactic heparin bridging in patients on chronic warfarin undergoing elective surgery or other invasive procedures was associated with no differences in thromboembolic events (OR 0.30; 95 % CI, 0.04 2.09), but a greater than three-fold increased risk of major bleeding (OR, 3.60; 95 % CI, 1.52 8.50) (16). Lastly, a recently published study (BRUISE CONTROL) also found an excess of post-procedural bleeding events in patients on chronic warfarin undergoing pacemaker or defibrillator surgery with full therapeutic dose bridging therapy with UFH or LMWH with no differences in thromboembolic complications over the group that continued warfarin (17). Our study adds to this growing body of evidence that questions the benefits of using therapeutic-dose anticoagulant bridging during warfarin initiation or re-initiation in patients undergoing surgical procedures to prevent thromboembolic events in the post-procedural period including patients at perceived high thromboembolic risk such as those with mechanical heart valves. Our results also support the findings of previous studies showing significantly increased length of hospital stay in patients receiving IV therapeutic bridging anticoagulation (13, 15), and is the first to show this when directly comparing patients receiving therapeutic vs prophylactic bridging. Patients who received therapeutic bridging in our study were at higher baseline risk for arterial thromboembolism with a higher rate of mitral valve replacement, atrial fibrillation and previous thromboembolic events. Due to the retrospective nature of this study, we cannot exclude the possibility that these high-risk patients were protected by the use of therapeutic doses of bridging anticoagulation, leading to similar rates of thromboembolic complications compared to patients receiving prophylactic bridging. However, even after propensity matching there continued to be no difference in thromboembolic complications between patients receiving therapeutic vs prophylactic bridging. Our study also demonstrates that study centre is a major factor influencing treatment selection, which supports existing evidence that choice of post-operative bridging after mechanical valve replacement is largely based on surgeon and institutional preference due to the current What is known about this topic? Patients with mechanical heart valves require lifelong anticoagulation with a vitamin K antagonist to prevent thromboembolic complications. Many surgeons bridge their patients with a rapidly acting parenteral anticoagulant early after mechanical heart valve replacement until warfarin reaches therapeutic levels. Practice patterns for bridging anticoagulation after mechanical valve replacement vary considerably among cardiac surgery centres, both in the choice of anticoagulant (e.g. unfractionated vs low-molecular-weight heparin) and in the intensity of therapy (e.g. therapeutic vs prophylactic ). There is limited evidence to guide the use of parenteral anticoagulation in the early postoperative period after mechanical valve replacement, which is highlighted by conflicting guideline recommendations. What does this paper add? In the early postoperative period after mechanical valve replacement, therapeutic-dose bridging compared with prophylactic bridging was associated with similar 30-day rates of thromboembolic complications, but a significantly increased risk of major bleeding and prolonged hospital stay. This study adds to a growing body of evidence that questions the benefits of using therapeutic-dose anticoagulant bridging during warfarin initiation or re-initiation in patients undergoing surgical procedures to prevent thromboembolic events in the post-procedural period, including patients at perceived high thromboembolic risk such as those with mechanical heart valves. Thrombosis and Haemostasis 112.6/2014 Schattauer 2014
Mathew et al. Bridging anticoagulation after mechanical heart valve replacement 1128 lack of evidence to guide treatment and inconsistency in existing guidelines (6). Although this study cannot identify which particular subset of patients may benefit from therapeutic bridging due to limitation of sample size, the results suggest that therapeutic anticoagulation should not be routinely used in all patients undergoing mechanical valve replacement due to the substantial risk of major bleeding. While therapeutic bridging may still be warranted in patients at significantly increased risk of thromboembolism such as patients with mechanical mitral valve prostheses in addition to atrial fibrillation or mechanical valve patients with high CHADS 2 scores, there are currently no definitive studies to address which particular set of risk factors warrant therapeutic bridging. Furthermore, as detailed above, there is growing evidence that therapeutic dose heparin bridging, even in patients at moderateto-high risk of TE such as those with high CHADS 2 score, atrial fibrillation and mechanical heart valves, is harmful and without concurrent reduction in post-procedural thromboembolic risk. If therapeutic bridging is to be administered, our study suggests that therapeutic LMWH heparin is likely safer then therapeutic UFH in this population. Ours is the largest comparison of different bridging regimens in patients early after mechanical valve replacement. The strengths of our study are that we included consecutive patients over an eightyear period which minimises the potential for selection biases and our primary efficacy and safety outcomes were defined using objective criteria. We also collected detailed pre-operative and postoperative data and used propensity score analysis to adjust for factors that bias treatment selection. Finally, the results were consistent across different analysis approaches: propensity score adjustment, propensity matched, and stratification by propensity score quintiles. The most important limitation of our study is the potential for confounding. We used propensity score to adjust for known potential confounders but we cannot exclude the potential effect of unknown confounders given the observational study design. Although some patients received both therapeutic and prophylactic bridging regimens, we addressed this by classifying exposure according to the predominant anticoagulant regimen and by demonstrating consistent results when exposure was defined by the first anticoagulant regimen received. Finally, we are unable to account for variability in warfarin and quality of anticoagulation control which may have impacted our results. These issues will be addressed in future randomised trials that will further inform clinicians as to the safety and efficacy of bridging therapy in patients at high risk for thromboembolism. (i. e. PERIOP-2 and BRIDGE Study, www.clinicaltrials.gov) In conclusion, we demonstrated that therapeutic dose bridging anticoagulation early after mechanical valve replacement was associated with a similar risk of TE and a 2.5 to 3-fold increased risk of major bleeding compared with prophylactic bridging. Acknowledgements This study was funded by a Clinical Research Grant from the McMaster University Surgical Associates. Conflict of interest None declared. References 1. Mok CK, Boey J, Wang R, et al. Warfarin versus dipyridamole- aspirin and pentoxifylline-aspirin for the prevention of prosthetic heart valve thromboembolism: a prospective randomized clinical trial. Circulation 1985; 72: 1059 1063. 2. Cannegieter SC, Rosendaal FR, Briet E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994; 89: 635 641. 3. Butchart EG, Gohlke-Bärwolf C, Antunes MJ, et al.; Working Groups on Valvular Heart Disease, Thrombosis, and Cardiac Rehabilitation and Exercise Physiology. Recommendations for the management of patients after heart valve surgery. Eur Heart J 2005; 26: 2463 2471. 4. Whitlock RP, Sun JC, Fremes SE, et al.; American College of Chest Physicians. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e576s-600s. 5. Bonow RO, Carabello BA, Chatterjee K, et al.; American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008; 52 :e1 142. 6. Kulik A, Rubens FD, Baird D, et al. Early postoperative anticoagulation after mechanical valve replacement: a Canadian survey. J Heart Valve Dis 2006; 15: 581 587. 7. Austin PC. Primer on statistical interpretation or methods report card on propensity-score matching in the cardiology literature from 2004 to 2006: a systematic review. Circ Cardiovasc Qual Outcomes 2008; 1: 62 67. 8. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011; 46: 399 424. 9. Heinze G, Jüni P. An overview of the objectives of and the approaches to propensity score analyses. Eur Heart J 2011; 32: 1704 1708. 10. Kulik A, Rubens FD, Wells PS, et al. Early postoperative anticoagulation after mechanical valve replacement: a systematic review. Ann Thorac Surg 2006; 81: 770 781. 11. Ageno W, Turpie AG, Steidl L, et al. Comparison of a daily fixed 2.5-mg warfarin dose with a 5-mg, international normalized ratio adjusted, warfarin dose initially following heart valve replacement. Am J Cardiol 2001; 88: 40 44. 12. Montalescot G, Polle V, Collet JP, Leprince P, Bellanger A, Gandjbakhch I, Thomas D.. Low molecular weight heparin after mechanical heart valve replacement. Circulation 2000; 101: 1083 1086. 13. Fanikos J, Tsilimingras K, Kucher N, et al. Comparison of efficacy, safety, and cost of low-molecular-weight heparin with continuous-infusion unfractionated heparin for initiation of anticoagulation after mechanical prosthetic valve implantation. Am J Cardiol 2004; 93: 247 250. 14. Iliuta L, Candea V, Vasilescu A, et al. Fraxiparine versus unfractionated heparin for the perioperative anticoagulant therapy in patients undergoing mechanical prosthetic heart valve replacement. Arch Union Med Balkan 2003; 38: 141 148. 15. Spyropoulos AC, Turpie AG, Dunn AS, et al.; REGIMEN Investigators. Perioperative bridging therapy with unfractionated heparin or low-molecular-weight heparin in patients with mechanical prosthetic heart valves on long-term oral anticoagulants (from the REGIMEN Registry). Am J Cardiol 2008; 102: 883 889. 16. Siegal D, Yudin J, Kaatz S, et al. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates. Circulation 2012; 126: 1630 1639. 17. Birnie DH, Healey JS, Wells GA, et al.; BRUISE CONTROL Investigators. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013; 368: 2084 2093.