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Urgent surgery or procedures in patients taking dabigatran or warfarin: Analysis of perioperative outcomes from the RE-LY trial
Thrombosis Research 139 (2016) 77–81
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Urgent surgery or procedures in patients taking dabigatran or warfarin: Analysis of perioperative outcomes from the RE-LY trial☆,☆☆ James D. Douketis a,⁎, Jeff S. Healey a,b, Martina Brueckmann c,e, Mandy Fraessdorf c, Alex C. Spyropoulos d, Lars Wallentin g, Jonas Oldgren g, Paul Reilly h, Michael D. Ezekowitz f, Stuart J. Connolly a,b, Salim Yusuf a,b, John W. Eikelboom a,b a
Department of Medicine, McMaster University, Hamilton, Canada Population Health Research Institute, McMaster University, Hamilton, Canada c Boehringer Ingelheim Pharma GmbH & Co, Ingelheim am Rhein, Germany d Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, NY, USA e Medical Faculty, Mannheim University of Heidelberg, Germany f Jefferson Medical College, Wynnewood, PA, USA g Uppsala Clinical Research Centre and Department of Medical Sciences Cardiology, Uppsala University, Sweden h Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA b
a r t i c l e
i n f o
Article history: Received 24 October 2015 Received in revised form 4 January 2016 Accepted 5 January 2016 Available online 9 January 2016 Keywords: Urgent surgery Dabigatran Warfarin Perioperative
a b s t r a c t Background: There is concern about the management of anticoagulated patients with atrial fibrillation (AF) who require an urgent surgery/procedure, especially in those who are receiving a direct oral anticoagulant such as dabigatran. Methods: We accessed the database from RE-LY, a randomized trial comparing dabigatran (110 mg and 150 mg twice daily) with warfarin for stroke prevention in AF, to assess patients who had an urgent and elective surgery/ procedure. We compared the risk for thromboembolism, major bleeding and mortality according to treatment allocation (dabigatran 110 mg or 150 mg, or warfarin) or surgery/procedure type (urgent or elective). Outcomes were assessed from day-7 to day 30 after a surgery/procedure. Results: 353 patients (2.0% of study population) had an urgent surgery/procedure and 4168 patients (23.1% of study population) had an elective surgery/procedure. In patients on dabigatran 110 mg, dabigatran 150 mg and warfarin who had an urgent surgery/procedure: rates of thromboembolism were 16.1%, 7.4%, and 10.5%; rates of major bleeding were 17.0%, 17.6%, and 22.9%; rates of mortality were 6.3%, 1.5%, and 2.9%, respectively (P N 0.50 for all comparisons). Rates of these outcomes were multi-fold higher in patients having an urgent rather than an elective surgery/procedure (P b 0.5 for all comparisons). Conclusion: In anticoagulated patients with atrial fibrillation who require an urgent surgery/procedure, the risks for thromboembolism, major bleeding and mortality did not differ depending on treatment with dabigatran or warfarin, but rates of these outcomes were multi-fold higher than in patients having an elective surgery/ procedure. © 2016 Elsevier Ltd. All rights reserved.
1. Introduction ☆ Role of the funding sourceThere was no funding provided for this study. ☆☆ DisclosuresThe following authors are employed by Boehringer Ingelheim, which manufactures dabigatran: Martina Brueckmann, Mandy Fraessdorf, and Paul Reilly. The following authors have received consulting fees and/or research grants from Boehringer Ingelheim, and/or have participated in advisory boards by Boehringer Ingelheim, which manufactures dabigatran: James D. Douketis, Jeff S. Healey, Michael D. Ezekowitz, Jonas Oldgren, Alex C. Spyropoulos, Lars Wallentin, Stuart J. Connolly, John W. Eikelboom. ⁎ Corresponding author at: St. Joseph's Healthcare Hamilton, Room F-544, 50 Charlton Ave. East, Hamilton, ON L8N 4A6, Canada. E-mail address: [email protected] (J.D. Douketis).
http://dx.doi.org/10.1016/j.thromres.2016.01.004 0049-3848/© 2016 Elsevier Ltd. All rights reserved.
The management of anticoagulated patients who need an urgent surgery or procedure poses a major concern for clinicians, especially if they are receiving a direct oral anticoagulant (DOAC) such as dabigatran, rivaroxaban, apixaban or edoxaban. This concern may be related, in part, to uncertainty as to the risks for thromboembolic, bleeding and mortality outcomes in anticoagulated patients who need an urgent surgery/procedure. Thus, although these risks have been assessed in patients taking a DOAC or warfarin who have an elective surgery/procedure [1–6], and in non-anticoagulated patients
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who undergo urgent surgery [7,8], studies involving anticoagulated patients who require an urgent surgery/procedure are lacking. Concerns may also arise from the perception that DOAC-treated patients are more difficult to manage in an urgent perioperative setting or may suffer more adverse outcomes than patients who are taking warfarin. Thus, whereas the anticoagulant effect of warfarin can be promptly reversed with prothrombin complex concentrates and vitamin K [9], the efficacy of these and other prohemostatic agents to rapidly reverse the anticoagulant effect of DOACs is uncertain [10,11], and specific reversal agents (antidotes) for all DOACs are still lacking [12,13]. Moreover, the anticoagulant effect of warfarin can be rapidly and reliably measured in an urgent perioperative setting with the international normalized ratio (INR), whereas widely available tests to rapidly and reliably measure the anticoagulant effect of DOACs are lacking [14,15]. Against these concerns about the management of DOAC-treated patients who require an urgent surgery/procedure are emerging data that DOAC-associated major bleeds, though occurring outside of a perioperative setting, confer a lower mortality than warfarin-associated bleeds [16]. This may infer that DOAC-associated bleeds in a perioperative setting also may not have worse outcomes than warfarin-associated bleeds. In addition, the recent availability of a specific reversal agent for dabigatran (idarucizumab), which rapidly reverses the anticoagulant effect of dabigatran in patients who require an urgent surgery/ procedure or with life-threatening bleeding [17], may further mitigate concerns about the perioperative management of patients who are taking DOACs, at least for those patients on dabigatran. Building on this emerging knowledge, we accessed the database of the RE-LY trial, which compared dabigatran (110 mg or 150 mg twice-daily) with warfarin for stroke prevention in atrial fibrillation, focusing on patients who required an urgent surgery/procedure [18]. Our objectives were: 1) to compare rates of perioperative outcomes (thromboembolism, bleeding and mortality) across dabigatran- and warfarin-treated patients who required an urgent surgery/procedure; 2) to compare rates of these outcomes in patients who required an urgent or elective surgery/procedure; and 3) to identify predictors of these outcomes in patients having an urgent surgery/procedure. 2. Methods 2.1. Study development This study was a post hoc analysis of a pre-specified sub-study that was planned during the RE-LY trial. In this sub-study, we compared perioperative clinical outcomes in dabigatran- and warfarin-treated patients who required treatment interruption, focusing on patients who underwent an elective surgery/procedure [4]. The present study is distinguished from our previous work by focusing on patients who were receiving anticoagulant therapy and required an urgent surgery/procedure. Specifically, the following analyses were performed which were not done in the previous study: 1) we quantified thromboembolic and mortality outcomes in patients having an urgent surgery/procedure and compared these (along with bleeding outcomes) according to anticoagulant treatment (dabigatran or warfarin); 2) we compared thromboembolic, bleeding and mortality outcomes among patients having an urgent or elective surgery/procedure; and 3) we assessed putative predictors of perioperative thromboembolic and bleeding outcomes after an urgent surgery/procedure. 2.2. Patient population Patients for this study were derived from the RE-LY trial population [18], which consisted of adults, age ≥ 18 years, with non-valvular atrial fibrillation (i.e., without a prosthetic heart valve or significant valvular heart disease) and one or more of the following stroke risk factors: age ≥ 75 years; hypertension; diabetes; congestive heart failure; or prior stroke or transient ischemic attack. In RE-LY, patients were
randomly allocated in an open-label manner to receive either warfarin (target INR range: 2.0–3.0) or dabigatran, 110 mg or 150 mg twicedaily. The dose of dabigatran was randomly allocated and administered in a double-blinded manner. Patients were included if they had a first elective or urgent surgery/ procedure. If a patient had multiple surgeries/procedures, we only considered the first surgery/procedure to limit intra-patient correlation for the development of clinical outcomes during a subsequent surgery/ procedure (i.e., expectation bias). Patients were excluded if the surgery/procedure classification as elective or urgent was not specified or if anticoagulant therapy was not interrupted perioperatively, as might occur with some minor procedures such as dental extractions [19]. 2.3. Documentation and classification of surgery/procedure types The RE-LY protocol required documentation of the surgery/ procedure type patients underwent during treatment interruption and whether the surgery/procedure was deemed urgent or elective. An urgent surgery/procedure was considered unplanned whereas an elective surgery/procedure was planned. 2.4. Perioperative management of dabigatran and warfarin The RE-LY protocol required documentation of treatment interruptions for a surgery/procedure and detailed data collection of perioperative anticoagulant management and clinical outcomes. There was no guidance as to the management of patients who required treatment interruption for an urgent surgery/procedure, although the administration of blood products (e.g., fresh frozen plasma, prothrombin complex concentrates), vitamin K or other prohemostatic agents (e.g., tranexamic acid) was allowed at the discretion of the treating clinician and tailored according to whether a patient was receiving warfarin or dabigatran, since there was an open-label allocation of these two drugs. The management of patients who required an elective surgery/ procedure was guided by a pre-specified dabigatran interruption protocol whereby dabigatran was stopped one day before a low bleeding risk surgery/procedure and 2–5 days before a high bleeding risk surgery/ procedure, depending on patients' renal function. After a surgery/ procedure, the timing of dabigatran resumption was at the discretion of the treating clinician. 2.5. Period of observation This started 7 days before the surgery/procedure and ended 30 days afterwards. A focused observation period was intended to exclude clinical outcomes that might be unrelated to the perioperative period and related management, and is supported by a pertinent consensus statement [20]. 2.6. Clinical outcomes Clinical outcomes were defined by the same criteria used in the RE-LY trial and were all independently reviewed by adjudicators who were blinded to patients' treatment allocation. These clinical outcomes consisted of: 1) thromboembolism, comprising stroke, systemic embolism, myocardial infarction, pulmonary embolism, and any vascular death; 2) major bleeding, comprising non-life-threatening, lifethreatening and fatal bleeding; 3) life-threatening bleeding (as a subgroup of major bleeding); and 4) all-cause mortality. Other outcomes, comprising minor bleeding and deep vein thrombosis, were not considered for analysis, as these events were not adjudicated in the RE-LY trial. 2.7. Statistical analyses i) Descriptive analyses. We used descriptive statistics, comprising mean and standard deviation (SD) for continuous variables,
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and number and frequencies for categorical variables to describe patient baseline characteristics, surgery/procedure types and clinical outcomes. The t-test and Fisher exact test were used to compare baseline characteristics in patients having and elective or urgent surgery/procedure. ii) Comparison of clinical outcomes. We compared perioperative rates of thromboembolism, major bleeding, life-threatening bleeding and all-cause mortality, from day-7 to day 30, across treatment groups (dabigatran 110 mg, dabigatran 150 mg, warfarin) who had an elective or urgent surgery/procedure. We also compared rates of these outcomes between patients who had an urgent or urgent surgery/procedure within each of these three treatment groups. Comparisons of outcome rates were done using Fisher's exact test and were expressed as an odds ratio (OR), with an associated 95% confidence interval (CI) and P-value. iii) Determinants of thromboembolism or major bleeding. Multivariable Cox logistic regression was used to determine the effect of surgery/procedure type (urgent vs. elective) on adverse outcomes and the effect of anticoagulant therapy (dabigatran vs. warfarin) on these outcomes, after adjusting for the following covariates: patient age (b 75 or ≥75 years); patient sex (male or female); treatment allocation (warfarin or dabigatran); heparin bridging (yes vs. no) CHADS2 score (≤2 or N 2); and creatinine clearance (CrCl) (b 50 or ≥50 mL/min). This regression model was only done in patients where all baseline clinical variables and the surgery/procedure date were documented.
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Table 1 Patient characteristics. Characteristica
Elective Urgent P-value surgery/procedureb surgery/procedureb
Number (% of total population) Mean (SD) age, years Gender, % female Mean (SD) BMI, kg/m2 Mean (SD) CrCl, mL/min Moderate renal impairment (CrCl 30 to b50 mL/min), % Mean (SD) CHADS2 score Peripheral arterial disease, n (%) Concurrent medications, n (%) ASA Clopidogrel β-Blocker Surgery/procedure type, n (%) Pacemaker or ICD Surgery Dental procedure Other diagnostic procedure Other procedure
4168 (23.1) 72.5 (7.5) 31.0 29.4 (5.8) 75.4 (28.2) 16.5
353 (2.0) 72.6 (8.7) 38.5 29.0 (6.0) 71.7 (27.9) 21.8
n/a 0.8823 0.0042 0.2753 0.0170 0.0145
2.1 (1.1) 220 (5.3)
2.1 (1.1) 28 (7.9)
0.5596 0.050
1698 (40.7) 263 (6.3) 2708 (65.0)
153 (43.3) 25 (7.1) 232 (65.7)
0.339 0.567 0.816
409 (9.8) 1879 (45.1) 455 (10.9) 976 (23.4) 449 (10.8)
47 (13.3) 218 (61.8) 5 (1.4) 41 (11.6) 42 (11.9)
0.042 b0.001 0.001 0.001 0.532
Legend: SD, standard deviation; BMI, body mass index; CrCl, creatinine clearance; ICD, implantable cardiac defibrillator;; n, number; n/a, not applicable. a Documented at the time of entry into the trial. b Surgery/procedure type (elective or urgent) defined based on local investigator assessment; percutaneous biopsy, catheter placement, diagnostic angiography, or bronchoscopy.
3. Results
4. Discussion
3.1. Patients
There are two main findings from our study that focused on patients with atrial fibrillation who were on dabigatran or warfarin and required an urgent surgery/procedure. First, among patients having an urgent surgery/procedure, rates of thromboembolism, major bleeding, lifethreatening bleeding, and mortality were not significantly different according to the anticoagulant patients were receiving, whether it was dabigatran (110 mg or 150 mg dose) or warfarin. Second, perioperative rates of thromboembolism, major bleeding, and mortality were approximately 5- to 10-fold higher in patients having an urgent rather than an elective surgery/procedure, and the need for urgent surgery was the strongest predictor of the combined outcome of thromboembolism or major bleeding. The validity of our findings is supported because the RE-LY trial required detailed documentation of patient management and clinical outcomes during the perioperative interruption of anticoagulant therapy, and because the adjudication of outcomes was blinded to patients' treatment allocation. Moreover, the validity of outcome comparisons between dabigatran- and warfarin-treated patients who had an urgent surgery/procedure is supported because these comparisons were made across randomly allocated groups. Few studies have assessed thromboembolic and bleeding outcomes in anticoagulated patients who need an urgent surgery/procedure, especially if they are receiving a DOAC [21,22]. Our finding that rates of thromboembolism, bleeding and mortality were not significantly different among dabigatran- and warfarin-treated patients who had an urgent surgery/procedure is important because of the perception that DOAC-treated patients may be more difficult to manage in the setting of an urgent surgery/procedure or in cases of major bleeding. Given the emerging availability of specific reversal agents to DOACs, such as idarucizumab and andexanet-α, for patients requiring an urgent surgery, additional study is needed to assess if these agents can mitigate the risk for perioperative major bleeding and mortality in a manner similar to that observed with tranexamic acid use in trauma patients [23]. However, use of rapidly acting prohemostatic agents such as recombinant factor VIIa have not had the desired effect of mitigating the risk
There were 353 patients (2.0% of study population) who required an urgent surgery/procedure and 4168 patients (23.1% of study population) who required an elective surgery/procedure. The clinical characteristics of these patients, documented at the time of entry into the RE-LY trial, and the surgery/procedures types these patients underwent are shown in Table 1. Overall, patients who had an urgent or elective surgery/procedure were comparable in terms of age and CHADS2 score but patients who required an urgent surgery/procedure were more likely to be female, had more moderate renal impairment (CrCl 30 to b 50 mL/min) and had more peripheral arterial disease. 3.2. Comparison of clinical outcomes These were determined in patients having an urgent or elective surgery/procedure and in patients receiving dabigatran (110 mg or 150 mg twice-daily doses) or warfarin, as shown in Table 2. There were no significant differences in rates of thromboembolism, major bleeding, lifethreatening bleeding, and mortality in patients who were receiving dabigatran (110 mg or 150 mg twice-daily regimens) or warfarin and required an urgent surgery/procedure. Within each treatment group (dabigatran 110 mg, dabigatran 150 mg, warfarin), rates of thromboembolism and bleeding were significantly higher in patients having an urgent as compared with an elective surgery/procedure. 3.3. Determinants of major bleeding or thromboembolism When combining patients having urgent and elective surgery/ procedures, determinants of the pooled outcome of thromboembolism or major bleeding, based on multivariate analysis, were as follows: urgent surgery/procedure (OR = 7.49; 95% CI: 5.61–10.01); heparin bridging (OR = 2.84; CI: 2.17–3.72); CrCl b 50 mL/min (OR = 1.71; CI: 1.25–2.34); and age ≥ 75 years (OR = 1.35; CI: 1.02–1.78).
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Table 2 Incidence and comparison of clinical outcomes in patients according to urgent or elective surgery/procedure and dabigatran or warfarin treatment. Outcome
Major bleeding, n (%)
Surgery/procedure type
Dabigatran, 150 mg BID
Warfarin
OR (95% CI)a
19 (17.0)
24 (17.6)
24 (22.9)
37 (2.7)
51 (3.7)
47 (3.3)
7.3 (4.0–13.2) P b 0.001 13 (11.6)
5.6 (3.3–9.4) P b 0.001 15 (11.0)
8.7 (5.1–15.0) P b 0.001 12 (11.4)
0.70 (0.4–1.2) P = 0.228 1.0 (0.7–1.4) P = 0.899 –
12 (0.9)
17 (1.2)
16 (1.1)
14.7 (6.5–33.1) P b 0.001 18 (16.1)
10.0 (4.9–20.4) P b 0.001 10 (7.4)
11.4 (5.2–24.8) P b 0.001 11 (10.5)
14 (1.0)
15 (1.1)
15 (1.0)
Urgent
18.4 (8.9–38.1) P b 0.001 7 (6.3)
7.2 (3.2–16.4) P b 0.001 2 (1.5)
11.0 (4.9, 24.7) P b 0.001 3 (2.9)
Elective
6 (0.4)
6 (0.4)
5 (0.3)
OR (95% CI)b
15.0 (5.0–45.4) P b 0.001
3.4 (0.7–17.1) P = 0.134
8.4 (2.0–35.6) P = 0.004
Urgent Elective OR (95% CI)
Life-threatening bleeding, n (%)
b
Urgent Elective OR (95% CI)
Thrombo-embolism, n (%)c
b
Urgent Elective OR (95% CI)
All-cause mortality, n (%)
Treatment group Dabigatran, 110 mg BID
b
1.0 (0.5–2.0) P = 0.970 0.90 (0.5–1.7) P = 0.859 – 1.1 (0.5–2.3) P = 0.823 1.0 (0.5–1.9) P = 0.976 – 1.3 (0.3–4.8) P = 0.715 1.3 (0.4–3.6) P = 0.671 –
Legend: OR, odds ratio; CI, confidence interval; n, number. a Odds ratios comparing outcomes with dabigatran (110 mg and 150 mg doses combined) vs. warfarin within urgent or elective surgery/procedure groups. b Odds ratios comparing outcomes with urgent vs. elective surgery; outcomes documented from day-7 to day 30 after surgery/procedure. c Comprises stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death.
for bleeding-related morbidity and mortality in patients who bleed, with or without hemophilia [24,25]. Moreover, the administration of prothrombin complex concentrates may increase the risk for thromboembolism due to their effect of sharply increasing thrombin generation [26,27]. There are potential limitations of our study. First, the classification of a surgery/procedure (urgent or elective) was not based on standardized criteria with the potential for misclassification that may affect comparisons of post-procedure outcome rates. However, although some surgery/procedure type misclassification is likely, it is unlikely that local investigators would have systematically misclassified patients across the three treatment groups (dabigatran 110 mg, dabigatran 150 mg, warfarin) where outcome comparisons were done. Second, we could not assess the use of procoagulant blood products, such as prothrombin complex concentrates, for anticoagulant reversal in patients having an urgent surgery/procedures as use of such agents was not consistently documented in RE-LY. Third, caution is needed when interpreting outcomes rates in dabigatran- and warfarin-treated patients because although these comparisons yielded no statistically significant differences in outcomes, the precision in these estimates were limited by small number of events. Finally, the RE-LY trial was not specifically designed to assess perioperative adverse outcomes and there were no prespecified statistical power calculations for these outcomes. However, the randomized design of RE-LY would allow balanced representation of urgent and elective surgery/procedure types across the three treatment groups (dabigatran, 110 mg and 150 mg, warfarin). To summarize, in anticoagulated patients with atrial fibrillation who require an urgent surgery/procedure, the risks for thromboembolism, major bleeding and mortality did not differ depending on treatment with dabigatran or warfarin, but rates of these outcomes were multi-fold higher than in patients having an elective surgery/procedure. Additional research is needed to determine risks for adverse outcomes in patients on DOACs who need an urgent surgery/procedure and to assess the effect of rapid anticoagulation reversal strategies on these outcomes.
Disclosures The following authors are employed by Boehringer Ingelheim, which manufactures dabigatran: Martina Brueckmann and Mandy Fraessdorf. The following authors have received consulting fees and/or research grants from Boehringer Ingelheim, and/or have participated in advisory boards by Boehringer Ingelheim, which manufactures dabigatran: James D. Douketis, Jeff S. Healey, Michael D. Ezekowitz, Jonas Oldgren, Alex C. Spyropoulos, Lars Wallentin, Stuart J. Connolly, Salim Yusuf, and John W. Eikelboom. Author contributions Study conception and design (JDD, MB, JWE), statistical analysis (MB, MF), analysis of results (JDD, MB, MF, JH, ACS, JWE), and critical review of manuscript (JDD, MB, MF, JSH, MDE, JO, ACS, LW, SJC, SY, JWE). Acknowledgments None. References [1] D. Siegal, J. Yudin, S. Kaatz, J.D. Douketis, W. Lim, A.C. Spyropoulos, Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates, Circulation 126 (13) (2012) 1630–1639. [2] D. Garcia, J.H. Alexander, L. Wallentin, D.M. Wojdyla, L. Thomas, M. Hanna, S.M. AlKhatib, P. Dorian, J. Ansell, P. Commerford, G. Flaker, F. Lanas, D. Vinereanu, D. Xavier, E.M. Hylek, C. Held, F.W. Verheugt, C.B. Granger, R.D. Lopes, Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures, Blood 124 (25) (2014) 3692–3698. [3] M.W. Sherwood, J.D. Douketis, M.R. Patel, J.P. Piccini, A.S. Hellkamp, Y. Lokhnygina, A.C. Spyropoulos, G.J. Hankey, D.E. Singer, C.C. Nessel, K.W. Mahaffey, K.A. Fox, R.M. Califf, R.C. Becker, ROCKET AF Investigators, Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF), Circulation 129 (18) (2014) 1850–1859.
J.D. Douketis et al. / Thrombosis Research 139 (2016) 77–81 [4] J.S. Healey, J. Eikelboom, J. Douketis, L. Wallentin, J. Oldgren, S. Yang, E. Themeles, H. Heidbuchel, A. Avezum, P. Reilly, S.J. Connolly, S. Yusuf, M. Ezekowitz, RE-LY investigators, Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial, Circulation 126 (3) (2012) 343–348. [5] B.A. Steinberg, E.D. Peterson, S. Kim, L. Thomas, B.J. Gersh, G.C. Fonarow, P.R. Kowey, K.W. Mahaffey, M.W. Sherwood, P. Chang, J.P. Piccini, J. Ansell, Outcomes registry for better informed treatment of atrial fibrillation investigators and patients. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the outcomes registry for better informed treatment of atrial fibrillation (ORBIT-AF), Circulation 131 (5) (2015) 488–494. [6] J. Beyer-Westendorf, V. Gelbricht, K. Forster, F. Ebertz, C. Kohler, S. Werth, E. Kuhlisch, T. Stange, C. Thieme, K. Daschkow, N. Weiss, Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry, Eur. Heart J. 35 (28) (2014) 1888–1896. [7] P.J. Devereaux, L. Goldman, S. Yusuf, K. Gilbert, K. Leslie, G.H. Guyatt, Surveillance and prevention of major perioperative ischemic cardiac events in patients undergoing noncardiac surgery: a review, CMAJ 173 (7) (2005) 779–788. [8] Vascular Events In Noncardiac Surgery Patients Cohort Evaluation Study I, P.J. Devereaux, M.T. Chan, P. Alonso-Coello, M. Walsh, O. Berwanger, C.Y. Wang, R.I. Garutti, M.J. Jacka, A. Sigamani, S. Srinathan, B.M. Biccard, C.K. Chow, V. Abraham, M. Tiboni, S. Pettit, W. Szczeklik, G. Lurati Buse, F. Botto, G. Guyatt, et al., Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery, JAMA 307 (21) (2012) 2295–2304. [9] R. Sarode, T.J. Milling Jr., M.A. Refaai, A. Mangione, A. Schneider, B.L. Durn, J.N. Goldstein, Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study, Circulation 128 (11) (2013) 1234–1243. [10] S. Kaatz, P.A. Kouides, D.A. Garcia, A.C. Spyropolous, M. Crowther, J.D. Douketis, A.K. Chan, A. James, S. Moll, T.L. Ortel, E.M. Van Cott, J. Ansell, Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors, Am. J. Hematol. 87 (Suppl. 1) (2012) S141–S145. [11] D. Faraoni, J.H. Levy, P. Albaladejo, C.M. Samama, Groupe d'interet en hemostase P, Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants, Crit. Care 19 (2015) 203. [12] M.N. Lauw, M. Coppens, J.W. Eikelboom, Recent advances in antidotes for direct oral anticoagulants: their arrival is imminent, Can J Cardiol. 30 (4) (2014) 381–384. [13] D.M. Siegal, A. Cuker, Reversal of target-specific oral anticoagulants, Drug Discov. Today 19 (9) (2014) 1465–1470. [14] A. Cuker, D.M. Siegal, M.A. Crowther, D.A. Garcia, Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants, J. Am. Coll. Cardiol. 64 (11) (2014) 1128–1139. [15] T. Baglin, A. Hillarp, A. Tripodi, I. Elalamy, H. Buller, W. Ageno, Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the subcommittee on control of anticoagulation of the Scientific and Standardisation Committee
[16]
[17]
[18]
[19]
[20]
[21]
[22] [23] [24]
[25]
[26]
[27]
81
of the International Society on Thrombosis and Haemostasis, J. Thromb. Haemost. (2013). A. Majeed, K. Meijer, R. Larrazabal, F. Arnberg, G.J. Luijckx, R.S. Roberts, S. Schulman, Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate, Thromb. Haemost. 111 (2) (2014) 233–239. C.V. Pollack Jr., P.A. Reilly, J. Eikelboom, S. Glund, P. Verhamme, R.A. Bernstein, R. Dubiel, M.V. Huisman, E.M. Hylek, P.W. Kamphuisen, J. Kreuzer, J.H. Levy, F.W. Sellke, J. Stangier, T. Steiner, B. Wang, C.W. Kam, J.I. Weitz, Idarucizumab for dabigatran reversal, N. Engl. J. Med. 373 (6) (2015) 511–520. S.J. Connolly, M.D. Ezekowitz, S. Yusuf, J. Eikelboom, J. Oldgren, A. Parekh, J. Pogue, P.A. Reilly, E. Themeles, J. Varrone, S. Wang, M. Alings, D. Xavier, J. Zhu, R. Diaz, B.S. Lewis, H. Darius, H.C. Diener, C.D. Joyner, A. Wallentin, Dabigatran versus warfarin in patients with atrial fibrillation, N. Engl. J. Med. 361 (12) (2009) 1139–1151. J.D. Douketis, A.C. Spyropoulos, F.A. Spencer, M. Mayr, A.K. Jaffer, M.H. Eckman, A.S. Dunn, R. Kunz, Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines, Chest 141 (2 Suppl) (2012) e326S–e350S. A.C. Spyropoulos, J.D. Douketis, G. Gerotziafas, S. Kaatz, T.L. Ortel, S. Schulman, Subcommittee on the control of anticoagulation of the SSC of the ISTH. Periprocedural antithrombotic and bridging therapy: recommendations for standardized reporting in patients with arterial indications for chronic oral anticoagulant therapy, J. Thromb. Haemost. 10 (4) (2012) 692–694. C.C. Acevedo, F. Velasco, C. Herrera, Reversal of rivaroxaban anticoagulation by nonactivated prothrombin complex concentrate in urgent surgery, Futur. Cardiol. 1–5 (2015). T. Puttick, R. Bahl, H. Mohamedbhai, Emergency reversal of dabigatran for emergency surgery, BMJ Case Rep. 2015 (2015). I. Roberts, H. Shakur, K. Ker, T. Coats, collaborators C-T, Antifibrinolytic drugs for acute traumatic injury, Cochrane Database Syst. Rev. 1 (2011), CD004896. E. Simpson, Y. Lin, S. Stanworth, J. Birchall, C. Doree, C. Hyde, Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia, Cochrane Database Syst. Rev. 3 (2012), CD005011. A. Coppola, J. Windyga, A. Tufano, C. Yeung, M.N. Di Minno, Treatment for preventing bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgery, Cochrane Database Syst. Rev. 2 (2015), CD009961. O. Grottke, R. Rossaint, Y. Henskens, R. van Oerle, H. Ten Cate, H.M. Spronk, Thrombin generation capacity of prothrombin complex concentrate in an in vitro dilutional model, PLoS ONE 8 (5) (2013), e64100. F. Dentali, C. Marchesi, M. Giorgi Pierfranceschi, M. Crowther, D. Garcia, E. Hylek, D.M. Witt, N.P. Clark, A. Squizzato, D. Imberti, W. Ageno, Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis, Thromb. Haemost. 106 (3) (2011) 429–438.
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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Full Length Article
Urgent surgery or procedures in patients taking dabigatran or warfarin: Analysis of perioperative outcomes from the RE-LY trial☆,☆☆ James D. Douketis a,⁎, Jeff S. Healey a,b, Martina Brueckmann c,e, Mandy Fraessdorf c, Alex C. Spyropoulos d, Lars Wallentin g, Jonas Oldgren g, Paul Reilly h, Michael D. Ezekowitz f, Stuart J. Connolly a,b, Salim Yusuf a,b, John W. Eikelboom a,b a
Department of Medicine, McMaster University, Hamilton, Canada Population Health Research Institute, McMaster University, Hamilton, Canada c Boehringer Ingelheim Pharma GmbH & Co, Ingelheim am Rhein, Germany d Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, NY, USA e Medical Faculty, Mannheim University of Heidelberg, Germany f Jefferson Medical College, Wynnewood, PA, USA g Uppsala Clinical Research Centre and Department of Medical Sciences Cardiology, Uppsala University, Sweden h Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA b
a r t i c l e
i n f o
Article history: Received 24 October 2015 Received in revised form 4 January 2016 Accepted 5 January 2016 Available online 9 January 2016 Keywords: Urgent surgery Dabigatran Warfarin Perioperative
a b s t r a c t Background: There is concern about the management of anticoagulated patients with atrial fibrillation (AF) who require an urgent surgery/procedure, especially in those who are receiving a direct oral anticoagulant such as dabigatran. Methods: We accessed the database from RE-LY, a randomized trial comparing dabigatran (110 mg and 150 mg twice daily) with warfarin for stroke prevention in AF, to assess patients who had an urgent and elective surgery/ procedure. We compared the risk for thromboembolism, major bleeding and mortality according to treatment allocation (dabigatran 110 mg or 150 mg, or warfarin) or surgery/procedure type (urgent or elective). Outcomes were assessed from day-7 to day 30 after a surgery/procedure. Results: 353 patients (2.0% of study population) had an urgent surgery/procedure and 4168 patients (23.1% of study population) had an elective surgery/procedure. In patients on dabigatran 110 mg, dabigatran 150 mg and warfarin who had an urgent surgery/procedure: rates of thromboembolism were 16.1%, 7.4%, and 10.5%; rates of major bleeding were 17.0%, 17.6%, and 22.9%; rates of mortality were 6.3%, 1.5%, and 2.9%, respectively (P N 0.50 for all comparisons). Rates of these outcomes were multi-fold higher in patients having an urgent rather than an elective surgery/procedure (P b 0.5 for all comparisons). Conclusion: In anticoagulated patients with atrial fibrillation who require an urgent surgery/procedure, the risks for thromboembolism, major bleeding and mortality did not differ depending on treatment with dabigatran or warfarin, but rates of these outcomes were multi-fold higher than in patients having an elective surgery/ procedure. © 2016 Elsevier Ltd. All rights reserved.
1. Introduction ☆ Role of the funding sourceThere was no funding provided for this study. ☆☆ DisclosuresThe following authors are employed by Boehringer Ingelheim, which manufactures dabigatran: Martina Brueckmann, Mandy Fraessdorf, and Paul Reilly. The following authors have received consulting fees and/or research grants from Boehringer Ingelheim, and/or have participated in advisory boards by Boehringer Ingelheim, which manufactures dabigatran: James D. Douketis, Jeff S. Healey, Michael D. Ezekowitz, Jonas Oldgren, Alex C. Spyropoulos, Lars Wallentin, Stuart J. Connolly, John W. Eikelboom. ⁎ Corresponding author at: St. Joseph's Healthcare Hamilton, Room F-544, 50 Charlton Ave. East, Hamilton, ON L8N 4A6, Canada. E-mail address: [email protected] (J.D. Douketis).
http://dx.doi.org/10.1016/j.thromres.2016.01.004 0049-3848/© 2016 Elsevier Ltd. All rights reserved.
The management of anticoagulated patients who need an urgent surgery or procedure poses a major concern for clinicians, especially if they are receiving a direct oral anticoagulant (DOAC) such as dabigatran, rivaroxaban, apixaban or edoxaban. This concern may be related, in part, to uncertainty as to the risks for thromboembolic, bleeding and mortality outcomes in anticoagulated patients who need an urgent surgery/procedure. Thus, although these risks have been assessed in patients taking a DOAC or warfarin who have an elective surgery/procedure [1–6], and in non-anticoagulated patients
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who undergo urgent surgery [7,8], studies involving anticoagulated patients who require an urgent surgery/procedure are lacking. Concerns may also arise from the perception that DOAC-treated patients are more difficult to manage in an urgent perioperative setting or may suffer more adverse outcomes than patients who are taking warfarin. Thus, whereas the anticoagulant effect of warfarin can be promptly reversed with prothrombin complex concentrates and vitamin K [9], the efficacy of these and other prohemostatic agents to rapidly reverse the anticoagulant effect of DOACs is uncertain [10,11], and specific reversal agents (antidotes) for all DOACs are still lacking [12,13]. Moreover, the anticoagulant effect of warfarin can be rapidly and reliably measured in an urgent perioperative setting with the international normalized ratio (INR), whereas widely available tests to rapidly and reliably measure the anticoagulant effect of DOACs are lacking [14,15]. Against these concerns about the management of DOAC-treated patients who require an urgent surgery/procedure are emerging data that DOAC-associated major bleeds, though occurring outside of a perioperative setting, confer a lower mortality than warfarin-associated bleeds [16]. This may infer that DOAC-associated bleeds in a perioperative setting also may not have worse outcomes than warfarin-associated bleeds. In addition, the recent availability of a specific reversal agent for dabigatran (idarucizumab), which rapidly reverses the anticoagulant effect of dabigatran in patients who require an urgent surgery/ procedure or with life-threatening bleeding [17], may further mitigate concerns about the perioperative management of patients who are taking DOACs, at least for those patients on dabigatran. Building on this emerging knowledge, we accessed the database of the RE-LY trial, which compared dabigatran (110 mg or 150 mg twice-daily) with warfarin for stroke prevention in atrial fibrillation, focusing on patients who required an urgent surgery/procedure [18]. Our objectives were: 1) to compare rates of perioperative outcomes (thromboembolism, bleeding and mortality) across dabigatran- and warfarin-treated patients who required an urgent surgery/procedure; 2) to compare rates of these outcomes in patients who required an urgent or elective surgery/procedure; and 3) to identify predictors of these outcomes in patients having an urgent surgery/procedure. 2. Methods 2.1. Study development This study was a post hoc analysis of a pre-specified sub-study that was planned during the RE-LY trial. In this sub-study, we compared perioperative clinical outcomes in dabigatran- and warfarin-treated patients who required treatment interruption, focusing on patients who underwent an elective surgery/procedure [4]. The present study is distinguished from our previous work by focusing on patients who were receiving anticoagulant therapy and required an urgent surgery/procedure. Specifically, the following analyses were performed which were not done in the previous study: 1) we quantified thromboembolic and mortality outcomes in patients having an urgent surgery/procedure and compared these (along with bleeding outcomes) according to anticoagulant treatment (dabigatran or warfarin); 2) we compared thromboembolic, bleeding and mortality outcomes among patients having an urgent or elective surgery/procedure; and 3) we assessed putative predictors of perioperative thromboembolic and bleeding outcomes after an urgent surgery/procedure. 2.2. Patient population Patients for this study were derived from the RE-LY trial population [18], which consisted of adults, age ≥ 18 years, with non-valvular atrial fibrillation (i.e., without a prosthetic heart valve or significant valvular heart disease) and one or more of the following stroke risk factors: age ≥ 75 years; hypertension; diabetes; congestive heart failure; or prior stroke or transient ischemic attack. In RE-LY, patients were
randomly allocated in an open-label manner to receive either warfarin (target INR range: 2.0–3.0) or dabigatran, 110 mg or 150 mg twicedaily. The dose of dabigatran was randomly allocated and administered in a double-blinded manner. Patients were included if they had a first elective or urgent surgery/ procedure. If a patient had multiple surgeries/procedures, we only considered the first surgery/procedure to limit intra-patient correlation for the development of clinical outcomes during a subsequent surgery/ procedure (i.e., expectation bias). Patients were excluded if the surgery/procedure classification as elective or urgent was not specified or if anticoagulant therapy was not interrupted perioperatively, as might occur with some minor procedures such as dental extractions [19]. 2.3. Documentation and classification of surgery/procedure types The RE-LY protocol required documentation of the surgery/ procedure type patients underwent during treatment interruption and whether the surgery/procedure was deemed urgent or elective. An urgent surgery/procedure was considered unplanned whereas an elective surgery/procedure was planned. 2.4. Perioperative management of dabigatran and warfarin The RE-LY protocol required documentation of treatment interruptions for a surgery/procedure and detailed data collection of perioperative anticoagulant management and clinical outcomes. There was no guidance as to the management of patients who required treatment interruption for an urgent surgery/procedure, although the administration of blood products (e.g., fresh frozen plasma, prothrombin complex concentrates), vitamin K or other prohemostatic agents (e.g., tranexamic acid) was allowed at the discretion of the treating clinician and tailored according to whether a patient was receiving warfarin or dabigatran, since there was an open-label allocation of these two drugs. The management of patients who required an elective surgery/ procedure was guided by a pre-specified dabigatran interruption protocol whereby dabigatran was stopped one day before a low bleeding risk surgery/procedure and 2–5 days before a high bleeding risk surgery/ procedure, depending on patients' renal function. After a surgery/ procedure, the timing of dabigatran resumption was at the discretion of the treating clinician. 2.5. Period of observation This started 7 days before the surgery/procedure and ended 30 days afterwards. A focused observation period was intended to exclude clinical outcomes that might be unrelated to the perioperative period and related management, and is supported by a pertinent consensus statement [20]. 2.6. Clinical outcomes Clinical outcomes were defined by the same criteria used in the RE-LY trial and were all independently reviewed by adjudicators who were blinded to patients' treatment allocation. These clinical outcomes consisted of: 1) thromboembolism, comprising stroke, systemic embolism, myocardial infarction, pulmonary embolism, and any vascular death; 2) major bleeding, comprising non-life-threatening, lifethreatening and fatal bleeding; 3) life-threatening bleeding (as a subgroup of major bleeding); and 4) all-cause mortality. Other outcomes, comprising minor bleeding and deep vein thrombosis, were not considered for analysis, as these events were not adjudicated in the RE-LY trial. 2.7. Statistical analyses i) Descriptive analyses. We used descriptive statistics, comprising mean and standard deviation (SD) for continuous variables,
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and number and frequencies for categorical variables to describe patient baseline characteristics, surgery/procedure types and clinical outcomes. The t-test and Fisher exact test were used to compare baseline characteristics in patients having and elective or urgent surgery/procedure. ii) Comparison of clinical outcomes. We compared perioperative rates of thromboembolism, major bleeding, life-threatening bleeding and all-cause mortality, from day-7 to day 30, across treatment groups (dabigatran 110 mg, dabigatran 150 mg, warfarin) who had an elective or urgent surgery/procedure. We also compared rates of these outcomes between patients who had an urgent or urgent surgery/procedure within each of these three treatment groups. Comparisons of outcome rates were done using Fisher's exact test and were expressed as an odds ratio (OR), with an associated 95% confidence interval (CI) and P-value. iii) Determinants of thromboembolism or major bleeding. Multivariable Cox logistic regression was used to determine the effect of surgery/procedure type (urgent vs. elective) on adverse outcomes and the effect of anticoagulant therapy (dabigatran vs. warfarin) on these outcomes, after adjusting for the following covariates: patient age (b 75 or ≥75 years); patient sex (male or female); treatment allocation (warfarin or dabigatran); heparin bridging (yes vs. no) CHADS2 score (≤2 or N 2); and creatinine clearance (CrCl) (b 50 or ≥50 mL/min). This regression model was only done in patients where all baseline clinical variables and the surgery/procedure date were documented.
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Table 1 Patient characteristics. Characteristica
Elective Urgent P-value surgery/procedureb surgery/procedureb
Number (% of total population) Mean (SD) age, years Gender, % female Mean (SD) BMI, kg/m2 Mean (SD) CrCl, mL/min Moderate renal impairment (CrCl 30 to b50 mL/min), % Mean (SD) CHADS2 score Peripheral arterial disease, n (%) Concurrent medications, n (%) ASA Clopidogrel β-Blocker Surgery/procedure type, n (%) Pacemaker or ICD Surgery Dental procedure Other diagnostic procedure Other procedure
4168 (23.1) 72.5 (7.5) 31.0 29.4 (5.8) 75.4 (28.2) 16.5
353 (2.0) 72.6 (8.7) 38.5 29.0 (6.0) 71.7 (27.9) 21.8
n/a 0.8823 0.0042 0.2753 0.0170 0.0145
2.1 (1.1) 220 (5.3)
2.1 (1.1) 28 (7.9)
0.5596 0.050
1698 (40.7) 263 (6.3) 2708 (65.0)
153 (43.3) 25 (7.1) 232 (65.7)
0.339 0.567 0.816
409 (9.8) 1879 (45.1) 455 (10.9) 976 (23.4) 449 (10.8)
47 (13.3) 218 (61.8) 5 (1.4) 41 (11.6) 42 (11.9)
0.042 b0.001 0.001 0.001 0.532
Legend: SD, standard deviation; BMI, body mass index; CrCl, creatinine clearance; ICD, implantable cardiac defibrillator;; n, number; n/a, not applicable. a Documented at the time of entry into the trial. b Surgery/procedure type (elective or urgent) defined based on local investigator assessment; percutaneous biopsy, catheter placement, diagnostic angiography, or bronchoscopy.
3. Results
4. Discussion
3.1. Patients
There are two main findings from our study that focused on patients with atrial fibrillation who were on dabigatran or warfarin and required an urgent surgery/procedure. First, among patients having an urgent surgery/procedure, rates of thromboembolism, major bleeding, lifethreatening bleeding, and mortality were not significantly different according to the anticoagulant patients were receiving, whether it was dabigatran (110 mg or 150 mg dose) or warfarin. Second, perioperative rates of thromboembolism, major bleeding, and mortality were approximately 5- to 10-fold higher in patients having an urgent rather than an elective surgery/procedure, and the need for urgent surgery was the strongest predictor of the combined outcome of thromboembolism or major bleeding. The validity of our findings is supported because the RE-LY trial required detailed documentation of patient management and clinical outcomes during the perioperative interruption of anticoagulant therapy, and because the adjudication of outcomes was blinded to patients' treatment allocation. Moreover, the validity of outcome comparisons between dabigatran- and warfarin-treated patients who had an urgent surgery/procedure is supported because these comparisons were made across randomly allocated groups. Few studies have assessed thromboembolic and bleeding outcomes in anticoagulated patients who need an urgent surgery/procedure, especially if they are receiving a DOAC [21,22]. Our finding that rates of thromboembolism, bleeding and mortality were not significantly different among dabigatran- and warfarin-treated patients who had an urgent surgery/procedure is important because of the perception that DOAC-treated patients may be more difficult to manage in the setting of an urgent surgery/procedure or in cases of major bleeding. Given the emerging availability of specific reversal agents to DOACs, such as idarucizumab and andexanet-α, for patients requiring an urgent surgery, additional study is needed to assess if these agents can mitigate the risk for perioperative major bleeding and mortality in a manner similar to that observed with tranexamic acid use in trauma patients [23]. However, use of rapidly acting prohemostatic agents such as recombinant factor VIIa have not had the desired effect of mitigating the risk
There were 353 patients (2.0% of study population) who required an urgent surgery/procedure and 4168 patients (23.1% of study population) who required an elective surgery/procedure. The clinical characteristics of these patients, documented at the time of entry into the RE-LY trial, and the surgery/procedures types these patients underwent are shown in Table 1. Overall, patients who had an urgent or elective surgery/procedure were comparable in terms of age and CHADS2 score but patients who required an urgent surgery/procedure were more likely to be female, had more moderate renal impairment (CrCl 30 to b 50 mL/min) and had more peripheral arterial disease. 3.2. Comparison of clinical outcomes These were determined in patients having an urgent or elective surgery/procedure and in patients receiving dabigatran (110 mg or 150 mg twice-daily doses) or warfarin, as shown in Table 2. There were no significant differences in rates of thromboembolism, major bleeding, lifethreatening bleeding, and mortality in patients who were receiving dabigatran (110 mg or 150 mg twice-daily regimens) or warfarin and required an urgent surgery/procedure. Within each treatment group (dabigatran 110 mg, dabigatran 150 mg, warfarin), rates of thromboembolism and bleeding were significantly higher in patients having an urgent as compared with an elective surgery/procedure. 3.3. Determinants of major bleeding or thromboembolism When combining patients having urgent and elective surgery/ procedures, determinants of the pooled outcome of thromboembolism or major bleeding, based on multivariate analysis, were as follows: urgent surgery/procedure (OR = 7.49; 95% CI: 5.61–10.01); heparin bridging (OR = 2.84; CI: 2.17–3.72); CrCl b 50 mL/min (OR = 1.71; CI: 1.25–2.34); and age ≥ 75 years (OR = 1.35; CI: 1.02–1.78).
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Table 2 Incidence and comparison of clinical outcomes in patients according to urgent or elective surgery/procedure and dabigatran or warfarin treatment. Outcome
Major bleeding, n (%)
Surgery/procedure type
Dabigatran, 150 mg BID
Warfarin
OR (95% CI)a
19 (17.0)
24 (17.6)
24 (22.9)
37 (2.7)
51 (3.7)
47 (3.3)
7.3 (4.0–13.2) P b 0.001 13 (11.6)
5.6 (3.3–9.4) P b 0.001 15 (11.0)
8.7 (5.1–15.0) P b 0.001 12 (11.4)
0.70 (0.4–1.2) P = 0.228 1.0 (0.7–1.4) P = 0.899 –
12 (0.9)
17 (1.2)
16 (1.1)
14.7 (6.5–33.1) P b 0.001 18 (16.1)
10.0 (4.9–20.4) P b 0.001 10 (7.4)
11.4 (5.2–24.8) P b 0.001 11 (10.5)
14 (1.0)
15 (1.1)
15 (1.0)
Urgent
18.4 (8.9–38.1) P b 0.001 7 (6.3)
7.2 (3.2–16.4) P b 0.001 2 (1.5)
11.0 (4.9, 24.7) P b 0.001 3 (2.9)
Elective
6 (0.4)
6 (0.4)
5 (0.3)
OR (95% CI)b
15.0 (5.0–45.4) P b 0.001
3.4 (0.7–17.1) P = 0.134
8.4 (2.0–35.6) P = 0.004
Urgent Elective OR (95% CI)
Life-threatening bleeding, n (%)
b
Urgent Elective OR (95% CI)
Thrombo-embolism, n (%)c
b
Urgent Elective OR (95% CI)
All-cause mortality, n (%)
Treatment group Dabigatran, 110 mg BID
b
1.0 (0.5–2.0) P = 0.970 0.90 (0.5–1.7) P = 0.859 – 1.1 (0.5–2.3) P = 0.823 1.0 (0.5–1.9) P = 0.976 – 1.3 (0.3–4.8) P = 0.715 1.3 (0.4–3.6) P = 0.671 –
Legend: OR, odds ratio; CI, confidence interval; n, number. a Odds ratios comparing outcomes with dabigatran (110 mg and 150 mg doses combined) vs. warfarin within urgent or elective surgery/procedure groups. b Odds ratios comparing outcomes with urgent vs. elective surgery; outcomes documented from day-7 to day 30 after surgery/procedure. c Comprises stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death.
for bleeding-related morbidity and mortality in patients who bleed, with or without hemophilia [24,25]. Moreover, the administration of prothrombin complex concentrates may increase the risk for thromboembolism due to their effect of sharply increasing thrombin generation [26,27]. There are potential limitations of our study. First, the classification of a surgery/procedure (urgent or elective) was not based on standardized criteria with the potential for misclassification that may affect comparisons of post-procedure outcome rates. However, although some surgery/procedure type misclassification is likely, it is unlikely that local investigators would have systematically misclassified patients across the three treatment groups (dabigatran 110 mg, dabigatran 150 mg, warfarin) where outcome comparisons were done. Second, we could not assess the use of procoagulant blood products, such as prothrombin complex concentrates, for anticoagulant reversal in patients having an urgent surgery/procedures as use of such agents was not consistently documented in RE-LY. Third, caution is needed when interpreting outcomes rates in dabigatran- and warfarin-treated patients because although these comparisons yielded no statistically significant differences in outcomes, the precision in these estimates were limited by small number of events. Finally, the RE-LY trial was not specifically designed to assess perioperative adverse outcomes and there were no prespecified statistical power calculations for these outcomes. However, the randomized design of RE-LY would allow balanced representation of urgent and elective surgery/procedure types across the three treatment groups (dabigatran, 110 mg and 150 mg, warfarin). To summarize, in anticoagulated patients with atrial fibrillation who require an urgent surgery/procedure, the risks for thromboembolism, major bleeding and mortality did not differ depending on treatment with dabigatran or warfarin, but rates of these outcomes were multi-fold higher than in patients having an elective surgery/procedure. Additional research is needed to determine risks for adverse outcomes in patients on DOACs who need an urgent surgery/procedure and to assess the effect of rapid anticoagulation reversal strategies on these outcomes.
Disclosures The following authors are employed by Boehringer Ingelheim, which manufactures dabigatran: Martina Brueckmann and Mandy Fraessdorf. The following authors have received consulting fees and/or research grants from Boehringer Ingelheim, and/or have participated in advisory boards by Boehringer Ingelheim, which manufactures dabigatran: James D. Douketis, Jeff S. Healey, Michael D. Ezekowitz, Jonas Oldgren, Alex C. Spyropoulos, Lars Wallentin, Stuart J. Connolly, Salim Yusuf, and John W. Eikelboom. Author contributions Study conception and design (JDD, MB, JWE), statistical analysis (MB, MF), analysis of results (JDD, MB, MF, JH, ACS, JWE), and critical review of manuscript (JDD, MB, MF, JSH, MDE, JO, ACS, LW, SJC, SY, JWE). Acknowledgments None. References [1] D. Siegal, J. Yudin, S. Kaatz, J.D. Douketis, W. Lim, A.C. Spyropoulos, Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates, Circulation 126 (13) (2012) 1630–1639. [2] D. Garcia, J.H. Alexander, L. Wallentin, D.M. Wojdyla, L. Thomas, M. Hanna, S.M. AlKhatib, P. Dorian, J. Ansell, P. Commerford, G. Flaker, F. Lanas, D. Vinereanu, D. Xavier, E.M. Hylek, C. Held, F.W. Verheugt, C.B. Granger, R.D. Lopes, Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures, Blood 124 (25) (2014) 3692–3698. [3] M.W. Sherwood, J.D. Douketis, M.R. Patel, J.P. Piccini, A.S. Hellkamp, Y. Lokhnygina, A.C. Spyropoulos, G.J. Hankey, D.E. Singer, C.C. Nessel, K.W. Mahaffey, K.A. Fox, R.M. Califf, R.C. Becker, ROCKET AF Investigators, Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF), Circulation 129 (18) (2014) 1850–1859.
J.D. Douketis et al. / Thrombosis Research 139 (2016) 77–81 [4] J.S. Healey, J. Eikelboom, J. Douketis, L. Wallentin, J. Oldgren, S. Yang, E. Themeles, H. Heidbuchel, A. Avezum, P. Reilly, S.J. Connolly, S. Yusuf, M. Ezekowitz, RE-LY investigators, Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial, Circulation 126 (3) (2012) 343–348. [5] B.A. Steinberg, E.D. Peterson, S. Kim, L. Thomas, B.J. Gersh, G.C. Fonarow, P.R. Kowey, K.W. Mahaffey, M.W. Sherwood, P. Chang, J.P. Piccini, J. Ansell, Outcomes registry for better informed treatment of atrial fibrillation investigators and patients. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the outcomes registry for better informed treatment of atrial fibrillation (ORBIT-AF), Circulation 131 (5) (2015) 488–494. [6] J. Beyer-Westendorf, V. Gelbricht, K. Forster, F. Ebertz, C. Kohler, S. Werth, E. Kuhlisch, T. Stange, C. Thieme, K. Daschkow, N. Weiss, Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry, Eur. Heart J. 35 (28) (2014) 1888–1896. [7] P.J. Devereaux, L. Goldman, S. Yusuf, K. Gilbert, K. Leslie, G.H. Guyatt, Surveillance and prevention of major perioperative ischemic cardiac events in patients undergoing noncardiac surgery: a review, CMAJ 173 (7) (2005) 779–788. [8] Vascular Events In Noncardiac Surgery Patients Cohort Evaluation Study I, P.J. Devereaux, M.T. Chan, P. Alonso-Coello, M. Walsh, O. Berwanger, C.Y. Wang, R.I. Garutti, M.J. Jacka, A. Sigamani, S. Srinathan, B.M. Biccard, C.K. Chow, V. Abraham, M. Tiboni, S. Pettit, W. Szczeklik, G. Lurati Buse, F. Botto, G. Guyatt, et al., Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery, JAMA 307 (21) (2012) 2295–2304. [9] R. Sarode, T.J. Milling Jr., M.A. Refaai, A. Mangione, A. Schneider, B.L. Durn, J.N. Goldstein, Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study, Circulation 128 (11) (2013) 1234–1243. [10] S. Kaatz, P.A. Kouides, D.A. Garcia, A.C. Spyropolous, M. Crowther, J.D. Douketis, A.K. Chan, A. James, S. Moll, T.L. Ortel, E.M. Van Cott, J. Ansell, Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors, Am. J. Hematol. 87 (Suppl. 1) (2012) S141–S145. [11] D. Faraoni, J.H. Levy, P. Albaladejo, C.M. Samama, Groupe d'interet en hemostase P, Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants, Crit. Care 19 (2015) 203. [12] M.N. Lauw, M. Coppens, J.W. Eikelboom, Recent advances in antidotes for direct oral anticoagulants: their arrival is imminent, Can J Cardiol. 30 (4) (2014) 381–384. [13] D.M. Siegal, A. Cuker, Reversal of target-specific oral anticoagulants, Drug Discov. Today 19 (9) (2014) 1465–1470. [14] A. Cuker, D.M. Siegal, M.A. Crowther, D.A. Garcia, Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants, J. Am. Coll. Cardiol. 64 (11) (2014) 1128–1139. [15] T. Baglin, A. Hillarp, A. Tripodi, I. Elalamy, H. Buller, W. Ageno, Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the subcommittee on control of anticoagulation of the Scientific and Standardisation Committee
[16]
[17]
[18]
[19]
[20]
[21]
[22] [23] [24]
[25]
[26]
[27]
81
of the International Society on Thrombosis and Haemostasis, J. Thromb. Haemost. (2013). A. Majeed, K. Meijer, R. Larrazabal, F. Arnberg, G.J. Luijckx, R.S. Roberts, S. Schulman, Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate, Thromb. Haemost. 111 (2) (2014) 233–239. C.V. Pollack Jr., P.A. Reilly, J. Eikelboom, S. Glund, P. Verhamme, R.A. Bernstein, R. Dubiel, M.V. Huisman, E.M. Hylek, P.W. Kamphuisen, J. Kreuzer, J.H. Levy, F.W. Sellke, J. Stangier, T. Steiner, B. Wang, C.W. Kam, J.I. Weitz, Idarucizumab for dabigatran reversal, N. Engl. J. Med. 373 (6) (2015) 511–520. S.J. Connolly, M.D. Ezekowitz, S. Yusuf, J. Eikelboom, J. Oldgren, A. Parekh, J. Pogue, P.A. Reilly, E. Themeles, J. Varrone, S. Wang, M. Alings, D. Xavier, J. Zhu, R. Diaz, B.S. Lewis, H. Darius, H.C. Diener, C.D. Joyner, A. Wallentin, Dabigatran versus warfarin in patients with atrial fibrillation, N. Engl. J. Med. 361 (12) (2009) 1139–1151. J.D. Douketis, A.C. Spyropoulos, F.A. Spencer, M. Mayr, A.K. Jaffer, M.H. Eckman, A.S. Dunn, R. Kunz, Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines, Chest 141 (2 Suppl) (2012) e326S–e350S. A.C. Spyropoulos, J.D. Douketis, G. Gerotziafas, S. Kaatz, T.L. Ortel, S. Schulman, Subcommittee on the control of anticoagulation of the SSC of the ISTH. Periprocedural antithrombotic and bridging therapy: recommendations for standardized reporting in patients with arterial indications for chronic oral anticoagulant therapy, J. Thromb. Haemost. 10 (4) (2012) 692–694. C.C. Acevedo, F. Velasco, C. Herrera, Reversal of rivaroxaban anticoagulation by nonactivated prothrombin complex concentrate in urgent surgery, Futur. Cardiol. 1–5 (2015). T. Puttick, R. Bahl, H. Mohamedbhai, Emergency reversal of dabigatran for emergency surgery, BMJ Case Rep. 2015 (2015). I. Roberts, H. Shakur, K. Ker, T. Coats, collaborators C-T, Antifibrinolytic drugs for acute traumatic injury, Cochrane Database Syst. Rev. 1 (2011), CD004896. E. Simpson, Y. Lin, S. Stanworth, J. Birchall, C. Doree, C. Hyde, Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia, Cochrane Database Syst. Rev. 3 (2012), CD005011. A. Coppola, J. Windyga, A. Tufano, C. Yeung, M.N. Di Minno, Treatment for preventing bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgery, Cochrane Database Syst. Rev. 2 (2015), CD009961. O. Grottke, R. Rossaint, Y. Henskens, R. van Oerle, H. Ten Cate, H.M. Spronk, Thrombin generation capacity of prothrombin complex concentrate in an in vitro dilutional model, PLoS ONE 8 (5) (2013), e64100. F. Dentali, C. Marchesi, M. Giorgi Pierfranceschi, M. Crowther, D. Garcia, E. Hylek, D.M. Witt, N.P. Clark, A. Squizzato, D. Imberti, W. Ageno, Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis, Thromb. Haemost. 106 (3) (2011) 429–438.