Peri-Procedural Bleeding and Thromboembolic Events ... - Circulation

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DOI: 10.1161/CIRCULATIONAHA.111.090464

Peri-Procedural Bleeding and Thromboembolic Events with Dabigatran Compared to Warfarin: Results from the RE-LY Randomized Trial Running title: Healey et al.; Peri-procedural bleeding with Dabigatran Jeff S. Healey, MD, MSc1; John Eikelboom, MD1; James Douketis, MD2; Downloaded from http://circ.ahajournals.org/ by guest on September 16, 2017

Lars Wallentin, MD, PhD3; Jonas Oldgren, MD, PhD3; Sean Yang, MSc1; Ellison Themeles, BA1; Hein Heidbuchle, MD4; Alvaro Avezum, MD5; Paul Reilly, PhD6; Stuart J. Connolly, MD1; Salim Yusuf, MD, DPhil1; Michael Ezekowitz, MB, C ChB, hB,, DP hB DPhi DPhil hill7 on behalf of the RELY investigators 1

Poopu Population pula lati tion on H Hea Health alt lthh Research Institute, McMaste McMaster er Un U University; iversity; 2St. Jose Joseph’s seph ph’s Healthcare Hamilton, ph McMaster McMa Mc Master er U Un University, nive veersi rsity, Hamilton, Canada; 3Upps Uppsala psal a a Clinical Research Ressea e rchh Centre, Ce Uppsala, Sweden; 4 University Univer rsi s ty y Hospitals Hos H ospi pita pi tals ta ls Leuven, Leu L eu uve ven, n, University Uni U nive ni v rs ve rsit ityy of it o L Leuven, euve veen, L Leu Leuven, e ve eu ven, n, Belgium; Bel elgi gium gi um;; 5 In Instituto Inst stit st i ut it utoo Da Dant Dante ntee nt 6 Pazzenese Pazzenese de C Cardiologia, arrdiol diollog giaa, Ho Hosp Hospital spiita sp i ta l D Do o Co Coraca Coracao, ao, Sao ao P Paolo, aolo ao lo, Br Brazil; razil il;; Boeh Boehringer-Ingelheim B oeh ehri ring ngeer-I - ngel -I elhe heim im Pharmaceuticals, Phar Ph a maceut uttic i als,, Rid Ridgefield, dgefiield, d C CT; T; 7L Lankenau anken nau u Ins Institute stiitu tute te ffor or M Medical ed dicaal Re Research, eseearrch ch,, Wy Wynnewood, ynnnew wood,, P PA A

Correspondence: C d Jeff S. Healey, MD, MSc Room C3-121, DBCVSRI Building Hamilton Health Sciences, General Site 237 Barton St. East Hamilton, Ontario, Canada, L8L 2X2 Tel: 905-577-8004 Fax: 905-523-9165 E-mail: [email protected]

Journal Subject Codes: [5] Arrhythmias, clinical electrophysiology, drugs; [53] Embolic stroke; [70] Anticoagulants; [184] Coumarins; [185] Other anticoagulants 1

DOI: 10.1161/CIRCULATIONAHA.111.090464

Abstract: Background - Dabigatran reduces ischemic stroke compared to warfarin; however, given the lack of antidote, there is concern that it might increase bleeding when surgery or invasive procedures are required. Methods and Results - The current analysis was undertaken to compare the peri-procedural bleeding risk of patients in the RE-LY trial treated with dabigatran and warfarin. Bleeding rates were evaluated from 7 days prior until 30 days following invasive procedures, considering only the first procedure for each patient. A total of 4591 patients underwent at least one invasive procedure: 24.7% of patients receiving dabigatran-110; 25.4% on dabigatran-150 and 25.9% on Downloaded from http://circ.ahajournals.org/ by guest on September 16, 2017

warfarin, p=0.34. Procedures included: pacemaker/ defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy 8.6%) and joint replacement (6.2%). Among patients assigned to either dabigatran dabigatraan dose d se the do the last llas at (8.6%) to 114 11 14 (87-144) (87(8 7-14 7144) 14 4) dose of study drug was given 49 (35-85) hours prior to the procedure; comparedd to hours in patients receiving warfarin, p1 hour. The perioperative management of warfarin was according to local practice. From December 22nd, 2005 until August 7th, 2008, the RE-LY protocol recommended discontinuation of dabigatran 24 hours prior to a procedure or surgery in all patients. Based on an improved understanding of the anticoagulant effect of dabigatran 10-12, from August 7th, 2008 until the end of the study on March 31st, 2009, a protocol amendment recommended that dabigatran be discontinued 24 hours prior to surgery or Downloaded from http://circ.ahajournals.org/ by guest on September 16, 2017

procedures deemed to be associated with a low risk of bleeding, such as coronary angiography or pacemaker implantation. For surgery or procedures deemed to be associated with a high risk of bleeding (such as cardiac, abdominal and neurosurgery or procedures requiring spinal spina pin l anesthesia), dabigatran was to be discontinued 2 to 5 days prior to surgery, depending on renal fu unccti tioon on ((Ta Tab Ta blee 11). ). In all cases, dabigatran wass re ). rre-started -started post-pr proced pr ed dur uree once adequate function (Table post-procedure hhem emostasis mo had ad bbee en aachieved. chi hiev hi e ed ev ed. hemostasis been F orr tthi hiss analysis, analys ana alyssiss, the th peri-procedural p ri pe ri-p -prroce -p roceedu dura rall period ra peri pe riood od was waas defined deffine de nedd ass llas ne a ting as ngg fr from om m 7 dda ays pr ays rio iorr to o For this lasting days prior he procedure procedurre un unti tiil 30 dday ayss af afte er. r Al All ou outc tcom tc omes om es we were re ddef efin ef in ned uusing sing si ngg tthe he ssam amee cr am crit iter it eria er ia that that were the until days after. outcomes defined same criteria used in the main RE-LY trial 9. Bleeding outcomes of interest included: major bleeding, fatal bleeding, bleeding requiring surgery and all-cause bleeding. Major bleeding, was the primary bleeding outcome for all analyses and was defined as a reduction in hemoglobin of at least 20 g per liter, transfusion of at least 2 units of blood or symptomatic bleeding into a critical area or organ 1. Thrombo-embolic complications included ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and death. The primary analysis was limited to the first surgery or procedure for each patient during the course of the study, to avoid the influence of intra-patient correlation for subsequent events; however, data are also presented for all

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DOI: 10.1161/CIRCULATIONAHA.111.090464

surgeries performed during the trial. All cases of peri-procedural stroke, systemic embolism and myocardial infarction were reviewed to exclude outcomes where the procedure or surgery was performed secondary to a clinical event (e.g., embolectomy to treat systemic embolism). The rate of bleeding and thrombotic complications in patients receiving warfarin was compared with the rate in those receiving dabigatran 110 mg bid or dabigatran 150 mg bid was presented using the relative risk and compared using a chi-squared test. Sub-group analyses were pre-specified in the analysis plan to evaluate the outcome of major bleeding in patients Downloaded from http://circ.ahajournals.org/ by guest on September 16, 2017

having elective vs. urgent surgery; major vs. minor surgery and for those whose dabigatran was managed using the original vs. amended protocol. The effect of these sub-groups was evaluated interruption major using an interaction p-value. The effect off the timing of anticoagulant interruptio io on on o m ajor aj or bleeding was a post-hoc analysis and was evaluated using the Cochran-Armitage test for trend. secondary done A se eco ond ndar ary ar y aanalysis nal alyysis al ysi of major bleeding was don ne uusing sing data from m aall ll pprocedures roce ro c dures performed during including subsequent patients who more This duriing duri n the study, stu udy dy,, in ncllud u in ingg su subs bseq eq que uennt pprocedures roceeduress ffor or pa pati tieentts ts w ho hhad ad m orre th than an n oone. ne. T ne hiss hi analysis marginal logistic generalized an nal alys ysis ys i involved is iinv nvvol o ve vedd fitting fittin fitt in ng a ma arg rgin inal in al llog og gissti ticc regression reg egre eg ress ssio ionn model moddell wi mo with th ggen en ner eral aliz izzed eestimating sttim mattin ingg equation method) mettho hod) d and d) and n the th treatment tre reat a me ment nt effect eefffec ectt presented pres pr esen es ente en tedd using te usin us ingg th in thee od odds dss rratio. atio at io.. io

Results During a mean follow-up of 2 years, 4591 patients in the RE-LY trial had oral anticoagulant therapy interrupted at least once to have surgery or another invasive procedure. This represented 24.7% of patients assigned to dab-110, 25.4% on dab-150 and 25.9% on warfarin, p=0.34. The baseline characteristics of patients having interruption of oral anticoagulant therapy for surgery or procedures were similar between the three treatment groups (Table 2). The most common surgeries and procedures were: pacemaker or defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy 5

DOI: 10.1161/CIRCULATIONAHA.111.090464

(8.6%) and joint replacement (6.2%), with other types of surgery each accounting for a smaller proportion of cases (Table 2). Peri-procedural bridging with intra-venous heparin or low molecular weight heparin was used in 15.3% of patients assigned to dabigatran 110 mg twicedaily, 17.0% of patients assigned to dabigatran 150 mg twice daily and 28.5% of patients assigned to warfarin (p