Timing the First Postoperative Dose of Anticoagulants Lessons Learned From Clinical Trials

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1 [ Commentary ] Timing the First Postoperative Dose of Anticoagulants Lessons Learned From Clinical Trials Jeremy S. Paikin, MD ; Jack Hirsh, MD ; Noel C. Chan, MBBS ; Jeffrey S. Ginsberg, MD ; Jeffrey I. Weitz, MD, FCCP ; and John W. Eikelboom, MBBS The non-vitamin K antagonist oral anticoagulants (NOACs), rivaroxaban, apixaban, and dabigatran, have been shown in phase 3 trials to be effective for thromboprophylaxis in patients undergoing elective hip or knee arthroplasty. Results from prior studies suggested that the safety of anticoagulants in such patients was improved if the first postoperative dose was delayed for at least 6 h after surgery. The timing of the first postoperative dose of the NOACs tested in phase 2 studies differed among the three NOACs: dabigatran was started 1 to 4 h postoperatively, whereas rivaroxaban and apixaban were started at least 6 and 12 h, postoperatively, respectively. Our review of the timing of initiation of thromboprophylaxis in randomized trials provides three related lessons. First, clinical trials performed before the NOACs were evaluated demonstrated that delaying the first dose of prophylactic anticoagulation until after major surgery is effective and safe. Second, the optimal timing of the first dose of prophylactic anticoagulation after surgery depends on the dose that is selected. Third, the results of the phase 3 trials with NOACs for thromboprophylaxis support the concept that acceptable efficacy and safety can be achieved when the appropriate first postoperative dose of anticoagulant is delayed for at least 6 h after surgery. CHEST 2015; 148( 3 ): ABBREVIATIONS: BISTRO 5 Boehringer Ingelheim Study in Thrombosis; LDUH 5 low-dose unfractionated heparin; LMWH 5 low-molecular-weight heparin; NOAC 5 non-vitamin K antagonist oral anticoagulant; OD 5 once daily; VKA 5 vitamin K antagonist Rivaroxaban, apixaban, and dabigatran are non-vitamin K antagonist oral anticoagulants (NOACs) that have been evaluated in phase 3 trials for prevention of VTE in patients undergoing elective hip or knee arthroplasty. The NOACs were first evaluated in phase 2 trials that examined two important variables: (1) total daily dose and (2) dose frequency (once daily [OD] or bid). 1-5 None of the phase 2 studies investigated the optimal timing of the first postoperative dose. Rather, in the phase 2 trials, each NOAC was given at a fixed time postoperatively, presumably with the plan of using the same timing of initial dosing in subsequent phase 3 studies. However, earlier studies with older anticoagulants had provided useful information about the relationship between Manuscript received November 1, 2014; revision accepted March 20, 2015; originally published Online First April 30, AFFILIATIONS: From Hamilton General Hospital (Drs Paikin, Weitz, and Eikelboom), Department of Medicine (Drs Hirsh, Ginsberg, Weitz, and Eikelboom), Population Health Research Institute (Drs Chan and Eikelboom), and Thrombosis and Atherosclerosis Research Institute (Drs Weitz and Eikelboom), McMaster University, Hamilton, ON, Canada. CORRESPONDENCE TO: Jeremy S. Paikin, MD, Hamilton Health Sciences-Hamilton General Hospital, McMaster University, 237 Barton St E, Hamilton, ON, L8L 2X2, Canada; paikinjs@mcmaster.ca 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: /chest journal.publications.chestnet.org 587

2 the timing of the first postoperative dose and both efficacy and safety. In this commentary, we consider the lessons learned from earlier studies about the timing of the first postoperative dose of anticoagulant prophylaxis and review the timing of the first postoperative dose with the three NOACS in both the phase 2 dose-finding studies and phase 3 trials. Clinical Trials With Older Anticoagulants Before the evaluation of the NOACs, phase 3 trials had been performed with vitamin K antagonists (VKAs), lowdose unfractionated heparin (LDUH), low-molecularweight heparin (LMWH), and fondaparinux for VTE prevention in high-risk surgical patients ( Table 1 ). The results of the phase 3 trials provided important information about the relationship between the first perioperative dose and both safety and efficacy of anticoagulant prophylaxis. In the earlier trials of subcutaneous LDUH, the first dose of the drug (5,000 units) was given 2 h before surgery followed by 5,000 units every 8 to 12 h thereafter until the patient was ambulatory The rationale for giving the first dose preoperatively was based on the results of radiolabeled fibrinogen leg scanning, which revealed that small thrombi often formed during surgery. 12 It seemed logical, therefore, to modulate coagulation during surgery, a conclusion that dominated thinking for decades despite the fact that VKAs were effective for VTE prophylaxis even though they failed to produce a measurable anticoagulant effect for at least 2 days after surgery. These two apparently conflicting positions can be reconciled by the thesis that small thrombi, formed during or soon after surgery, can be prevented from growing into larger clinically important thrombi by a level of anticoagulation that would not be tolerated during or immediately after surgery. When LMWH was first introduced for VTE prophylaxis, the first dose was given 2 h preoperatively based on experience with LDUH. However, this practice was abandoned after Bergqvist and colleagues 6 reported the results of a randomized trial comparing dalteparin with LDUH. Both subcutaneously administered anticoagulants were initiated in doses of 5,000 units 2 h preoperatively and continued postoperatively ( Table 1 ). Dalteparin and LDUH were similarly effective in preventing postoperative VTE, but dalteparin caused more bleeding (11.6% vs 4.6%, P 5.007). 6 In an attempt to reduce peri-operative bleeding, a second trial compared 5,000 units of dalteparin initiated 12 h preoperatively and continued OD postoperatively with LDUH in patients undergoing general abdominal surgery. There was a trend toward a lower risk of postoperative VTE in patients receiving dalteparin compared with LDUH (5.5% vs 8.3%; P 5.08), but dalteparin was again associated with more bleeding than LDUH (6.7% vs 2.7%, P 5.03). 7 However, because the majority of bleeding was considered clinically insignificant, and (presumably) because of the greater importance placed upon the trend for lower VTE rates and the convenience of OD vs bid dosing, LMWH, given 12 h preoperatively, became standard practice in Europe ( Table 1 ). In the early 1980s, Turpie and colleagues 8 performed a randomized trial in patients undergoing elective hip surgery in North American centers; patients were randomized to receive LMWH bid (enoxaparin 30 mg bid) or placebo with the first dose of study drug given 12 to 24 h after surgery ( Table 1 ). 8 The rationale for starting enoxaparin postoperatively was based on three considerations. First, Bergqvist and colleagues 6,7 had shown that an early preoperative dose caused excessive bleeding during and soon after surgery. Second, North American orthopedic surgeons were particularly concerned about mitigating peri-operative bleeding complications. Third, VKAs started postoperatively were shown to be effective and safe for VTE prophylaxis despite their delayed anticoagulant effect. 15 The study by Turpie and colleagues 8 showed that postoperative initiation of enoxaparin at a dose of 30 mg bid was highly effective at reducing the risk of DVT (enoxaparin vs placebo: 10.8% vs 51.3%, P ) without increasing the risk of major bleeding (enoxaparin vs placebo: 4.0% vs 4.0%, P value not reported). 8 Two subsequent randomized trials compared enoxaparin 30 mg bid and 40 mg OD with enoxaparin 10 mg OD 16 or LDUH 5,000 units tid 17 within 24 h after elective hip replacement surgery. The first study showed that enoxaparin 30 mg bid (11% vs 25%, P,.001) and 40 mg OD (14% vs 25%, P 5.02) were more effective than enoxa parin 10 mg OD at preventing VTE. 16 A comparison between enoxaparin 30 mg bid and 40 mg OD demonstrated similar rates of VTE (11% vs 14%, P..2) and bleeding (13% vs 11%, P value not reported). The second study showed that enoxaparin 30 mg bid was more effective than both LDUH 5,000 units bid (6% vs 15%, P 5.03) and enoxaparin 40 mg OD (6% vs 21%, P ) at preventing VTE. Rates of bleeding were similar with enoxaparin 30 mg bid and both LDUH 5,000 units bid (12% vs 12%, P value not reported) and enoxaparin 40 mg OD (10% vs 12%, P value not reported). Based on these results, the enoxaparin 30-mg bid regimen and 588 Commentary [ 148 # 3 CHEST SEPTEMBER 2015 ]

3 TABLE 1 ] RCTs of Older Anticoagulants Informing on the Effect of Timing of Preoperative and Postoperative Dose on Efficacy and Safety Study/Year Population Intervention Control Efficacy Outcome, Intervention vs Control Safety Outcome, Intervention vs Control Bergqvist et al 6 /1986 Elective general abdominal surgery, n LMWH 5,000 units, 2 h preoperatively, then 5,000 units daily LDUH 5,000 units, 2 h preoperatively, then 5,000 units q12h DVT on radiolabeled fibrinogen uptake scan 4.3% vs 6.4% ( P 5 ns) Hemorrhagic complications 11.6% vs 4.6% ( P 5.007) Bergqvist et al 7 /1988 Elective general abdominal surgery, n 5 1,040 LMWH 5,000 units on the evening before surgery then OD LDUH 5,000 units, 2 h preoperatively, then 5,000 units q12h DVT on radiolabeled fibrinogen uptake scan 5.0% vs 9.7% ( P 5.01) Hemorrhagic complications 5.9% vs 3.0% ( P 5.03) Turpie et al 8 /1986 Elective hip replacement, n Enoxaparin 30 mg bid, started h postoperatively Saline placebo Venographic DVT 10.8% vs 51.3% ( P ) Major bleeding 4.0% vs 4.0% ( P 5 ns) Hull et al 9 /2000 Elective hip arthroplasty, n 5 1,472 (A) Preoperative arm: dalteparin 2,500 units, 2 h preoperatively, then 2,500 units postoperatively at mean 6.6 h (B) Postoperative arm: dalteparin 2,500 units postoperatively, mean 6.6 h, followed by 5,000 units OD in both arms (C) warfarin INR Venographic DVT A vs C: 10.7% vs 24.0% ( P,.01) B vs C: 13.1% vs 24.0% ( P,.01) Adjudicated major bleeding A vs B vs C: 6.7% vs 5.7% vs 4.1% Colwell et al 10 /2006 Elective hip or knee arthroplasty, n 5 2,046 Delayed fondaparinux 2.5 mg started morning after surgery, followed by 2.5 mg daily Standard fondaparinux 2.5 mg started 8 h 2 h postoperatively, followed by 2.5 mg daily Symptomatic VTE 2.0% vs 1.9% ( P 5.89) Major bleeding 1.2% vs 0.7% ( P 5.19) INR 5 international normalized ratio; LDUH 5 low-dose unfractionated heparin; LMWH 5 low-molecular-weight heparin; ns 5 nonsignificant; OD 5 once daily; RCT 5 randomized controlled trial. journal.publications.chestnet.org 589

4 not the 40-mg OD regimen was initially approved by the US Food and Drug Administration and widely adopted by North American orthopedic surgeons. In an attempt to refine the peri-operative timing of the first dose of anticoagulant, Hull and associates 9 p e r- formed a randomized trial evaluating the relative efficacy and safety of two regimens of dalteparin given in close proximity to surgery ( Table 1 ). They compared three groups: preoperative dalteparin (2,500 units started within 2 h of surgery, then 2,500 units at least 4 h postoperatively, followed by 5,000 units OD), postoperative dalteparin (2,500 units started at least 4 h postoperatively, then 5,000 units OD), and VKA prophylaxis. The results showed lower rates of VTE with both preoperative and postoperative dalteparin compared with VKA (10.7% and 13.1% vs 24.0%, respectively; P,.001 for both comparisons). However, the rate of major bleeding was significantly higher with preoperative dalteparin than with postoperative dalteparin (2.2% vs 0.8%; P value not reported) or VKA (2.2% vs 0.4%; P 5.01). Early vs Late First Postoperative Dose of Anticoagulant The next important series of studies that informed on the timing of the first postoperative dose included four randomized trials comparing enoxaparin with fondaparinux in patients undergoing major orthopedic surgery. Two trials 18,19 compared fondaparinux (2.5 mg OD starting 6 h after surgery) with enoxaparin (40 mg OD starting 12 h preoperatively; the common European dosing regimen), while the other two trials compared fondaparinux (2.5 mg OD starting 6 h after surgery) with enoxaparin (30 mg bid starting h after surgery; the common North American dosing regimen). 20,21 A meta-analysis of all four studies (N 5 7,344) showed that fondaparinux was more effective than enoxaparin in reducing the incidence of asymptomatic DVT detected by mandatory venography (6.8% vs 13.7%, P,.001), but there was no difference in the incidence of symptomatic VTE (0.6% vs 0.4%, P 5.25) or in fatal pulmonary embolism (0.1% vs 0.1%, no P value reported) and fondaparinux was associated with an increased rate of major bleeding (2.7% vs 1.7%, P 5.008). 22 A lt hou g h compared with enoxaparin, fondaparinux reduced the rate of asymptomatic DVT, it did not replace LMWH for thromboprophylaxis in patients undergoing major orthopedic surgery, presumably because of the high concern placed on bleeding by orthopedic surgeons and because it did not reduce the rate of symptomatic events. Two secondary analyses were performed to investigate the influence of timing of the first postoperative dose of fondaparinux on safety and efficacy. The first reported that the bleeding risk was significantly increased in patients who were given their first dose earlier than 6 h after surgery compared with later than 6 h (3.2% vs 2.1%, P 5.045). 23 The second reported that the risk of postoperative bleeding was related to the timing of the first postoperative dose (over a 3-9 h postoperative window), while the efficacy of fondaparinux was not affected by timing. 10 Although the results of these post hoc analyses are not definitive, their findings are supported by the results of a large randomized trial (N 5 2,046) comparing standard postoperative administration of fondaparinux (at 8 h) with delayed administration (the morning after surgery), which showed similar rates of symptomatic VTE in both arms (2.0% vs 1.9%, P 5.89) and a trend for increased major bleeding in the standard arm (1.2% vs 0.7%, P 5.19) ( Table 1 ). Lessons Learned From Trials of Older Anticoagulants Several conclusions can be drawn from these earlier studies. First, prophylactic doses of LMWH administered 2 h before surgery cause more bleeding than LDUH. Second, anticoagulants are effective when started 12 h or more after surgery. Third, there is a strong suggestion that starting treatment with anticoagulants within 6 h of surgery increases the risk of bleeding without improving efficacy compared with a later start. Fourth, in the context of designing trials for regulatory approval, enoxaparin 30 mg bid starting 12 h postoperatively is a formidable comparator, both in terms of efficacy and safety. Timing of the First Postoperative Dose of Anticoagulants in the NOAC Trials Table 2 details the timing of the first postoperative dose of the NOACs in phase 2 and phase 3 studies. Rivaroxaban was tested in three phase 2 2,3,5 and four phase 3 studies, apixaban in one phase 2 4 and three phase 3 studies, and dabigatran in two phase 2 1,31 and four phase 3 studies, although only one of the phase 2 studies 1 (Boehringer Ingelheim Study in Thrombosis [BISTRO] II) used the dabigatran formulation that was subsequently tested in the phase 3 studies. None of the phase 2 studies evaluated the optimal timing of the first dose of the NOACs. With each of the NOACs, the timing of the first postoperative dose used in the phase 3 studies was the same as that evaluated in phase 2 studies with the exception of the Dabigatran Etexilate vs Enoxaparin in Prevention of Venous 590 Commentary [ 148 # 3 CHEST SEPTEMBER 2015 ]

5 TABLE 2 ] Novel Oral Anticoagulants in Phase 2 VTE Prevention Studies and Key Efficacy Results of Phase 3 RCTs Drug Time of First Dose of NOAC in Phase 3 Studies Phase 3 Studies: Acronym (N) All VTE or Death, n/n (%): NOAC vs Enoxaparin % RR (95% CI) All VTE or Death: NOAC vs Enoxaparin Major Bleeding, n/total No. (%): NOAC vs Enoxaparin % RR (95% CI) Rivaroxaban 6-8 h postop RECORD-1 a,b (4,541) 18/1,595 (1.1) vs 58/1,558 (3.7) 0.30 ( ) Superior 6/2,209 (0.3) vs 2/2,224 (0.1) 3.02 ( ) RECORD-2 a,b (2,509) 17/864 (2.0) vs 81/869 (9.3) 0.21 ( ) Superior 1/1,228 (0.1) vs 1/1,229 (0.1) 1.0 ( ) RECORD-3 a,c (2,531) 79/824 (9.6) vs 166/879 (18.9) 0.51 ( ) Superior 7/1,220 (0.6) vs 6/1,239 (0.5) 1.19 ( ) RECORD-4 c,d (3,148) 67/965 (6.9) vs 97/959 (10.1) 0.87 ( ) Superior 10/1,526 (0.7) vs 4/1,508 (0.3) 2.47 ( ) Apixaban h postop ADVANCE-1 c,d (3,195) 104/1,157 (9.0) vs 100/1,130 (8.8) 1.02 ( ) Did not meet noninferiority criteria 11/1,596 (0.7) vs 22/1,588 (1.4) 0.50 ( ) ADVANCE-2 a,c (3,057) 147/976 (15.1) vs 243/997 (24.4) 0.62 ( ) Superior 9/1,501 (0.6) vs 14/1,508 (1.0) 0.65 ( ) ADVANCE-3 a,b (5,407) 27/1,949 (1.4) vs 74/1,917 (3.9) 0.36 ( ) Superior 22/2,673 (0.8) vs 18/2,659 (0.7) 1.22 ( ) Dabigatran 1-4 h postop RE-MODEL a,c (2,076) 213/526 (40.5) LD 1.07 ( ) 9/703 (1.3) LD 0.99 ( ) 183/503 (36.4) HD 0.97 ( ) 10/679 (1.5) HD 1.14 ( ) 193/512 (37.7) 9/694 (1.3) RE-NOVATE a,b (3,494) 75/874 (8.6) LD 1.28 ( ) 15/1,163 (1.3) LD 0.83 ( ) 53/880 (6.0) HD 0.9 ( ) 23/1,146 (2.0) HD 1.29 ( ) 6-12 h postop 60/897 (6.7) 18/1,154 (1.6) RE-NOVATE II a,b (2,055) 61/792 (7.7) vs 69/785 (8.8) 0.88 ( ) 14/1,010 (1.4) vs 9/1,003 (0.9) 1.55 ( ) Major Bleeding: NOAC vs Enoxaparin (Continued) journal.publications.chestnet.org 591

6 TABLE 2 ] (continued) Major Bleeding: NOAC vs Enoxaparin % RR (95% CI) Major Bleeding, n/total No. (%): NOAC vs Enoxaparin All VTE or Death: NOAC vs Enoxaparin % RR (95% CI) All VTE or Death, n/n (%): NOAC vs Enoxaparin Phase 3 Studies: Acronym (N) Time of First Dose of NOAC in Phase 3 Studies Drug Inferior 5/871 (0.6) HD 0.42 ( ) 219/649 (33.7) HD 1.33 ( ) RE-MOBILIZE c,d (2,615) 5/857 (0.6) LD 0.42 ( ) 188/604 (31.1) LD 1.23 ( ) 163/643 (25.3) 12/868 (1.4) ADVANCE 5 Apixaban Dose Orally vs Anticoagulation With Enoxaparin; HD 5 higher-dose dabigatran regiment; LD 5 lower-dose dabigatran regimen; NOAC 5 non-vitamin K antagonist oral anticoagulant; postop 5 postoperatively; RECORD 5 Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism; RE-MOBILIZE 5 Dabigatran Etexilate vs Enoxaparin in Prevention of Venous Thromboembolism (VTE) Post Total Knee Replacement; RE-MODEL 5 The Dabigatran Etexilate 150 mg or 220 mg Once Daily Versus Enoxaparin 40 mg Once Daily for Prevention of Thrombosis After Knee Surgery; RE-NOVATE 5 Dabigatran Etexilate Compared With Enoxaparin in Prevention of VTE Following Total Hip Arthroplasty; RR 5 relative risk. See Table 1 legend for expansion of other abbreviations. a Comparator arm was enoxaparin 40 mg OD initiated the evening before surgery. b Indication for surgery is total hip replacement. c Indication for surgery is total knee replacement. d Comparator arm was enoxaparin 30 mg bid initiated 12 to 24 h postoperatively. Thromboembolism (VTE) Post Total Knee Replacement (RE-MOBILIZE) study, 34 in which dabigatran was initiated 6 to 12 h postoperatively instead of 1 to 4 h postoperatively. Rivaroxaban Phase 2: Three phase 2 studies with rivaroxaban collectively included 2,216 patients undergoing total knee or hip arthroplasty. 2,3,5 The first dose was given 6 h after surgery in all three studies. The results of the single phase 2 study evaluating OD doses of rivaroxaban are summarized in Figure 1A.5 The two additional studies evaluated identical bid dosing regimens of rivaroxaban. 2,3 Based upon the efficacy and safety dose-response curves and comparison with control, rivaroxaban 10 mg OD was selected for evaluation in phase 3 studies. Phase 3: Four phase 3 trials that included. 12,500 patients demonstrated that rivaroxaban 10 mg OD (started 6 h postoperatively) was more effective than enoxaparin in preventing VTE ( Table 2 ) but caused slightly more bleeding Apixaban Phase 2: One phase 2 study was performed with apixaban in. 1,200 patients undergoing total knee arthroplasty. 4 The first dose was given 12 to 24 h after surgery. Apixaban was tested in multiple doses and was compared with both warfarin and enoxaparin. The results of the phase 2 trial are summarized in Figure 1B. Based upon the efficacy and safety observed in the doseresponse curves and the comparison with the two control groups, apixaban 2.5 mg bid and 5 mg bid doses showed the most favorable benefit-to-risk ratios, and the 2.5 mg bid dose was selected for phase 3 testing ( Table 2 ). Phase 3: Three phase 3 trials were performed in over 11,500 patients. The results from two trials showed that apixaban 2.5 mg bid (started 12 to 24 h postoperatively) was more effective than enoxaparin 40 mg daily (started 12 h preoperatively) In a third trial, which compared apixaban 2.5 mg bid with enoxaparin 30 mg bid, the efficacy event rates with apixaban and enoxaparin were almost identical (9.0% vs 8.8%, respectively), but the prespecified noninferiority criteria were not met (Table 2 ). 28 Apixaban and enoxaparin were associated with similar rates of bleeding. Dabigatran Phase 2: BISTRO II included. 1,900 patients undergoing total knee or hip arthroplasty and compared multiple doses of dabigatran with enoxaparin. 1 The first dose of dabigatran was reduced by one-half compared 592 Commentary [ 148 # 3 CHEST SEPTEMBER 2015 ]

7 with subsequent doses and was administered 1 to 4 h postoperatively, compared with enoxaparin 40 mg OD started 12 h preoperatively ( Table 2 ). The results of BISTRO II are summarized in Figure 1C. The two dabigatran dose regimens selected for the phase 3 studies were an initial dose of 75 mg or 110 mg, given 1 to 4 h postoperatively followed by 150 mg or 220 mg OD, respectively. Neither regimen was evaluated in phase 2 studies; instead, the doses were selected based on the results of a pharmacokinetic modeling substudy. Phase 3: Dabigatran was compared with enoxaparin in four phase 3 studies In each trial, dabigatran regimens consisted of either a 75 mg initial dose followed by a dose of 150 mg OD thereafter, or a 110 mg starting dose followed by 220 mg OD thereafter. In three of the four trials, dabigatran was started 1 to 4 h after surgery ( early dabigatran ) and enoxaparin 40 mg was administered OD with the first dose given 12 h before surgery and the second dose 12 h after surgery. 32,33,35 The fourth study introduced two variables that were not tested in the phase 2 program. 34 Thus, the first dose of dabigatran was administered 6 to 12 h postoperatively ( late dabigatran ) and enoxaparin was given in a regimen of 30 mg bid with the first dose started 12 to 18 h after surgery. In the first three trials, early dabigatran was associated with similar rates of VTE and all-cause mortality, and similar rates of major bleeding compared with enoxaparin 40 mg OD. 32,33,35 In the fourth trial, late dabigatran was inferior to enoxaparin 30 mg bid for reduction in the rate of VTE and all-cause mortality (Table 2 ). 34 Discussion Ideally, selection of dose regimens for phase 3 trials of thromboprophylaxis after orthopedic surgery should be based on the results of appropriately designed phase 2 studies. When choosing regimens for testing in dosefinding studies, it would be logical to take into account Figure 1 Efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in phase 2 studies of VTE prevention in major orthopedic surgery. A, Efficacy (composite of any DVT, objectively diagnosed pulmonary embolism [PE], and all-cause mortality) and safety (total bleeding) of OD oral rivaroxaban (dose range, 5-40 mg OD initiated 6-8 h after surgery) compared with subcutaneous enoxaparin 40 mg OD (initiated the evening before surgery). In this figure, only the results of the ODIXa-HIP study are presented; the other two studies are referred to in the text. 5 B, Effi cacy (composite of any DVT, symptomatic PE, and all-cause mortality) and safety (total bleeding) of oral apixaban (dose range, 5-20 mg total dose/d initiated h after surgery and given either OD or bid) compared with subcutaneous enoxaparin 30 mg bid (initiated h after surgery). 4 C, Efficacy (VTE detected by bilateral leg venography or symptomatic events) and safety (total bleeding) of oral dabigatran (dose range, 50 mg bid, 150 mg bid, 300 mg bid, and 225 mg bid initiated 1 to 4 h after surgery compared with subcutaneous enoxaparin 40 mg OD (initiated 12 h prior to surgery). 1 Solid white bar 5 efficacy outcome as previously defined; horizontal pattern bar 5 total bleeding. * and # denote statistical significance in comparison with enoxaparin and warfarin control, respectively. Enox 5 enoxaparin; OD 5 once daily. journal.publications.chestnet.org 593

8 the experience from earlier clinical trials with other anticoagulants. The choice of timing of the first postoperative dose in the phase 2 studies with rivaroxaban and apixaban (6-8 h and h postoperatively, respectively) was consistent with the experience obtained from the earlier studies, which showed that delaying postoperative initiation of anticoagulants did not compromise efficacy but improved safety. Furthermore, the dosage regimens used in the phase 3 studies with rivaroxaban and apixaban were identical to those used in the phase 2 studies. In contrast, the phase 2 studies with dabigatran used an earlier (1-4 h) start for the first postoperative dose, as did the initial three phase 3 studies with dabigatran; these three studies showed noninferiority of dabigatran compared with enoxaparin 40 mg OD. In the fourth phase 3 trial, a modified regimen of dabigatran, untested in phase 2 trials, was used; it was found to be inferior to enoxaparin 30 mg bid. We speculate that the unfavorable results in this fourth study could have been caused by a combination of a less effective dosage regimen (than the other three trials) and a more effective comparator. Our review of the timing of initiation of anticoagulant prophylaxis in randomized trials provides three related lessons. First, clinical trials performed prior to introduction of the NOACs demonstrated that delaying the first dose of prophylactic anticoagulation until after major surgery is effective and safe. Second, the optimal timing of the first dose of prophylactic anticoagulation after surgery depends on the dose that is selected. Third, the results of the phase 3 trials with NOACs for thromboprophylaxis after elective hip or knee arthroplasty support the concept that acceptable efficacy and safety can be achieved when an appropriate first dose of anticoagulant is given at least 6 h after surgery. Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Paikin reports honoraria from Boehringer Ingelheim GmbH. Dr Weitz reports personal fees from Bayer AG, Bristol-Myers Squibb Company, Pfizer Inc, Merck Sharp & Dohme Corp, Daiichi Sankyo Company Limited, Janssen Global Services LLC, Portola Pharmaceuticals Inc, and Boehringer Ingelheim GmbH, outside of the submitted work. Dr Eikelboom reports grant support and honoraria from AstraZeneca, Bayer AG, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company/Pfizer Inc, Daiichi Sankyo Company Limited, GlaxoSmithKline plc, Janssen Global Services LLC, and sanofi-aventis US LLC and grant support from Eli Lilly and Company. Drs Hirsh, Chan, and Ginsberg have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. References 1. 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