TR-05734; No of Pages 6 Thrombosis Research xxx (2014) xxx–xxx

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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres

Regular Article

Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants for secondary prevention Cynthia Wu a,⁎, Ghazi S. Alotaibi a, Khalid Alsaleh b, Lori-Ann Linkins c, M. Sean McMurtry a a b c

Department of Medicine, University of Alberta, Edmonton, Alberta, Canada Department of Medicine, King Saud University, Riyadh, Saudi Arabia Department of Medicine, McMaster University, Hamilton, Ontario, Canada

a r t i c l e

i n f o

Article history: Received 8 July 2014 Received in revised form 24 October 2014 Accepted 31 October 2014 Available online xxxx Keywords: Case-fatality thrombosis bleeding venous thromboembolism deep venous thrombosis pulmonary embolism

a b s t r a c t Introduction: The duration of anticoagulation after venous thromboembolic events (VTE) is based on the balance between the risk of recurrent VTE and bleeding. The purpose of this study was to estimate the frequency and case-fatality rate of major bleeding and recurrent VTE during secondary prevention of VTE. Materials and methods: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched through September 2014. Two reviewers independently screened citations to identify trials that enrolled patients for secondary prevention of VTE with direct oral anticoagulants (DOACs), vitamin K antagonists (VKAs), aspirin or placebo. Two reviewers independently extracted data onto standardized forms. Results: Twelve RCTs that enrolled 10,542 patients were included. The rate of major bleeding was 1.6 per 100 patient-years (95% CI, 1.2-2.1), and 0.58 per 100 patient-years (95% CI, 0.24-1.1) on VKAs and DOACs, respectively, with an incidence rate ratio of 0.35 (95% CI, 0.17-0.68, p = 0.0023). The case-fatality rates for DOACs and VKAs were not significantly different at 0% (95% CI, 0.0-15.4) and 6.8% (95% CI, 1.4-18.6), respectively. The rate of recurrent VTE was not different between DOACs and VKA, IRR 0.88 (95% CI, 0.15-4.8, p = 0.88). Case-fatality rates for recurrent VTE for DOAC and VKAs were 10.8% (95% CI, 4.4-20.9) and 5.6% (95% CI, 1.2-15.4), respectively. Only DOACs showed a significant reduction in the composite outcome of fatal recurrent VTE and fatal bleeding when compared to placebo, IRR 0.40 (95% CI, 0.14-1.0, p = 0.03). Conclusion: Case-fatality rates for major bleeding and recurrent VTE for DOACs appear to be similar to those for VKA and the composite of fatal events is lower for DOACs than placebo. Overall, given the favorable safety profile and comparable efficacy of DOAC therapy, the threshold to continue anticoagulation with DOACs after unprovoked VTE should be low if the baseline risk of anticoagulation-related bleeding is not high. © 2014 Elsevier Ltd. All rights reserved.

Introduction Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common chronic disease with a high recurrence rate after anticoagulant therapy is discontinued [1,2]. Vitamin K antagonists (VKAs) have been the traditional agents used for treatment of acute VTE and secondary prevention of recurrent VTE [3]. While recurrent VTE rate decreases over time, with the highest rates within the first 6 to 12 months after stopping anticoagulation, it never falls back to baseline [4]. The cumulative rate of recurrent VTE is high especially for idiopathic (i.e., unprovoked) VTE and it is estimated at 25% at 5 years and 30-40% at 10 years [1,2,5]. Previous meta-analyses of prospective studies evaluating treatment of VTE with VKAs have ⁎ MD, FRCPC Assistant Professor, University of Alberta 4-112 Clinical Sciences Building 11350-83rd Avenue, Edmonton, AB, T6G 2G3 Tel: 780-407- 1584 Fax: 780-407-2680. E-mail address: [email protected] (C. Wu).

shown that the rate of recurrent VTE for patients who discontinue anticoagulant therapy after initial treatment is higher than the rate of major bleeding for patients who remain on anticoagulant therapy (7.6 per 100 patient-years [6], and 2.74 per 100 patient-years [7], respectively). However, the case-fatality rate of recurrent VTE is lower (5.1%) [6,8] than the case-fatality of major bleeding (9.1%– 11%) [6,7]. Consequently, it has generally been considered acceptable to discontinue anticoagulant therapy after the initial treatment period in patients with an estimated risk of recurrent VTE of less than 5% per year [9]. Recently, four direct oral anticoagulant agents (DOACS; apixaban, dabigatran, rivaroxaban, and edoxaban), have been shown to be noninferior to VKAs for the initial treatment of VTE [10–14]. These agents have the potential to reduce the burden of long-term anticoagulant treatment because they do not require laboratory monitoring and are less likely to be affected by diet or other medications. Furthermore, two RCTs have shown that aspirin reduces the risk of recurrent VTE by 32%, suggesting that it is another option for long-term prevention of recurrent

http://dx.doi.org/10.1016/j.thromres.2014.10.033 0049-3848/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article as: Wu C, et al, Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants ..., Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.10.033

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C. Wu et al. / Thrombosis Research xxx (2014) xxx–xxx

VTE [15,16]. Whether these agents offer an advantage over VKAs for secondary prevention of VTE with respect to case-fatality is unclear. The objective of this study was to compare the rates and case-fatality of recurrent VTE and major bleeding in patients receiving DOACs for secondary prevention of VTE with patients receiving VKAs, aspirin or placebo. Material and methods Data sources and studies identification Using the OVID interface, we searched MEDLINE, EMBASE, and Cochrane Register of Controlled Trials (no language restrictions) from inception to December 2013 and updated prior to publication in September, 2014 to identify randomized controlled trials (RCTs) that enrolled adult patients (≥ 18 years old) who were treated with DOACs, VKAs, aspirin or placebo for secondary VTE prevention after a minimum of 3 months of anticoagulant therapy. We used MeSH terms venous thrombosis, pulmonary embolism and recurrent venous thrombosis. The following terms were also added to the search: new oral anticoagulants, dabigatran, rivaroxaban, edoxaban, apixaban, acenocoumarol, warfarin, aspirin, and placebo. We also screened abstracts from major hematology conferences and clinical trials registries. The electronic search strategy was complemented by manual review of the reference lists of articles that were identified for full-text review, as well as through contact with content experts. The review was reported according to the PRISMA statement [17,18]. Study selection Included studies satisfied the following criteria: 1) involved adults patients randomized to receive an oral anticoagulant agent (rivaroxaban, apixaban, dabigatran or VKA), aspirin, or placebo for secondary prevention of VTE after completion of at least 3 months of acute treatment; II) reported at least one of the following outcomes: a) recurrent VTE objectively confirmed by compression ultrasonography (CUS), venography, ventilation-perfusion lung scan or pulmonary angiography; b) major bleeding events as defined by ISTH [19], or as defined by the investigators; and c) mortality attributed to bleeding or a venous thromboembolic event. Exclusion criteria were as follows: 1) patients were risk stratified after initial acute VTE treatment (i.e., randomized to extended treatment based on their estimated long-term risk of recurrence); II) if they used a non-approved dose of a DOAC or a target INR less than 2-3 in case of VKAs. The title and abstract were reviewed independently and in duplicate by two reviewers (CW, GA) to assess suitability for inclusion. Studies considered relevant by one or both reviewers were retrieved and disagreements were resolved by consensus. Outcome measures and data extraction The primary outcome measures were episodes of: 1) major bleeding; 2) fatal bleeding; 3) recurrent VTE (fatal and non-fatal); and 4) fatal recurrent VTE. Fatal recurrent VTE was defined as VTE diagnosed on autopsy; a high probability ventilation–perfusion scan, a new intraluminal filling defect detected on computed tomography, or venography preceding death; or a high clinical suspicion of fatal pulmonary embolism, as defined by study investigators. Fatal bleeding was defined as major bleeding event directly leading to death or death was reported as “associated with bleeding”. Two reviewers independently abstracted the data and discrepancies were solved by consensus. Quality assessment Two reviewers independently assessed the methodological quality of included studies using the Cochrane Collaboration’s tool for assessing

risk for in randomized trials [20] and disagreements were resolved by consensus.

Data synthesis and analysis Based on the intention-to-treat principle the results of all studies were pooled to determine the following rates: major bleeding, fatal bleeding, recurrent VTE, and fatal recurrent VTE. We also calculated the rate of all combined fatal events (fatal recurrent VTE and fatal bleeding). The case-fatality rate of recurrent VTE was defined as the proportion of recurrent VTE (fatal and nonfatal) resulting in death. The case-fatality rate of major bleeding was defined as the proportion of all major bleeding events causing or associated with death [8]. All rates were expressed as events per 100 patient-years of anticoagulation to standardize for different durations of follow-up across studies [21, 22]. Study estimates were converted to person-time rates of follow-up based on the mean (or median) reported follow-up. Proportions were transformed using the Freeman-Tukey double arcsine method [23,24] and pooled using a DerSimonian–Laird random-effects model [25]. After pooling, point estimates and their 95% CIs limits were backtransformed to rates per 100 patient-years of follow-up. The pooled random effect incidence rate ratio (IRR) [26] was used to estimate the effect of DOACs versus VKA and the effect of all agents (DOACs, VKA, aspirin) versus placebo. The IRR provides a relative measure of the effect of the experimental drug—it was derived as the incidence rate for anticoagulant (A) divided by the incidence rate for anticoagulant (B) and is interpreted in a similar fashion to an odds ratio. The I2 statistic was used to estimate total variation among the pooled estimates across studies. An I2 value less than 25% was considered low-level heterogeneity, 25% to 50% was moderate-level, and greater than 50% was high-level [27].Statistical analysis was performed using StatsDirect statistical software (version 2.8.0).

Results Study selection Of 13071 potentially eligible studies (Fig. 1), 12 RCTs [12,15,16,28–35], published in 11 manuscripts, were included in the analysis. Out of the included studies, 4366 patients received a DOAC (4287 patientyears), 1920 patients received a VKA (2769 patient-years), 3640 received placebo (4702 patient-years) and 616 patients received aspirin (1705 patient-years; Table 1). Three of the studies compared a DOAC (dabigatran, apixaban, and rivaroxaban) to placebo [12,28, 29], and one study, the RE-MEDY trial, used an active comparator (dabigatran vs. warfarin). In addition to the VKA arm in the REMEDY trial [28], we included four additional trials that either compared different durations of VKA therapy [30–32] or compared extended VKA therapy to placebo [34]. Eight studies were included in the analysis of placebo [13,15,16,28,29,33–35]. Two trials compared aspirin with placebo for secondary VTE prevention [15,16]. Table 1 shows characteristics of included studies.

Quality assessment and risk of bias The overall risk of bias for the included studies was low [12,13]. All studies were randomized with adequate sequence generation, with no evident attrition or selective reporting. Three studies [30–32] were open label of which two had a blinded outcome adjudicator and unclearly reported allocation concealment [30,31]. Although most of the studies were funded by the pharmaceutical industry, few studies allowed the sponsor to store or analyze the data [13,28,29,33] (Fig. 1, 2 in Supplementary appendix).

Please cite this article as: Wu C, et al, Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants ..., Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.10.033

C. Wu et al. / Thrombosis Research xxx (2014) xxx–xxx

13071 Potentially relevant references from databases screened. (Medline 1009, EMBASE 9802, CENTRAL 2260)

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Additional records identified through other sources (n =3)

Records after duplicates removed (n =7342)

Records screened (n =7342)

Records excluded (n =7289)

Full-text articles excluded (n =41): -Not relevant design (n= 11) -Withdrawn drug (n=2) -Multiple publication (n = 3) -Not relevant population (n = 14) -Studies for acute VTE prevention (n=8) - Enrolled patients for observation (n=3)

Articles retrieved and evaluated in full for inclusion (n =53)

Studies included in result synthesis (n =12)

Fig. 1. Search strategy and study selection as per PRISMA checklist.

Table 1 Characteristics of studies enrolled patients for secondary treatment of VTE events. Study

RE-MEDY [28]

WARFASA [16] ASPIRE [15] AMPLIFY-Ext, [29]

RE-SONATE [28]

EINSTEIN-Ext [12]

Agnelli, 2001 [31] Agnelli, 2003 [30] Schulman, 1997 [32] Schulman, 2003 [33] Kearon, 1999 [34] Ridker, 2003 [35]

Treatment regimens

Dabigatran 150 mg Warfarin Aspirin 100 mg daily Placebo Aspirin 100 mg daily Placebo Apixaban 5 mg and 2.5 mg Placebo Dabigatran 150 mg Placebo Rivaroxaban 20 mg Placebo Observation* VKA Observation* VKA Observation* VKA Ximelagatran* Placebo Placebo VKA Placebo Low intensity VKA*

Duration, months

N (included)

Patients characteristics

Efficacy outcome

Safety outcome

Male

Age, mean (SD)

2856

61%

55.4 ± 15.0 53.9 ± 15.3

Recurrent VTE 1.8% dabigatran, 1.3% warfarin

Major bleeding: 0.9% dabigatran, 1.8% warfarin

≥ 24

402

63%

62 ± 15

4 yrs (actual 27) 12

822

54%

Median 54

2486

58%

56 ± 15

Recurrent VTE 13.7% aspirin, 21.8% placebo Recurrent VTE 13.9% aspirin, 17.8% placebo Recurrent VTE 1.7% apixaban, 8.8% placebo

Major bleeding: 0.5% aspirin, 0.5% placebo Major bleeding: 1.1% aspirin, 1.5% placebo Major bleeding 0.2% apixaban, 0.5% placebo

6

1343

55%

56.1 ± 15.5 55.5 ± 15.1

Recurrent VTE 0.4% dabigatran, 5.5% placebo

Major bleeding: 0.3% dabigatran, 0.0% placebo

6–12

1196

58%

58 ± 16

Recurrent VTE 1.3% rivaroxaban, 7% placebo

Major bleeding 0.7% rivaroxaban, 0.0% placebo

37.8

134

54.5%

66.8 ± 6.7

34.9

165

39.4%

62.9 ± 16.3

48

116

59%

64 ± 12.5

18

611

51%

58 ± 15

24

162

53%

58 ± 16

6.5

253

47.1%

54.25

Recurrent VTE 15.7% in the extended VKA arm Recurrent VTE 9.1% in the extended VKA arm Recurrent VTE 2.6% in the extended VKA arm Recurrent VTE 11.6% in the extended placebo arm Recurrent VTE 1.3% in the extended VKA arm Recurrent VTE 14.6% in the extended placebo arm

Major bleeding 3% in the extended VKA arm Major bleeding 1.8% in the extended VKA arm Major bleeding 8.6% in the extended VKA arm Major bleeding 18.2% in the extended placebo arm Major bleeding 3.8% in the extended VKA arm Major bleeding 0.8% in the extended placebo arm

18–36

*This arm was excluded; SD: standard deviation; VTE: venous thromboembolism; VKA: vitamin k antagonists.

Please cite this article as: Wu C, et al, Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants ..., Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.10.033

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C. Wu et al. / Thrombosis Research xxx (2014) xxx–xxx

Table 2 Rates of outcomes stratified by treatment arm. Outcomes

DOACs per 100 patient-years (95% CI)

VKA per 100 patient-years (95% CI)

Placebo per 100 patient-years (95% CI)

Aspirin per 100 patient-years (95% CI)

Rate of major bleeding

0.58 (0.24-1.1) 0.0 (0.0-0.09) 0.0% (0.0-15.4) 1.5 (1.2-1.9) 0.18 (0.06-0.37) 10.8% (4.4-20.9%) 0.18 (0.06-0.37)

1.6 (1.2-2.1) 0.14 (0.04-0.32) 6.8% (1.4-18.6) 3.7 (0.89-8.3) 0.14 (0.04-0.32) 5.6% (1.2-15.4%) 0.31 (0.08-0.69)

0.42 (0.26-0.62) 0.1 (0.03-0.2) 16.7% (3.6-41.4) 9.6 (7.5-12.0) 0.38 (0.18-0.65) 4.1% (2.3-6.5%) 0.44 (0.26-0.67)

0.57 (0.27-0.99) 0.0 (0.0-0.16) 0.0% (0.0-33.6) 5.2 (2.8-8.3) 0.16 (0.03-0.40) 2.5% (0.31-8.8%) 0.16 (0.03-0.40)

Rate of fatal bleeding Case-fatality for bleeding Rate of recurrent VTE Rate of fatal VTE Case-fatality for recurrent VTE Rate of composite fatal events

DOACs, direct oral anticoagulants; VKA: vitamin K antagonist; VTE: venous thromboembolism.

Synthesis of results Tables 2 and 3 summarizes the rates and the comparison between treatments. Supplementary Tables S1-S2 summarizes the frequency of each outcome as reported by studies. Major bleeding DOACs and VKA Major bleeding occurred at a rate of 0.58 per 100 patient-years (95% CI, 0.24 -1.1, I2 = 62.2%) in patients receiving a DOAC compared to 1.6 per 100 patient-years (95% CI, 1.2-2.1, I2 = 0.0%) for patients receiving a VKA. There were no fatal bleeding events in any of the DOAC arms compared to a rate of 0.14 per 100 patient-years (95% CI, 0.04-0.32, I2 = 0.0%) of fatal bleeding events in the VKA study arms. The casefatality rate for major bleeding with DOACs was 0% (95% CI, 0.0-15.4). In the VKA arms, 3 out of 44 major bleeding events were fatal yielding a case-fatality rate of 6.8% (95% CI, 1.4-18.6). Placebo and aspirin In the placebo arms, the rate of major and fatal bleeding was 0.42 per 100 patient-years (95% CI, 0.26-0.62, I2 = 0.0%) and 0.1 per 100 patientyears (95% CI, 0.03-0.2, I2 = 0.0%), respectively. The rate of major bleeding in patients who received aspirin was 0.57 per 100 patient-years (95% CI, 0.27-0.62) with no documented fatal bleeding events in the aspirin arms. However, out of 18 major bleeding events in patients receiving placebo, 3 were fatal yielding a case-fatality rate of 16.7% (95% CI, 3.6-41.4). Comparison of bleeding rates DOACs and VKA. The IRR of major bleeding for DOACs compared to VKA was 0.35 (95% CI, 0.17-0.68, p = 0.002) in favor of DOACs, but

not significant when DOACs were compared to placebo 1.7 (95% CI, 0.65-4.6, p = 0.28). In contrast, the IRR of major bleeding and fatal bleeding for VKA compared to placebo was 3.57 (95% CI, 1.7-7.7, p = 0.0012) and 0.29 (95% CI, 0.02-4.6, p = 0.38), respectively. Placebo and aspirin. The IRR of major bleeding for ASA compared to placebo was 1.66 (95% CI, 0.35-7.9, p = 0.52). Recurrent VTE DOACs and VKA The rate of recurrent VTE was 1.5 per 100 patient-years (95% CI, 1.21.9, I2 = 0.0%) in patients receiving a DOAC with a fatal recurrent VTE rate of 0.18 per 100 patients-years (95% CI, 0.06-0.37, I2 = 20.6%). The rate of recurrent VTE in patients receiving a VKA was 3.7 per 100 patient-years (95% CI, 0.89-8.3, I2 = 94.2%) and the rate of fatal recurrent VTE was 0.14 per 100 patient-years (95% CI, 0.04-0.32, I2 = 0.0%). Sixty-five episodes of recurrent VTE were recorded in patients on DOACs, of which 7 were fatal, yielding a case-fatality rate for recurrent VTE of 10.8% (95% CI, 4.4-20.9). In the VKA study arms, 3 out of 54 recurrent VTEs were fatal, yielding a case-fatality rate of 5.6% (95% CI, 1.2-15.4). Placebo and aspirin The recurrent VTE rate was 9.6 per 100 patient-years (95% CI, 7.512.0, I2 = 83.7%) for patients receiving placebo with a fatal recurrent VTE rate of 0.38 per 100 patient-years (95% CI, 0.18-0.65, I2 = 36.8%). In the aspirin arms, the rate of recurrent VTE was 5.2 per 100 patientyears (95% CI, 2.8-8.3) and the rate of fatal recurrent VTE was 0.16 per 100 patient-years (95% CI, 0.03-0.40). A total of 393 events of recurrent VTE were reported during treatment with placebo, of which 16 were fatal. This resulted in a recurrent VTE case-fatality rate of 4.1% (95% CI,

Table 3 Comparison between the rate of bleeding and Recurrent VTE in patients on DOACs vs VKA for extended VTE treatment. Incidence Rate Ratios

Major bleeding (95% CI)

Recurrent VTE (95% CI)

Fatal Bleeding (95% CI)

Fatal recurrent VTE (95% CI)

composite fatal bleeding and fatal recurrent VTE (95% CI)

DOACs versus VKA

0.35 (0.17-0.68, P = 0.0023) 1.7 (0.65-4.6, P = 0.28) 3.57 (1.7-7.7, P = 0.0012) 1.66 (0.35-7.9, P = 0.52)

0.88 (0.16-4.8, P = 0.88) 0.15 (0.08-0.25, P b 0.0001) 0.23 (0.08-0.67, P = 0.007) 0.39 (0.17-0.88, P = 0.023)

N/A⁎

1.1 (0.15-7.5, P = 0.95) 0.48 (0.17-1.2, P = 0.1) 0.32 (0.06-1.1, P = 0.06) 0.34 (0.04-1.5, P = 0.14)

0.75 (0.22-2.7, P = 0.61) 0.40 (0.14-1.0, P = 0.03) 0.54 (0.18-1.4, P = 0.18) 0.29 (0.03-1.2, P = 0.08)

DOACs versus placebo VKA versus placebo ASA versus placebo

N/A⁎ 0.29 (0.02-4.6, P = 0.38) N/A⁎

⁎ : No case of fatal bleeding in the numerator; DOACs, direct oral anticoagulants; VKA: vitamin K antagonists; ASA: aspirin.

Please cite this article as: Wu C, et al, Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants ..., Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.10.033

C. Wu et al. / Thrombosis Research xxx (2014) xxx–xxx

2.3-6.5). In the aspirin arms, out of 79 events of recurrent VTE, 2 were fatal yielding a recurrent VTE case-fatality rate of 2.5% (95% CI, 0.31-8.8). Comparison of recurrent VTE rates DOACs and VKA. The IRR of recurrent VTE for the DOACs compared to VKA was 0.88 (95% CI, 0.16-4.8, P = 0.88). Compared to placebo the IRRs for recurrent VTE for DOACs and VKA were 0.15 (95% CI, 0.08-0.25, p b 0.0001) and 0.23 (95% CI, 0.08-0.67, p = 0.007), respectively. The IRR of fatal recurrent VTE for DOACs and VKAs was 1.1 (95% CI, 0.15-7.5, p = 0.95). There was no difference between DOACs and placebo with respect to fatal recurrent VTE, IRR 0.48 (95% CI, 0.17-1.2, p = 0.1). The difference between VKAs and placebo for fatal VTE trended toward statistical significance, IRR 0.32 (95% CI, 0.06-1.1, p = 0.06). Placebo and aspirin. The IRR of recurrent VTE between ASA and placebo was 0.39 (95% CI, 0.17-0.88, p = 0.023). For fatal recurrent VTE, there was no difference between aspirin and placebo with an IRR of 0.34 (95% CI, 0.04-1.5, p = 0.14). Composite fatal bleeding and recurrent fatal VTE DOACs and VKA The rate of the composite outcome of fatal bleeding and fatal recurrent VTE was 0.18 per 100 patient-years of DOAC therapy (95% CI, 0.06-0.37, I2 = 19.6%) compared to 0.31 per 100 patients-years of VKA therapy (95% CI, 0.08-0.69, I2 = 28.8%). Placebo and aspirin The rate of the composite outcome of fatal bleeding and VTE events was 0.44 per 100 patient-years of placebo therapy (95% Cl, 0.26-0.67, I2 = 10.9%) compared to 0.16 per 100 patients-years of aspirin therapy (95% CI, 0.03-0.40). Comparison of composite fatal events DOACs and VKA. The IRR of combined fatal events in DOACs compared to VKA was not significantly different 0.75 (95% CI, 0.22-2.7, p = 0.61). When compared to placebo, the IRR of combined fatal events was in favor of DOACs, IRR 0.40 (95% CI, 0.14-1.0, p = 0.03). On the contrary, there was no significant difference in IRR between VKAs and placebo: 0.54 (95% CI, 0.18-1.4, p = 0.18). Placebo and aspirin. The IRR of fatal events in aspirin compared to placebo was not significantly different 0.29 (95% CI, 0.03-1.22, p = 0.08). Discussion During secondary prevention of VTE with anticoagulant therapy, patients who received DOACs had case-fatality rates for recurrent VTE and major bleeding that were similar to those for patients who received VKAs. Similarly, the rate of recurrent VTE was not significantly different between these two groups. However, patients who received DOACs had fewer major bleeding complications compared to patients who received VKAs (IRR 0.35, 0.17-0.68) with a rate for major bleeding events for DOACs that was not statistically different from placebo (IRR 1.7, 0.65-4.6). In the current analysis, we estimated the rate of major bleeding on placebo to be 0.42 per 100 patient-years (95% CI, 0.26-0.62). This is similar to a rate of 0.45 per 100 patient-years that has been shown in a previous analysis of bleeding rates in patients randomized to placebo or observation during secondary prevention of VTE [36]. Additionally, the risk of recurrent VTE after 3 months of anticoagulant therapy for unprovoked VTE has been estimated at 10% within the first year off anticoagulation [37,38], which is similar to 9.64 per 100 patient-years (7.5-12.0) in our analysis. The consistency of the results in our placebo group with previously reported rates supports the premise for comparing rates in the antithrombotics and antiplatelet groups.

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Several observations in our study are worthy of discussion. Firstly, DOAC therapy showed a statistically significant better safety profile with respect to major bleeding compared to VKA therapy. Given the difficulties with maintaining a therapeutic INR, this is not unexpected. However, finding that the case-fatality for bleeding with DOAC therapy is similar to VKA therapy was surprising given the lack of reversal agents for DOACs. This observation is consistent with that of Majeed et al [39] who reported a trend toward a lower 30-day mortality due to bleeding in patients who received dabigatran compared to those who received VKA in the context of atrial fibrillation. Secondly, the efficacy of DOAC therapy with respect to preventing recurrent VTE and VTE related death was similar to VKA therapy with an IRR of 0.88 (0.16-4.8) and 1.1 (0.157.5). Lastly, there is an underlying risk of major and fatal hemorrhage even on placebo [36], and of the therapies studied, DOAC therapy was the only therapy that was superior to placebo for the composite outcome of fatal bleeding and fatal recurrent VTE (0.40, 0.14-1.0, p = 0.03). The risk of recurrent VTE while on placebo is an order of magnitude higher than the increased risk of major bleeding while receiving therapeutic anticoagulant therapy, which underscores the need to at least consider extended anticoagulant therapy in patients with unprovoked VTE. However, the rates of recurrent VTE and bleeding should always be interpreted in combination with case-fatality. In previous analyses evaluating VKA therapy [6,7], the net benefit of continuing anticoagulant therapy required a high risk of recurrent VTE to compensate for the higher case-fatality of major bleeding. Our analysis suggests that the threshold for net benefit in continuing DOAC may be lower than for VKA therapy. This should be balanced against the small absolute difference between DOACs and VKAs as well as drug cost and patient preference. In select situations, ability to monitor anticoagulant effect and/or reverse the anticoagulant effect may be desirable and therefore play a role in the choice of anticoagulant. Finally, it is worthy of note that while aspirin lowers the risk of recurrent VTE, it is still associated with a risk of major bleeding. This risk appears to be similar to that seen with DOACs therapy; 0.57 per 100 patient-years (95% CI, 0.27-0.62) for aspirin compared to 0.58 per 100 patient-years (95% CI, 0.24-1.10) for DOACs. At the same time, DOAC therapy offers a larger risk reduction for recurrent VTE. These results are consistent with the similar bleeding risk seen in patients receiving apixaban compared to aspirin in a clinical trial for stroke prevention in the context of atrial fibrillation [40]. While ASA may have had a role in patients deemed inappropriate for VKA therapy secondary to higher bleeding risk but still requiring antithrombotic therapy for higher thrombotic risk, these lower rates of major and fatal bleeding on DOAC therapy suggest DOACs may be superior to ASA, with comparable safety and superior efficacy, for this clinical situation. This study has some limitations. First, all estimates were derived from clinical trials with strict inclusion and exclusion criteria and thus the results may not be generalizable to all patients. Second, we believe that due to the inclusion of studies with variable follow-up period and the fact that pooled studies participated with different follow-up periods, which suggest that all studies were not estimating the same quantity, are likely explanations for the heterogeneity. Additionally, due to the inclusion of only 2 trials in the aspirin arms, the calculation of I2 is statistically not feasible. Third, the number of fatal events was low, particularly in the DOAC group, resulting in large confidence intervals for our estimates of case-fatality. More real-world data on DOAC therapy are needed to improve these estimates and to help patients make informed decisions regarding therapy to prevent recurrent VTE. Our study has several strengths. First, to our knowledge, this is the first study that reports case-fatality and incidence rate ratios of patient important outcomes for patients receiving anticoagulant and antiplatelet therapy for secondary prevention of VTE. Second, all outcomes were derived from methodologically rigorous clinical trials with similar design, and independent adjudication. Third, we calculated person-time rates to adjust for the differences in follow-up time and allow for more accurate estimates of annual risk.

Please cite this article as: Wu C, et al, Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants ..., Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.10.033

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C. Wu et al. / Thrombosis Research xxx (2014) xxx–xxx

Conclusion Case-fatality rates for major bleeding and recurrent VTE for DOACs appear to be similar to those for VKA and the composite of fatal events is lower for DOACs than placebo. Overall, given the favorable safety profile and comparable efficacy of DOAC therapy, the threshold to continue anticoagulation with DOACs after unprovoked VTE should be low if the baseline risk of anticoagulation-related bleeding is not high. Funding None. Declarations of interest M.S. McMurtry and Wu C, are investigators for eTRIS, a randomized, open label, and multicenter study evaluating the efficacy and safety of edoxaban monotherapy versus low molecular weight heparin and warfarin in subjects with symptomatic deep vein thrombosis sponsored by Daiichi Sankyo, and an investigator for XALIA, a multicenter observational study of rivaroxaban as initial anticoagulation for venous thromboembolism. Dr Wu has served on the advisory board for Leo-Pharma. Dr. L Linkins holds an investigator-sponsored grant from Bayer for a study evaluating the use of rivaroxaban for treatment of heparininduced thrombocytopenia. Acknowledgements M.S. McMurtry is supported by the Heart and Stroke Foundation of Canada. Alotaibi GS received a scholarship from King Saud University, Riyadh, Saudi Arabia. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.thromres.2014.10.033. References [1] Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1–7. [2] Heit JA, Mohr DN, Silverstein MD, Petterson TM, O'Fallon WM, Melton 3rd LJ. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 2000;160:761–8. [3] Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133: 454S–545S. [4] Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585–93. [5] Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007;92:199–205. [6] Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010;152:578–89. [7] Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003;139:893–900. [8] Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998;279:458–62. [9] Kearon C, Iorio A, Palareti G. Subcommittee on Control of Anticoagulation of the SSCotI. Risk of recurrent venous thromboembolism after stopping treatment in cohort studies: recommendation for acceptable rates and standardized reporting. J Thromb Haemost 2010;8:2313–5. [10] Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799–808. [11] Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342–52.

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Please cite this article as: Wu C, et al, Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants ..., Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.10.033

Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants for secondary prevention.

The duration of anticoagulation after venous thromboembolic events (VTE) is based on the balance between the risk of recurrent VTE and bleeding. The p...
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