European Heart Journal Advance Access published December 12, 2014 European Heart Journal doi:10.1093/eurheartj/ehu463

CLINICAL RESEARCH Thrombosis and antithrombotic therapy

Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial Claes Held 1*, Elaine M. Hylek 2, John H. Alexander 3, Michael Hanna4, Renato D. Lopes 3, Daniel M. Wojdyla 3, Laine Thomas 3, Hussein Al-Khalidi 3, Marco Alings 5, Dennis Xavier 6, Jack Ansell7, Shinya Goto 8, Witold Ruzyllo 9, Ma˚rten Rosenqvist10, Freek W. A. Verheugt 11, Jun Zhu 12, Christopher B. Granger 3, and Lars Wallentin 1

Received 6 June 2014; revised 19 September 2014; accepted 3 November 2014

Aim

In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced the risk of stroke, major bleed, and death in patients with atrial fibrillation. In this ancillary study, we evaluated clinical consequences of major bleeds, as well as management and treatment effects of warfarin vs. apixaban. ..................................................................................................................................................................................... Methods Major International Society on Thrombosis and Haemostasis bleeding was defined as overt bleeding accompanied by a decrease in haemoglobin (Hb) of ≥2 g/dL or transfusion of ≥2 units of packed red cells, occurring at a critical site or and results resulting in death. Time to event [death, ischaemic stroke, or myocardial infarction (MI)] was evaluated by Cox regression models. The excess risk associated with bleeding was evaluated by separate time-dependent indicators for intracranial (ICH) and non-intracranial haemorrhage. Major bleeding occurred in 848 individuals (4.7%), of whom 126 (14.9%) died within 30 days. Of 176 patients with an ICH, 76 (43.2%) died, and of the 695 patients with major non-ICH, 64 (9.2%) died within 30 days of the bleeding. The risk of death, ischaemic stroke, or MI was increased roughly 12-fold after a major non-ICH bleeding event within 30 days. Corresponding risk of death following an ICH was markedly increased, with HR 121.5 (95% CI 91.3–161.8) as was stroke or MI with HR 21.95 (95% CI 9.88–48.81), respectively. Among patients with major bleeds, 20.8% received vitamin K and/or related medications (fresh frozen plasma, coagulation factors, factor VIIa) to stop bleeding within 3 days, and 37% received blood transfusion. There was no interaction between apixaban and warfarin and major bleeding on the risk of death, stroke, or MI. ..................................................................................................................................................................................... Conclusion Major bleeding was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following ICH, and this risk was similarly elevated regardless of treatment with apixaban or warfarin. These results underscore the importance of preventing bleeding in anti-coagulated patients. ..................................................................................................................................................................................... Clinical Trials. NCT00412984.

gov identifier

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Atrial fibrillation † Bleeding † Factor Xa inhibitor

* Corresponding author. Tel: +46 186119508, Fax: +46 18515570, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].

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1 Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjo¨lds va¨g 14B, Uppsala 751 85, Sweden; 2Boston University Medical Center, Boston, MA, USA; 3Duke University, Medical Center, Durham, NC, USA; 4Bristol-Myers Squibb, Princeton, NJ, USA; 5Working Group on Cardiovascular Research the Netherlands, Utrecht, Netherlands; 6Department of Pharmacology, Division of Clinical Research and Training, St John’s Medical College and Research Institute, Bangalore, India; 7 Hofstra-North Shore/LIJ School of Medicine, New York, NY, USA; 8Department of Medicine, Tokai University, School of Medicine, Isehara, Japan; 9Institute of Cardiology, Warsaw, Poland; 10Karolinska Institutet, Department of Clinical Sciences, Danderyd University Hospital, Stockholm, Sweden; 11Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands; and 12Fuwai Hospital, Beijing, China

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C. Held et al.

Translational perspective Major bleedings in patients with atrial fibrillation treated on anti-coagulation therapy was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following intracranial haemorrhage. This risk was similarly elevated regardless of treatment with apixaban or warfarin. The results underscore the importance of preventing bleeding in anti-coagulated patients.

Introduction

Methods The ARISTOTLE trial design has been reported previously.10 In summary, it was a double-blind, double-dummy, randomized clinical trial enrolling 18 201 patients with AF and at least 1 CHADS2 risk factor for stroke or systemic embolism. Patients were randomized to warfarin (n ¼ 9081) or apixaban (n ¼ 9120). The primary endpoint was stroke or systemic embolism. The primary safety outcome was bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) criteria. The median length of follow-up was 1.8 years. Patients with AF and at least one risk factor for stroke were randomized to either dose-adjusted warfarin or apixaban 5 mg twice daily. A reduced dose of apixaban 2.5 mg twice daily was designated for participants with two or more of the following criteria: an age of at least 80 years, a body weight of no .60 kg, or a serum creatinine level of 1.5 mg/dL (133 mmol/L) or more. To enhance the quality of warfarin management,

Bleeding definitions This study captured bleeding events occurring between randomization and efficacy censoring date, in all randomized patients. Major bleeding was defined according to the criteria of the ISTH as clinically overt bleeding accompanied by a decrease in the Hb level of at least 2 g/dL or transfusion of at least two units of packed red cells, occurring at a critical site (intra-cranial, intra-ocular, intra-spinal, intra-articular, intra-muscular with compartment syndrome, pericardial, retroperitoneal) or resulting in death. No time restrictions were applied to this definition but the Hb drop occurred most often within 24 – 48 h. Laboratory and transfusion data coupled with clinical event details were used to identify and adjudicate potential bleeding events. Routine collection of Hb occurred every 3 months. Location of bleeding was extracted from the case report form. Additional source documents were collected when necessary. The primary safety outcomes were adjudicated on the basis of pre-specified criteria by a clinical events committee whose members were not aware of study-group assignments. We evaluated the consequences of recent major bleeding (within 30 days) on efficacy endpoints, including death and thrombotic events (stroke or MI). The 30-day window was selected in order to focus on efficacy events that were potentially attributable to circumstances surrounding the bleed, rather than underlying comorbidities which would dominate long-term differences. In addition, changes in anti-thrombotic therapy, study drug discontinuation, and transfusions after the bleeding were evaluated.

Statistical analyses Demographic and clinical characteristics were presented for patients with at least one ISTH major bleeding and patients without major bleedings. Continuous variables were summarized as medians and quartiles and categorical variables as frequencies and percentages. In the full randomized population, multivariable Cox regression models were used to evaluate the increase in efficacy events within 30 days of ISTH major bleeding. Specifically, separate time-dependent indicators were included for non-intra-cranial and intra-cranial bleeding, taking a value of 1 during the 30-day window following a bleed and 0 otherwise. Therefore, we assessed the elevation in risk of events during the immediate 30 days after a bleed. In patients with multiple ISTH major bleedings, only the first event was evaluated. An interaction term with randomized treatment was added to evaluate whether the risk associated with recent bleeding differed in apixaban- vs. warfarin-treated patients. These models were adjusted for a pre-specified set of clinical and demographic factors including type of AF, age, sex, region, history of MI, congestive heart failure, stroke/TIA or systemic embolism, diabetes, time with AF, hypertension, history of bleeding, prior vitamin K antagonist (VKA) use, CHADS2 score, history of vascular disease, creatinine clearance, and baseline medications including aspirin, statins, ACE inhibitors/ARBs, and amiodarone. This analysis was repeated in sensitivity analyses, where ISTH major bleeding was replaced by other definitions of bleeding (i.e. any bleeding). Among patients who experienced major bleeding, information about

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Atrial fibrillation (AF) is an important risk factor for stroke. Anti-coagulation is highly effective for reducing thrombo-embolic complications. Bleeding complications during anti-coagulation are, however, common and associated with increased risk of subsequent death and thrombotic events. Warfarin is known to be associated with bleeding and medication related emergent hospitalizations that relate to a narrow therapeutic window and difficulties in adjusting the dose due to a variable dose response.1,2 The direct acting oral anti-coagulants that have emerged in recent years as alternatives to warfarin are proven to reduce these events (similar to or more than warfarin) with a similar or lower risk of bleeding complications.3 – 6 In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin significantly reduced the risk of stroke, major bleeding, and death in patients with AF.3 Bleeding among patients on anticoagulant therapy often leads to cessation of anti-coagulant treatment, which may increase the risk of subsequent thrombotic events. Termination of warfarin after a gastrointestinal (GI) bleed was shown in one study to increase the risk of death and thrombotic events.7 In a realworld registry, patients who experienced serious bleeding had a threefold increase in the risk of thrombotic events even though the majority of patients did not permanently stop oral anti-coagulation.8 We have in a recent report presented data on the location and characteristics of bleeding, and the 30-day mortality associated with the first major bleed in the ARISTOTLE trial.9 In the present study, we evaluate the clinical consequences of major bleeds, including risk of death, ischaemic stroke, and myocardial infarction (MI) in the 30 days preceded by a major bleed. We also report the consequences of a major bleed in terms of management, such as therapeutic actions to stop the bleeding and to decrease subsequent bleeding risk, change in anti-thrombotic therapy, or study drug discontinuation and also treatment effects of apixaban vs. warfarin on clinical outcomes.

a dosing algorithm was provided and a program implemented to provide regular feedback to sites regarding their level of international normalized ratio (INR) control.

Page 3 of 9

Insights from the ARISTOTLE trial

change in anti-thrombotic therapy, study drug discontinuation and resumption, and transfusion were summarized as frequencies and percentages. Also in this subgroup, the cumulative incidence of all-cause death and thrombotic events after major bleeding events were presented as Kaplan–Meier curves. All analyses were performed with SAS System, version 9.2.

Results Baseline characteristics International Society on Thrombosis and Haemostasis major bleeding occurred in 848 (4.7%) patients of whom 126 (14.9%) died. Baseline characteristics for patients with and without major bleeds are shown in Table 1. Patients with major bleeds were generally older (P , 0.001), had lower body weight (P , 0.01), more often had a previous MI (P , 0.01), prior stroke/TIA/systemic embolism (P , 0.001) or previous bleeding (P , 0.001) and more often had impaired renal function (P , 0.001). The CHADS2 (P , 0.001), CHA2DS2-VASc (P , 0.001), and HASBLED (P , 0.001) scores were all higher. In addition, they more often were treated with drugs with anti-platelet function, such as aspirin (P , 0.001), clopidogrel (P , 0.001), and NSAIDs (P , 0.001).

Of the randomized population, 695 patients experienced major non-intra-cranial haemorrhage (ICH) bleeding during follow-up, and among them 64 (9.2%) patients died within 30 days of the bleeding, including 28 (8.9%) in the apixaban and 36 (9.5%) in the warfarin groups, respectively. Patients with a major non-ICH bleeding had a 12-fold elevation in the risk of death or thrombotic events during the 30 days after major non-ICH bleeding, after multivariable adjustment for baseline comorbidities (Table 2), compared with patients without major non-ICH bleeding. Intra-cranial haemorrhage occurred in 176 patients, among whom 76 (43.2%) patients died within 30 days of the bleeding. Twenty-four of the 53 patients with ICH in the apixaban group died within 30 days (45.3%) and 52 of the 123 patients with ICH in the warfarin arm died within 30 days (42.3%). Fourteen patients died within 30 days of both an ICH and major non-ICH bleeding. After multivariable adjustment, risk of death was markedly increased within 30 days of an ICH with an HR of 121.5 (95% CI 91.3– 161.8) as was risk of stroke or MI, HR 21.95 (95% CI 9.88–48.81). Figure 1 presents the Kaplan –Meier curves for the 30-day incidence in mortality, among patients with ICH and non-ICH major bleeding. There was no interaction between randomized treatment and recent ICH bleeding for either death (P ¼ 0.77) or ischaemic stroke or MI (P ¼ 0.15), nor for non-ICH bleeds (P ¼ 0.11 and 0.61, respectively). Evaluating the consequence of any bleed category (non-ICH), the risk of death was significantly increased but to a lower level than for major bleeds [adjusted HR 2.88 (95% CI 2.23– 3.74)], as was ischaemic stroke or MI [adjusted HR 3.05 (95% CI 2.02– 4.59)].

Change in anti-thrombotic therapy About half of patients (49%) with a major ISTH bleeding had their anti-thrombotic therapy changed (Table 3) but with no apparent difference between apixaban- and warfarin-treated patients. For the

Management of bleedings Of the patients with major ISTH bleedings, 176 patients (20.8%) received vitamin K and/or related medications to stop the bleeding within 3 days from the bleed. Of these 88 patients (10.4%) received vitamin K, thrombin, prothrombin complex concentrates (PCC), Factor IX, or Factor VII) and 120 patients (14.3%) were given fresh frozen plasma during the management of the bleeding. There was a higher use of vitamin K and/or related medication (15.2 vs. 3.9%), fresh frozen plasma transfusion (18.7 vs. 8.0%) in the patients who bled on warfarin than in the apixaban arm. Blood transfusions after a major ISTH bleed were administered in 37% of all major bleeds without a difference between apixaban and warfarin (Table 5). Gastrointestinal bleeds led to the highest rate of transfusion. Less severe bleedings led to lower transfusion rates. However, the rate of transfusion in apixaban vs. warfarin-treated patients did not differ significantly (P . 0.5).

Treatment effect of apixaban vs. warfarin in patients with atrial fibrillation and a bleeding event Figure 2 presents 30 day all-cause mortality by randomized treatment with apixaban or warfarin among patients with major bleeding. There was no difference between apixaban and warfarin with hazard ratio 0.770; 95% CI: 0.537–1.103. Similar levels of risk were seen also when evaluating all-cause death and thrombotic events/MI after major/clinically relevant non-major bleeds, GUSTO moderate/ severe bleeds, or TIMI major/minor bleeds (data not shown).

Discussion Despite the benefits of anti-coagulation for patients with AF, major bleeding is a well-known complication. In the present study, we found increased risk of subsequent death and of thrombotic events within 30 days following major bleeding. A major bleeding event often led to changes in anti-thrombotic therapy, and/or to interruptions of the study drug. These actions to stop the bleeding would have rendered the patients less protected from thrombotic events, and

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Mortality and thrombotic events

category any bleed, the overall rate of change in anti-thrombotic therapy was 32.4% and a slightly higher rate change in warfarin than in apixaban-treated patients (34.8 vs. 29.3%; P ¼ , 0.001). The 70.8% of patients that were on study drug experienced a temporary or permanent interruption of study drug after a major bleed (Table 4). For ICH and GI bleeds, 90.7 and 75%, respectively, had their study drug interrupted. For less severe bleeds the proportion was lower. Resumption of study drugs was differential, with 43.7% after major ISTH bleeds with a median time of 15 days after bleeding. For ICH bleeds, only 11.7% resumed study drug treatment with a median time of 25 days. For GI bleeds specifically, the resumption rate was 50.9% with a median duration of stopping study drugs of 15 days. The resumption rates for apixaban and for warfarin did not differ significantly, except for major ISTH/clinically relevant non-major bleed, where the rate of resumption was higher for apixaban than warfarin (62.5 vs. 53.1%; P ¼ 0.01). Median days to resumption of treatment were 15 days.

Baseline characteristics by International Society on Thrombosis and Haemostasis major bleeding ISTH major bleeding 5 YES

ISTH major bleeding 5 NO

......................................................................... ............................................................................... Overall (n 5 848)

Apixaban (n 5 361)

Warfarin (n 5 487)

74 (68–79) 291 (34.3)

74 (67–79) 116 (32.1)

74 (68–79) 175 (35.9)

North America Latin America

268 (31.6) 161 (19.0)

121 (33.5) 63 (17.5)

Europe

263 (31.0)

Asia Pacific

156 (18.4)

Overall (n 5 17 353)

Apixaban (n 5 8759)

Warfarin (n 5 8594)

70 (62–76) 6125 (35.3)

70 (63– 76) 3118 (35.6)

70 (62– 76) 3007 (35.0)

147 (30.2) 98 (20.1)

4206 (24.2) 3307 (19.1)

2128 (24.3) 1680 (19.2)

2078 (24.2) 1627 (18.9)

122 (33.8)

141 (29.0)

7080 (40.8)

3550 (40.5)

3530 (41.1)

55 (15.2)

101 (20.7)

2760 (15.9)

1401 (16.0)

1359 (15.8)

P-value*

Interact. P-value**

Page 4 of 9

Table 1

............................................................................................................................................................................................................................................. Age (median, 25th–75th) Female Region

Systolic blood pressure (median, 25th– 75th)

130 (120– 140)

Weight (median, 25th–75th) Prior MI Prior clinically relevant or spontaneous bleeding History of fall within previous year Type of AF Paroxysmal

130 (120– 140)

130 (120– 140)

80 (68–93) 151 (17.8)

83 (70–94) 66 (18.3)

78 (68–92) 85 (17.5)

202 (23.9)

90 (25.0)

64 (8.2)

27 (8.1)

130 (120– 140)

130 (120 –140)

130 (120 –140)

,0.0001 0.5326

0.5237 0.1926

,0.0001

0.0722

0.1231

0.5295

82 (70–96) 2434 (14.0)

82 (70– 96) 1253 (14.3)

82 (70– 96) 1181 (13.8)

,0.0001 0.0014

0.0248 0.8340

112 (23.0)

2838 (16.4)

1435 (16.4)

1403 (16.3)

,0.0001

0.4523

37 (8.3)

689 (4.4)

359 (4.4)

330 (4.2)

,0.0001

0.8257

0.1458

0.6372

117 (13.8)

51 (14.1)

66 (13.6)

2669 (15.4)

1323 (15.1)

1346 (15.7)

Persistent or permanent

731 (86.2)

310 (85.9)

421 (86.5)

14681 (84.6)

7434 (84.9)

7247 (84.3)

Prior use of VKAs (.30 days) Qualifying risk factors

499 (58.8)

210 (58.2)

289 (59.3)

9902 (57.1)

4998 (57.1)

4904 (57.1)

0.2107

0.7320

Age ≥75

404 (47.6)

168 (46.5)

236 (48.5)

5274 (30.4)

2682 (30.6)

2592 (30.2)

,0.0001

0.4925

Prior stroke or TIA or systemic embolism

205 (24.2)

87 (24.1)

118 (24.2)

3333 (19.2)

1661 (19.0)

1672 (19.5)

,0.0001

0.8505

Heart failure or reduced LVEF Diabetes

304 (35.9) 244 (28.8)

131 (36.3) 118 (32.7)

173 (35.5) 126 (25.9)

6147 (35.4) 4303 (24.8)

3104 (35.4) 2166 (24.7)

3043 (35.4) 2137 (24.9)

0.4485 0.0032

0.8221 0.0289

303 (83.9)

416 (85.4)

15 197(87.6)

7659 (87.4)

7538 (87.7)

0.0132

0.6730

2.39 (1.14) 84 (23.3)

2.38 (1.19) 125 (25.7)

2.10 (1.10) 5974 (34.4)

2.10 (1.09) 3016 (34.4)

2.11 (1.11) 2958 (34.4)

,0.0001 ,0.0001

0.7107 0.6985

308 (36.3)

134 (37.1)

174 (35.7)

6208 (35.8)

3128 (35.7)

3080 (35.8)

331 (39.0) 3.87 (1.50)

143 (39.6) 3.88 (1.44)

188 (38.6) 3.86 (1.55)

5171 (29.8) 3.40 (1.51)

2615 (29.9) 3.40 (1.51)

2556 (29.7) 3.39 (1.50)

,0.0001

0.9781

≤2

162 (19.1)

59 (16.3)

103 (21.2)

5213 (30.0)

2634 (30.1)

2579 (30.0)

,0.0001

0.0671

3– 4 ≥5

425 (50.1) 261 (30.8)

194 (53.7) 108 (29.9)

231 (47.4) 153 (31.4)

8323 (48.0) 3817 (22.0)

4150 (47.4) 1975 (22.5)

4173 (48.6) 1842 (21.4)

2 ≥3 CHA2DS2 VASc score (mean, SD)

C. Held et al.

719 (84.8) 2.38 (1.16) 209 (24.7)

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Hypertension requiring treatment CHADS2 score (mean, SD) ≤1

2.18 (1.05)

2.11 (1.06)

1.76 (1.05)

1.76 (1.05)

1.75 (1.05)

,0.0001

0.3551

233 (27.5)

93 (25.8)

140 (28.8)

7228 (41.7)

3648 (41.6)

3580 (41.7)

,0.0001

0.4432

2

332 (39.1)

139 (38.5)

193 (39.6)

6236 (35.9)

3143 (35.9)

3093 (36.0)

283 (33.4)

129 (35.7)

154 (31.6)

3889 (22.4)

1968 (22.5)

1921 (22.3)

ACE inhibitor or ARB

584 (70.3)

257 (71.8)

327 (69.1)

12 248(71.7)

6207 (72.1)

6041 (71.3)

0.3692

0.5232

Amiodarone Beta-blocker

93 (11.2) 534 (64.3)

36 (10.1) 239 (66.8)

57 (12.1) 295 (62.4)

1958 (11.5) 10 948(64.1)

973 (11.3) 5558 (64.6)

985 (11.6) 5390 (63.6)

0.8607 0.9408

0.4400 0.3103

≥3 Medications at time of randomization

Clopidogrel

26 (3.1)

11 (3.1)

15 (3.1)

312 (1.8)

159 (1.8)

153 (1.8)

0.0049

0.9756

Digoxin Calcium blocker

258 (31.1) 262 (31.5)

115 (32.1) 121 (33.8)

143 (30.2) 141 (29.8)

5570 (32.6) 5303 (31.1)

2801 (32.6) 2623 (30.5)

2769 (32.7) 2682 (31.7)

0.4779 0.9592

0.5420 0.1254

Statin

394 (47.4)

177 (49.4)

217 (45.9)

7079 (41.5)

3573 (41.5)

3506 (41.4)

0.0005

0.2893

Nonsteroidal anti-inflammatory agent

106 (12.8)

45 (12.6)

61 (12.9)

1414 (8.3)

707 (8.2)

707 (8.4)

,0.0001

0.9366

212 (25.3) 321 (37.9)

97 (27.1) 145 (40.2)

115 (24.3) 176 (36.1)

3138 (18.4) 5311 (30.6)

1586 (18.4) 2714 (31.0)

1552 (18.3) 2597 (30.2)

,0.0001 ,0.0001

0.3857 0.3289

,0.0001

0.1130

230 (27.2) 381 (45.1)

105 (29.2) 171 (47.5)

125 (25.8) 210 (43.3)

7288 (42.2) 7206 (41.7)

3656 (41.9) 3646 (41.8)

3632 (42.4) 3560 (41.6)

203 (24.0)

73 (20.3)

130 (26.8)

2544 (14.7)

1292 (14.8)

1252 (14.6)

31 (3.7)

11 (3.0)

20 (4.1)

239 (1.4)

126 (1.4)

113 (1.3)

8 (0.9)

4 (1.1)

4 (0.8)

506 (2.9)

262 (3.0)

244 (2.8)

Gastric antacid drugs Aspirin on randomization day Renal function Normal (80 mL/min) Mild impairment (.50–80 mL/min) Moderate impairment (.30–50 mL/min) Severe impairment (≤30 mL/min) Liver dysfunction

0.0010

0.7615

Haematocrit Platelet count

42.0 (38.4–45.0) 211 (178– 250)

41.7 (38.0 –45.0) 204 (172– 248)

42.0 (39.0–45.0) 213 (180– 255)

43.0 (40.0– 46.0) 211 (176– 253)

43.0 (40.0 –46.0) 210 (178 –249)

43.0 (40.0 –46.0) 212 (179 –251)

,0.0001 0.9518

0.3370 0.3414

INR at screening

1.67 (1.20–2.34)

1.70 (1.20 –2.40)

1.65 (1.20–2.30)

1.60 (1.20– 2.30)

1.56 (1.20 –2.30)

1.60 (1.20 –2.30)

0.5180

0.2287

Insights from the ARISTOTLE trial

2.14 (1.06)

0– 1

HASBLED score (mean, SD)

*

P-value comparing patients with and without ISTH major bleeding. P-value for treatment by covariable interaction.

**

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Page 6 of 9

C. Held et al.

Table 2. Elevation in risk of death or ischaemic stroke/myocardial infarction within 30 days after International Society on Thrombosis and Haemostasis major bleeding All cause death

.............................................. a

Ischaemic stroke/MI

...............................................

HR (95% CI)

P-value

HR (95% CI)a

P-value

121.5 (91.3– 161.8) 11.57 (8.47– 15.81)

,0.0001 ,0.0001

21.95 (9.88– 48.81) 12.64 (7.33– 21.80)

,0.0001 ,0.0001

............................................................................................................................................................................... A. Model without treatment assignment Intracranial bleeding (Yes vs. No) Non-intracranial bleeding (Yes vs. No)

............................................................................................................................................................................... B. Interaction model (treatment by bleeding) Intracranial bleeding (Yes vs. No) in apixaban

132.8 (82.12– 214.9)

Intracranial bleeding (Yes vs. No) in warfarin

121.3 (85.3– 172.6)

Non-intracranial bleeding (Yes vs. No) in apixaban Non-intracranial bleeding (Yes vs. No) in warfarin

15.35 (9.87– 23.86) 9.27 (6.05– 14.22)

0.7654†

48.19 (14.27– 162.70)

0.1532†

14.92 (5.19– 42.88) 0.1066†

10.66 (4.52– 25.13) 14.22 (7.02– 28.82)

0.6106†

a Multivariable adjusting by type of AF, age (non-linear), sex, region, history of MI, congestive heart failure, stroke, stroke/TIA or systemic embolism, diabetes, time with AF (non-linear), hypertension, history of bleeding, prior VKA use, CHADS2 score, history of vascular disease, the following meds at randomization: aspirin, statins, ACE inhibitors/ARBs, amiodarone, creatinine clearance, and randomized treatment. A sensitivity analysis including interactions between intracranial bleeding and the following covariates: type of AF, sex, region, time with AF, and amiodarone produced similar results. † P-value for interaction between treatment and bleeding.

bleeding itself may be related to increased risk including through effects on inflammation and on adrenergic state. The risk of death, MI, or ischaemic stroke following a major bleed was elevated regardless of the apixaban or warfarin group. Lower mortality in apixaban-treated patients in the ARISTOTLE study may be explained by the lower rate of major bleeding with apixaban treatment.3 These results complement our previous analyses on major bleeding and further highlight the deleterious effects of major bleeding in an AF population.9 Intra-cranial haemorrhage remains the most feared bleeding complication associated with the use of anti-coagulant therapy. This analysis highlighted the impact of ICH on subsequent death. Dabigatran, rivaroxaban, apixaban, and edoxaban have each shown a significant reduction in ICH,3 – 5,11 and an 10% relative reduction in mortality, when compared with warfarin with a target INR 2– 3. Furthermore, the risk of thrombotic events such as ischaemic stroke or MI is

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Figure 1 All cause death after major bleeding.

also substantially increased after a major bleed. This may be due to actions focused to stop the bleed, such as cessation of study drugs, interventions to reverse the coagulopathy, other anti-thrombotic drugs, and transfusions. During a severe bleed, patients may undergo a transition from an overly anti-coagulated state to a pro-thrombotic state with increased risk of thrombotic events especially if the anticoagulation therapy is stopped.7 Our findings are also corroborated by a Danish nationwide retrospective cohort study showing that interruption of warfarin treatment for various reasons, was associated with an increased risk of death and thrombo-embolic events, especially during the first 3 months.12 In another view, increased haemostatic activity to stop bleeding at the site of major bleed may increase in vivo thrombogenicity as previously demonstrated with higher risk of thrombotic events even though the use of oral anti-coagulant was not changed.8 Finally, another potential explanation is that a patient experiencing serious bleeding is also already at high risk of thrombotic events as demonstrated by the association of CHADS2 and CHA2DS2VASc with major haemorrhage. Changes in anti-thrombotic treatment due to bleeding consisted of various actions. About a fifth of the patients received either vitamin K or related medications and/or fresh frozen plasma, all common interventions to stop bleeding. More than a third of the bleedings led to a blood transfusion indicating the severity of many bleeds. The higher use of vitamin K and related medication and of fresh frozen plasma among warfarin-treated patients may have several explanations. A conditioning on bleeding leads to non-randomized comparisons. In addition, there were more intra-cranial bleeds in warfarin compared with apixaban-treated patients, which might influence the management of the bleeding. A difference in the severity and type of bleeding requiring these interventions could partly explain the difference in distribution. However, the discrepancy persisted after excluding ICH, which suggests that unblinding is possible. Unblinding was allowed in the trial if the knowledge of the assigned treatment might change the treatment of the bleeding which would be the case concerning the use of

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Insights from the ARISTOTLE trial

Table 3.

Changes in antithrombotic therapy after bleeding event

Bleeding type

Overall

........................................... Events

n

Change in anti-thrombotic therapy n (%)

Apixaban

...........................................

Events

n

Change in anti-thrombotic therapy n (%)

Warfarin

...........................................

Events

n

Change in anti-thrombotic therapy n (%)

............................................................................................................................................................................... ISTH majora ISTH major or clinically relevant non-majora GUSTO moderate– severea TIMI major– minora Any b

848 1569

388 (49.1) 775 (51.3)

361 664

169 (49.9) 328 (51.1)

487 905

219 (48.5) 447 (51.4)

576

250 (48.2)

225

100 (49.3)

351

150 (47.5)

663

292 (48.2)

272

125 (50.0)

391

167 (46.9)

5464

1752 (32.4)

2381

691 (29.3)

3083

1061 (34.8)

a

Missing information for change in anti-thrombotic therapy in 57 patients. Missing information for change in anti-thrombotic therapy in 59 patients.

b

Table 4.

Study drug discontinuation after bleeding events Events

Not on study druga

On study druga

No interruptionb

Interruptionb

Not resumedc

Resumedc

Days to resumption median (25th– 75th)

............................................................................................................................................................................... Overall Apixaban

848 361

208 (24.5) 102 (28.3)

640 (75.5) 259 (71.7)

187 (29.2) 86 (33.2)

453 (70.8) 173 (66.8)

255 (56.3) 91 (52.6)

198 (53.7) 82 (47.4)

15 (8– 41) 17 (8– 43)

Warfarin

487

106 (21.8)

381 (78.2)

101 (26.5)

280 (73.5)

164 (58.6)

116 (41.4)

15 (8– 37)

............................................................................................................................................................................... ISTH major/CRNM bleeding Overall Apixaban

1569 664

298 (19.0) 149 (22.4)

1271 (81.0) 515 (77.6)

505 (39.7) 222 (43.1)

766 (60.3) 293 (56.9)

332 (43.3) 110 (37.5)

434 (56.7) 183 (62.5)

11 (6– 28) 12 (6 –34)

Warfarin

905

149 (16.5)

756 (83.5)

283 (37.4)

473 (62.6)

222 (46.9)

251 (53.1)

10 (5– 24)

Overall

176

25 (14.2)

151 (85.8)

14 (9.3)

137 (90.7)

121 (88.3)

16 (11.7)

25 (11–42)

Apixaban Warfarin

53 123

7 (13.2) 18 (14.6)

46 (86.8) 105 (85.4)

3 (6.5) 11 (10.5)

43 (93.5) 94 (89.5)

40 (93.0) 81 (86.2)

3 (7.0) 13 (13.8)

. 24 (7– 32)

............................................................................................................................................................................... Intra-cranial bleeding

............................................................................................................................................................................... Gastro-intestinal bleeding Overall 264

52 (19.7)

212 (80.3)

53 (25.0)

159 (75.0)

78 (49.1)

81 (50.9)

15 (7– 38)

Apixaban

131

26 (19.9)

1055 (80.1)

27 (25.7)

78 (74.3)

36 (46.2)

42 (53.8)

16 (6– 39)

Warfarin

133

26 (19.6)

107 (80.4)

26 (24.3)

81 (75.7)

42 (51.9)

39 (48.2)

15 (7– 35)

On Study drug based on the day prior to the bleeding event. Interruption defined as stopping the study drug for at least 1 day on the day of the bleeding or the following 3 days. a Percentages over the number of events. b Percentages over the number of events on study drug. c Percentages over the number of interruptions.

vitamin K and PCC. Unblinding might even occur without breaking the treatment code, if in case of bleeding, a partial thromboplastin time/INR test was performed. While that bleeding rates were lower with apixaban, we did not observe a differential effect of apixaban and warfarin regarding the risk of death or thrombotic events after a bleed occurred. In a similar trial comparing rivaroxaban and warfarin,13 the risk of stroke or non-CNS embolism did not differ between the study drugs after temporary or permanent interruption of the anti-coagulation, regardless of reason. The rate of transfusion did not differ between apixaban and

warfarin. Results from the open-label RE-LY trial differed somewhat in that patients who experienced major bleeding on dabigatran required more red cell transfusions but received less plasma, required a shorter stay in intensive care, and had a trend to lower mortality compared with those who had major bleeding on warfarin,14 possibly due to the open design of that trial. The effects of anti-coagulation treatment, is correlated to the quality of therapy, that is, time in treatment range (TTR). However, we have previously shown that the benefit of apixaban over warfarin in lower bleeding risk was observed regardless of the level of predicted centre and patient TTR.15 Our analyses do not

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ISTH major bleeding

Page 8 of 9

Table 5.

C. Held et al.

Transfusion after bleeding events

Bleeding type

Overall

...............................

Events n

Led to t ransfusion n (%)

Apixaban

................................

Events

Warfarin

................................

n

Led to transfusion n (%)

Events n

Led to transfusion n (%)

............................................................................................................................................................................... ISTH majora ISTH major or clinically relevant non-majora Intra-cranial bleedinga Gastro-intestinal bleeding

848

295 (37.3)

361

128 (37.8)

487

167 (37.0)

1569

328 (21.7)

664

139 (21.7)

905

189 (21.7)

176 264

11 (9.2) 134 (50.8)

53 131

4 (3.4) 64 (48.9)

123 133

7 (5.9) 70 (52.6)

a

Missing information for change in anti-thrombotic therapy in 57 patients.

anti-coagulated patients as well as highlight the medical complexities and treatment decision challenges among individuals with bleeding.

Acknowledgements

Funding The ARISTOTLE trial was funded by Bristol-Myers Squibb/Pfizer.

Figure 2 All cause death after major bleeding (intra-cranial and non-intra-cranial) by randomized treatment.

support a differential effect of bleeding on mortality by apixaban or warfarin. However, the lower rate of bleedings overall on apixaban over warfarin is likely to explain the lower rate of mortality and stroke in the overall trial.

Limitations There was a relatively high rate of missing information for changes in anti-thrombotic therapy. Some of the analyses performed were based on non-randomized comparisons and thus confer the risk of confounding with both measured and unmeasured differences. Thus, multivariable adjustments have been performed but we cannot exclude the possibility of residual confounding. Finally, we cannot exclude that some of the differences in the use of VKA, transfusion and resumption of treatment between the treatment groups may have been related to unblinding.

Conclusion Major bleeding during oral anti-coagulant treatment in patient with AF is associated with a substantially increased subsequent risk of both death and of thrombotic events such as ischaemic stroke or MI. Our results underscore the importance of prevention of bleeding in

Conflicts of interest: C.H. reports institutional research grants from AstraZeneca, Merck, GlaxoSmithKline, Roche, and Bristol-Myers Squibb; advisory board fees and honoraria from AstraZeneca. E.M.H. reports advisory board fees and symposium fees from Bayer, BoehringerIngelheim, and Bristol-Myers Squibb/Pfizer; advisory board fees from Daiichi-Sankyo, Janssen, and Roche. J.H.A. reports research grants and honoraria from Bristol-Myers Squibb/Pfizer; consultancy/advisory board fees from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, and Ortho-McNeil-Janssen. M.H. reports being an employee of Bristol-Myers Squibb and receiving stock as a part of compensation. R.D.L. reports institutional research grants from Bristol-Myers Squibb/Pfizer; consultancy fees from Bayer, Boehringer-Ingelheim, and Bristol-Myers Squibb/Pfizer. M.A. reports advisory board fees from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, and Sanofi. J.A. reports consultancy fees/honoraria from Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, and Janssen. S.G. reports research grants and lecture fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Otsuka, and Sanofi; consultancy fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi-Sankyo. M.R. reports research grants from Bayer, BoehringerIngelheim, Bristol-Myers Squibb/Pfizer, and Medtronic; consultancy fees from Medtronic, Sanofi, St Jude Medical, and Zenicor; lecture fees from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, and St Jude Medical. F.W.A.V. reports advisory board fees as well as speaker honoraria from Bristol-Myers Squibb/Pfizer, Bayer Health care, Daiichi-Sankyo, and Boehringer-Ingelheim. C.B.G. reports research grants from BoehringerIngelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Medtronic Foundation, Merck & Co, Sanofi-Aventis, Takeda, and The Medicines Company; Consultancy fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi, GlaxoSmithKline, Hoffman-La Roche, Janssen, Lilly,

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Ebba Bergman, PhD, and Martina Tillberg, MSc, at Uppsala Clinical Research Center, Uppsala, Sweden, provided editorial assistance which was funded by Bristol-Myers Squibb and Pfizer.

Insights from the ARISTOTLE trial

Sanofi-Aventis, Ross Medical Corporation, Salix Pharmaceuticals, Takeda, and The Medicines Company. L.W. reports research grants from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and Merck & Co; consultancy fees from Abbott, AstraZeneca, Athera Biotechnologies, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck & Co, and Regado Biosciences; lecture fees and honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline; travel support from AstraZeneca, Bristol-Myers Squibb/ Pfizer, and GlaxoSmithKline.

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