Introduction. CLINICAL RESEARCH Atrial fibrillation

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1 European Heart Journal (2014) 35, doi: /eurheartj/ehu048 CLINICAL RESEARCH Atrial fibrillation Efficacy and safety of apixaban compared with aspirin in patients who previously tried but failed treatment with vitamin K antagonists: results from the AVERROES trial Michiel Coppens 1,2 *, David Synhorst 3, John W. Eikelboom 1, Salim Yusuf 1, Olga Shestakovska 1, and Stuart J. Connolly 1 1 Population Health Research Institute, McMaster University, Hamilton, ON, Canada; 2 Academic Medical Center, Amsterdam, The Netherlands; and 3 Bristol-Myers Squibb, Princeton, NJ, USA Received 26 December 2012; revised 13 December 2013; accepted 27 January 2014; online publish-ahead-of-print 25 February 2014 Aim The AVERROES double-blinded, randomized trial demonstrated that apixaban reduces the risk of stroke or systemic embolism (SSE) by 55% compared with aspirin without an increase in major bleeding in patients with atrial fibrillation either who previously tried but failed vitamin K antagonists (VKA) therapy or who were expected to be unsuitable for VKA therapy. In this pre-specified analysis, we explored the consistency of the results in the subgroup of patients who tried but failed VKA therapy.... Methods Of 5599 patients, 2216 (40%) had previously failed VKA treatment [main reasons: poor international normalized ratio and results (INR) control 42%, refusal 37%, bleeding on VKA 8%]. Compared with those expected to be unsuitable for VKA therapy, those who had previously failed were older, more often male, had higher body mass index, more likely to have moderate renal impairment and a history of stroke and less likely to have heart failure or to be medically undertreated. The effects of apixaban compared with aspirin were consistent in those who previously failed and those who were expected to be unsuitable, for both SSE (P interaction 0.13) and major bleeding (P interaction 0.74) and were also consistent among different subgroups of patients who had previously failed VKA therapy defined by reasons for unsuitability, age, sex, renal function, CHADS 2 score, aspirin dose, duration, indication, and quality of INR control of prior VKA use.... Conclusion The efficacy and safety of apixaban compared with aspirin is consistent in subgroups of patients who have previously attempted but failed VKA therapy, irrespective of the reason for discontinuation Keywords Atrial fibrillation Stroke Bleeding Vitamin K antagonists Apixaban Aspirin Introduction Vitamin K antagonists (VKAs) are effective for the prevention of ischaemic stroke or systemic embolism (SSE) in patients with atrial fibrillation (AF) but can be challenging to use in clinical practice because of their high propensity for food, alcohol, and drug interactions, need for routine coagulation monitoring and risk of bleeding. 1,2 These limitations of VKAs contribute to their underutilization; surveys in North America and Europe have shown that VKAs are used in only 50 60% of patients for whom this treatment is recommended by the guidelines. 3,4 Most Phase 3 randomized controlled trials of new oral anticoagulants for stroke prevention in AF have compared the new drug against warfarin, 5 7 and it is therefore uncertain whether these new drugs are also beneficial for patients unsuitable for VKA therapy. In the AVERROES trial, the efficacy and safety of apixaban was compared with that of aspirin in AF patients with additional risk factors for stroke who are deemed to be unsuitable for VKA therapy, either * Corresponding author. Tel: , Fax: , michiel.coppens@phri.ca Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com

2 Apixaban vs. aspirin in patient that failed VKA therapy 1857 because they had previously tried but discontinued treatment with VKAs or because they were expected to be unsuitable for VKA therapy. 8 However, patients who have previously received VKA therapy may differ from patients that never received VKA therapy with regard to risks of stroke and bleeding. In the AVERROES trial, the rates of bleeding were. 50% higher in patients who had previously failed warfarin compared with those who were deemed unsuitable for warfarin but had not previously been treated with VKAs. 8 Similarly, patients who were taken off VKA therapy because of a serious bleeding episode may differ from those who failed VKA therapy because of inadequate international normalized ratio (INR) control and from those who refused further VKA therapy. It is unclear whether the efficacy and safety results of the AVERROES trial can be uniformly applied to these patients. The first aim of this pre-specified subgroup analysis was to examine the consistency of the efficacy and safety of apixaban compared with aspirin in patients who had previously failed VKA therapy, according to different subgroups including the reason for discontinuation. The second aim was to explore the differences between patients that previously failed VKA therapy and those that were expected to be unsuitable but had never received warfarin in the past. Methods AVERROES trial design The AVERROES trial design has been published previously. 9 Briefly, the primary study objective was to establish the superiority of apixaban compared with aspirin for stroke prevention in patients with AF and at least one additional risk factor for stroke who were unsuitable for VKA therapy. The AVERROES investigators randomized 5599 patients to receive apixaban of 5 mg twice daily or aspirin at a dose of mg once daily (dose determined by local investigator). Patients that met two of the three following criteria including the age of 80 years or older, body weight of 60 kg or less, and serum creatinine level of 133 mmol/l (1.5 mg/dl) or higher, received a study dose of 2.5 mg apixaban or apixaban-placebo twice daily. Among the exclusion criteria were an indication for anticoagulation other than AF, severe renal insufficiency [creatinine of.221 mmol/l (.2.5 mg/dl) or estimated glomerular filtration rate (egfr) of,25 ml/min] or a serious bleeding episode in the preceding 6 months. 9 Baseline data on the reasons for VKA unsuitability and details of prior VKA use were obtained by structured questionnaires. Outcome definitions The primary efficacy outcome of the AVERROES trial was SSE. Stroke was a clinical diagnosis that was made on the basis of typical symptoms lasting at least 24 h. Brain imaging, which was available in the vast majority of patients, was not required but was recommended for the diagnosis of stroke; however, it was required to differentiate ischaemic from haemorrhagic events. Systemic embolism was defined as an acute arterial occlusion of an extremity or organ and documented by means of imaging, surgery, or autopsy. Major bleeding was the primary safety outcome and was defined as clinically overt bleeding accompanied by one or more of the following: decrease in haemoglobin of 1.2 mmol/l (2 g/dl) or more over a 24-h period, transfusion of two or more units of packed red cells, bleeding into a critical site (intra-cranial, intra-spinal, intra-ocular, pericardial, intra-articular, intra-muscular with compartment syndrome, or retroperitoneal), or fatal bleeding. All clinically overt bleeding not meeting these criteria was considered minor bleeding. All efficacy and safety outcomes were confirmed by a Blinded Central Adjudication Committee. Statistical analyses Analyses were based on the intention-to-treat principle. Patients were kept in the treatment group to which they were randomized and were followed as long as possible from the randomization until either study end, loss to follow-up or death. We compared baseline characteristics between patients unsuitable for warfarin because they had previously failed VKA therapy and patients who were expected to be unsuitable but had not previously received VKA treatment using the Pearson x 2 test for categorical variables and the Wilcoxon two-sample test for continuous variables. We assessed the effect of apixaban vs. aspirin on the risk or SSE and major bleeding in subgroups of patients who previously failed VKA therapy using Cox proportional-hazards regression models fitted separately within each level of a subgroup variable. We examined the homogeneity of treatment effect with apixaban by including a treatment by subgroup interaction in the Cox model fitted to all patients. Subgroups were defined by age (,65, 65,75, 75 years), sex, egfr (,50, 50,80, 80 ml/min, as calculated by the CKD-EPI equation 10 ), CHADS 2 score (0 1, 2, 3 6), history of stroke or transient ischaemic attack (TIA), aspirin dose (,162 or 162 mg), presence of heart failure, indication for prior VKA use (AF, non-af), duration of prior VKA use (,6, 6 24,.24 months), prior bleeding (any bleeding and major bleeding only), and quality of prior INR control (INR out of range,25, 25 to,40, 40 to,50, 50% of time). Analyses were performed using the SAS software, version 9.2 (SAS Institute, Inc., Cary, NC, USA). A two-sided P-value of 0.05 was considered statistically significant. Results associated with a P-value between 0.05 and were interpreted with caution because of multiple testing. The AVERROES trial complied with the Declaration of Helsinki and was approved by all appropriate regulatory authorities and ethics committees (ClinicalTrials.gov no. NCT ). All the patients provided written informed consent before study entry. The authors of the manuscript had full access to the data and planned the statistical analyses. Results In the AVERROES trial, 5599 patients were randomized to treatment with apixaban or aspirin. Of those, 2216 patients (40%) had previously received and failed treatment with VKA; 3383 patients (60%) had not previously received VKA treatment but were expected to be unsuitable. The AVERROES trial was terminated early after two consecutive interim analyses showed overwhelming evidence of a treatment benefit in favour of apixaban over aspirin for the primary efficacy outcome (.4 SD). The mean follow-up duration was 1.1 years. 8 Compared with patients who had not previously received VKA treatment, those who had failed VKA therapy were older (mean age 70.3 vs years, P ¼ 0.01), more often male (60 vs. 58%, P ¼ 0.04), had a higher body mass index (28.9 vs kg/m 2, P, 0.001), had a similar CHADS 2 score (2.1 vs. 2.0, P ¼ 0.40), and a higher proportion had moderate renal impairment (17 vs. 15% with an egfr of ml/min, P ¼ 0.004, Table 1). Other differences included more patients with prior stroke or TIA (15 vs. 13%, P ¼ 0.02), fewer patients with heart failure (35 vs. 42%, P, 0.001), and fewer patients that were medically undertreated (more use of verapamil or diltiazem, beta-blocker, and statin). Forty-eight per cent of patients enrolled in North America or Western Europe

3 1858 M. Coppens et al. Table 1 Baseline characteristics of patients according to unsuitability for treatment with vitamin K antagonists Previously failed VKA Expected unsuitable for P-value* treatment (n ) VKA treatment (n ) Age, year Heart rate (b.p.m.) Systolic blood pressure (mmhg) Body mass index (kg/m 2 ) a ,0.001 Male sex 1333 (60) 1944 (58) 0.04 Classification of atrial fibrillation Paroxysmal 543 (25) 969 (29) Persistent 464 (21) 713 (21) Permanent 1209 (55) 1699 (50) Renal function egfr,50 ml/min 378 (17) 506 (15) egfr 50 to,80 ml/min 1242 (56) 1842 (55) egfr 80 ml/min 594 (27) 1034 (31) Previous bleeding episodes on VKA therapy 533 (24) n/a n/a Major bleeding 96 (4) n/a Minor bleeding 437 (20) n/a Risk factors for stroke Prior stroke or transient ischaemic attack 331 (15) 433 (13) 0.02 Hypertension, receiving treatment 1907 (86) 2930 (87) 0.50 Heart failure 768 (35) 1403 (42),0.001 Diabetes mellitus, receiving treatment 448 (20) 648 (19) 0.34 Left ventricular ejection fraction 35% 117 (5) 171 (5) 0.72 Peripheral arterial disease 71 (3) 81 (2) 0.08 Mitral stenosis 48 (2) 66 (2) 0.44 CHADS 2 score (mean score) b (38) 1196 (35) (34) 1258 (37) (29) 926 (27) Concomitant treatment ACE inhibitor or ARB 1405 (64) 2171 (65) 0.46 Verapamil or diltiazem 252 (11) 247 (7),0.001 b-blocker 1311 (59) 1786 (53),0.001 Digoxin 617 (28) 958 (28) 0.65 Amiodarone 238 (11) 388 (12) 0.38 Statin 890 (40) 974 (29),0.001 Regular alcohol consumption (at least once/week) 639 (29) 718 (21),0.001 Region North America or Western Europe 1082 (49) 980 (29),0.001 Other regions 1134 (51) 2403 (71) Study dose of aspirin or aspirin-placebo,162 mg 1325 (60) 2277 (67), mg 890 (40) 1106 (33) Study dose of 2.5 mg apixaban twice daily or apixaban-placebo 140 (6) 221 (7) 0.75 Continuous variables are expressed as means+ standard deviation, categorical variables as number of patients (%). ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; egfr, estimated glomerular filtration rate calculated with the CKD-EPI formula. 10 a The body mass index is the weight in kilograms divided by the square of the height in metres. b CHADS 2 is a stroke risk score (ascending risk from 1 to 6), which gives one point each for a history of heart failure, hypertension, the age of 75 years, and diabetes, and two points for either stroke or transient ischaemic attack. There were 15 patients (nine patients with VKA therapy demonstrated unsuitable) with a CHADS 2 score of 0, 11 7 of whom had either peripheral artery disease or left ventricular ejection fraction of 35%. *P-value is from the Pearson x 2 test for categorical variables and from the Wilcoxon two-sample test for continuous variables.

4 Apixaban vs. aspirin in patient that failed VKA therapy 1859 Table 2 Reason for unsuitability for vitamin K antagonist use and details of prior vitamin K antagonist use in patients who previously failed vitamin K antagonist treatment All (n ) Aspirin (n ) Apixaban (n ) Reasons for VKA unsuitability Unable to maintain INR in target range 932 (42) 468 (42) 464 (42) INR outside target range of ,25% of time 537 (24) 282 (25) 255 (23) 25 to,40% 262 (12) 127 (11) 135 (12) 40 to,50% 195 (9) 94 (8) 101 (9) 50% 525 (24) 270 (24) 255 (23) unknown 697(31) 334 (30) 363 (33) Adverse event during VKA therapy, not related to bleeding 180 (8) 94 (9) 86 (8) Bleeding event during VKA therapy 173 (8) 82 (7) 91 (8) Patient refuses VKA treatment 819 (37) 418 (37) 401 (36) Details of prior VKA use Duration of past VKA use,6 months 978 (44) 493 (45) 485 (44) 6 24 months 547 (25) 275 (25) 272 (25).24 months 687 (31) 339 (31) 348 (31) Bleeding episode on VKA 533 (24) 264 (24) 269 (24) Major bleeding 96 (4) 48 (4) 48 (4) Minor bleeding 437 (20) 216 (20) 221 (20) Indication for past VKA use Atrial fibrillation 2088 (94) 1039 (94) 1049 (95) Non-atrial fibrillation 68 (3) 40 (4) 28 (3) Both 56 (3) 28 (3) 28 (3) All data are presented as number of patients (%). VKA, vitamin K antagonist; INR, international normalized ratio. had never received VKA therapy compared with 68% of patients included in other regions (Table 1). Among 2216 patients who previously failed VKA therapy, a bleeding episode during VKA therapy was the reason for unsuitability in 8% of patients, although 24% (n ¼ 533) had experienced an episode of minor (n ¼ 437) or major (n ¼ 96) bleeding during prior VKA treatment (Table 2). Other reasons for unsuitability were inability to maintain the INR in the target range (42%), patient refusal of further VKA treatment (37%), and adverse events not related to bleeding (8%). Atrial fibrillation was the most common indication for prior VKA treatment (97%), and 44% of patients were treated with VKA for a period shorter than 6 months. These variables were equally distributed between the randomized apixaban and aspirin treatment groups (Table 2). The effects of apixaban compared with aspirin were consistent in those who previously failed warfarin and those who were expected to be unsuitable for warfarin, for both SSE (P interaction 0.13) and major bleeding (P interaction 0.74; Table 3, adapted from Connolly et al. 8 ). In patients who failed warfarin therapy (n ¼ 2216), apixaban compared with aspirin reduced the risk of SSE by 68% [event rate 1.4 vs. 4.2 per 100 patient-years; hazard ratio (HR) 0.32, 95% confidence interval (CI) , P, 0.001; Table 3], and the incidence of major bleeding was similar in both treatment groups (event rate 1.8 vs. 1.7 per 100 patient-years; HR: 1.06, 95% CI: , P ¼ 0.84; Table 2). In an on-treatment analysis, which included only events that occurred in patients while they were receiving the study treatment (i.e. 2 days after permanent discontinuation of the study medication), the event rate of major bleeding of 1.8 per 100 patient-years in the apixaban group, when compared with 1.3 per 100 patient-years in the aspirin group (HR: 1.43, 95% CI: , P ¼ 0.27). Patients who were unsuitable for VKA therapy because of prior bleeding episodes had higher incidences of both SSE and major bleeding than patients without previous bleeding episodes. However, the superiority of apixaban vs. aspirin with regard to stroke prevention and the similar incidence of major bleeding was preserved in those high-risk patients, as well as in the patients that were unsuitable due to inability to maintain the target INR (Figures 1 and 2). Except in subgroups that had few outcome events, the effects of apixaban vs. aspirin were consistent in the subgroups examined, including reason for VKA unsuitability, age, sex, renal function, CHADS 2 score, history of stroke, or heart failure, and aspirin dose (Figures 1 and 2). Discussion The AVERROES trial demonstrated that apixaban compared with aspirin reduced stroke by 55% and did not increase major bleeding in patients with AF deemed unsuitable for warfarin. In the present

5 1860 M. Coppens et al. Table 3 Incidence and relative risk of stroke or systemic embolism and major bleeding in apixaban- and aspirin-treated patients according to previous vitamin K antagonist therapy Aspirin... Apixaban... Apixaban vs. Aspirin... N n Rate (/100 N n Rate (/100 Hazard ratio P-value Interaction patient-years) patient-years) (95% CI) P-value Stroke or systemic embolism All ( ),0.001 Tried and failed VKA therapy ( ), Expected to be unsuitable for ( ) VKA therapy Major bleeding All ( ) 0.57 Tried and failed VKA therapy ( ) Expected to be unsuitable for VKA therapy ( ) 0.52 N isthe numberof patients; n isthe numberof events. Events aredefined as the first occurrenceof strokeor systemic embolism. Time to eventisthe time between randomization date and the event first occurrence. The rate is the number of outcome events per 100 patient-years of follow-up. Data adapted from Connolly et al. 8 P-value and interaction P-value are from the likelihood ratio test. Hazard ratios were estimated with Cox proportional-hazards regression models fit separately to each subgroup. Hazard ratio confidence interval limits are the profile likelihood limits. Interaction between the effect of apixaban vs. aspirin and subgroups was assessed with the Cox model fit to all patients. AF, atrial fibrillation; CI, confidence interval; Egfr, estimated glomerular filtration rate calculated with the CKD-EPI formula; 10 INR, international normalized ratio; TIA, transient ischaemic attack; VKA, vitamin K antagonist. analyses, we demonstrate that patients deemed unsuitable because they had previously failed warfarin compared with those who were warfarin naive and expected to be unsuitable were older, heavier, and more likely to be male. They were also more likely to have had a prior stroke or TIA, and less likely to have had heart failure or to be medically undertreated. It is hard to speculate on the reasons that patients who failed VKA therapy seem to have more stroke risk factors than VKA-naive patients, and in fact, the opposite might have anticipated because in the most frail patients VKA therapy may not be attempted. This suggests that other factors, not related to stroke risk such as access to and cost of healthcare, may be more important determinants of prior antithrombotic therapy. For example, 71% of VKA-naive patients were enrolled outside North America or Western Europe, compared with 51% of patients that tried and failed VKA therapy. While some of these characteristics are important risk factors for stroke and bleeding, the differences were rather small and unlikely to be clinically relevant. Moreover, despite the differences in baseline characteristics, the effects of apixaban compared with aspirin were consistent in patients who previously failed warfarin and in those who were expected to be unsuitable. Apixaban compared with aspirin also produced consistent treatment effects among different subgroups of patients who had previously failed warfarin therapy defined by reasons for failure of warfarin treatment, age, renal function, and CHADS 2 score. Patients who have failed warfarin therapy because of bleeding complications or inadequate INR control are usually excluded from trials of anticoagulation and might be expected to have different risks of adverse events when treated with an anticoagulant such as apixaban than those who are expected to be unsuitable for warfarin therapy. One of the major strengths of the present analysis is the large number of these patients included in the trial, with.500 patients having previously experienced bleeding during warfarin therapy. Our data demonstrating uniformly consistent estimates for efficacy and safety irrespective of the reasons for warfarin failure suggest that the results of the AVERROES trial can be broadly generalized to patients who have failed warfarin therapy. The only exception was a statistically significant interaction for major bleeding between randomized treatment and quality of previous INR control that suggested more major bleeding in apixabantreated patients. To explore if this interaction is truly significant or due to random chance, we looked at this interaction for the composite endpoint of major and clinically relevant non-major bleeding, where no such interaction was observed (see Supplementary material online, Table S1). The optimal antithrombotic therapy for patients that are unsuitable for VKA therapy remains a challenge. The results of the AVER- ROES trial show that aspirin monotherapy is inferior to twice daily apixaban 8 and accordingly, the most recent update from the European Societyof Cardiology guidelinenow advises against aspirin monotherapy. 11 Furthermore, the effect of addition of clopidogrel to aspirin in unsuitable patients was studied in the ACTIVE-A study. 12 Although combined clopidogrel and aspirin treatment led to a 30% reduction in stroke compared with aspirin alone, combination therapy also increased the risk of major bleeding by 55%. 12 Therefore, apixaban seems a more attractive alternative for patients unsuitable for VKA therapy. Previous comparisons between VKA-naive- and VKAexperienced patients, such as the one from the RE-LY trial, 13 show similarly consistent treatment effects of anticoagulant therapy. However, patients in the present analysis were not simply VKA experienced; they were both experienced and unsuitable for VKA therapy. The results in this unsuitable population, therefore, provide valuable additional data that may help to guide these patients.

6 Apixaban vs. aspirin in patient that failed VKA therapy 1861 Figure 1 Incidence and relative risk of stroke or systemic embolism in apixaban- and aspirin-treated patients who previously failed VKA therapy, according to subgroups. N is the number of patients; n is the number of events. Events are defined as the first occurrence of stroke or systemic embolism. Time to event is the time between randomization date and the event first occurrence. The rate is the number of outcome events per 100 patient-years of follow-up. P-value and interaction P-value are from the likelihood ratio test. Hazard ratios were estimated with Cox proportionalhazards regression models fit separately to each subgroup. Hazard ratio confidence interval limits are the profile likelihood limits. Interaction between the effect of apixaban vs. aspirin and subgroups was assessed with the Cox model fit to all patients. AF, atrial fibrillation; CI, confidence interval; egfr, estimated glomerular filtration rate calculated with the CKD-EPI formula; 10 INR, international normalized ratio; TIA, transient ischaemic attack; VKA, vitamin K antagonist.

7 1862 M. Coppens et al. Figure 2 Incidence and relative risk of major bleeding in apixaban- and aspirin-treated patients who previously failed VKA therapy, according to subgroups. N is the number of patients; n is the number of events. Events are defined as the first occurrence of stroke or systemic embolism. Time to event is the time between randomization date and the event first occurrence. The rate is the number of outcome events per 100 patient-years of follow-up. P-value and interaction P-value are from the likelihood ratio test. Hazard ratios were estimated with Cox proportional-hazards regression models fit separately to each subgroup. Hazard ratio confidence interval limits are the profile likelihood limits. Interaction between the effect of apixaban vs. aspirin and subgroups was assessed with the Cox model fit to all patients. AF, atrial fibrillation; CI, confidence interval; egfr, estimated glomerular filtration rate calculated with the CKD-EPI formula; 10 INR, international normalized ratio; TIA, transient ischaemic attack; VKA, vitamin K antagonist.

8 Apixaban vs. aspirin in patient that failed VKA therapy 1863 The early termination and consequent lower than anticipated number of outcome events of the AVERROES trial is the most important limitation of this analysis. Sample size calculations for randomized trials are usually aimed to provide sufficient statistical power for the primary outcome only and thereby, subgroup analyses are generally underpowered. The early termination further limits the power to explore subgroups. Thus, this subgroup analysis within the subgroup of patients who previously failed VKA therapy should be considered exploratory and results should be cautiously interpreted, especially in subgroups with low-outcome events. Nevertheless, the consistency of treatment effects in most key subgroups is re-assuring. In conclusion, this analysis indicates that the beneficial effects of apixaban vs. aspirin found in the AVERROES trial apply across a wide spectrum of patients, irrespective of the reason for unsuitability of VKA therapy, including patients with prior bleeding episodes and patients with poor INR control. Supplementary material Supplementary material is available at European Heart Journal online. Funding The AVERROES trial was supported by Bristol-Myers Squibb and Pfizer. Conflict of interest: M.C. has received grant support and lecturing fees from Boehringer Ingelheim. D.S. was formerly employed by Bristol- Myers Squibb. J.W.E. has received consulting and lecturing fees and grant support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Johnson & Johnson, Novartis, Pfizer, and Portola. S.Y. has received consulting fees and grant support from Astra- Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Glaxo-Smith Kline, Novartis, and Sanofi-Aventis. 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