Initiation of warfarin in patients with atrial fibrillation: early effects on ischaemic strokes

Response to D'Angelo et al.

Laurent Azoulay PhD1,2, Christel Renoux MD PhD1,3,4, Samy Suissa PhD1,4

1 Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada 2 Department of Oncology, McGill University, Montreal, Quebec, Canada 3 Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada 4 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada

Total word count: 298

Corresponding author: Dr. Samy Suissa Centre for Clinical Epidemiology Lady Davis Institute, Jewish General Hospital 3755 C?te-Sainte-Catherine, H-461 Montreal, Quebec, Canada, H3T 1E2 Tel: 514.340.8222; Fax: 514.340.7510 Email: [email protected]

January 13, 2014

Dear Editor: We thank D'Angelo et al. for their interest in our study.1 As they suggest, while one possible reason for the increased risk of stroke in the initial days of warfarin treatment could be related to poor dosing or monitoring, it is important to note that we compared new users of warfarin to non-users of any antithrombotic therapy. With careful matching and adjustment for a wide range of potential confounders, it would have been expected that these groups would have had a similar risk of stroke. Thus, the 71% increased risk of stroke in the first 30 days is more suggestive of a transient hypercoagulable state than poor dosing or monitoring. Moreover, in a secondary analysis, the increased risk was highest in first 3 days after warfarin initiation, which is consistent with the pharmacodynamics of this treatment. A meta-analysis comparing warfarin-na?ve to warfarin-experienced patients would not allow making the distinction between a transient hypercoagulable state and a delay in warfarin's therapeutic effect. Ideally, a meta- analysis comparing warfarin to placebo (as was done in the original trials) with an analysis limited to the first 30 days of follow-up would allow studying the impact of a hypercoagulable state. It is for this precise reason that our comparator group consisted of patients not using any antithrombotic therapy. Finally, we agree with the authors that a faster obtainment of a therapeutic INR with a loading dose is not a good indicator of anti- thrombotic activity and should be discouraged. As for heparin bridging strategies in atrial fibrillation, their usefulness at the initiation of warfarin should be further assessed in future studies.

Funding source This study was funded by Bristol-Myers Squibb and Pfizer Inc.

Acknowledgments Drs Azoulay and Renoux are recipients of a Chercheur-Boursier Award from the Fonds de la recherche en sant? du Qu?bec (FRSQ), and Dr Suissa is the recipient of the James McGill Chair.

References

1. Azoulay L, Dell'Aniello S, Simon TA, Renoux C, Suissa S. Initiation of warfarin in patients with atrial fibrillation: early effects on ischaemic strokes. Eur Heart J. 2013 Dec 18.

Conflict of Interest:

LA and CR have no conflicts of interest to declare, and SS has received research funding and has participated in advisory committees for Bristol-Myers Squibb, Boehringer-Ingelheim and Bayer-Schering.

To the Editor:

In their analysis of a very large cohort of patients with atrial fibrillation (AF), Azoulay et al [1] report that compared with non-use, warfarin was associated with a 71% increased risk of stroke in the first month of use. They suggest analogy of these findings with the increased risk of stroke observed in the Rocket AF [2] and Aristotle [3] trials when patients were transitioned to open label warfarin at the end of the study. However both stroke/systemic embolism and major bleeding events were increased to a similar extent during transitioning from rivaroxaban (HR of 3.72 and 3.62 respectively) or from apixaban (HR of 4.06 and 2.52 respectively) to open label vitamin K antagonists [2,3], and less than 50% of patients had a therapeutic INR 30 days after last dose of rivaroxaban [2]. Rather than an increased thrombotic risk in the early days of warfarin use, poor dosing/monitoring of vitamin K antagonists is a likely explanation for these findings. More suggestive of initial hypercoagulability with warfarin are the data at enrolment in VKA-naive and VKA-experienced patients. In the Rocket AF trial VKA-naive patients assigned to warfarin had their first therapeutic INR at a median of 26 days; during the first month after randomization few thromboembolic events occurred in VKA-experienced patients, but no direct comparison of the early event rate in VKA-naive and VKA-experienced patients assigned to warfarin is reported [4]. In the Aristotle trial and during the first month after randomization, VKA-naive patients assigned to warfarin had a 380% increased risk of stroke/systemic embolism compared to VKA- experienced patients assigned to warfarin [3]. A metanalysis of the early thromboembolic events rate in VKA-naive and VKA-experienced patients in the warfarin group of all phase III trials evaluating direct oral anticoagulants in non-valvular AF is highly desirable. Nevertheless, before determining whether a heparin bridging strategy reduces the risk of stroke [1], the use of a VKA loading dose should be discouraged. A loading dose of warfarin is inherently prothrombotic because it increases the unbalance between procoagulant vitamin K-dependent factors with a longer half-life and the short-lived anticoagulant protein C [5]. At the initial phase of warfarin treatment, nadir levels of prothrombin fragment 1.2 - i.e. of in vivo thrombin generation - are attained in parallel with nadir levels of factor II [6]. The INR is a valid monitoring tool in patients on stable VKA treatment because it adjusts for the different sensitivity of thromboplastin reagents to the reduction in factor II [7], but this is not true at initiation of VKA treatment because of the much faster reduction in factor VII levels [6]. Hence, the faster obtainment of "therapeutic" INRs with a loading dose is meaningless with respect to antithrombotic activity. Based on data from patients with acute VTE - and heparin bridging -, the 2012 ACCP guidelines suggest (grade 2C) initiating therapy with warfarin 10 mg for the first two days rather than starting with the estimated maintenance dose [8]. The implication of a 2C suggestion is that higher-quality research may well change the estimate: isn't it time for a change ?

1. Azoulay L, Dell'Aniello S, Simon TA, Renoux C, Suissa S. Inititation of warfarin in patients with atrial fibrillation:early effects on ischaemic strokes. Eur Heart J. 2013 Dec 18.

2. Patel MR, Hellkamp A, Lokhnygina Y, Piccini JP, Zhang Z, Mohanty S, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Becker RC, Nessel CC, Berkowitz SD, Califf RM, Fox KAA, Mahaffey KW. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF Trial. J Am Coll Cardiol. 2013;61:651-8.

3. Granger CB, Alexander JH, Hanna M,Wang J, Mohan P, Lawrence J, Hylek E, Ansell J, Wallentin L. Events after discontinuation of randomized treatment at the end of the ARISTOTLE trial. Eur Heart J. 2012;33(suppl 1) p. 685.

4. Mahaffey KW, Wojdyla D, Hankey GJ, White HD, Nessel CC, Piccini JP, Patel MR, Berkowitz SD, Becker RC, Halperin JL, Singer DE, Califf RM, Fox KA, Breithardt G, Hacke W. Clinical outcomes with rivaroxaban in patients transitioned from vitamin K antagonist therapy: a subgroup analysis of a randomized trial. Ann Intern Med. 2013;158:861-8.

5. Vigano D'Angelo S, Comp PC, Esmon CT, D'Angelo A. Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states. J Clin Invest. 1986;77:416 -25.

6. D'Angelo A, Della Valle P, Crippa L, Fattorini A, Pattarini E, Vigan? D'Angelo S. Relationship between international normalized ratio values, vitamin K-dependent clotting factor levels and in vivo prothrombin activation during the early and steady phases of oral anticoagulant treatment. Haematologica. 2002;87:1074-80.

7. Testa S, Morstabilini G, Fattorini A, Galli L, Denti N, D'Angelo A. Discrepant sensitivity of thromboplastin reagents to clotting factor levels explored by the prothrombin time in patients on stable oral anticoagulant treatment: impact on the international normalized ratio system. Haematologica. 2002;87:1265-73.

8. Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH; American College of Chest Physicians. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S-84S.

Conflict of Interest:

None declared