Authors: Partha Sardar MDa; Saurav Chatterjee MDb; Joydeep Ghosh MDc; Debabrata Mukherjee MD, MS d, Gregory Y H Lip MD, FRCP, FACC, FESCe.

Transcription

1 Risk of Major Bleeding in Different Indications for New Oral Anticoagulants: Insights from a Meta- Analysis of Approved Dosages from 48 Randomized Trials Authors: Partha Sardar MDa; Saurav Chatterjee MDb; Joydeep Ghosh MDc; Debabrata Mukherjee MD, MS d, Gregory Y H Lip MD, FRCP, FACC, FESCe. Institutions: a. New York Medical College-Metropolitan Hospital Center, Department of Medicine, New York, NY; b. Brown University and the Providence VAMC, Providence, RI; c. Columbia University of Physicians and Surgeons, New York, NY; d. Texas Tech University Health Sciences Center, El Paso, Texas, e. University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom

2 Disclosure Partha Sardar- None Saurav Chatterjee-None Joydeep Ghosh-None Debabrata Mukherjee-None Gregory Y H Lip - Served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, BMS/Pfizer, and Boehringer Ingelheim and has been on the speaker bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, and Sanofi. Source of Funding: None

3 Introduction New oral anticoagulant agents (NOACs) developed for use in different indications. The new agents have specific advantages over the conventional anticoagulants. Factor Xa (FXa) inhibitors- rivaroxaban, apixaban, edoxaban and darexaban Direct thrombin inhibitors-dabigatran and ximelagatran Miller CS, Grandi SM, Shimony A,et al. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012; 110:

4 Introduction-cont d Rivaroxaban- USA -Atrial fibrillation (AF), after orthopedic surgery, venous thromboembolism (VTE), Europe- also acute coronary syndrome (ACS) Apixaban- USA-AF only; Europe -AF and orthopedic surgery. Dabigatran- United States-AF ; Europe-also orthopedic surgery Ximelagatran is no longer available Edoxaban and darexaban phase II trials; ENGAGE AF- TIMI 48 for edoxaban presented yesterday. Adam SS, McDuffie JR, Ortel TL, Williams JW Jr. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med. 2012;157:

5 Introduction-cont d The major disadvantage of the NOACs is the lack of specific antidotes that would reverse their action in a patient with major bleeding. Also, no reliable laboratory tests are available to monitor the effects of these agents. No major systematic review focusing only on comparative bleeding risk with NOACs. No previous or ongoing, head-to-head trial among these new agents Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood. 2012;119:

6 Objective We performed a meta-analysis of published randomized clinical trials to evaluate the risk of major bleeding with new oral anticoagulants. NOAC versus conventional anticoagulants Indirect comparisons among the NOACs

7 Methods-Search Strategy Databases Searched-PubMed, Embase,CINAHL and Cochrane CENTRAL English language, peer-reviewed publications evaluating NOACs January 2001 through February 28, 2013 Search terms- new oral anticoagulants, oral thrombin inhibitors, oral factor Xa inhibitors, dabigatran, rivaroxaban, apixaban, darexaban, edoxaban, DU-176b, YM150.

8 Methods-Study Selection Randomized clinical trials; dabigatran, rivaroxaban, apixaban, edoxaban or darexaban. The comparator- any active pharmacologic agents or placebo Indications Thromboprophylaxis after hip surgery, thromboprophylaxis after knee surgery. Treatment of VTE or PE, extended treatment of VTE. Atrial fibrillation; Acute coronary syndrome Thromboprophylaxis in medically ill patients.

9 Methods-Data Extraction and Quality Assessment Two authors abstracted the data Checked for accuracy by the other authors Disagreements resolved by consensus Objective assessment of the trials-cochrane Handbook of Systematic Reviews

10 Methods-Outcomes Assessment The outcome of interest -major bleeding events. NOAC dosage selections We used the outcome related to the approved total daily dose/closely related dose For phase II trials we used the dose, which was subsequently tested in phase III trials, Only phase II data-we chose the most frequently used dose of those drugs (for specific indications) in all trials with acceptable efficacy profile

11 NOAC dosage selection Orthopedic surgery: (riva 5mg BID/10 mg daily, apixa 2.5 mg BID/ 5 mg daily, dabi 220 mg daily, edoxa 30 mg daily and darexa 60 mg daily). Atrial fibrillation: (riva 20 mg/15 mg daily, apixa 5 mg BID, dabi 150 mg BID and edoxa 30 mg daily). Acute VTE/PE : (riva mg daily, apixa 5 mg BID, dabi150 mg BID)

12 NOAC dosage selection ACS: (riva 5mg BID, apixa 5 mg BID/10 mg daily, dabigatran 150 mg BID and darexa 60 mg daily). Extended VTE: (riva 20 mg daily, apixa2.5 mg BID or 5 mg BID, dabi150 mg BID) Medically ill patients (riva10 mg daily, apixa2.5 mg BID).

13 Methods-Statistical Analysis Cochrane collaboration-preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) statement We calculated odds ratio (OR) estimates and associated 95% confidence intervals (CIs) for each of the oral anticoagulants and for each indication of use. We assessed the heterogeneity using the Cochran Q test and the Higgins I 2 test.

14 Methods-Statistical Analysis Random effects model Indirect comparisons between NOACs (with indication specific conventional drug as common comparator) Publication bias was estimated - Funnel plots, Regression test of Egger Review Manager Version 5.1 and Stata 11.2 (StataCorp LP, College Station, Texas)

15 Results: Search Strategy

16 Results-Study Characteristics 48 trials- total 141,932 patients Hip surgery (12 studies), knee surgery (9 studies), acute VTE/PE (6 studies), ACS (6 studies), AF (10 studies), extended VTE (4 studies), and medically ill patients (2 studies). The numbers of included trials appraising rivaroxaban, apixaban, dabigatran, edoxaban and darexaban were eighteen, eleven, twelve, four and three respectively.

17 Results Pooled analysis of all NOACs for all indications: No significant difference between NOACs and pharmacologically active comparators (PAC) (Odds Ratio [OR] 0.98, 95% CI ) NOACs caused significantly less major bleeding compared to vitamin K antagonists (0.82, ). Individual NOACs showed risk of major bleeding was not different with rivaroxaban, apixaban or dabigatran compared to PAC or VKA.

18 Results Cont. Indication specific analysis No significant difference was found between NOACs and comparators in treatment of AF and for extended treatment of VTE. NOACs was associated with significantly higher major bleeding after hip surgery (1.43, ), in ACS (3.27, ), and for medically ill patients (2.79, ). For the treatment of acute VTE/PE, NOAC was associated with significantly less bleeding (0.64, ).

19 NOACs versus pharmacologically active agents

20 Three approved/available new oral anticoagulants (rivaroxaban, dabigatran and apixaban) versus vitamin K antagonists

21

22

23 NOACs versus comparators

24 Direct comparisons : Different indications

25 Indirect comparisons between Rivaroxaban, Dabigatran, Apixaban, Edoxaban and Darexaban

26 Limitations Differences in study and patients characteristics. Widened confidence intervals for few agents Definitions of major bleeding varied. All included studies reported major bleeding as a composite outcome (ISTH criteria); ranging from severe intracranial bleeding to comparatively less important outcomes. Effects of older age and impaired renal function on bleeding risks could not be pooled due to non-availability of data.

27 Conclusions Risk of major bleeding with NOACs varies with their indication for use. NOACs may be related to higher risk of bleeding in hip surgery, ACS and in medically ill patients. In patients with AF, knee surgery and extended treatment of VTE, NOACs may not necessarily be associated with increased bleeding risk when used in approved doses.

28 Conclusions Collectively and individually the NOACs may cause equal or even less major bleeding when compared to vitamin K antagonists. NOACs may be associated with less bleeding in treatment of acute VTE/PE Large head to head randomized controlled trials required.

29 Thank You