Novel Anti-coagulants

A brief rundown of the players:

Dabigatran (Pradaxa) is a direct thrombin inhibitor, FDA approved in October 2010 for the prevention of CVA in patients with Afib.  In December 2011, the FDA initiated an investigation into reports of higher than expected rates of serious bleeding events.  Rates of dyspepsia and GI bleed are also concerning, and a small but significant increase in MI has been shown in safety outcome data from multiple trials.

Rivaroxaban (Xarelto) is a direct Factor Xa inhibitor, FDA approved July 2011 for DVT prophylaxis, and in November 2011 for prevention of CVA in patients with Afib.

Apixaban (Eliquis), another direct Factor Xa inhibitor, will likely be FDA approved in June 2012 for prevention of CVA in patients with Afib. 

This journal club examined the 3 major studies published in NEJM used to support the use of these novel anticoagulants in the prevention of CVA in patients with Afib.  Interestingly, these drugs are struggling when studied in ACS; APPRAISE-2 (study of apixaban + antiplatelet therapy after ACS) was stopped early in 2011 due to increase in major bleeding without significant reduction in recurrent ischemic events.  One other general note:  in all three of these studies, ICH (the bleeding complication that counts) was significantly less with the study drug as compared to warfarin.  All 3 of these drugs do ok in these non-inferiority studies-the important question is how they will perform in the real world, and it may be several years before safety conclusions and community effectiveness data give us the answer.


1.  Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361(12):1139-1151.  (RE-LY)

Dabigatran 150mg BID or 110mg BID (blinded) vs Dose adjusted warfarin (unblinded)

Randomized, noninferiority trial of 18,113 patients, median follow-up 2 years.

Condition: AF within 6 months prior to randomization + 1 risk factor for CVA.  Use of                antiplatelets acceptable.  Mean CHADS2 score 2.1.  Intention to treat.

Primary endpoint: Stroke or systemic embolism

  • Warfarin 1.7%
  • Dabigatran 110mg 1.5% (p=0.34)
  • Dabigatran 150mg 1.1%   (p<0.001 for superiority)

Major Bleeding

  • Warfarin 3.4%
  • Dabigatran 110mg 2.7% (p=0.003)
  • Dabigatran 150mg 3.1% (p=0.31)


  • Warfarin 0.74%
  • Dabigatran 110mg 0.23% (p<0.001)
  • Dabigatran 150mg 0.3% (p<0.001)

Conclusion: Lower dose dabigatran similar to warfarin for preventing stroke/systemic embolism and caused less major bleeding than warfarin.  Higher dose dabigatran superior to warfarin for preventing stroke with similar rates of major bleeding to warfarin (trade off with dosing between benefit and bleeding).  Both doses of dabigatrin with significantly less ICH than warfarin.  Significantly higher rate of GI bleeding in higher dose dabigatran group as compared with warfarin.

Comments:  Tony-higher discontinuation rate with dabigatran, likely from dyspepsia rates.  What happens with the effectiveness of these drugs in the real world (external validity) when people don’t take them due to side effects, and there is no monitoring such as INR to reinforce compliance?  Also likely to see less of a difference between the drugs in motivated patients on warfarin with very well controlled INRs.  In real world, INR is maintained in therapeutic range only about 55% of the time.  You can improve warfarin safety and effectiveness if you use point of care monitoring and have motivated patients.  Brad-bottom line, concern about increased MI and GI bleed rates, and no easy reversal agent.


2.  Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine. 2011;365(10):883-891.  (ROCKET)

Rivaroxaban 20mg QD vs Dose adjusted Warfarin

Randomized double blind, noninferiority trial of 14,000 patients, median follow-up 707 days.

Condition: AF within 6 months prior to randomization + at least 2 risk factors for CVA.  Mean          CHADS2 score 3.5.

Primary endpoint: Stroke and systemic embolism

  • Warfarin  2.4%
  • Rivaroxaban 2.1% (ITT p=0.12 for superiority, p<0.001 for noninferiority)

Major Bleeding

  • Warfarin 3.4%
  • Rivaroxaban 3.6% (p=0.58)


  • Warfarin 0.7%
  • Rivaroxaban 0.5% (p=0.02)

Conclusion:  Rivaroxaban non-inferior to warfarin in the prevention of stroke/systemic embolism with no significant difference in major bleeding events and less ICH.

Comments:  Mark-patients in this study with higher CHADS2 scores-more like our patients.  Also noted the increased risk for thrombotic events after stopping rivaroxaban.  This is also something seen with clopidogrel (Plavix).  Brian noted the heavily subsidized authors. Three statistical analyses used in this study:  intention to treat, per-protocol and as treated safety analyses.  Superiority was achieved only in the as treated safety analysis.  It seems like a lot of data torturing to find a way to demonstrate superiority.

Statistics Rant about noninferiority studies.  We commonly read superiority studies-attempts to show that drug A is better than drug B.  Why do a noninferiority study?  It’s a logical choice when you can’t use a placebo arm, and want to show drug A is as “good as” drug B.  Also, choosing the noninferiority margin, or how close the results for drug A need to be to drug B in order to conclude that they are similar, is arbitrary.   Pick a margin, and if you’re dealing with FDA approval, you just need to pick a margin that the FDA will swallow in order to approve your drug.  For the apixaban study, if apixaban was shown to be at least 50% as good as wafarin, it was judged noninferior.  In general the requirements for noninferiority studies are much more lax than for superiority studies, making them attractive to Big Pharma.  Also, in the end, if you able to demonstrate and report superiority, your results looks even better.  As far as analyzing results, in randomized studies trying to demonstrate superiority, intention to treat (ITT) is the best approach.  With non-inferiority studies, it’s actually preferable to do both ITT and per-protocol analyses, as per-protocol analyses bias against demonstrating significant differences (is a stronger analysis).  When in doubt though, as Erik always stresses, look at effect size (number needed to treat, absolute risk reduction), the comparison between benefits and harms, and expense…not statistics, and certainly not p values.


3.  Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2011;365(11):981-992.  (ARISTOTLE)

Apixaban 5mg BID vs Dose adjusted Warfarin

Randomized double blind noninferiority trial of 18,201 patients, median duration of followup                1.8 years.  Mean CHADS2 score 2.1.

Condition: AF within 6 months prior to randomization + at least 1 risk factor for CVA

Primary endpoint: Stroke or systemic embolism

  • Apixaban 1.3%
  • Warfarin 1.6% (p<0.001 for noninferiority, p=0.01 for superiority)

Major Bleeding

  • Apixaban 2.1%
  • Warfarin 3.1% (p<0.001)


  • Apixaban 0.2%  
  • Warfarin 0.5% (p<0.001)

Conclusion: Apixaban superior to warfarin in preventing stroke/systemic embolism with less major bleeding and lower rates of ICH.

Comments:  Paarul-questioned the costs of these agents.  Paarul and Pikul both felt the drug is promising, but have concerns about external validity, as there were significant inclusion/exclusion criteria.  Dabigatran costs 8 $/day, warfarin is 30 cents.  Need to factor in costs of INR testing, and as Mary pointed out, also costs of bridging with enoxaparin (Lovenox) if INR subtherapeutic.  Christine pointed out that the study stressed relative risk reduction, which can sound good, but is less appropriate than using absolute risk reduction.  Kelly wondered about the outcomes of the patients who bled-not discussed in the paper.  Harwood pointed out that although results superior to warfarin, small effect size:  NNT to prevent stroke/embolism 303, NNT to prevent a major bleed 104, NNT to save a life 238, and outside of carefully monitored study setting, real world effect size will likely be even less.

In my humble opinion, this is the strongest study of the three.  Then again, apixaban isn’t even FDA approved yet-unlike iPhones, there are potentially big downsides to being the early adopter for new drugs…meaningful safety conclusions are still years in the future.


BONUS!!  AVERROES - Apixaban in Patients with Atrial Fibrillation (this was a background article, but interesting as it compared Apixaban to ASA; relevant for patients who aren’t candidates for warfarin)

Apixaban 5mg BID vs ASA

5,600 patients

Condition: AF within 6 months prior to randomization + 1 risk factor for CVA

Primary endpoint: Stroke and systemic embolism

  • ASA 3.9%
  • Apixaban 1.7% (p<0.001)

Major Bleeding

  • ASA 1.2%           
  • Apixaban  1.4% (p=0.33)


  • ASA 0.3%           
  • Apixaban  0.4% (p=0.83)

Conclusion: Apixaban superior to aspirin with similar rate of major bleeding and ICH. Study stopped early due to benefit of apixaban over aspirin.