Jan 17, 2014

Comparing trials of new anticoagulants in atrial fibrillation: overview

UPDATED FEB 17, 2014

Four new drugs: dabigatran, rivaroxaban, apixaban, and edoxaban.
Four landmark clinical trials: RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF - TIMI 48.
All published in The New England Journal of Medicine.
All compared a new oral anticoagulant (NOAC) with warfarin in patients with atrial fibrillation.
This post summarizes the main findings of these trials.

Table. Relevant characteristics and summary of efficacy and safety in landmark trials comparing new oral anticoagulants (NOACs) with warfarin in stroke prevention in atrial fibrillation.
RE-LY ROCKET-AF ARISTOTLE ENGAGE AF - TIMI 48
Drug Dabigatran Rivaroxaban Apixaban Edoxaban
n 18,113 14,264 18,201 21,105
Median follow up (years) 2.0 1.9 1.8 2.8
Age (years) 71 (mean) 73 (median) 70 (median) 72 (median)
Female (%) 36 40 35 38
Mean CHADS2 2.1 3.5 2.1 2.8
Median TTR (%) 66 58 66 68
Discontinuation rate (%) 20.7 (D110), 21.2 (D150), 16.6 (W) 23.7 (RIVA), 22.2 (W) 25.3 (API), 27.5 (W) 33.0 (E30), 34.4 (E60), 34.5 (W)
Summary of efficacy and safety
D110 D150 RIVA API E30 E60
Stroke or systemic embolism
   - Noninferiority? Yes Yes Yes Yes Yes Yes
   - Superiority? (ITT analysis) 167 See below* 303 p=0.10 p=0.08**
Ischemic stroke 357 192
Major bleeding 143 104 55 147
Intracranial bleeding 196 227 500 213 169 217
Gastrointestinal bleeding 204 ~167 244 357
Myocardial infarction p=0.09 p=0.12 p=0.13
All cause mortality p=0.051 p=0.073 238 182 p=0.082
Net clinical outcome*** p=0.10 137 93 76 118
* Superiority was shown for rivaroxaban when considering the intention-to-treat (ITT) population during the treatment period. See more details at Comparing trials of new anticoagulants in atrial fibrillation: stroke and systemic embolism.
**  This is an analysis according to the intention-to-treat (ITT) principle. A modified ITT analysis in the treatment period showed superiority of edoxaban over warfarin. See more details at Comparing trials of new anticoagulants in atrial fibrillation: stroke and systemic embolism.
*** Net clinical outcome means stroke, systemic embolism, major bleeding, or death from any cause. It includes pulmonary embolism and myocardial infarction for dabigatran.

Legend:
NNT means "favoring NOAC compared with warfarin" with statistical significance (p <0.05). The number denotes the NNT, or number needed to treat with NOAC, instead of warfarin, to prevent 1 event in 1 year. NNT is the reciprocal (or inverse) of the absolute risk reduction (ARR): NNT = 1/ARR.

positive trend means "some evidence of or trend (p ≥0.05 and ≤0.10) toward superiority of NOAC compared with warfarin".

NNH means "favoring warfarin compared with NOAC" with statistical significance (p <0.05). The number denotes the NNH (number needed to harm), or number needed to treat with NOAC, instead of warfarin, to cause 1 event in 1 year. NNH is the reciprocal (or inverse) of the absolute risk increase (ARI): NNH = 1/ARI.

negative trend means "some concern about or evidence of or trend toward superiority of warfarin compared with NOAC".

API: apixaban
D110: dabigatran 110 mg twice daily
D150: dabigatran 150 mg twice daily
E30: edoxaban 30 mg once daily
E60: edoxaban 30 mg once daily
ITT: intention to treat
RIVA: rivaroxaban
TTR: time in the therapeutic range for INR
W: warfarin

 KEY POINTS 
1. Note that there are differences among the trials:
  • mean CHADS2 of the population was higher in ROCKET AF, lower in RE-LY and ARISTOTLE, and intermediate in ENGAGE AF – TIMI 48;
  • median time in the therapeutic range (TTR) for the international normalized ratio (INR) (2.0–3.0) in the warfarin arm was lower in ROCKET AF than in the other trials.

2. Trial results showed broadly similar efficacy and safety trends for each of the NOACs compared with warfarin. When NOAC was better than warfarin (green cells), the absolute risk reduction was usually small (considering event rate per year), and consequently the number need to treat (NNT) with NOAC, instead of warfarin, to prevent 01 event in 01 year is relatively high. The same phenomenon occurs when NOAC was worst than warfarin (red cells), leading to relatively high numbers needed to harm (NNH). Of course, the longer the term, the lower the NNT/NNH.

3. Major strenghts of NOACs, compared with warfarin:
  • at least noninferior for the primary endpoint of stroke or systemic embolism;
  • less major bleeding with dabigatran 110 twice daily, apixaban, and edoxaban (although usually with high NNT );
  • less intracranial bleeding (although with high NNT).  
  • at least a trend for lower all cause mortality and/or net clinical benefit (although usually with high NNT).

4. Major concerns about NOACs, compared with warfarin:
  • more gastrointestinal bleeding with dabigatran 150 mg twice daily, rivaroxaban, and edoxaban 60 mg daily (although with high NNH);
  • some evidence of or trend for higher risk of myocardial infarction with dabigatran;
  • higher risk of ischemic stroke and possible trend for higher risk of stroke or systemic embolism (ITT analysis) and myocardial infarction with low dose edoxaban.

 REFERENCES 
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. Epub 2009 Aug 30. Erratum in: N Engl J Med. 2010 Nov 4;363(19):1877. Abstract. Full article.

Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. Epub 2011 Aug 10. Abstract. Full article.

Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92. Epub 2011 Aug 27. Abstract. Full article.

Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. Epub 2013 Nov 19. Abstract. Full article.

 SEE ALSO  other comparisons of these trials of new anticoagulants in atrial fibrillation:
Primary endpoint (stroke or systemic embolism)
Bleeding outcomes
Risk of myocardial infarction
Mortality rates
Net clinical outcome

 SEE ALSO  
Be careful when comparing trials of NOACs in AF
This review, written by experts from the Brigham and Women's Hospital (Boston, USA), “mainly focuses on study designs, enrollment criteria, populations studied, quality metrics, and transition strategies between oral anticoagulants” in trials of dabigatran, rivaroxaban, apixaban, and edoxaban versus vitamin K antagonists in atrial fibrillation. The authors remind that “substantial differences exist in terms of drug pharmacology and trial characteristics”, and there are “substantial heterogeneity in the trial populations and designs and procedures used to conduct the trials.”

Reference:
Gonzalez-Quesada CJ, Giugliano RP. Comparison of the Phase III Clinical Trial Designs of Novel Oral Anticoagulants Versus Warfarin for the Treatment of Nonvalvular Atrial Fibrillation: Implications for Clinical Practice. Am J Cardiovasc Drugs. 2014 Feb 7. [Epub ahead of print]. Abstract.