The INR percentage time in therapeutic range (TTR) is unknown in this study, but presumably was in the mid fifties.
What would these results look like in an environment where TTRs are in the range of 75% or greater, such as was achieved
in the University of Auckland's Community Pharmacist-led Anticoagulation Management Service study? Also, there is latitude
to improve warfarin management through the use of computer decision support software and INR point of care testing. With
dabigatran, there is no such potential.
Finally, as the time within therapeutic range affects the hemorrhagic stroke rate, the stroke and systemic embolism
rate, the total bleeding rate and the mortality rate, perhaps the RE-LY data should be adjusted to properly place it
in context with the real world in Canada, as the valid transferability of the RE-LY (Rocket-AF and Aristotle) findings
to Canada (and perhaps New Zealand) is highly in question in our minds.
Thank you for your comments regarding recent BPJ articles on the role of dabigatran in the reduction of thromboembolism
in patients with atrial fibrillation (BPJ 50, Feb 2013 and BPJ
38, Sept 2011). We believe the RE-LY multi-centre study provides valuable information for improving patient focused
decision making for therapeutic options for patient with atrial fibrillation in New Zealand.
Your comments raise a number of questions:
Are the rates of intracranial haemorrhage over-represented in the New Oral Anti-Coagulant Trials (RE-LY, Rocket-AF
The intracranial haemorrhage rate is influenced by the characteristics of the group studied. Cohorts with a higher
prevalence of hypertension, previous TIA/stroke and those with higher average CHADS2 scores will be at increased risk
of intracranial haemorrhage.1 The concurrent use of aspirin was the most important modifiable independent
risk factor for intracranial haemorrhage in RE-LY.2
The Canadian review looked at a real-world population initiated on warfarin for atrial fibrillation, and followed
up for five years. The intracranial haemorrhage rate in this study was 0.4% per person year in the first 30 days and
0.2% over the subsequent five years.3 The two year RE-LY study had an intracranial haemorrhage rate of 0.23%
for dabigatran 110 mg, twice daily, 0.32% for 150 mg, twice daily and 0.76% for the matched warfarin arm.4 Individuals
enrolled in the RE-LY and Canadian studies had similar risk factors for intracranial haemorrhage (mean CHADS2 scores
of approximately 2 and similar rates of previous stroke and hypertension). However, participants in the RE-LY study
had nearly twice the rate of aspirin use which may account in part for the higher intracranial haemorrhage rate.
The Rocket- AF trial had a cohort that were much more “at risk” for intracranial haemorrhage. Past history of TIA
and stroke was 52% compared to 21.3% in the Canadian study, mean CHADS2 score was 3.48 as opposed to just over 2 and
an aspirin use was 29% as opposed to 20% in the Canadian study. The intracranial haemorrhage rate for the warfarin arm
in Rocket was 0.7%. The higher rate of intracranial haemorrhage can be, in part, explained by the different cohort characteristics.5
What are the benefits of dabigatran over well-managed warfarin, as represented by time in therapeutic range
For patients taking warfarin, the TTR also has an effect on intracranial haemorrhage rates.3 In RE-LY
the INR control was relatively poor (TTR – 64%).6 TTR was not evaluated in the Canadian AF warfarin study.
To analyse the effect of warfarin control on the end points of the study, RE-LY looked at two measures: the individual
time in therapeutic range (iTTR) and the mean time in therapeutic range for each study centre (cTTR).6
The table below illustrates the reduction in end point events with improving TTR for individual patients taking warfarin
in RE-LY. The greater the time in the therapeutic range, the better the outcomes.
AF Warfarin patients – Percentage Time in Therapeutic Range (iTTR)
Divided up in quartiles i.e. 25% of patients fell into following groups6
||< 53.6 %
||53.6 – 67.2 %
||67.2 – 78.4 %
||> 78.4 %
|Stroke and systemic embolic episodes
Irrespective of the centres quality of warfarin management (cTTR) the rate of intracranial bleeds was lower for both
doses of dabigatran than with warfarin, and this did not change even for centres that had a cTTR of > 72.6%. However,
dabigatran 150 mg was not superior to warfarin in reducing the risk of non-haemorrhagic stroke when the cTTR was > 72.6%.
Also, there were no advantages for dabigatran over warfarin for outcomes such as non-haemorrhagic events and mortality,
when cTTR for warfarin was >72.6%.6
These results show the importance of clinicians understanding the mean cTTR for all patients in their practice taking
warfarin, and calculating individual iTTRs when considering changing patients from warfarin to dabigatran.
What are the implications for clinicians making decisions on treatment options for individual patients?
From “The use of dabigatran in general practice”, BPJ 38 (Sep,
Patients with non-valvular atrial fibrillation who may benefit from dabigatran include those who:
- Require anticoagulation but are currently on no treatment, e.g. patients who have declined treatment with warfarin
or aspirin or those taking medicines that are contraindicated with warfarin
- Are already on warfarin but where there are difficulties with monitoring, e.g. difficult venous access, problems
with accessing lab facilities due to mobility issues, cost or lack of time, those who are non-compliant with monitoring
- Are already on warfarin but have INR values that are often sub-therapeutic or difficult to control
- Wish to change for convenience
Patients who may not benefit from dabigatran include those who:
- Are on warfarin with a stable (or easy to control) INR and who are comfortable with the need for INR monitoring.
- Patients on warfarin who have INR values that are consistently within the therapeutic range are less likely to
benefit from a switch to dabigatran.
- Are unlikely to be compliant with the twice daily dosing required for dabigatran
- Prefer to continue with warfarin (some patients may like the reassurance of periodic monitoring)
- Require blister packed medicines
Decision support tools for warfarin management
We agree with the correspondent that every effort should be made to improve TTR when warfarin is the preferred therapeutic
option for preventing thromboembolism in atrial fibrillation. Decision support has an important role in:
- Deciding to initiate oral anticoagulants over aspirin/clopidogrel in atrial fibrillation.
- Deciding when TTR for warfarin is insufficient to be comparable to dabigatran.
- Advising on warfarin dose and review periods to maintain cTTR above 72.6% at practices.
- Lip G, Andreotti F, Fauchier L, et al. Bleeding risk assessment and management in atrial fibrillation patients:
a position document from the European Heart Rhythm Association. Europace 2011;13(5):723-46.
- Hart R, Diener H, Yang S, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation
with warfarin or dabigatran: the RE-LY trial. Stroke 2012;43(6):1511-7.
- Gomes T, Mamdani M, Holbrook A, et al. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ
- Connolly S, Ezekowitz M, Yusef S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl
J Med 2009;361(12):1139-51.
- Singer D, Hellkamp A, Piccini J, et al. Impact of global geographic region on time in therapeutic range on warfarin
anticoagulant therapy: Data from the ROCKET AF clinical trial. J Am Heart Assoc 2013;2(1):e000067.
- Wallentin L, Yusef S, Ezekowitz M, et al. Efficacy and safety of dabigatran compared with warfarin at different
levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the
RE-LY trial. Lancet 2010;376(9745):975–83.