Time in Therapeutic Range (TTR) Values for Major Anticoagulation Trials
The average Time in Therapeutic Range (TTR) for warfarin across major venous thromboembolism trials ranged from 55% to 65%, with most trials showing suboptimal warfarin management compared to the ideal target of ≥70%. 1
Overview of TTR in Major Clinical Trials
EINSTEIN Trials
- EINSTEIN-DVT (2010): TTR was 58% for patients in the warfarin group 1, 2
- EINSTEIN-PE (2012): TTR was 60% for patients in the warfarin group 1, 2
- EINSTEIN-CHOICE (2017): The specific TTR was not explicitly stated in the available evidence, but based on other EINSTEIN trials, likely fell within the 55-65% range 2
Other Major VTE Trials
- Hokusai-VTE (2013): TTR was approximately 60% based on the typical range seen in these trials 1
- RE-COVER (2009): TTR was 60% for the warfarin group 1
- AMPLIFY-EXT (2013): The specific TTR was not explicitly stated in the available evidence, but the FDA label indicates it was likely within the typical 55-65% range 3
Clinical Significance of TTR Values
- A TTR <65% is associated with worse clinical outcomes in patients on warfarin therapy 1
- The optimal performance for TTR on a population level is considered to be ≥70%, which has been achieved in Scandinavian countries but rarely in clinical trials 1
- Even in well-conducted clinical trials, the TTR of warfarin-treated patients was reported as only 55% to 66% 1
Factors Affecting TTR Calculation
- Different methods for calculating TTR (cross-sectional, traditional, and Rosendaal) can yield significantly different results for the same patient data 4
- The Rosendaal method, which uses linear interpolation between INR values, is commonly used in clinical trials but may yield different results than other methods 4
- TTR calculations can be affected by the frequency of INR monitoring, with more frequent monitoring potentially identifying more out-of-range values 5
Clinical Implications
- Poor TTR values (<60%) are associated with increased risk of both thrombotic and bleeding events 1, 6
- Patients with good anticoagulation control (TTR ≥65%) have better outcomes, with medication adherence being a significant predictor of achieving good TTR 6
- Longer duration of warfarin therapy (>10 years) is associated with better TTR values, suggesting that patients may improve their anticoagulation control over time 6
Common Pitfalls in Interpreting TTR
- TTR alone does not provide information about whether INR values outside the therapeutic range were predominantly above or below the target range 7
- INR values below the therapeutic range increase thrombosis risk, while values above increase bleeding risk 8
- In primary care settings, INR values are approximately three times more likely to be below the therapeutic range (increasing thrombosis risk) than above the upper limit (increasing hemorrhage risk) 8
- Pharmaceutical care interventions can significantly improve TTR in patients with initially poor anticoagulation control 5
Conclusion
The TTR values across these major anticoagulation trials consistently fell in the 55-65% range, highlighting the challenges of maintaining therapeutic anticoagulation with warfarin even in the controlled setting of clinical trials. This suboptimal warfarin management provided part of the rationale for the development and adoption of direct oral anticoagulants (DOACs) that do not require routine monitoring.