Physicians' Academy for Cardiovascular Education

Frequency and consequences of off-label dosing of NOACs

Literature - Steinberg BA et al., JACC 2016

Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II registry

 
Steinberg BA, Shrader P, Thomas L, et al.
J Am Coll Cardiol 2016; 68:2597604
 

Background

NOACs do not require routine laboratory monitoring, and they have been found to be at least as safe and effective as dose-adjusted warfarin, for stroke prevention in patients with non-valvular AF [1].
Each NOAC is approved at a specific dose, with adjustments based on age, renal function or concomitant medications [2-5], but there are concerns whether there is adherence to these dose recommendations.
In this analysis of the ORBIT-AF II study, the frequency of NOACs off-label dosing was evaluated, factors associated with under- and overdosing of NOACs were identified, and the clinical outcomes of patients receiving under- and overdosing of NOACs were assessed.
 

Main results

Percentages of off-label NOACs dosing:
  • 9.4% of patients were receiving doses lower than the recommended
  • 3.4% of patients were receiving doses higher than the recommended
Compared to patients who received the recommended NOACs doses, patients who received under- or overdoses of NOACs were:  
  • significantly older (median 79 and 80 years of age vs. 70 years of age, respectively; P < 0.0001)
  • more likely female (48% and 67% vs. 40%, respectively; P < 0.0001)
  • more likely to have a CHA2DS2-VASc score ≥ 2 (96% and 97% vs. 86%, respectively; P < 0.0001)
  • more likely to have high (≥ 4) ORBIT bleeding scores (25% and 31% vs. 11%, respectively; P < 0.0001).
Specific NOACs:
  • Dabigatran: patients with an estimated CrCl of 30 to 50 ml/min had the highest rates of off-label dosages, with 23% under-dosed
  • Rivaroxaban: patients with a CrCl of 15 to 50 ml/min had the highest rates of off-label dosages, with 34% over-dosed
  • Apixaban: 32% undergoing haemodialysis were receiving off-label doses.  
The rates of adverse events were higher in under- and overdosed patients than in those receiving the indicated NOAC dose:
  • overdosing was significantly associated with increased risk of all-cause mortality (adjusted HR: 1.91; 95% CI: 1.02 - 3.60)
  • underdosing was significantly associated with increased risk of CV hospitalisation (adjusted HR: 1.26; 95% CI: 1.07 - 1.50; P = 0.007)

Conclusion

Many AF patients on NOAC therapy do not receive recommended doses for stroke prevention, and are at increased risk for CV hospitalisation and all-cause mortality.
 

Editorial comment [6]

In their editorial article, Witt and Hansen note that the results of the Steinberg et al analysis ‘underestimate the true magnitude of non-approved NOAC doses in real-world clinical practice and represent an important warning to clinicians prescribing NOACs.’
Moreover, they challenge the notion of NOACs being easier to use compared with warfarin because ‘NOACs have introduced a new set of unanticipated problems into anticoagulation therapy management, the need for renal function monitoring, dose adjustments in renal dysfunction, drug interaction management without the ability to monitor coagulation status, and so forth. Six years after NOACs hit the market, health systems are still struggling with how best to manage NOAC therapy and whether specialized anticoagulation services should monitor patients receiving NOACs in addition to those receiving warfarin therapy.’
They outline the need for a quality metric for patients receiving NOACs, and they conclude: ‘Whatever the reason for failing to follow approved dose recommendations, the results of the study by Steinberg et al provide important evidence indicating that clinicians prescribing NOACs should ensure that doses are consistent with approved product labeling.’
 
Find this article online at JACC
 

References

1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955–62.
2. Connolly SJ, Ezekowitz MD, Yusuf S, et al., for the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51.
3. Granger CB, Alexander JH, McMurray JJV, et al., for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92.
4. Patel MR, Mahaffey KW, Garg J, et al., for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.
5. Giugliano RP, Ruff CT, Braunwald E, et al., for the ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104.
6. Witt DM, Hansen AL. Non-vitamin K anticoagulant dose selection: it's best to read and follow the directions. J Am Coll Cardiol 2016;68:2605-7.