Pull the plug on NOACs? Not so fast

We were disappointed to read Dr Trusler’s article regarding novel oral anticoagulants (NOACs) for prevention of stroke in nonvalvular atrial fibrillation.[1]

We absolutely acknowledge some nonvalvular atrial fibrillation patients are well served by warfarin: their INRs remain stable, thus risk of stroke is reduced by two-thirds. However, for many, monitoring is poorly tolerated, or INRs are labile. The risks of even small INR deviations are profound: compared with an INR of 2-2.5, risk of embolism increases nearly fourfold at an INR of 1.4-1.7; risk of intracerebral hemorrhage (ICH) increases similarly at 3.6-4.5.[2]

Even in the controlled environment of clinical trials, where INR is regularly monitored, time in therapeutic range rarely broaches 70%. Times in therapeutic range for RE-LY and ENGAGE are representative of large clinical trials of warfarin for stroke prevention, not merely NOAC trials (Table). Incidentally, that time in therapeutic range was 71% in Canadian RE-LY data as compared to 64% overall is not a point of pride or evidence that the system “works”: Even though INR is optimized in this context, nearly one-third of patient-time remained outside therapeutic range.

In addition to their ease of use as compared with warfarin, with lack of monitoring or constant dose adjustments and fewer drug interactions, the chief appeal of the NOACs is their decreased risk of anticoagulant-associated ICH (risk reduction of 49% in a recent meta-analysis),[3] a devastating potential complication. Even despite reversal of laboratory coagulation parameters, patients with warfarin-associated ICH experience higher rates of morbidity and mortality than patients with spontaneous ICH.[4] The “prolonged and expensive resuscitations for bleeding complications” invoked by Dr Trusler apply to all anticoagulant-associated hemorrhages, not just those from NOACs.

Though Dr Trusler quotes one observational study using retrospective administrative data to show that rates of intracranial hemorrhage in the NOAC trials do not reflect the Canadian experience, this is a spurious comparison.[5] The accuracy of that method of data collection is inferior to that of clinical trials and one cannot meaningfully compare these different populations.

NOACs have provided clinicians and patients with a new armament against the ever-increasing burden of nonvalvular atrial fibrillation and its risk of stroke.
—Thalia S. Field, MD 
—Samuel Yip, MD
On behalf of the Vancouver Stroke Program, Vancouver General Hospital

Competing interests
Drs Field and Yip have an unrestricted research grant from Boehringer Ingelheim. This letter was submitted to the BC Medical Journal prior to receiving the grant. Dr Yip receives speaker honoraria from Boehringer Ingleheim, Pfizer, BMS, Servier, and Bayer.

References

1.    Trussler M. It’s time to pull the plug on the new oral anticoagulants for nonvalvular atrial fibrillation. BCMJ 2014;56:391-394.
2.    Singer DE, Chang Y, Fang MC, et al. Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: The ATRIA study. Circ Cardiovasc Qual Outcomes 2009;2:297-304.
3.    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;383:955-962.
4.    Dowlatshahi D, Butcher KS, Asdaghi N, et al. Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke 2012;43:1812-1817.
5.    Gomes T, Mamdani MM, Holbrook AM, et al. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ 2013;185:E121-127.