How do we figure out the “optimal dose” of a NOAC for our patients?

Goldhaber first outlined the advantages of currently used options. Warfarin has a long track record of excellent efficacy and it is cheap, and monitoring INRs allows adjusting the precise desired intensity of anticoagulation. Novel oral anticoagulants (NOACs) have rapid onset, show practically no drug-food interactions and few drug-drug interactions. They are used in fixed doses and do not require routine lab monitoring. Due to their short half-life, bridging is not needed around a procedure.

3 out of 4 pivotal trials evaluating NOACs for stroke prevention in atrial fibrillation, ROCKET, ARISTOTLE and ENGAGE, used a reduced dose for patients with renal dysfunction. Only one of the pivotal trials on NOACs

in venous thromboembolism (VTE), on the other hand, incorporated dose reduction in case of chronic kidney disease (HOKUSAI-VTE).

Dabigatran levels were measured in patients enrolled in the RE-LY trial. Dabigatran levels and bleeding correlated with clinical features. More bleeding was seen in the presence of lower renal function, older age, lower weight, female sex, use of aspirin and presence of DM.8 A steep dose-response curve was observed between dabigatran trough concentration at steady state and the probability of major bleeding. Octogenarians showed the steepest curve. The relationship between dabigatran trough concentration and probability of ischemic stroke shows a shallower curve, except for the first part reflecting very low dabigatran concentrations. Thus, there is discrepancy between the effect of dabigatran levels on the risk of

stroke and risk of bleeding complications.

*"Is giving a lower dose of NOAC underdosing or smart dosing?*

These observations imply that clinical features can be used to tailor the balance between stroke and bleeding

events, taking into account that the therapeutic window is steepest for bleedings, shallower for stroke, and nearly flat for ICH.

Considering the principle that first, a doctor should do noharm, the question may apply whether also patients with VTE and CKD should be treated with reduced NOAC doses. Giving a lower than licensed dose has become more popular for dosing of tissue plasminogen activator (TPA) to treat pulmonary embolism, based on the MOPETT study.9 Also other clinical situations, lower dosing appears to become more popular. The question that arises is whether giving a lower dose of NOAC is underdosing or smart dosing.

A study at Brigham and Women’s Hospital looked at 224 underdosed patients of whom 43% did not meet official criteria for NOAC dose reduction. Many patients would not have qualified for RCTs due to comorbidities.

The data showed that baseline characteristics such as renal dysfunction, history of bleeding and drug-drug interactions, or eGFR, did not explain the use of a lower dose.10 Thus, the data suggest that there is a whole range of other factors that influence NOAC dosing.

References

Disclosures

Samuel Z Goldhaber, MD – Director of Vascular Medicine & Director, Thrombosis Research Group and Professor of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA