Pharmacokinetics of new oral anticoagulants: implications for use in routine care

ABSTRACT

Introduction: Since 2008, new oral anticoagulants (NOACs) have been approved for the prevention of venous thromboembolism (VTE) in patients receiving hip or knee replacement surgery, prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), treatment of deep vein thrombosis (DVT), and pulmonary embolism (PE). Premarketing randomized clinical trials (RCTs) of NOACs demonstrated their non-inferiority in terms of efficacy vs. warfarin (traditional oral anticoagulant – TOA), with lower risk of serious adverse drug reactions, especially cerebral hemorrhages. In clinical practice, pharmacokinetic aspects of NOACs have to be carefully taken into account to optimize the benefit-risk profile of these drugs.

Areas covered: An overview of major issues related to pharmacokinetics of NOACs, such as drug–drug interactions, over- and underdosage in special populations (e.g. elderly, underweight, and chronic kidney disease patients), and impact on adherence and persistence to NOACs therapy and ultimately clinical outcomes in real-world setting, is provided.

Expert opinion: NOACs have been proven to be a better option than traditional anticoagulants due to better tolerability and ease of use. However, given specific pharmacokinetic characteristics, NOAC therapy has to be carefully tailored and monitored in relation to patient characteristics with the final goal of maximizing benefits and minimizing risks.

KEYWORDS:

• Adherence
• bleeding
• interactions
• new oral anticoagulants
• over- and underdosage
• persistence
• pharmacokinetics
• real-world evidence

Article highlights

• NOACs have a better safety profile than TAOs, as they can be administered in fixed daily doses and do not require periodic monitoring of the INR.

• All NOACs are both CYP450 and P-gp substrates; since many drugs are inducers or inhibitors of the cytochrome system and of this ATP-dependent drug efflux pump, their concomitant use is not reasonably recommended in NOAC users, due to a potential higher risk of bleeding or a reduction in anticoagulant effect.

• Failure to reduce the dose in patients with severe kidney disease may increase bleeding risk; however, dose reductions without a clear indication may decrease the effectiveness of stroke prevention in NVAF.

• In clinical practice, adherence and persistence to NOAC therapy are essential for preventing NVAF-related thromboembolic complications and for reducing the risk of stroke.

• Inappropriate NOAC under-treatment due to low dose is not uncommon in clinical practice, even without any clinical reason for such reduction.

• NOACs must be correctly prescribed, taking into account the patients’ clinical characteristics, in order to minimize any risks associated with these drugs.

This box summarizes key points contained in the article.

Declaration of interest

G Trifirò coordinates a pharmacoepidemiology research team at the University of Messina, which received in recent years research grants for projects funded by Amgen Inc, Novartis, IBSA, AstraZeneca, Daiichi-Sankyo also related to real world studies on NOAC. In addition, G Trifirò participated to advisory board on NOAC organized by Daiichi-Sankyo. G Andò declares his participation to advisory board, speakers’ honorarium and non-financial support from Bayer, advisory board and speakers’ honorarium from Daiichi-Sankyo, advisory Board from Pfizer-BMS, non-financial support from Boeringer-Ingelheim, speakers’ honorarium and non-financial support from Menarini, speakers’ honorarium from AstraZeneca. S Corrao declares his participation to advisory board from Bayer, Daiichi-Sankyo and Boeringer-Ingelheim and honorarium for educational activities from Pfizer-BMS. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The study received an unconditional grant from Daiichi-Sankyo, which did not play any role in the drafting of the manuscript and the decision to publish.