Novel anticoagulants for stroke prevention in atrial fibrillation: safety issues in the elderly

Abstract

Vitamin K antagonists (VKAs) are the most widely used anticoagulants for stroke prevention in patients with atrial fibrillation (AF). Recently, the US FDA approved three novel anticoagulants that work through inhibition of coagulation cascade independent of Vitamin K-dependent enzymatic reactions and, therefore, should have less food–drug interactions. Since AF is a disease of the aging heart, it is important to assess safety and efficacy of these new anticoagulants in elderly patients. We reviewed age-related changes in pharmacokinetics and pharmacodynamics observed with senescence and the effects of these changes on novel anticoagulants, known and anticipated drug and food interactions, and challenges related to bleeding complications and temporary discontinuation prior to surgery or interventional procedure. Although advantageous to VKA in age groups represented in trials, there are lack of data on VKA usage in older–elderly patients; additional research and post-marketing analysis in older–elderly patients are needed.

Keywords::

• atrial fibrillation
• apixaban
• bleeding
• dabigatran
• drug–drug interaction
• elderly • novel anticoagulants
• rivaroxaban
• stroke
• warfarin

Acknowledgements

The authors gratefully acknowledge J Grundle and K Klein for their editorial assistance.

Financial & competing interests disclosure

A Jahangir and M Mirza’s research effort was in part supported by the National Heart, Lung and Blood Institute grants (RO1 HL101240 and R01 HL089542). 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.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The epidemic of atrial fibrillation (AF) is growing with the aging of the population, increasing the risk of stroke and thromboembolism requiring intervention to reduce the rate of this devastating complication.

• Anticoagulant therapy is effective in reducing the risk of stroke in AF, but suffers from increased risk of bleeding and patient quality of life issues due to use of traditional anticoagulants with vitamin K antagonists (VKA). This is expected to be ameliorated with new anticoagulants that have fewer drug–drug and drug–food interactions.

• New anticoagulants demonstrate noninferior or superior efficacy and safety compared with warfarin in randomized clinical trials enrolling middle-aged and younger-elderly patients with AF; however, data supporting their efficacy and safety in older–elderly patients is limited.

• Concerns exist in the use of direct thrombin inhibitor and factor Xa inhibitors in the older–elderly with higher risk of bleeding, presence of impaired renal function and other aging-associated comorbidities and concomitant use of other drugs affecting transport and metabolism of new anticoagulants, thus increasing the risk of bleeding or reducing their efficacy.

• The lack of accurate tests to assess the level of anticoagulation is a serious limitation, particularly in conditions where the risk of bleeding is high or emergent situations, such as life-threatening bleeding or emergent surgery.

• The lack of a specific antidote that can rapidly and specifically reverse the anticoagulation and accomplish normal hemostasis without increasing thromboembolic complication is a major drawback that needs to be urgently addressed to allow safe use in the more vulnerable older–elderly population.

• Understanding the pharmacokinetics and pharmacodynamics of the new agents will help determine the optimal time for interruption and resumption before and after invasive procedures.

• Prescribing providers should be ready to guide patients in the event of inadvertent overdose of the new agents especially since routine drug-level monitoring is not readily available.

Notes