Direct oral anticoagulants (DOACs) are the medications used in the prevention of thrombosis in several cardiovascular contexts viz. in the treatment and prevention of blood clots in veins, and for the prevention of stroke and embolism in people with atrial fibrillation.

DOACs are direct factor Xa (activated factor X) inhibitors which included apixaban (Eliquis and generic brands), edoxaban (Lixiana and Roteas), and rivaroxaban (Xarelto and generic brands) as well as the direct thrombin inhibitor, dabigatran etexilate (Pradaxa).

Health Authority:

Ireland – HPRA drug safety newsletter & Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA).

Risk of serious hemorrhages (bleeding reactions) after the use of DOAC is quite expected owing to their mechanism of action. In order to minimize the expected side effects of undesirable hemorrhagic reactions, product label documents are equipped with importance information for warnings, contraindications, dosage recommendations based on population group etc., for the safe & effective usage of these medicines.

EMA conducted a retrospective, non-interventional study using real-world data from Denmark, France, Germany, Spain, the Netherlands and the United Kingdom for assessing the risk of major bleeding associated with the use of DOACs when compared to vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation, and to identify significant non-adherence to recommendations from product information documents during the usage of these medicines in clinical practice. Based on the data produced from the study EMA stated that the benefit-risk balance remains positive for all three DOACs investigated (apixaban, dabigatran, rivaroxaban) within the authorized indications.

There was an observation of increased risk of bleeding for dabigatran and rivaroxaban in older patients (>75 years), however, the data were not sufficient at this time to recommend additional dosage changes in this population, and further evaluations by the license holders were requested in this regard.

Important note for Healthcare professionals (HCP):

Adherence: Please refer the reference safety information (Product labels) before prescribing, dispensing, administering the DOAC class of medicines for effective implementation of risk minimization measures.

Individual Benefit-risk ratio: HCPs are advised to consider these class of medicines ONLY when there is favorable benefit-risk ratio in the context of individual patient’s current medical condition, usage of concomitant medications, viz after consideration of all risk factors (described below), contraindications, warnings & feasibility of recommendations implementations for the safe & effective usage of these medicines.

Transparency: Please discuss both the risk & benefits with patients/care providers and advise for close monitoring of any signs/symptoms of bleeding for early reporting and early implementations of actions for a better patient safety and public health.

The key recommendations summarized below to reduce the known risk of hemorrhage reactions from the usage of DOACs class of medications are described below.

1. Contraindication : DOACs use are not favourable for patients who are concurrently using their anticoagulants such as unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin).
2. Caution: Advised to be more cautious and consider IBR analysis (described above), if patients are treated concomitantly with selective serotonin reuptake inhibitors (SSRIs) or serotonin noradrenaline reuptake inhibitors (SNRIs), or non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid,
3. Dose reduction: Please note that P-glycoprotein (P-gp) inhibitors (like amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole) has the potential for increasing circulating levels of DOACs. Hence, consider reducing the dose of DOACs in patients with concomitant use of drugs with potential for P-gp inhibition.
4. Usage in special population: below patients were considered special with existing risk factors for more severe bleeding reactions.

• Elder patients (>75 years)
• Patients with impairment in renal & hepatic functions
• Patient with low body weight (<60 kg)
• Patients with gastritis, oesophagitis or gastroesophageal reflux

Important note for Public (Patients/patient care providers):

Patients with the conditions of non-valvular atrial fibrillation, deep vein thrombosis and pulmonary embolism, please be aware of serious bleeding risks associated with the use of apixaban (Eliquis), edoxaban (Lixiana and Roteas), rivaroxaban (Xarelto), and dabigatran etexilate (Pradaxa).

Please discuss with your respective doctor or healthcare professional with the below information

• Medical conditions (Past & concurrent)
• Medicine usage details (Past & concurrent)
• Age, Body weight, specific allergies, other risk factors which are discussed above

This facilitates the effective assessment of benefit-risk ratio and identification of suitability of the medicine for use/or looking for alternative medicine with the favorable benefit risk ratio.

Be conscious of bleeding signs and symptoms and inform your respective healthcare professional or report to your national ADR reporting system.

Voluntary ADR reporting:

Every medicinal product has both benefits and risks. Medicines are authorized to market based on the favorable benefit-risk profile anticipated at the time of regulatory approval/entry into market. However, the safety profile of medicine would continuously updates owing to safety data from the post marketing experience from public. If the rate of reporting of suspected adverse drug reactions (ADR) from public is line with the actual occurrence of ADRs, the time lapse for taking regulatory action can be reduced and thereby improving patient safety.

All health care professionals and consumers of pharmaceutical medicinal products are encouraged to be aware of this fact and observe/monitor for any possible adverse events, reactions, medication errors, or quality complaints of medicinal products and report the same to your respective national health authority.

This would accumulate safety evidence for medicinal products which in turn help health authorities to take regulatory actions at the earliest possibility for a better patient safety and overall public health.