Oral anticoagulants play a crucial role in preventing and treating venous thromboembolism and reducing the risk of strokes in patients with atrial fibrillation. The two main types of anticoagulants in use today are warfarin and direct oral anticoagulants (DOACs). Over time, the prescription of warfarin has declined as the use of DOACs has risen, leading to a significant overall increase in anticoagulant prescriptions. In the United States, prescriptions have grown by 54%, while in the United Kingdom, they have increased by 71%. In England alone, as of 2019, warfarin was prescribed at a rate of 170 per 1000 residents, while DOACs were prescribed at a rate of 231 per 1000 residents.
Warfarin has been used for decades and requires careful monitoring due to its interactions with numerous medications, foods, and physiological conditions. Patients on warfarin require frequent blood tests to measure the International Normalised Ratio (INR), which indicates how effectively the blood is clotting. Maintaining a therapeutic INR is essential because deviations can result in excessive bleeding or inadequate anticoagulation, which increases the risk of thrombotic events.
DOACs, on the other hand, offer a more predictable response with fewer interactions and do not require routine INR monitoring. These medications have simplified anticoagulation therapy, making it more convenient for patients. However, despite their advantages, DOACs still present risks, particularly concerning bleeding complications, and their effects may be influenced by concurrent illnesses and other medications.
Risks Associated with Anticoagulants
While anticoagulants are effective in preventing thromboembolic events, they come with notable risks, primarily related to bleeding. Both warfarin and DOACs can lead to gastrointestinal and intracranial bleeding. Warfarin, in particular, is known for its significant interactions with certain antibiotics, including macrolides and fluoroquinolones, which can elevate bleeding risks. Though DOACs offer fewer drug-drug interactions and provide a more predictable response, they still pose bleeding concerns, especially when used alongside macrolide antibiotics. However, the extent to which bleeding is caused by the interaction between anticoagulants and antibiotics versus the underlying infection itself remains uncertain.
Bleeding risks are influenced by various factors, including the patient’s age, kidney function, liver function, and the presence of other medical conditions such as hypertension or gastrointestinal ulcers. Patients who are older or have chronic kidney disease are at a higher risk of experiencing major bleeding events. Additionally, alcohol consumption and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) can further increase bleeding risks.
Clinicians must weigh the benefits and risks of anticoagulant therapy for each individual, considering their medical history and concurrent medications. This process is particularly important when patients develop acute illnesses such as infections, which can affect anticoagulant metabolism and increase bleeding risks.
Respiratory Tract Infections in Bleeding Risks
A study was conducted to explore the link between community-acquired respiratory tract infections (RTIs) and bleeding in users of oral anticoagulants. Using a self-controlled case series study design, researchers analysed data from 1208 anticoagulant users. The findings demonstrated that within the 0-14 day period following an untreated RTI, there was more than a two-fold increase in both major bleeding and clinically relevant non-major bleeding (CRNMB). The peak risk periods varied, with CRNMB occurring between 0-5 days and major bleeding peaking between 11-15 days. Interestingly, when both treated and untreated RTIs were considered, a slight reduction in bleeding risk was observed.
The study suggests that infections themselves, rather than antibiotics, may be a significant factor in increasing bleeding risks. The physiological response to infections, including fever, inflammation, and metabolic changes, may alter the metabolism of anticoagulants. Additionally, dehydration and reduced food intake during illness may impact drug levels, further complicating anticoagulation management.
Strengths and Limitations
The study’s design provided several strengths. The self-controlled case series approach helped minimise confounding by comparing risk periods within the same individuals. Adjustments were made for essential time-varying factors such as age, year, and seasonal influences. Additionally, linked hospital data were utilised to ensure comprehensive documentation of bleeding events. With a larger sample size than previous studies, the findings produced more precise estimates.
However, the study also had limitations. It lacked sufficient power to detect risks beyond 14 days and may have been affected by residual confounding, particularly from the use of over-the-counter medications such as NSAIDs and paracetamol during RTIs. Additionally, RTI cases were identified through general practice records, potentially omitting unreported cases or consultations outside regular hours. Adherence to anticoagulant prescriptions was also challenging to measure. Another possible bias could stem from clinician interventions, such as increased INR monitoring in warfarin users during infections, which might have influenced the findings.
Comparison with Previous Research
Prior studies have shown that acute infections can elevate INR levels in warfarin users, though most of these studies were limited by small sample sizes. A retrospective cohort study previously demonstrated that INR values exceeding 5 were more frequent in warfarin users with both treated and untreated RTIs. The current study builds upon these findings by focusing on bleeding outcomes rather than solely INR elevation and by including DOAC users, providing a more comprehensive understanding of the risks associated with anticoagulant use during infections.
The findings align with previous research suggesting that acute illnesses can disrupt anticoagulant metabolism. Fever, inflammation, and changes in hepatic function during infections may alter drug clearance, leading to fluctuations in anticoagulant levels. Understanding these mechanisms is essential for developing strategies to mitigate bleeding risks in anticoagulant users during acute illnesses.
Clinical and Policy Implications
Despite the growing evidence linking infections with anticoagulant-related bleeding risks, current clinical guidelines lack detailed recommendations on how to manage anticoagulants during acute illnesses. The National Institute for Health and Care Excellence (NICE) guidelines recognise that warfarin effects may be heightened during acute illness, but no equivalent guidance exists for DOACs. The study’s findings suggest that infection itself may contribute to bleeding risk, independent of interactions with antibiotics.
Potential clinical responses could include increased INR monitoring for warfarin users during infections and the development of specific guidance on DOAC use in such situations. Further research is needed to better understand how clinicians and patients manage anticoagulants during infections and to refine guidelines for safer anticoagulant use.
Patients taking anticoagulants should be educated on the potential risks associated with infections and should be advised to seek medical advice if they develop symptoms suggestive of an infection. Clinicians should consider closer monitoring of anticoagulant levels and bleeding symptoms during periods of acute illness.
Future Research
To build on these findings, larger studies are necessary to confirm risks beyond the 14-day period and to explore potential interactions with over-the-counter medications. Further research should also investigate how patient and clinician behaviours influence anticoagulant management during infections. Additionally, qualitative research may provide insights into awareness and decision-making regarding bleeding risks associated with anticoagulant use. Also, these efforts could contribute to the development of comprehensive guidelines for managing oral anticoagulants during acute illnesses, improving patient safety and clinical outcomes.
Future studies should also explore the role of inflammation and immune response in altering anticoagulant metabolism. Understanding these pathways could lead to targeted interventions that minimise bleeding risks while ensuring effective anticoagulation during infections. Additionally, assessing the impact of different types of infections on anticoagulation therapy could provide a more nuanced understanding of how infections influence bleeding risks.
Reference
Ahmed, H., Whitaker, H., Farewell, D., Hippisley-Cox, J., & Noble, S. (2021). Respiratory tract infection and risk of bleeding in oral anticoagulant users: self-controlled case series. BMJ (Clinical Research Ed.), 375, e068037. https://doi.org/10.1136/bmj-2021-068037
Panneerselvam, S., Baglin, C., Lefort, W., & Baglin, T. (1998). Analysis of risk factors for over-anticoagulation in patients receiving long-term warfarin. Br J Haematol, 103, 422–424. https://doi.org/10.1046/j.13652141.1998.00988.x
Clark, N. P., Delate, T., & Riggs, C. S. (2014). Warfarin-Associated Research Projects and Other Endeavors Consortium. Warfarin interactions with antibiotics in the ambulatory care setting. JAMA Intern Med, 174, 409–416. https://doi.org/10.1001/jamainternmed.2013.13957