NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.
Akshay Amaraneni ; Venu Chippa ; Andrew C. Rettew .
Last Update: April 17, 2023 .
One class of drugs that has been implicated in serious adverse drug reactions for many decades is oral anticoagulants, especially warfarin. There are countless case reports indicating the use of oral anticoagulants is more likely to require hospital admission, and prolonged hospital stays from adverse events such as bleeding. Oral anticoagulants have been classified as high alert medications according to the Institute of Safe Medication Practices (ISMP) because they have the potential for harm when used clinically. This activity reviews anticoagulation safety and highlights the role of the interprofessional team in managing patients who need anticoagulants
Identify the etiology of anticoagulation related bleeding. Describe the differences between warfarin and novel oral anticoagulants. Identify the treatment and management options available for anticoagulation associated bleeding.Discuss how the interprofessional team can invoke strategies for improving the evaluation and management of patients with anticoagulation related bleeding.
One class of drugs that has been implicated in serious adverse drug reactions for many decades is oral anticoagulants, especially warfarin. There are countless case reports indicating the use of oral anticoagulants is more likely to require hospital admission, and prolonged hospital stays from adverse events such as bleeding.
Oral anticoagulants have been classified as high alert medications according to the Institute of Safe Medication Practices (ISMP) because they have the potential for harm when used clinically. Many reports have appeared on the risk of bleeding when the anticoagulants are used concurrently with other similar agents (antiplatelet drugs), when the drug treatment is duplicated, in the presence of dosing errors, when there is accidental discontinuation of treatment and when there are problems with monitoring.
Unlike warfarin, the newer oral anticoagulants do not have a long track record in clinical medicine and hence, it is too soon to claim that they are safer. In any case, proactive measures and targeted education should be encouraged to prevent adverse effects associated with the newer anticoagulants. More importantly, the Joint Commission has designated cautious use of an oral anticoagulant as part of the National Patient Safety Goals (NQF).[1][2][3]
How serious is the problem with oral anticoagulants?
From published studies, the incidence of major bleeding in patients treated with warfarin ranges from 0.4% to 7.2% per year. Minor bleeding rates have been found to be high as 15% per year. This wide range in bleeding inside is primarily due to patient-specific comorbid factors. To be consistent in reporting, however, most clinicians define major bleeding as bleeding that required admission, a fatal hemorrhage, bleeding at a critical site like the brain or retroperitoneum, or bleeding that requires transfusion of at least 2 units of packed red blood cells. A major bleed is associated with a several-fold increase in death for up to 12 months following the incident.[4][5]
Many studies have shown that the risk of bleeding is increased in patients treated with warfarin. This risk of bleeding in patients treated with atrial fibrillation has been calculated to be about 0.3-0.5% per year and is often associated with intracranial bleeding, which is a major cause of disability and death.
Patients with deep vein thrombosis who are treated with warfarin appear to have a higher risk for bleeding than those treated for atrial fibrillation. This is thought to be due to the concomitant comorbid conditions in these patients. The risk of bleeding in venous thrombosis has been calculated to be about 1.31 per 100 person-years, with a case fatality rate of 13.4 %.[6]
Even though intracranial hemorrhage is devastating, it is not the most common site of bleeding following the use of oral anticoagulants; the most common site is the gastrointestinal tract. However, the mortality associated with an intracranial bleed is 50%, compared with 5.1% with gastrointestinal tract bleeding.
The association between venous thrombosis and malignancy is well established. Many studies report a high incidence of both minor and major bleeding in patients with cancer who are treated with oral anticoagulants. There appears to be greater fluctuation in the INR in these patients, which could be due to the comorbidity and/or concomitant medications.
In one large retrospective 5-year study, nearly 48.8% of adverse drug events that involved anticoagulation were due to medication errors. In the same study, the 30-day mortality was increased by 11% of patients who experienced an adverse drug effect due to the anticoagulation drug. Other studies have revealed that emergency hospitalization as a result of bleeding due to warfarin is common. Data on the long-term safety of the newly available oral anticoagulation are very limited or not available. Thus, it is obvious that most of the data on the newer anticoagulants will reflect fewer adverse events or appear positive.
Prior to 2010, warfarin was the only approved oral anticoagulant on the market but since then several newer oral anticoagulants have been introduced like dabigatran, apixaban, edoxaban, and rivaroxaban. Warfarin acts by altering the clotting factors 2,7,9,10 and protein C and S. Comparatively, the target-specific oral anticoagulants except for dabigatran work by inhibiting activation of platelets and fibrin clot formation by reversible inhibition of factor Xa. On the other hand, dabigatran works by reversibly inhibiting thrombin which results in decreased thrombin-mediated platelet aggregation.[7]
What are the differences between warfarin and the newer oral anticoagulants?
One of the major differences between warfarin and the target-specific oral anticoagulants is that the latter cannot be monitored using the INR or other blood coagulation tests. In addition, these agents also do not require modification in diet. Cost is also a factor; the newer oral anticoagulants are prohibitively expensive compared to warfarin. So far these newer oral anticoagulants have shown to be safe, but long-term data are lacking. Another important fact is that most healthcare workers who prescribe these oral anticoagulants have little idea on how to deal with them when a patient who is booked for surgery suffers trauma or has a sudden bleeding emergency. Unlike warfarin which can be reversed with plasma or vitamin K, the factor X inhibitors or direct thrombin inhibitors have reversal agents that are more expensive and less readily available.[4][8][7]
Another difference between warfarin and the newer oral anticoagulants is the time to reach peak therapeutic effect. Warfarin often takes 4-6 days to reach the peak effects, but the newer oral anticoagulants have peak therapeutic effects in less than 24 hours. However, one area of similarity between the two classes of drugs is that they both have the potential for significant drug interactions.
Finally, after dosing with warfarin, monitoring can also be affected by the diet. Foods that contain vitamin K like kale and spinach can delay the peak therapeutic effect. On the other hand, the target-specific oral anticoagulants are highly protein-bound and this makes it difficult to remove them even with dialysis.
Where do most adverse events regarding anticoagulants occur?
