Monitoring OAC Therapy
Vitamin K antagonists (VKAs) are the most widely used oral anticoagulants. Despite certain limitations, VKAs have a vast clinical experience in addition to the published evidence which has proven its efficacy, and thus, they remain the mainstay of oral anticoagulant (OAC) therapy.78
Why Monitoring VKA Therapy is Necessary?
Many factors interfere with VKA uptake and metabolism by the liver, including food, other medications and comorbidities. A fixed low-dose regimen of VKAs is not very beneficial. Wide range of inter- and intra-patient variations in the dose requirement of VKAs that warrants the need of individualized dosage regimens to the desired international normalized ratio (INR) level. Thus, the primary objectives of monitoring VKA therapy are to help in deciding the initial VKA dose and the maintenance doses on the basis of level of anticoagulation.
Apart from assisting in deciding the appropriate dosage regimen, monitoring helps in avoiding overcoagulation. With the help of routine monitoring, such dangerous situations can be detected well in time allowing dose adjustment, as well as actions taken to prevent recurrence of such situations.78
How is VKA Therapy Monitored?
The prothrombin time (PT) test is the most common test used to monitor VKA therapy. It is expressed as INR. The PT signifies the reduction of three pro-coagulant clotting factors (i.e., II, VII, X) out of the four vitamin K-dependent clotting factors that are reduced by warfarin at a rate proportional to their respective half-lives. Thus, it would be safe to state that during the first few days of VKA therapy, the PT reflects mainly a reduction of factor VII during the half-life (approx. 6 h). Consequently, the reduction of factors X and II contributes to prolongation of the PT.
The time within the therapeutic range (TTR) is a good overall measure of the quality of antithrombotic treatment with VKAs. Wide variations in TTR have been observed. A country-wise analysis of Randomized Evaluation of Long-Term Anticoagulation Therapy (RELY) study data revealed that average TTR, excluding first week of treatment, varied from 44% in Taiwan to 77% in Sweden. Even a good level of TTR, such as nearly 75% in the Netherlands, suggests that INR values are either too low or too high in 25% of the time while anticoagulant therapy is continued.
For achieving appropriate laboratory control, patients need to have their blood withdrawn about 20 times a year, which poses a significant burden.78 Thus, TTR provides a clearer picture of the quality of anticoagulation, guiding the clinicians to take appropriate steps to achieve better TTRs to balance the benefit–risk ratios.
Before initiating VKA therapy, the baseline INR should be determined and initial dose of VKAs should be administered. It is recommended that during the initiation phase, INR should be monitored every 2-4 days, until INR is in the target therapeutic range for two consecutive values. Once stabilized, INR should be monitored weekly. The interval can be gradually increased up to every 4 weeks if the INR remains stable and within therapeutic range.79
In the 9th edition of evidence‐based management of anticoagulant therapy, American College of Chest Physicians (ACCP) recommends that rather than 4-week monitoring, the patients with consistently stable INRs can be monitored after every 12 weeks.77
Whenever a new drug is being initiated, there is a risk of drug interaction. Thus, monitoring frequency should be increased with any substitution, deletion, or addition of any drug as a concomitant therapy during oral anticoagulation.
Self-Management of VKA Therapy
Self-management of VKA therapy is increasingly becoming popular, as it reduces patients’ inconvenience of visiting an outdoor anticoagulation clinic frequently for international normalized ratio (INR) testing. It positively influences the quality of life, as well as the therapeutic range (TTR), particularly in patients on long-term anticoagulant treatment.78 The Home INR Study (THINRS) reported that weekly home-based INR monitoring is as safe as clinical monitoring. Time in therapeutic INR range was significantly increased (7%) along with patient satisfaction with the anticoagulation therapy. Patients should be trained properly and competence in using home-based INR testing should be ensured.80
A recent pilot study on the impact of a novel patient self-management program on management of VKA therapy was conducted for 3 months. The study enrolled 44 patients with atrial fibrillation, who were on long-term anticoagulation therapy. The patients acted as their own controls; after 3 months of initial monitoring anticoagulation at outdoor clinics, self-testing program was introduced for the next 3 months.
The outcomes measured included TTR, number of INR tests performed, and episodes of major bleeding or thrombosis. No differences in the TTR were observed. The number of INR tests increased from 2.97, before the implementation of self-management program, to 4.38, during the self-management. The study concluded that self-management of VKA therapy was as effective as the outdoor INR testing, thus reducing the patient inconvenience to a significant extent.81
American College of Chest Physicians recommends the practice of self-management of patients over outdoor INR monitoring, in patients who are motivated, and can demonstrate competency in self-management strategies.80
Managing Under- or Overcoagulation With VKAs
Several measures can be taken to improve the therapeutic range (TTR) in patients on VKA therapy. These include78:
- Reminding the clinician to check if patient has problems that may hamper adequate medication intake (poor cognitive function, lack of social network, treatment of comorbid conditions, etc.)
- Supervision of medication intake, involving nurse, family or neighbors. Such a scenario is often encountered in anticoagulation clinics, as in about 40% of the cases, elderly population, due to comorbidities, need blood samples taken at home.
Management of Bleeding With VKAs
The prominent feature of anticoagulant overdose is bleeding, which may be manifested as nasal bleeds, hematemesis, hemoptysis, gastrointestinal bleeding, vaginal bleeding, hematuria, cutaneous hemorrhages, gingival bleeding, hematomata, bleeding into joints or menorrhagia. In case of bleeding with VKAs, following precautions should be taken.82
Reduce international normalized ratio (INR) to a safe level (<5) if excessive increase in prothrombin time and/or INR occur without bleeding or prospective surgery.
In case of serious bleeding, reduce INR to 1 as soon as possible.
In case of elective or urgent surgery, reduce INR to 1—1.5 at the time of surgery.
Temporary reduction in INR can be done by withdrawing anticoagulant therapy, and oral or parenteral vitamin K administration.
In case of moderate bleeding, vitamin K1 2–5 mg should be given orally.
In case of severe bleeding, vitamin K1 5–10 mg should be injected intravenously very slowly (at a rate <1 mg/min). Additional doses (up to a maximum of 40 mg daily) should be given at 4‐hour intervals.
In case of serious overdose or life‐threatening bleeding, immediate restoration of clotting factors can be achieved by transfusion of fresh frozen plasma or whole blood or prothrombin (factor IX) complex concentrate, along with vitamin K.
Initiating Anticoagulant Therapy After ICH
Intracranial hemorrhage (ICH) is the most feared and fatal complications of OAC. Once occurred, it is not certain how long after symptom onset the risk of ongoing bleeding continues. Clearly, the risk is high on the first day, but small after the first few days. The European Stroke Initiative recommends that patients with a strong indication for anticoagulation, such as a history of embolic stroke with atrial fibrillation, should be restarted on VKAs after 10 to 14 days, depending on the risk of thromboembolism and ICH recurrence.83
The American Heart Association suggests that, in patients with a very high risk of thromboembolism for whom restarting VKA is considered, it may be restarted 7 to 10 days after ICH onset.83
The rise in gastrointestinal bleeding with novel agents is a cause of concern, particularly in elderly population. In the absence of a specific antidote to reverse their effect, management of life‐threatening bleeding episodes is difficult.84 The only reversal option for direct thrombin inhibitors is fresh frozen plasma, or factor Xa concentrate, but it requires hospitalization and increases the cost.84 Also, the perioperative reversal and bridging of anticoagulation with the novel agents are not yet determined. Some may argue that shorter half-lives of the novel anticoagulants are helpful, but even that is applicable only in nonurgent situations. In case of emergencies, there is no established therapeutic procedure.84
It has been now well-recognized that the absence of proper laboratory tests as well as the lack of antidotes is a major limitation in the safe introduction of newer oral anticoagulants (NOACs). The best laboratory assays on a 24-hour basis should be made available to facilitate optimal drug management in emergency conditions such as an urgent surgery.78
A suitable point-of-care test is available in a few countries, but rest of the world is still not ready. Several steps can be taken towards a better management of anticoagulant therapy, of which a few are as follows.78
A general shift towards thrombosis care, aiming to provide good quality management of patients with thrombosis, should be initiated. Such a strategy will encompass describing and organizing the entire chain of care. Optimal communications such as protocols, based on guidelines, are crucial in situations such as perioperative management of anticoagulation.
Pharmaceutical companies should provide all the relevant data on drug levels and coagulation test responses, which may help when to expect over- and undercoagulation based on the drug levels, in situations where such tests are unavailable.
It should be realized that the already existing complex issue of thrombosis management is increasingly becoming more complex with the introduction of newer agents.78 All efforts should be made to maximize the benefits and reduce the risk to the patients.
Although VKAs are often criticized for the need of frequent monitoring, such a practice is very beneficial. Recommended 12-weekly monitoring, rather than 4-weekly, in patients with consistently stable international normalized ratios may help reduce patient inconvenience. The recommended use of patient self-management of anticoagulation in motivated and competent patients is further very helpful. In the absence of laboratory test and antidotes to reverse their effects, the use of newer oral anticoagulants is quite challenging.