How to improve the quality of warfarin anticoagulation therapy
Warfarin, the oldest oral anticoagulant, is the most commonly used drug for patients requiring long-term anticoagulation therapy, including primary and secondary prevention of venous thromboembolic disease (VTE), prevention of thromboembolism in atrial fibrillation, valvular disease, prosthetic valve replacement and intracardiac thrombosis. Warfarin has accumulated a large body of clinical evidence in these areas and is currently used by millions of patients worldwide. Although, newer oral anticoagulants are becoming available and gaining indications in venous thromboembolic disease and non-valvular atrial fibrillation. However, warfarin remains irreplaceable, for example, in the antithrombotic treatment of patients with valvular disease. The efficacy and safety of warfarin are associated with good control and monitoring, and POCT-assisted anticoagulation can greatly improve INR control and reduce bleeding complications. Therefore, clinicians still need to learn to use warfarin well.
I. The pharmacological mechanism of action of warfarin
Coagulation factors II, VII, IX and X need to undergo γ-carboxylation to become biologically active, and this process requires the participation of vitamin K. Warfarin is a bicoumarin derivative that exerts anticoagulant effects by inhibiting the interconversion of vitamin K and its 2,3 -epoxide (vitamin K epoxide). Carboxylation promotes the binding of coagulation factors to the phospholipid surface, which in turn accelerates blood clotting. In addition, warfarin is procoagulant because it inhibits the carboxylation of anticoagulant regulators C and S. The anticoagulant effect of warfarin can be antagonized by vitamin K1. Coumarins can also interfere with the carboxylation of glutamate residues synthesized in bone tissue, which may lead to bone abnormalities in fetuses taking warfarin during pregnancy.
II. Pharmacokinetics and pharmacogenetics of warfarin
Warfarin is a mixture of two different active racemic isomers, R and S type isomers. Warfarin is rapidly absorbed through the gastrointestinal tract and is highly bioavailable, with a peak blood concentration after 90 minutes of oral administration and a half-life of 36-42 hours. The dose-effect relationship of warfarin is influenced by genetic and environmental factors.
1. Genetic factors
The tolerated dose of warfarin is significantly different between Caucasians and Chinese when the same INR level is reached, and the main genetic factors include.
(1) warfarin-related pharmacogenetic polymorphisms. A large number of studies both at home and abroad have found that polymorphisms at certain loci encoding cytochrome P450 2C9 and VKORC1 can lead to a reduced requirement for warfarin and may also be associated with increased side effects.
(2) Congenital resistance to warfarin. Patients with congenital warfarin resistance require an average of 5 to 20 times higher doses to achieve anticoagulant efficacy, which may be related to altered affinity of warfarin for liver receptors. (3) Genetic mutations in coagulation factors.
2, environmental factors
Drugs, diet, and various disease states can alter the pharmacokinetics of warfarin. Therefore, patients taking warfarin should be monitored for INR when adding or stopping any drugs, including herbal medicines. s- warfarin isomer is 5 times more anticoagulant efficient than r- warfarin isomer, so factors that interfere with the metabolism of s- warfarin isomer are more important. The inhibition of S- warfarin isomer metabolism by pautazone, sulfinpyrazone, metronidazole, and sulfamethoxypyrimidine all significantly enhanced the effect of warfarin on PT. In contrast, cimetidine and omeprazole inhibited the clearance of the R- warfarin isomer and only mildly enhanced the effect of warfarin on PT. Amiodarone is a strong inhibitor of metabolic clearance of both R and S warfarin isomers, and may enhance the anticoagulant effect of warfarin. Drugs that enhance hepatic clearance of warfarin such as barbiturate, rifampin, and carbamazepine may inhibit its anticoagulant effects. Chronic alcohol consumption increases warfarin clearance, but consumption of large amounts of wine has little to no effect on patients’ PT. Dietary intake of vitamin K is one of the main influencing factors in patients on long-term warfarin and patients should be advised to maintain a more stable vitamin K intake and should be monitored more closely when significant changes occur.
Patients taking warfarin should avoid concomitant administration with nonsteroidal anti-inflammatory drugs, including cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs and certain antibiotics. Avoid concomitant administration with antiplatelet agents unless the benefit outweighs the risk of bleeding, such as in patients with acute coronary syndromes or in patients with recently placed stents.
Conditions that can affect the action of warfarin include prolonged diarrhea or vomiting, hypoxic states, chemotherapy, fever, and hyperthyroidism. Most importantly, abnormal liver function and the dose requirement of warfarin will be reduced in chronic renal insufficiency.
Dosage and monitoring of warfarin
The efficacy and safety of warfarin are closely related to its anticoagulant effect, and the dose-effect relationship varies greatly among individuals, so close monitoring is necessary to prevent overdose or underdose. The prothrombin time (PT) reflects the degree of inhibition of prothrombin, factor VII, and factor X. During the first few days of warfarin therapy, the PT mainly reflects the reduction of coagulation factor VII with a half-life of 6 hours. Subsequently, the PT mainly reflects the reduction of coagulation factor X and factor II. The evaluation of the anticoagulant strength of warfarin is based on the International Normalized Ratio (INR), which is calculated from PT measured by different laboratories and corrected by ISI. Therefore, the INR measured by different laboratories can be compared.
1.Anticoagulant strength
The optimal anticoagulation intensity of warfarin is INR2.0 to 3.0, when the risk of bleeding and thromboembolism are the lowest. Anticoagulation with a low intensity INR <2.0 is not recommended. Randomized controlled clinical studies comparing low-intensity anticoagulation with standard-intensity anticoagulation in patients with VTE and atrial fibrillation are rare. Large case-control studies suggest a significantly increased risk of stroke complicating AF with an INR <2.0. In this paper, warfarin intensities are in the INR target range of 2.0 to 3.0 unless otherwise stated.
2. Initial dose
The anticoagulant effect occurs after approximately 2 to 7 days of oral administration, depending on the warfarin dose. The American College of Chest Physicians Antithrombotic Guidelines, 9th edition (ACCP9) recommends an initial warfarin dose of 10 mg for healthier outpatients, with dose adjustment based on INR after two days, primarily from studies of VTE treatment. There are large differences in warfarin hepatic metabolizing enzymes in Asians compared to Westerners, and the mean warfarin dose is lower in Chinese than in Westerners. The maintenance dose of warfarin in antithrombotic studies in Chinese with atrial fibrillation is approximately 3 mg.
To reduce over-anticoagulation, loading doses are not usually recommended. When treatment is not urgent (e.g., chronic AF) and the drug is administered on an outpatient basis, a loading dose is also not recommended for safety due to the inconvenience of out-of-hospital monitoring.
The recommended initial dose for Chinese is 1 to 3 mg (2.5 mg and 3 mg are the main domestic dosage forms of warfarin), and the target range can be reached in 2 to 4 weeks.
The initial dose may be reduced in certain patients such as the elderly, patients with impaired liver function, congestive heart failure, and patients at high risk for bleeding.
If rapid anticoagulation is required, such as in the acute phase of VTE, regular heparin or low molecular heparin is given overlapping with warfarin for more than 5 days, i.e., warfarin is given on the first or second day of heparin administration, and the dose is adjusted, and regular heparin or low molecular heparin is discontinued when the INR reaches the target range and lasts for more than 2 days.
Mutations in genes relevant to the determination of warfarin dose have been commercialized nationally and internationally, primarily P450 2C9 and VKORC1. The US FDA also updated the warfarin instructions in 2008 to suggest that initial dose selection can be aided by testing for genetic polymorphisms. Genetic polymorphisms can only explain 30% to 60% of the individual variation in warfarin, and factors such as patient body surface area, liver and kidney function, and combination of drugs need to be taken into account to select the appropriate dose. Currently, foreign guidelines do not recommend routine genetic testing for all patients taking warfarin to determine dose. If available, genotype determination will be helpful for warfarin dose adjustment.
3.Dose adjustment
Dose adjustment during treatment should be cautious, frequent dose adjustment will cause INR fluctuation.
If the INR continuously measured results are outside the target range before starting to adjust the dose, an increase or decrease can be found without rushing to change the dose.
When warfarin dose adjustments are small, weekly dose calculations can be used, which are more accurate than daily dose adjustments.
If the INR exceeds the target range, the dose can be increased or decreased by 5% to 20% of the original dose, and the dose should be monitored more closely after adjustment.
If the INR has been stable, occasional fluctuations and the magnitude does not exceed the INR target range of 0.5 above and below, there is no need to adjust the dose, recheck the INR as appropriate, can be several days or 1 to 2 weeks.
4.Monitoring frequency
The frequency of treatment monitoring should be based on the patient’s bleeding risk and medical conditions.
Inpatients on oral warfarin for 2 to 3 days should be monitored daily or every other day until the INR reaches the therapeutic target and is maintained for at least 2 days. Thereafter, monitoring should be performed once a week for several days depending on the stability of INR results, or longer if appropriate, and every 4 weeks after discharge.
Outpatients should be monitored several days to weekly until the dose is stable, and then every 4 weeks once the INR has stabilized. If dose adjustment is required, the frequency of monitoring should be repeated as described previously until the dose is stable again.
Monitoring should be intensified in elderly patients due to reduced warfarin clearance, co-morbidities, or high levels of combined medications. The frequency of INR monitoring in patients on long-term warfarin is influenced by patient compliance, co-morbidities, combination medications, and dietary modifications. Patients on warfarin with a stable INR can have their INR monitored once every 3 months at the most.
5. Treatment of abnormal INR and/or bleeding
If the INR rises above the therapeutic range, different methods should be used depending on the degree of elevation and the patient’s risk of bleeding. In case of minor bleeding on warfarin and the INR is within the target range, it is not necessary to stop or reduce the dose immediately, but the cause should be sought and monitored. Patients who develop severe warfarin-related bleeding should first be immediately discontinued, given a prothrombin complex transfusion to rapidly reverse anticoagulation, and also require intravenous vitamin K1 5 to 10 mg.
Long-term therapy is very difficult when patients have bleeding complications but also require anticoagulation to prevent embolism (e.g., patients with mechanical heart valves or with atrial fibrillation and other risk factors). The following two approaches can be considered.
(1) Identifying and treating the cause of the bleeding ;
(2) whether the intensity of anticoagulation can be reduced. If a reversible cause of bleeding can be found, multiple approaches can be taken to treat the cause of the bleeding (e.g., aggressive anti-ulcer therapy) or to switch to antiplatelet agents in appropriate patients.
6. Adverse reactions
6.1 Hemorrhage
Anticoagulation therapy can increase the risk of bleeding complications in patients, so care should be taken to assess the patient’s risk of bleeding before and during treatment and to determine the appropriate treatment plan. The incidence of bleeding events due to warfarin varies by treatment population. For example, in a prospective clinical study of patients with non-valvular atrial fibrillation, the incidence of serious bleeding with a warfarin target INR of 2.0 to 3.0 ranged from 1.40% to 3.40% per year, and the incidence of intracranial hemorrhage ranged from 0.4% to 0.8% per year. In the ATRIA registry, the annual incidence of intracranial hemorrhage was 0.58% in patients with atrial fibrillation on warfarin and 0.32% in patients without anticoagulation.
The risk of bleeding in patients taking warfarin was related to the intensity of anticoagulation and also to whether the patient was on initial or long-term anticoagulation and whether coagulation was monitored. In addition, the most important bleeding risk factors associated with patients were history of bleeding, age, tumor, liver and kidney insufficiency, stroke, alcohol abuse, and combined medications, especially antiplatelet agents. There are several assessment methods used in clinical practice, among which the HAS-BLED scoring system is recommended for patients with atrial fibrillation. Patients with a score of 0 to 2 are considered to be at low risk of bleeding, and a score of ≥3 indicates an increased risk of bleeding.
It is important to note that patients at increased risk for bleeding tend to be at increased risk for thromboembolic events, and these patients may benefit more from anticoagulation therapy. Therefore, anticoagulant therapy should be administered as long as the patient has an indication for anticoagulation, and bleeding risk factors should not be considered a contraindication to anticoagulation. Such patients should be screened for and corrected for reversible factors that increase the risk of bleeding, and need to be monitored intensively. Patients taking warfarin should be regularly evaluated for thromboembolic risk and bleeding risk in a comprehensive manner.
6.2 Non-bleeding adverse reactions
In addition to bleeding, warfarin is associated with a rare adverse effect: acute thrombosis, including skin necrosis and limb gangrene. It usually occurs between days 3 and 8 of dosing and may be associated with protein c and protein S deficiency. In addition, warfarin can interfere with the synthesis of osteoproteins, leading to osteoporosis and vascular calcification.
IV. Management of anticoagulation therapy
Although warfarin has many limitations and dose adjustment and monitoring are cumbersome, follow-up and education of patients through specialized clinics and systematic management can significantly enhance patient compliance and medication safety. Therefore, it is recommended that specialized clinics be established in hospitals where available to enhance anticoagulation management for patients on long-term anticoagulation therapy. Monitoring INR as required is an important measure to ensure safe and effective anticoagulation therapy for patients. At present, INR testing for patients in China is mainly done in central hospital laboratories, which affects patient compliance to a certain extent because of the complicated process, long waiting time and the need to use venous blood specimens. China has started to introduce INR point-of-care test (POCT), which requires only a drop of finger blood and can report test results instantly, greatly simplifying the testing process for anticoagulation therapy and providing convenience for rapid outpatient and emergency testing of INR as well as home monitoring of patients. Clinical studies have shown that home self-monitoring by POCT is at least as safe and effective in patients taking warfarin as compared to monthly central laboratory testing. Patients should be managed systematically, incorporating patient education, systematic INR monitoring, follow-up, and good communication with the patient.
V. Significance of POCT monitoring
The test turnaround time (TAT) is important for early diagnosis and early treatment. In fact, the least time is spent in the analysis, and a lot of time is consumed in the pre-analysis and post-analysis, while the chance of error in the transmission of the sample after leaving the patient site also increases gradually. In order to meet the requirements of short time feedback, it is necessary not only to have a simple, fast and accurate method, but also to reduce the process of sample transfer and shorten the reporting time.
POCT is a test method that uses portable equipment to obtain test results within minutes. With TAT reduction as the root and core, POCT has been widely used in hospitals, communities, home health care networks, emergency systems and other fields, and is favored by society for its new test mode of miniaturization of laboratory technology instruments, simplicity of operation, and timely reporting of results. Laboratory professionals believe that “in the next 5 to 10 years, POCT should reach 70% to 80% of laboratory tests or more, basically changing the current pattern of laboratory medicine, of course, the central laboratory should exist at the same time, mainly for some complex tests.” POCT is a rapid test that can meet people’s requirements in terms of time and adapt to the needs of modern social development.
In the past, the PT/INR test was mainly performed in the central laboratory of the hospital, although the central laboratory could guarantee the reliability of the test quality, but the long delivery time of the blood specimen before the test largely affected the accuracy of the INR test results; because of the long waiting time for the results, the doctor could not handle the patient in time and passively caused the delay of treatment; at the same time, because the patient needed to repeatedly visit the hospital and repeatedly The POCT blood coagulation instrument requires only a drop of finger blood from the patient and reports the results instantly, greatly reducing the TAT time. It is easy to operate, easy to use, fast, and accurate, and is a beneficial supplement to central laboratory blood coagulation monitoring methods, especially for ICU, emergency room, operating room, and outpatients.
The accuracy, reproducibility and long-term reliability of POCT results have been confirmed in several clinical studies compared to the WHO-recommended INR assay and central biochemistry assays. Although clinical studies in Europe and the United States have confirmed the effectiveness, convenience and safety of POCT for anticoagulation therapy and patient self-management, further clinical data need to be accumulated in China. For the current status of anticoagulation therapy in China, the following recommendations are made.
(1) It is recommended that large hospitals establish anticoagulation or thromboembolism prevention and control clinics to interact with the community for systematic management, proactive services and anticoagulation monitoring education for anticoagulated patients;
(2) It is recommended to train medical personnel in rural county hospitals and urban communities in the use of anticoagulant drugs and anticoagulation monitoring methods;
(3) Recommend that anticoagulation clinics and county hospitals and communities capable of anticoagulation management prioritize the application of POCT hemagglutination for anticoagulation monitoring;
(4) Recommend that emergency rooms be equipped with POCT coagulation devices;
(5) POCT coagulation is recommended for patients with acute bleeding complications and thrombosis, as well as for those who require invasive procedures.