Environmental Factors
Medications, diet, and various disease states can alter the pharmacokinetics of warfarin. Therefore, patients taking warfarin should be monitored more closely for INR when adding or discontinuing any medications, including herbal medicines. the S-warfarin isomer is 5 times more anticoagulant efficient than the R-warfarin isomer, so factors that interfere with the metabolism of the S-warfarin isomer are more important. Inhibition of the metabolism of the S-warfarin isomer by protaxone, sulfinpyrazone, metronidazole and sulfamethoxypyrimidine all significantly enhanced the effect of warfarin on PT. In contrast, cimetidine and omeprazole inhibited the clearance of R-warfarin isomers and only mildly enhanced the effect of warfarin on PT. Amiodarone, a strong inhibitor of metabolic clearance of both R and S warfarin isomers, enhances the anticoagulant effect of warfarin. Drugs that enhance hepatic clearance of warfarin such as barbiturate, rifampin, and carbamazepine can inhibit its anticoagulant effects. Chronic alcohol consumption increases warfarin clearance, but consumption of large amounts of wine has little to no effect on PT in patients. Common drugs and foods that interact with warfarin are shown in Exhibit 1. Dietary intake of vitamin K is one of the major influencing factors in patients on long-term warfarin.
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, liver function abnormalities and warfarin dose requirements are reduced in chronic renal insufficiency.
Warfarin Dosing and Monitoring
The efficacy and safety of warfarin are closely related to its anticoagulant effect, and the dose-effect relationship varies considerably 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 treatment, PT mainly reflects the decrease in coagulation factor VII, which has a half-life of 6 hours. Subsequently, PT mainly reflects the reduction of coagulation factor X and factor II. Warfarin anticoagulation strength is evaluated using the international normalized ratio (INR), which is calculated from PT measured by different laboratories after ISI correction. Therefore, the INR measured by different laboratories can be compared.
Anticoagulant strength
The optimal anticoagulation intensity for warfarin is INR 2, 0-3, 0, when the risk of both bleeding and thromboembolism is lowest. Anticoagulation at low intensity INR
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 Therapy 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 derived from therapeutic studies of VTE. 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 of Chinese subjects with AF is approximately 3 mg.
3,2,1 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.
3,2,2 The recommended initial dose for Chinese is 1 to 3 mg (the main domestic dosage forms of warfarin are 2, 5 mg and 3 mg), and the target range can be reached in 2 to 4 weeks.
3,2,3 In certain patients such as the elderly, patients with impaired liver function, congestive heart failure and patients at high risk of bleeding, the initial dose may be reduced appropriately.
3,2,4 If rapid anticoagulation is required, such as for acute phase treatment of VTE, give regular heparin or low-molecular heparin overlapping with warfarin for more than 5 days, i.e., give warfarin on the first or second day of heparin administration and adjust the dose and discontinue regular heparin or low-molecular heparin 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 instructions for warfarin in 2008, suggesting that initial dose selection can be aided by testing for genetic polymorphisms. Genetic polymorphisms can only explain 30-60% of the individual variation in warfarin,[9] and factors such as patient’s body surface area, liver and kidney function, and combined dosing need to be taken into account to select the appropriate dose. Currently, foreign guidelines do not recommend routine genetic testing to determine dose for all patients taking warfarin. If available, genotype determination would be helpful for warfarin dose adjustment.
Dose adjustment
3,3,1 Dose adjustments should be made with caution during treatment; frequent dose adjustments can cause INR fluctuations.
3, 3, 2 If the INR continuous measured results lie outside the target range before starting dose adjustment, an increase or decrease can be found without rushing to change the dose.
3, 3, 3 Warfarin dose adjustment range is small, you can use the calculation of weekly dose, more accurate than adjusting the daily dose.
3, 3, 4 INR such as more than the target range, can be raised or lowered by 5-20% of the original dose, after adjusting the dose pay attention to strengthen monitoring.
3, 3, 5 If the INR has been stable and occasionally fluctuates and the magnitude does not exceed 0, 5 above or below the target range of INR, it is not necessary to adjust the dose, and the INR can be rechecked for several days or 1-2 weeks as appropriate.
Frequency of monitoring
The frequency of therapy monitoring should be based on the patient’s bleeding risk and medical condition.
Monitor INR daily or every other day starting after 2-3 days of oral warfarin in hospitalized patients until INR reaches therapeutic target and is maintained for at least two days. Thereafter, monitoring is performed once a week for several days depending on the stability of INR results, and may be extended as appropriate, and may be performed every 4 weeks after discharge.
Outpatients should be monitored several days to weekly until the dose is stable, and then may be monitored every 4 weeks when the INR is stable. If dose adjustment is required, the frequency of monitoring as previously described should be repeated until the dose is stable again.
Monitoring should be intensified in elderly patients due to reduced clearance of warfarin, comorbid other diseases, 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 up to once every 3 months.
Management in case of abnormal INR and/or bleeding
INR elevations above the therapeutic range are treated differently depending on the degree of elevation and the patient’s risk of bleeding (Table 1). When minor bleeding occurs on warfarin and the INR is within the target range, immediate discontinuation or dose reduction is not necessary; the cause should be sought and monitoring should be intensified. Patients who develop severe warfarin-related bleeding should first be immediately discontinued, given a prothrombin complex transfusion for rapid reversal of anticoagulation, and also require intravenous vitamin K1
5 to 10 mg.
Long-term treatment 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). Two approaches may be considered: (1) to identify and treat the cause of the bleeding; and (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 antiulcer therapy) or to switch to antiplatelet agents in appropriate patients.
Clinical applications of warfarin
Prevention and treatment of venous thromboembolism
Prevention of deep vein thrombosis and pulmonary thromboembolism is generally achieved with fast-acting intravenous or subcutaneous anticoagulants with a short half-life, which facilitate perioperative application, but in some cases long-term prophylaxis is required.
Warfarin can be considered as a long-term replacement after overlapping with heparin or low-molecular heparin. For example, in patients requiring extended prophylaxis after orthopedic joint replacement and in patients in the rehabilitation phase after spinal cord injury, long-term oral warfarin anticoagulation should be extended until at least 1 week after injury.
Patients with deep vein thrombosis and pulmonary embolism should be treated acutely with intravenous anticoagulants, including plain heparin, low-molecular heparin, or Juanda heparin sodium, with overlapping warfarin administration starting on day 2 until the INR reaches target values and is stable for more than 2 days. The duration of long-term treatment depends on the risk of bleeding and the risk of recurrence of venous thromboembolism.
Usually warfarin anticoagulation is required for at least 3 months after the acute phase in patients with VTE, and long-term anticoagulation should be considered if the cause of venous thromboembolism is unclear or if risk factors cannot be eliminated. All patients on long-term anticoagulation should be reevaluated periodically (annually) for thrombosis and bleeding risk.
5,1,1 If the onset of VTE is due to surgical procedures or transient factors, anticoagulation for 3 months is recommended.
5, 1, 2 Anticoagulation for 3 months is also recommended for first-ever VTE if the risk of bleeding is high.
5, 1, 3 Recurrent VTE with a high risk of bleeding should be treated with anticoagulation for 3 months; patients with a low risk of bleeding should be treated with long-term anticoagulation.
5, 1, 4 First occurrence of unprovoked VTE with a low risk of bleeding should be treated with long-term anticoagulation.
5, 1, 5 Patients with VTE combined with an active tumor have a low risk of bleeding and should be anticoagulated for a long time.
5, 1, 6 The duration of anticoagulation should also be prolonged in patients with a propensity for thrombosis and recurrence, such as primary proximal venous thrombosis, malignancy combined with thrombosis or patients with a predisposition to thrombosis, such as factor 5Leiden genotype as a pure subtype, antiphospholipid antibody syndrome, and antithrombin 3 protein c or protein S deficiency.
5,1,7 All patients with chronic thromboembolic pulmonary hypertension (CTPH) should be treated with warfarin for life.
Heart valve disease
Warfarin anticoagulation should be given for heart valve disease in combination with
5,2,1 Patients with rheumatic mitral valve disease combined with sinus rhythm, such as those with a left atrium greater than 55 mm or in whom a left atrial thrombus has been identified;
5, 2, 2 Patients with rheumatic mitral valve disease combined with atrial fibrillation or patients who have had an embolism.
5, 2, 3 Patients with unexplained stroke combined with oval orifice non-closure or atrial septal tumor, such as those who have recurrent stroke on aspirin.
5, 2, 4 Patients with implanted prosthetic bioprosthetic valves, warfarin is recommended for 3 months after mitral cuspidal valve replacement.
5,2,5 Patients with implanted prosthetic mechanical valves are anticoagulated depending on the type of prosthetic valve and the risk of concomitant thromboembolism. The INR goal is 2,0-3,0 after aortic valve replacement, whereas the recommended INR goal is 2,5-3,5 after mitral valve replacement and 2,5-3,5 for patients with two valve implants.
5,2,6 Patients who develop infective endocarditis with implanted prosthetic valves should first be discontinued from warfarin and subsequently evaluated for the need for surgical intervention and for signs of central nervous system involvement, and warfarin therapy can be restarted after confirming that the patient is stable and free of contraindications and neurologic complications.
Non-valvular atrial fibrillation
Appropriate anticoagulation therapy is an effective measure to prevent thromboembolic events in patients with atrial fibrillation, but it also increases the risk of bleeding complications. Therefore, the benefit-risk ratio should be assessed before determining whether a patient is suitable for anticoagulation, and anticoagulation should be initiated only when the benefit of preventing thromboembolic events outweighs the risk of bleeding complications.
The risk of ischemic stroke in patients with non-valvular atrial fibrillation is closely related to their baseline characteristics, and risk stratification of patients based on baseline characteristics is the basis for the development of a proper anticoagulation strategy [7]. Currently, the CHADS2 scoring system is the most widely used clinical assessment tool. As the CHADS2 score increases, the risk of future ischemic stroke in patients with non-valvular atrial fibrillation gradually increases. In the absence of contraindications, all patients with atrial fibrillation with a CHADS2 score ≥2 should be placed on long-term oral warfarin. Warfarin is also currently preferred over aspirin if the CHADS2 score is 1 in patients with non-valvular atrial fibrillation.
Intra-cardiac thrombosis
There is no direct clinical research evidence for antithrombotic therapy in patients with anterior wall myocardial infarction combined with left ventricular thrombosis. Warfarin combined with antiplatelet agents is recommended based on observational studies and clinical evidence for warfarin combined with aspirin, but the duration of combination therapy should be as short as possible, i.e., 1 month after bare metal stenting and 3-6 months for drug-coated stents.
Patients with anterior wall myocardial infarction with left ventricular thrombus or high risk of left ventricular thrombus (left ventricular ejection fraction <40%, abnormal apical anterior wall motion).
5,4,1 Not stented: Warfarin combined with low-dose aspirin 75-100 mg/day is applied for the first 3 months. Thereafter, warfarin is discontinued and dual antiplatelet therapy is administered until 12 months.
5,4,2
Placement of bare metal stent: triple therapy (warfarin, low-dose aspirin, clopidogrel 75 mg/day) is recommended for 1 month. For months 2-3, warfarin plus an antiplatelet therapy is applied, after which warfarin therapy is discontinued and the second antiplatelet therapy is continued for 12 months.
5,4,3
Drug-eluting stent (DES) placement: triple therapy (warfarin, low-dose aspirin, clopidogrel 75 mg/day) is recommended for 3 to 6 months, after which warfarin is discontinued and dual-combination antiplatelet therapy is continued until 12 months.
Treatment in special cases
Surgical perioperative management
Patients need to undergo invasive tests or surgery. At this time, the patient is at risk of continuing or interrupting anticoagulation therapy, and the patient’s risk of thrombosis and bleeding should be evaluated in a comprehensive manner. Complete discontinuation of anticoagulation therapy will increase the risk of thrombosis.
Patients on warfarin therapy need to be temporarily discontinued prior to surgery and bridged with heparin. Bridging therapy is the short-term application of plain heparin or low-molecular heparin as a substitute for anticoagulation therapy during discontinuation of warfarin.
In case of non-emergency surgery, warfarin is usually discontinued 5 days before surgery in most patients, and the following approaches are available depending on the risk of thromboembolism.
6,1,1 Patients with a low risk of thromboembolism can be treated without bridging, and the preoperative INR can be restored to near normal range after discontinuation (INR <1,5<
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6,1,2 Patients at moderate risk of thromboembolism should be treated with preoperative application of low-dose UFH 5000U subcutaneously or prophylactic dose of LMWH
subcutaneously, and then start low-dose UFH (or LMWH) postoperatively overlapping with warfarin.
6, 1, 3
Patients with a high risk of thromboembolism, start full-dose UFH or LMWH therapy when INR decreases (2 days before surgery). Continue intravenous UFH preoperatively and discontinue until 6 hours prior to surgery, or subcutaneously administer UFH or LMWH and discontinue 24 hours prior to surgery.
6,1,4 Patients undergoing dental procedures may rinse their mouth with tranexamic acid, aminoacetic acid, without discontinuing anticoagulants or warfarin 2-3 days prior to surgery.
6,1,5 If INR>1,5 but the patient needs early surgery, the patient can be given a small oral dose (1-2mg) of vitamin K to normalize INR as soon as possible.
After surgery, restart heparin anticoagulation therapy 12-24 hours after surgery depending on the bleeding from the surgery. For surgery with high bleeding risk, restart anticoagulation therapy and restart warfarin therapy until 48-72 hours after surgery.
Stable coronary artery disease
In patients taking oral warfarin in combination with stable angina, carotid atherosclerotic disease, or peripheral arterial disease, warfarin alone for secondary prevention is at least as effective as aspirin, and therefore warfarin-only therapy is recommended for such patients.
After acute coronary syndrome (ACS) or coronary artery stenting
Patients with warfarin indications who develop ACS or undergo PCI often require triple antithrombotic therapy, i.e. warfarin combined with clopidogrel and aspirin. Available evidence suggests that the short-term (e.g., 4 weeks) addition of warfarin does not significantly increase the risk of bleeding events compared with those treated with dual antiplatelet agents only, with an acceptable benefit/risk ratio, but the safety of long-term triple antithrombotic agents remains to be demonstrated. All patients are first evaluated for bleeding risk and bare metal stents are selected when possible. Coagulation monitoring should be intensified when warfarin is combined with clopidogrel and or aspirin, and INR should be regulated between 2,0 and 2,5.
6,3,1 Patients with atrial fibrillation after elective PCI with placement of metal bare stents may be treated with triple antithrombotic therapy for a short period of time (4 weeks), and longer triple antithrombotic therapy is required after placement of drug-eluting stents (sirolimus, everolimus, and tacrolimus-eluting stents should be treated for ≥3 months, and paclitaxel-eluting stents should be treated for at least 6 months).
6,3,2 Patients with ACS should be treated with triple antithrombotic therapy (warfarin, aspirin, and clopidogrel) if there is no contraindication. If the patient is at high risk of bleeding and has a bare metal stent, triple antithrombotic therapy is administered for 4 weeks; if the patient is at low risk of bleeding and high risk of thromboembolism, triple antithrombotic therapy is administered for 6 months;
Thereafter, warfarin with clopidogrel (75 mg, qd) or aspirin (75-100 mg, qd) for up to 1 year, combined with a proton pump inhibitor or H2 receptor antagonist if necessary; after 1 year, if the patient has stable coronary disease, use warfarin anticoagulation alone.
Anticoagulation during pregnancy. Warfarin is relatively contraindicated in the first trimester of pregnancy because it can cross the placenta and cause miscarriage, embryonic hemorrhage, and embryonic malformations. Heparin, on the other hand, does not cross the placenta and is a better choice during pregnancy, but is more expensive. Three treatment options are available during pregnancy.
6,4,1 Regular heparin or low molecular heparin throughout pregnancy;
6,4,2 Warfarin for the whole pregnancy and regular heparin or low molecular heparin at delivery;
6,4,3 Heparin in the first trimester and warfarin in the second trimester until delivery when they were switched to regular heparin and low molecular heparin.
6,4,4 Heparin and low-molecular heparin are discontinued 12 hours before delivery and overlapped with warfarin for 4-5 days after delivery; warfarin has no anticoagulant effect on the nursing infant.
However, pregnant patients with valvular atrial fibrillation are at high risk for thromboembolism and should be given heparin anticoagulation for the first 3 and second 3 months, respectively, with warfarin available for the middle 3 months, when the INR should be controlled at 2,0-2,5 to minimize the effect on the embryo. In patients with implanted prosthetic valves, the best strategy is to give warfarin and closely monitor the INR, as the efficacy of both plain heparin and low molecular heparin is uncertain. European guidelines consider the risk of embryopathy during pregnancy to be low if the dose of warfarin does not exceed 5 mg/day, and warfarin can be applied until 36 weeks of gestation. The [14] ACCP9 guidelines recommend that warfarin anticoagulation be given throughout pregnancy only if the pregnant patient is at very high risk of thrombosis, such as in patients with mitral valve replacement or a history of embolism. If the patient has a high warfarin dosage, the administration of plain heparin or low-molecular heparin at weeks 6-12 of pregnancy may also be considered. Warfarin application during this period should be monitored weekly. LMWH should be given for the prevention and treatment of VTE during pregnancy, but warfarin can be given after delivery.
Patients with cancer
The risk of VTE is 6 times higher in cancer patients than in non-oncology patients, and the survival rate of cancer patients is significantly lower once VTE has occurred. Risk factors for VTE in cancer patients include a history of venous thrombosis, inactivity, hormone therapy, and vascular growth inhibitor therapy. In hospitalized cancer patients, decisions about the need for prophylactic anticoagulation are made based on the risk of disease and surgery, and low-molecular heparin or normal heparin is generally given.
Non-hospitalized cancer patients without risk factors for VTE do not require routine administration of prophylactic anticoagulation including warfarin. Patients with solid tumors with risk factors for VTE and a low risk of bleeding are recommended to be given prophylactic doses of LMWH
or heparin. Routine anticoagulation is also not recommended in patients with central venous lines. After VTE in cancer patients, LMWH therapy is preferred, and if LMWH is not available, warfarin therapy should be given. The duration of treatment should be at least 3 months, and if the risk of bleeding is not high, longer-term treatment should be given.
Treatment after hemorrhagic stroke
Whether patients with a history of intracranial hemorrhage who have an indication for oral warfarin can be safely treated is a difficult clinical decision. Reference to foreign guidelines suggests the following.
6,6,1 long-term antithrombotic therapy to prevent ischaemic stroke is not usually recommended if the patient has a history of primary intracranial haemorrhage.
6,6,2 Anticoagulation may still be considered in certain patients who are at low risk of intracranial bleeding (e.g., deep bleeding) and extremely high risk of thrombosis, such as after mechanical flap implantation or in patients with a CHADS2 score of >4 in atrial fibrillation. At this point, close monitoring should be performed to minimize the risk of bleeding.
Primary intracranial hemorrhage refers primarily to bleeding due to hypertensive cerebral hemorrhage and cerebrovascular amyloidosis, but also includes bleeding that occurs while taking antiplatelet agents and taking anticoagulants within the therapeutic intensity range. Excluded are those patients with intracranial vascular malformations or tumors, and those with bleeding due to overdose of anticoagulation therapy.
Perioperative period of coronary intervention and device implantation
Approximately 5-10% of patients undergoing coronary interventions are on long-term warfarin. Current foreign guidelines for the perioperative period of interventional procedures and pacemaker implantation for patients on long-term warfarin recommend similar to surgical procedures: discontinuation of the drug 5 days before the procedure, followed by “bridging” therapy appropriate to the patient’s risk of thrombosis. European surveys have shown that the perioperative management strategy varies considerably by geographic region and hospital, with approximately 60% of physicians adopting bridging therapy. However, recent studies have found that it is safe to proceed directly to coronary angiography or PCI without therapeutic-strength warfarin, but there is a lack of large-scale RCT studies. In this case, the radial route is chosen to further reduce bleeding, which is increased in those using concomitant glycoprotein IIb/IIIa receptor antagonists. Similarly, in patients with implanted pacemakers, studies have shown that warfarin can also be discontinued, with a lower incidence of adverse events in patients who continue to take warfarin.