3 : 29. Gyannendra K Sharma, USA. Warfarin Sodium: Initiation of therapy:

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1 3 : 29 Anticoagulation Management in Medical Practice Millions of patients are treated with anticoagulation therapy in a variety of clinical settings. Anticoagulation therapy is used for both prophylaxis and treatment. 1, 2 Heparin or low-molecularweight heparins are used initially or in the acute setting followed by oral vitamin K antagonist (warfarin sodium) for long-term management. The management with warfarin sodium is quite challenging due to the potential risk of thrombosis from underanticoagulation, or bleeding from over-anticoagulation. 3 Dietary limitations and drug interactions add to the complexity of keeping international normalized ratio (INR) in the therapeutic range. The goal of treatment is to achieve maximum time in therapeutic range (TTR) to avoid hemorrhagic complications; with out compromising the efficacy. Success of therapy is dependent on the patient s understanding and adherence to the regimen, as well as the physician s knowledge and ability to make appropriate decisions regarding dosage and follow up. 4 This review summarizes the practical aspects of long-term oral anticoagulation therapy (OAT) with warfarin in the medical practice. Warfarin Sodium: Oral warfarin sodium is the most commonly utilized vitamin K antagonist that interferes with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). This reaction results in reduced activity of vitamin K dependent factors II, VII, Table 1: Drug Interactions with Warfarin 6, 7 Augmentation of effect Decreased effect Amiodarone, Diltiazem, Fenofibrate, Propranolol, Propafenone, Quinidine, Aspirin, Simvastatin Erythromycin, Ciprofloxacin, Cotrimoxazole, Fluconazole, Isoniazid, Metranidazole, Tetracycline, Cephalosporins (2nd and 3rd generation) Phenylbutazone, Piroxicam, Acetaaminophen Sertraline, Chloral hydrate, Phenytoin (biphasic) Omeprazole Thyroxine Rifampin Barbiturates Carbamazepine Haloperidol Oral contraceptives Stopping of above medications can result in increased INR and risk of bleeding. Gyannendra K Sharma, USA IX and X. Maximum blood concentration of warfarin is reached in about 90 minutes, and it has a half life of hours. Genetic mutations in cytochrome P450 2C9 or vitamin K oxide reductase enzyme complex (VKORC1) in different ethnic groups can affect the pharmacodynamics of warfarin. This decreases the amount of warfarin required to maintain a therapeutic international normalized ratio (INR). Increased vitamin K intake can interfere with the warfarin action, leading to higher dose requirement. On the other hand, low vitamin K intake or hepatic dysfunction can increase warfarin sensitivity. Dietary vitamin K is derived from phylloquinones in plants; therefore, consumption of foods like broccoli, Brussels sprouts, cabbage, collard greens, spinach, and raw turnip greens can reduce the anticoagulant effect of warfarin. A number of over-the-counter medications or dietary supplements may also interfere with warfarin. Warfarin is a racemic mixture of two active isomers, R and S enantiomers, that may be affected by different medications. This can result in undesirable anticoagulant activity. A selected list of commonly used drugs that can interfere with the action of warfarin 6, 7 is given in Table 1. Initiation of therapy: Evidence-based Clinical Practice Guidelines, published by the American College of Chest Physicians, are excellent resource for the standard of care regarding indications, administration and monitoring of anticoagulation therapy. 1, 2, 12, 13, 14 Once a patient is diagnosed with a condition requiring anticoagulation therapy (Table 2), it is imperative to identify the bleeding risk of the patient, including any contraindications (Tables 3 and 4). Warfarin is one of the most common drugs associated with serious adverse events. The bleeding risk is dependent on the degree of anticoagulation and predisposing risk factors. Recommendations for anticoagulation therapy should be based on a thorough assessment of the risk/ benefit ratio. In most cases initial anticoagulation is started with unfractionated heparin (UFH) or low low-molecular weight heparin (LMWH [Enoxaparin, Tinzaparin, Dalteparin or Fondaparinux]) and continued for first 4-5 days, or until therapeutic

2 Anticoagulation Management in Medical Practice Table 2: Indications of Anticoagulation Therapy 1. Atrial fibrillation 2. Mural thrombus in the left ventricle 3. Prosthetic heart valves 4. Following acute large anterior wall myocardial infarction/acute coronary syndrome 5. Venous thrombo-embolism (Deep venous thrombosis, pulmonary embolism) 6. Hypercoagulable state, anti-phospholipid syndrome 7. Prevention of cerebrovascular accidents 8. Arterial embolism or thrombosis 9. Arterial graft thrombosis INR is achieved on two consecutive days. Low-molecular-weight heparins have a more predictable bioavailability and do not require monitoring. A baseline complete blood count, prothrombin time (PT), activated partial thromboplastin time (PTT), and creatinine should be obtained before initiation of the therapy. Hemoglobin levels and platelet counts should be monitored periodically. Warfarin Dosing: Table 3: Bleeding Risk Factors: 1. Increasing age >65yrs (5) 2. Hypertension (>180 systolic or >100 mm Hg diastolic) 3. Diabetes mellitus 4. Female sex 5. Chronic kidney disease 6. Alcoholism 7. Liver disease 8. History of gastrointestinal bleeding 9. Prior stroke or intracranial bleeding 10. Non-adherence to medications 11. Fall risk 12. Anemia (Hematocrit <30%) 13. Thrombocytopenia 14. Malignancy 15. Concomitant use of aspirin, Clopidogrel, other antiplatelet therapy or nonsteroidal anti-inflammatory drugs (NSAIDS) and amiodarone (6) The usual starting dose of warfarin for the first two days is 5mg/ day, although a higher dose may be started in low-risk patients, or those known to have required a higher dose in the past. In highrisk groups like the elderly, malnourished, those with a history of congestive heart failure, patients with hepatic dysfunction, those that have undergone recent surgery, or are taking medication (eg, amiodarone) to cause warfarin sensitivity, a smaller starting dose (2-4 mg) is recommended. 2,9 A higher starting dose of warfarin carries a potential risk of transient decline in protein C levels associated with increased thrombosis. Moreover, it takes longer for the reduction in factor II to achieve adequate antithrombotic effect; initial prolongation in INR from drop in factor VII is not fully protective. 8 Warfarin can be safely started on the first day of the treatment in most of the patients. Patients with polymorphisms in the genes for CYP2C9 and vitamin-k oxide Table 4: Contraindications: 1. Pregnancy in the first trimester 2. Uncontrolled major bleeding 3. Active peptic ulcer 4. Proliferative retinopathy 5. Recent stroke 6. Recent trauma or surgery to the head, orbit or spine 7. Intracranial or intraspinal bleeding 8. Recent organ biopsy Table 5: Warfarin Initiation Algorithm Day INR Dosage (mg) * < >3 4 < > < > < > 3.0 reductase complex 1 (VKORC1) require a lower maintenance dose of warfarin; however, current guidelines do not recommend pharmacogenetic-based dosing. Subsequent dosing of warfarin is based on the INR response (Table 5). Although there are no firm rules to predict appropriate further dosing, guidance is available from various trials, normograms, and computer-based doseprediction 9, 10, 11, 12 programs PT/INR monitoring should be started after initial two or three doses of warfarin and then checked daily (inpatient) until the therapeutic INR is achieved and maintained for two consecutive days. At that point, unfractionated heparin or lowmolecular-weight-heparin should be discontinued. Subsequent PT/INR monitoring is done 2-3 times a week until stable INR is achieved. Further INR testing can be reduced to every 2-4 weeks if INR remains in the therapeutic range. The therapeutic range and duration of therapy is dependent on the indication for anticoagulation therapy (Table 6.) Maintenance of Warfarin Therapy: mg 7.5 mg 5 mg mg 5 mg * Consider to lower starting dose (<5mg) ACCP Grade IC: (i.e. 2.5 mg) for age 75, liver disease, malnutrition, and/or high bleeding risk If a patient is found to have a subtheraputic INR, every effort should be made to find out the reason, including nonadherence to the prescribed dose of warfarin, and/or dietary indiscretion. 317

3 Medicine Update 2010 Vol. 20 Table 6: Goal INR and duration of therapy ¹ INDICATION DURATION INTENSITY Atrial Fibrillation 13 Chronic or paroxysmal AF with prior ischemic stroke, TIA or systemic embolism AF with two or more risk factors (age >75 years, hypertension, diabetes mellitus, moderate/ severely impaired left ventricular systolic function and/ or heart failure) AF and one risk factor AF<75years, no risk factor AF>48 hrs with planned cardioversion indefinite Aspirin or warfarin Aspirin ( mg/day) 3 weeks prior to cardioversion and 4 weeks after normal sinus rhythm is obtained (Target 2.5) Mechanical/Bioprosthetic Heart Valves 14,15 Mitral mechanical valve Aortic mechanical valve 1. in presence of AF, CHF, or enlarged left atrium 2. with NSR, normal left atrium size, and normal EF Bioprosthetic heart valves mitral Bioprosthetic heart valves aortic (+ Aspirin mg) (+ Aspirin mg) 3 monthsoptional/ 3 months Treatment/ Prevention Venous Thromboembolism 1, 2 First VTE with reversible risk factor First idiopathic VTE First VTE in patient with cancer (until resolved), antiphospholipid antibodies, antithrombin deficiency Recurrent VTE, idiopathic or with thrombophilia Prophylaxis (e.g. orthopedic surgery/trauma) 3 months At least 3 months 1 year to life long* 4-6 weeks Coronary Artery Disease Anterior Q-wave myocardial infarction 2 3 months Cerebral Vascular Disease TIA or stroke on aspirin or ticlopidine Cardio-embolic stroke Acquired and Inherited Hypercoaguable States Antiphospholipid antibodies (no additional risk or recurrent events) Antiphospholipid antibodies (with additional risk, or recurrent events) Inherited hypercoaguable states Antithrombin III, protein C, protein S deficiency, or activated protein C resistance (Factor V Leiden Mutation) 1. Adapted from ACCP recommendations in Chest 2008; 113: (2) 2. If oral anticoagulant therapy is elected to prevent recurrent myocardial infarction, an INR of is recommended, consistent with ACCP recommendations. *ACCP recommends treatment with LMWH for first 3-6 months then either VKA/LMWH indefinitely or until cancer resolves (for patients with DVT and cancer) It is reasonable to repeat the test to exclude laboratory error. If INR is marginally low in the stable patients, the dose of warfarin can be increased by 5-10%. In most cases therapeutic INR can be achieved with dose modification of up to 20%. Recently, more emphasis is given to the weekly dose of warfarin. In case of a single missed dose, the patient should resume regular dosage without having to take double dose on the following day. If INR is only mildly elevated and a transient cause of such an elevation can be identified, no change in the dose is needed. As per ACCH guidelines 2 the management of supra-therapeutic INR is summarized in the table 7. Complications: Bleeding is the most common complication and can occur in high risk patients even when they are in the therapeutic range. Majority of the bleeding is minor and occurs from the gastrointestinal tract; intracerebral hemorrhage is seen in <1% cases. The incidence of major bleeding in patients on long term warfarin is % and is most common during the first three months of therapy. Patients at increased risk of bleeding require smaller dose of warfarin and closer monitoring of INR. Skin necrosis is very unusual with the lower starting dose of warfarin, and is more commonly seen in patients with protein C deficiency due to transient hypercoagulable state. Cholesterol embolization resulting in purple, mottled discoloration of feet and toes (blue 318

4 Anticoagulation Management in Medical Practice Table7: Management of hyper-anticoagulation INR and Bleeding Status Warfarin Adjustment Vitamin K Administration FFP Considerations INR <5, but above target range and no clinically significant bleeding present INR >5 and <9 no clinically significant bleeding INR >9 no clinically significant bleeding Omit one dose of warfarin Re-initiate warfarin at a lower dose Recheck INR within 1 week Omit 1-2 doses of warfarin Recheck INR within 48 hours Re-initiate warfarin at the readjusted lower dose once the INR has returned to desired goal range and recheck INR within 1 week Hold warfarin doses until INR returns to desired goal range Monitor INR daily if possible Re-initiate warfarin at lower dose with an increase in monitoring frequency until stable Serious bleeding with elevated INR Stop warfarin Monitor INR daily if possible Life threatening bleeding (e.g., intracranial bleeding) present with any INR Not recommended May give 1 to 2.5 mg oral vitamin K in patient at increased risk of bleeding or give <5mg if rapid reversal is required (i.e. Urgent surgery), if INR remains elevated an additional 1-2 mg may be administered orally (expected reduction in INR in 24 hours) Administer mg oral vitamin K (expected reduction 24 to 48 hours) Administer 10 mg vitamin K by slow IV infusion (not to exceed 1 mg/min). May repeat at 12 hours for persistent elevation. Supplement with FFP, prothrombin complex concentrate or recombinant factor VIIa infusion depending on urgency of the situation Stop warfarin Administer 10 mg vitamin K by slow IV infusion (not to exceed 1 mg/min). Supplement with FFP or prothrombin complex concentrate or recombinant factor VIIa infusion. May repeat vitamin K if INR remains elevated toe syndrome) is infrequent, and can occur late in the course of the treatment with warfarin. Warfarin is teratogenic and should not be used in the first trimester of pregnancy. Patient Education: Patient education is extremely important for the success of anticoagulation therapy. Written instructions should be provided the indication, duration of therapy and the dose of warfarin along with the date for future INR testing. The patients should be educated about: Symptoms of bleeding (epistaxis, hemetemesis, melena, hematuria and bruising), with the instruction to contact treating physician. Signs and symptoms of thromboembolic events Risks associated with falling or using sharp objects The importance of compliance with warfarin and potential drug interactions including prescription, over the counter medications, herbal products, diet and alcohol. A list of foods rich in vitamin K should be provided. Because warfarin and other vitamin K antagonists (VKA) increase the risk for birth defects and miscarriage, patient should be educated about contraception and women planning to be pregnant should ideally stop taking VKAs before 6 weeks of fetal gestation. Periprocedural management of anticoagulation: At this time, there is no consensus for appropriate management of perioperative anticoagulation therapy. 16 The therapeutic strategy is dependent on the underlying indication for warfarin therapy, risk of thrombosis and/or risk of bleeding from the planned surgery. The risk of thrombosis is low in patients with atrial fibrillation without prior transient ischemic attack/stroke; DVT/PE that occurred more than three months prior to the surgery. Patients with prior history of stroke, recent DVT/PE (<3 months), prior thromboembolism and mechanical prosthetic heart valves constitute a high risk group for periprocedural thromboembolic event. It is unusual to have a major bleeding from dental extractions, cutaneous biopsy, cataract surgery, colonoscopy/endoscopy without biopsy, and arthrocentsis. 17 Certain procedures like cardiac catheterization and epidural injections; and brain, thoracic, pelvic and abdominal surgeries are associated with increased risk of bleeding. Perioperative bridging therapy is inconvenient, increases the cost of treatment and has a potential for risk of bleeding. In the past UFH was used for bridging, but two recent trials in patients with atrial fibrillation and mechanical prosthetic valves showed that LMWH can be safely used without increased risk of bleeding or thrombosis 18, 319

5 Medicine Update 2010 Vol. 20 Table 8: Periprocedural Management of Anticoagulation Risk Category Plan Low risk of thrombosis and low risk of bleeding Low risk of thrombosis and high risk of bleeding High risk of thrombosis and low risk of bleeding Perform procedure at reduced anticoagulation (INR 1.5) Hold warfarin 3-5 days prior to procedure Restart warfarin evening of procedure Perform procedure at reduced anticoagulation (INR 1.5) Hold warfarin 4-5 days prior to procedure Restart warfarin once stable from surgery (usually within 24 hours post-procedure, and after consultation with the surgeon) Perform procedure at full anticoagulation No change in warfarin dose and no use of alternate anticoagulation Warfarin may be held on the day of procedure High risk of thrombosis and high risk Perform procedure with no of bleeding anticoagulation and INR in normal range. Hold warfarin 5 days prior to the procedure Begin alternate form of anticoagulation with UFH or LMWH 24 hours after last warfarin dose Stop UFH 6 hours prior to procedure or LMWH hours prior to procedure Warfarin and alternative anticoagulation should be resumed as soon as possible after procedure. Alternative anticoagulation should continue until INR is in the therapeutic range. 19 in an outpatient setting. The physician responsible to deliver such a therapy should use best judgment in the light of the risk/ benefit ratio to individualize the treatment, and discuss plan with the patient. Based on the review of current literature a practical approach for periprocedural management of anticoagulation is given in table 8. For emergent procedures, fresh frozen plasma and intravenous vitamin K are used to reverse anticoagulation. In less urgent situations, vitamin K 2.5 mg can be given by mouth on the day prior to the procedure. As a general rule, large doses of vitamin K should be avoided as it takes longer for INR to be therapeutic. Future direction: OAT is cumbersome due to its narrow therapeutic window, risk of bleeding, and need for repeated INR testing to achieve a high TTR. A recent trial (RE-LY) showed that oral direct thrombin inhibitor dabigatran etexilate is noninferior in the lower dose (110mg twice daily) and superior in the higher dose (150 mg twice daily) to warfarin for stroke prevention in patients with atrial fibrillation (20). Intracranial hemorrhage was less common at both doses of dabigatran, and major bleeding was at least noninferior to warfarin, regardless of INR control. This is likely to substantially change the treatment paradigm for stroke prevention in atrial fibrillation. The future of anticoagulation therapy lies in the discovery of an agent that can be given orally, does not require monitoring, and is effective in preventing thromoembolism without increasing risk of bleeding. Acknowledgements: I am grateful to Mr. Michael Konomos, medical illustrator at the section of cardiology, Medical College of Georgia, Augusta for providing editorial support in the preparation of this chapter. References: 1. Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8 th edition). Chest 2008; 133: Hirsh Jack, Guyatt Gordon, Albers GW, et. al. Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8 th edition). Chest 2008; 133; Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med 2007; 167: Garcia David A, Witt, Daniel M, Hylek Elaine, et al. Delivery of Optimized Anticoagulant therapy: Consensus statement from Anticoagulation Forum. Ann Pharmacother, 2008; 42(7); Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med Jun 1; 120(11): Juurlink DN. Drug interactions with warfarin: what clinician need to know. CMAJ 2007; 177: Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med. 1994; 121: Harrison L, Johnson M, Massicotte et al. Comparison of 5-mg and 10- mg loading doses in initiation of warfarin therapy. Ann Int Med 1997; 126: Gage BF, Fihn SD, White RH. Management and dosing of warfarin therapy. The American Jr. Med 2000,109, 6: Crowther MA, Harrison L, and Hirsh J. Warfarin: less may be better (Letter). Ann intern Med. 1997; 127: Kovasc MJ, Rodger M, Anderson DR, et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecularweight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med 2003; 138: Ansell J, Hirsh J, Poller L, et al Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest (suppl),160S- 198S 13. Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based 320

6 Anticoagulation Management in Medical Practice Clinical Practice Guidelines (8th Edition). Chest 2008 Jun; 133(6 Suppl):546S-592S. 14. Salem DN, O Gara PK, Madias C and Stephen Pauker G, Valvular and Structural Heart Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008 Jun; 133(6 Suppl):593S-629S. 15. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease): developed collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006; 114:e Dunn AS, Turpie AG. Perioperative management of patients receiving oral anticoagulants: a systematic review Arch Intern Med. 2003; 163: Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med. 1997;336: Dunn AS, Spyropoulos AC, Turpie AG. Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT). J Thromb Haemost. 2007;5: Spyropoulos AC, Turpie AG, Dunn AS, Kaatz S, Douketis J, Jacobson A, Petersen H; Perioperative bridging therapy with unfractionated heparin or low-molecular-weight heparin in patients with mechanical prosthetic heart valves on long-term oral anticoagulants (from the REGIMEN Registry). Am J Cardiol Oct 1; 102: Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et. al. RE-LY Steering Committee and Investigators. Dabigatran vesus warfarin in patients with atrial fibrillation. New Engl J Med. 2009;17; 361: