WARFARIN Monitoring(A Case with Prosthetic heart valve)

MN Arham

Case History

• 51 year old lady referred by the Bisho Hospital on 17th Jan 2008 with a letter stated she is have a pace maker, later on examination no pace maker was found.

• Patients presented with dizziness, generalized body weakness, loss of appetite, nausea, confusion and irritability started from last night.

• She has been operated for some valvular problem in 2001 at Cape Town

• Unmarried, non smoker and non alcoholic• She is on Digoxin 0.125mg daily, Coversyl 4 mg daily and

Warfrin 10 mg daily from local hospital• Known Hypertensive, No previous medical record found

Examination

• Pulse 52/min, Blood Pressure 67/30, R/R 24/min, Sa O2 95% at room air, afebrile, pale and no raised JVP

• Resp: Tachypanic, vertical scar mark on the chest, trachea central and vesicular breathing.

• GIT: Soft non tender and no vicero megaly• CVS: Bradycardia, Apex beat 5th ICS medial to MCL,

Atrial Fibrillation and Clicks audible• CNS: She is confused irritable and not responding to

commands properly. She is moving all her limbs, Pupil is constricted but responsive to light & no focal sign seen.

ECG

Rate is 100, Irregular Rhythm, Right axis deviation & Right bundle branch block

Differential

• Hypotension (Shock)• Warfarin Toxicity• Internal bleed• Digoxin toxicity• Atrail Fib

LabsTest 17/01/2009 17/01/2009 (post

transfusion FFP & PCV)18/01/2009

Sodium 131 137

Potassium 5.4 6.0

urea 15.5 38.6Creatinine 263 689CRP 35.6

WBC 12.50 27.92 27.4

Hb 5.4 12.3 10.7

MCV 92 89 89

Platelets 66 122 144

INR > 10 2.20 2.64

PTT > 180 31.2 37.9

c Calcium 2.58 D-dimers 1.28 Ref : < 0.25 mg/l

Digoxin: 1.9 nmol/L (1.0- 2.8)Alb 13

Mg 0.49 Blood Culture (Negative)

Pos 0.88

Blood Gases

17th 16:30 17th 23:31 18th 01:35 18th 06:30

Site V A A -

PH 7.33 7.26 7.3 7.5

Pco2 kPa 1.4 3.05 2.6 2.2

Po2 kPa 6.2 7.8 7.3 3.5

Hco3 mmol/L 25 12.4 14.5 17.8

BE mmol/L -10 -15.8 -12.5 -8

Diagnosis

• WARFARIN Toxicity• Internal Bleeding

Management

• Passed IV line rush 200 ml N/S X2• Shifted to ICU• Continue to push the fluids N/S to resolve the hypotension• Patients become tachypanic, desturating, exhausted and

still low BP planed to intubate during intubation went into arrest, CPR done, Later having Vent Fbrillation leading to cardioversion.

• Patients return to Atrial fib and continue the ventilator support.

• Blood (3 units) and FFP (2 units) transfused• Almost 4.2 litres of fluids pushed in 12 hours and urine

output was 300 + 37 ml (during her stay in ICU)• Next day patient RIP near 9:30 AM

WARFARIN

Normal haemostatic mechanisms: clotting factors of the intrinsic and extrinsic pathways.

The reactions (in the boxes) take place on the platelet surface. The dotted lines represent positive feedback effects from small amounts of thrombin. This greatly enhances the activity of the coagulation network and results in large amounts of thrombin generation and thus fibrin formation in the clot. Ref: Davidson’s Principles and practice of Medicine 20 e

Where the Warfarin (Coumarins) Act?

Lüllmann, Color Atlas of Pharmacology © 2000 Thieme

Mechanism of Action of WarfarinCoumarins (Warfarin) inhibit

hepatic synthesis of the vitamin K-dependent coagulation factors II (prothrombin), VII, IX, and X and the anticoagulant proteins C & S.

Vitamin K is a cofactor in the synthesis of these clotting factors. The vitamin K-dependent step involves carboxylation of glutamic acid residues and requires regeneration of vitamin K to its reduced form.

Coumarins and related compounds inhibit vitamin K 1 -2,3 epoxide reductase, preventing vitamin K from being reduced to its active form. The degree of effect on the vitamin K-dependent proteins depends on the dose and duration of treatment with warfarin.

Ref: Davidson’s Principles and practice of Medicine 20 e, emedicine and Medscape

MOA (continued...)Warfarin cant act so soon.........Each factor differs in its degradation half-life; • factor II requires 60 hours • factor VII requires 4-6 hours• factor IX requires 24 hours• factor X requires 48-72 hours. • The half-lives of proteins C and S are approximately 8 and 30

hours, respectively. • warfarin leads to hypercoagulable state occur shortly after

treatment with warfarin is started. • Rapid loss of protein C temporarily shifts the balance in favor

of clotting until sufficient time has passed for warfarin to decrease the activity of coagulant factors.

Pharmacokinetics• The oral bioavailability of warfarin is nearly 100%.

Warfarin is highly bound (approximately 97%) to plasma protein, mainly albumin. The high degree of protein binding is one of several mechanisms whereby other drugs interact with warfarin.

• Warfarin is distributed to the liver, lungs, spleen, and kidneys. It does not appear to be distributed to breast milk in significant amounts. It crosses the placenta and is a known teratogen.

• Warfarin is metabolized by hepatic cytochrome P-450 (CYP) isoenzymes and in kidney which are excreted in the bile, urine and stool*.

• Warfarin metabolism may be altered in the presence of hepatic dysfunction or advanced age but is not affected by renal impairment

* Majerus PW, Broze GJ, Miletich JP, Tollefsen DM. Anticoagulant thrombolytic, and antiplatelet drugs. In Hardman JG, Limbird LE, eds. Goodman and Gilman's The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996:1347-51.

Pharmacokinetics• The half-life of warfarin ranges from 20 to 60 hours.• The mean plasma half-life is approximately 40 hours, and the

duration of effect is two to five days*. Thus, the maximum effect of a dose occurs up to 48 hours after administration, and the effect lingers for the next five days.

• Drug interactions are numerous and include agents from a variety of pharmaceutical classes, such as antibacterials, antimycobacterials, antifungals, antiarrhythmics, anticonvulsants, antihyperlipidemics, antineoplastics, nonsteroidal anti-inflammatory agents, H2-receptor antagonists, immunosuppressive agents, and many others.

• Bleeding is the only expected symptom of significance in the history. Internal bleeding may present a vast array of symptoms or be occult.

* Majerus PW, Broze GJ, Miletich JP, Tollefsen DM. Anticoagulant thrombolytic, and antiplatelet drugs. In: Hardman JG, Limbird LE, eds. Goodman and Gilman's The pharmacological basis of therapeutics. 9th ed. NewYork: McGraw-Hill, 996:1347-51.

Drug Interactions (a long list)

• Lack of familiarity with these interactions may lead to clinically relevant and avoidable increases or decreases of prothrombin time (PT).

• Drugs that can prolong the prothrombin time• Inhibition of warfarin metabolism

Allopurinol, Amiodarone Azole antifungals Capecitabine, Chloramphenicol, Chlorpropamide, Cimetidine, Ciprofloxacin, Cotrimoxazole, Disulfiram, Ethanol (acute ingestion) Flutamide, Isoniazid (INH), Metronidazole, Norfloxacin, Ofloxacin, Omeprazole, Phenytoin, Propafenone, Propoxyphene, Quinidine, Statins (particularly lovastatin and pravastatin), Sulfinpyrazone, Sulfonamides, Tamoxifen, Tolbutamide, Zafirlukast, Zileuton

Drug Interactions (a long list)

• Inhibition of vitamin K activity– Oral antibiotics, especially parenteral cephalosporins (Oral

cefaclor, cefixime, cefpodoxime, cefuroxime, cephalexin, and cephradine have not been shown to interact with warfarin.)

– High dose of penicillins (possibly due to decreased GI flora synthesis of vitamin K)

• Additive anticoagulant effect– Aspirin– Heparin

Dosing• The initial dose of Warfarin should approximate the chronic

maintenance dose that is anticipated. In most patients, the average maintenance dose is 4 to 6 mg per day.

• Dose has an inverse relation with age. In patients 50 years old, the average daily dose is 6.3 mg; in patients 70 years old, the average daily dose is 3.6 mg*.

• As needed, doses can be easily changed by looking at the cumulative weekly dosage and adding or subtracting 10 to 20 percent evenly over the week*** (Figure 1). This approach is possible because of warfarin's long half-life. It is a safe and effective way to provide sufficient anticoagulation.

• Heparin and warfarin therapies should overlap for approximately four to five days.

• Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med 1992;116:901-4.

** Ansell JE. Oral anticoagulant therapy--50 years later. Arch Intern Med 1993;153:586-96. American Academy of Family Physicians

Dosing Algorithm (Figure 1)

Only one tablet strength (5 mg) is used. Fractions or multiples of the tablet can be used for different doses, or alternative doses can be given based on the day of the week. Dose adjustments should be made based on the total weekly dosage, with increases or decreases of 10 to 20 percent spread out over the week*.

* Carter BL. Therapy of acute thromboembolism with heparin and warfarin. Clin Pharm 1991;10: 503-18

Dosing Algorithm INR of 2 to 3 (Figure 2)

Algorithm for establishing a percentage change in the weekly warfarindosage to achieve an INR of 2 to 3. (INR=International Normalized Ratio)

Dosing Algorithm INR of 2.5 to 3.5 (Figure 3)

Anticoagulation (Prosthetic heart valves)

INR Duration

The goal of anticoagulant therapy is to administer the lowest possible dose of anticoagulant to prevent clot formation or expansion. The required degree of anticoagulation continues to evolve as studies provide more information about the efficacy and safety of lower doses*.

‡--Depending on the type of mechanical valve (i.e., caged ball or caged disk) and the valve position (mitral), some patients may benefit from INRs in the upper end of the range.* Stein PD, Alpert JS, Copeland J, Dalen JE, Goldman S, Turpie AG. Antithrombotic therapy in patients withmechanical and biologic prosthetic heart valves. Chest 1995;108(4 Suppl):371S-9S [Published erratum inChest 1996;109:592].

Laboratory Studies (in Toxicity)

• Blood levels of warfarin are neither readily available nor helpful. The anticoagulant effect is best quantified by baseline and daily repeated measurement of the PT and the international normalized ratio (INR), which may not be elevated until 1-2 days postingestion.– A normal PT 48-72 hours after ingestion rules out

significant ingestion.• Other lab tests that may be indicated include a blood count

for baseline hemoglobin and/or hematocrit or to assess for anemia if the ingestion is more remote.

• A blood type and crossmatch or antibody screening is indicated if substantial blood loss is suggested.

• In addition, other laboratory tests (eg, acetaminophen level) or toxicology screening may be indicated to rule out co-ingestions.

Toxic Dose Toxicity is related to the intensity of anticoagulation length of therapy the patient's underlying clinical state use of other drugs that may affect hemostasis or interfere with warfarin

metabolism. Fatal or nonfatal hemorrhage may occur from any tissue or organ• The toxic dose is highly variable.

– Generally, a single ingestion of warfarin (10-20 mg) does not cause serious intoxication.

– In contrast, chronic or repeated ingestion of even small amounts (2-5 mg/d) eventually can lead to significant anticoagulation, especially in the presence of interacting drugs.

– Patients with hepatic dysfunction, malnutrition, or a bleeding diathesis are at greatest risk.

Risk factor for Hemorrhagic Complications of Anticoagulation

• The most common complication of warfarin therapy is bleeding, which occurs in 6 to 39 percent of recipients annually **

Age greater than 65 years¹ Age greater than 75 years with concomitant atrial fibrillation (intracranial hemorrhage)² History of gastrointestinal bleeding³ Comorbid disease states* Hypertension³ Cerebrovascular disease** Serious heart disease Renal insufficiency¹ Landefeld CS, Rosenblatt MW, Goldman L. Major bleeding in outpatients treated with warfarin: incidence andprediction by factors known at the start of outpatient therapy. Am J Med 1989;87:144-52.² Albers GW. Atrial fibrillation and stroke: three new studies, three remaining questions. Arch Intern Med1994;154:1443-8 & Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449-57 [Published erratum in Arch Intern Med1994;10:2254].³ Routledge PA, Chapman DH, Davies DM, Rawlins MD. Pharmacokinetics and pharmacodynamics of warfarinat steady state. Br J Clin Pharmacol 1979; 8:243-7.* Fihn SD, McDonell M, Martin D, Henikoff J, Vermes D, Kent D, et al. Risk factors for complications ofchronic anticoagulation: a multicenter study. Ann Intern Med 1993;118:511-20.** Hirsh J, Dalen JE, Deykin D, Poller L, Bussey H. Oral anticoagulants: mechanism of action, clinicaleffectiveness, and optimal therapeutic range. Chest 1995;108(4 Suppl):231S-46S.

Complications• Hemorrhagic complications, are the major concern.• Skin necrosis, usually observed between the third and eighth days of therapy

– Can be extremely severe and disfiguring and may require treatment through debridement or amputation of the affected tissue, limb, breast, or penis.

– It occurs more frequently in women and in patients with preexisting protein C deficiency and, less commonly, in men and in patients with protein S deficiency. Patients initially become hypercoagulable because warfarin depresses levels of the anticoagulant proteins C and S more quickly than coagulant proteins II, VII, IX, and X.

– Extensive thrombosis of the venules and capillaries occurs within the subcutaneous fat. Women note an intense, painful burning in areas such as the thigh, buttocks, waist, and/or breast several days after beginning warfarin; skin necrosis and permanent scarring may follow.

– Immediate withdrawal of warfarin therapy is indicated. Heparin can be substituted safely for warfarin.

– Restarting warfarin therapy at a low dose (eg, 2 mg) while continuing heparin treatment for 2-3 days may be reasonable. The dosage of warfarin can be increased gradually over several weeks.

Complications (continued...)• Warfarin crosses the placenta during pregnancy and has the potential

to cause teratogenesis and bleeding in the fetus. Warfarin and other Coumadin derivatives cause an embryopathy commonly termed fetal warfarin syndrome (FWS)

• Other adverse reactions that occur infrequently with chronic warfarin therapy include agranulocytosis, alopecia, anaphylactoid reactions, anorexia, cold intolerance, diarrhea, dizziness, elevated hepatic enzyme levels, exfoliative dermatitis, headache, hepatitis, jaundice, leukopenia, nausea and/or vomiting, pruritus, and urticaria.

• Rare events of tracheal or tracheobronchial calcification are reported in association with long-term warfarin therapy. The clinical significance is not known. Priapism is associated with anticoagulant administration; however, a causal relationship with warfarin is not established.

How to Proceed for Toxicity?

• Initiate usual supportive measures, including intravenous access if any suggestion of remote or active bleeding is evident. After an acute intentional ingestion, administer activated charcoal per local protocols. Infuse crystalloid solution if signs of significant blood loss are present.

Emergency Department Care• Initiate usual advanced supportive measures. Evaluate for

current or remote bleeding with a thorough physical examination, including a rectal examination as indicated to check for occult GI bleeding. If significant bleeding has occurred and the patient is unstable, be prepared to treat the patient with transfusions of packed cells and fresh frozen plasma as first-line therapy. Further evaluation varies, depending on the situation.

How to Proceed for Toxicity?• For acute ingestions, with no bleeding

– Obtain a baseline PT/INR and repeat within 24-48 hs– Administer activated charcoal if it was not already given in the field.– Gastric lavage is unnecessary if rapid administration of activated charcoal is

feasible. Do not induce emesis.– Treat any co-ingestions, evaluate the patient for suicidal intention.– Avoid drugs that may enhance bleeding or decrease metabolism of the

anticoagulant.– Do not administer vitamin K prophylactically because 1. it is not needed in most patients2. its presence masks the onset of anticoagulant effects in patients who do require

prolonged treatment and follow-up care.– If the PT time is elevated, treatment with vitamin K is appropriate. Because vitamin

K does not immediately restore therapeutic levels of clotting factors, treat patients who are experiencing acute hemorrhage with fresh frozen plasma (FFP).

– Recombinant activated factor VII, while costly, may have an advantage over FFP in that it does not carry a risk of transmission of viral disease, allergic reaction, or volume overload*.

* Miller MA, Levy PD, Hile D. Rapid identification of surreptitious brodifacoum poisoning by analysis of vitamin K-dependent factor activity. Am J Emerg Med. May 2006;24(3):383

How to Proceed for Toxicity?• Chronic intoxication resulting from therapeutic use of warfarin can be evaluated with a

careful physical examination and a measurement of the PT and INR.– If INR is higher < 6 and the patient is not bleeding, withhold warfarin for 2-3 days and

restart when the INR approaches the therapeutic range.– If INR is >6 but less than 10 and the patient is not bleeding, or the INR is < 6 but the

patient requires more rapid reversal (eg, for elective surgery), administer 5-10 mg of vitamin K-1 orally with the expectation that the INR will begin to fall within 8 hours with a maximal effect in about 24 hours.

– If the INR is > 10 and the patient is not bleeding, a higher daily dose of oral vitamin K-1 may be administered.

– If very rapid reversal of anticoagulant effect is essential because of serious bleeding, administer fresh frozen plasma. Successful reversal of severe coagulopathy and life-threatening hemorrhage has been reported using recombinant activated factor VII. While costly, this therapy may have an advantage over FFP in that it does not carry a risk of transmission of viral disease, allergic reaction, or volume overload*.

Note: If the patient has a critical need for ongoing anticoagulation (eg, mechanical heart valve), heparin should be given as a temporary measure while fully reversing the effects of warfarin.

* Miller MA, Levy PD, Hile D. Rapid identification of surreptitious brodifacoum poisoning by analysis of vitamin K-dependent factor activity. Am J Emerg Med. May 2006;24(3):383

How to Proceed for Toxicity?• Packed red cells and fresh frozen plasma may be required for

immediate management of life-threatening hemorrhagic complications.

• Alternative treatments to FFP include prothrombin complex concentrates or recombinant factor VIIa. Data are limited on the use of recombinant factor VIIa for the reversal of warfarin-induced coagulopathy.

• Vitamin K is the only effective antidote for long-term management, but reversal of anticoagulation takes several hours.

• Administering vitamin K IV has no advantage, and reports have documented acute cardiovascular collapse after administration by this route, presumably caused by an anaphylactoid reaction. IM or SC administration may cause hematoma. In the authors' opinion, oral administration, when possible, is preferred.

Algorithm for Warfarin Rx patient

Algorithm for Warfarin Rx patient (continued..)

NOTE: Clinical judgment should be used when assessing the severity of bleeding. In addition, patients who are given doses of vitamin K that leave them refractory to warfarin should receive heparin until warfarin therapy is again therapeutic.

• *--Rapid reversal of major warfarin overdose should be treated by following the steps for managing serious bleeding.

• †--In patients with life-threatening bleeding or serious warfarin overdose, PCC should be given with IV vitamin K, 10 mg. If PCC (PCC=prothrombin complex concentrate) contains factor VII, vitamin K administration is not usually necessary.

• ‡--Patients with an INR of less than 6 may not require vitamin K administration for reversal; if vitamin K is administered, a dose of 0.5 to 1 mg is sufficient.

Studies support the use of Warfarin for Prosthetic heart valves

• The most convincing evidence that oral anticoagulants are effective in patients with prosthetic heart valves comes from a study of patients randomized to receive warfarin in uncertain intensity versus either of 2 aspirin-containing platelet-inhibitor drug regimens for 6 months*

• The incidence of thromboembolic complications in the group that continued warfarin was significantly lower than that of the groups that received antiplatelet drugs (relative risk reduction 60% to 79%). The incidence of bleeding was highest in the warfarin group.

* C.K. Mok, J. Boey, R. Wang et al., Warfarin versus dipyridamole-aspirin and pentoxifylline-aspirin for the prevention of prosthetic heart valve thromboembolism: a prospective clinical trial. Circulation 72 (1985), pp. 1059–1063

Studies support the use of Warfarin for Prosthetic heart valves

• Another study³ of patients with mechanical prosthetic valves treated with aspirin and dipyridamole found no difference in efficacy between moderate-intensity (INR 2.0 to 3.0) and high-intensity (INR 3.0 to 4.5) warfarin regimens, but more bleeding occurred with the high-intensity regimen.

• One study of patients with bioprosthetic heart valves found a moderate dose regimen (INR 2.0 to 2.25) as effective as a more intense regimen (INR 2.5 to 4.0) but associated with less bleeding ¹.

• A second study², involving patients with mechanical prosthetic heart valves, found no difference in effectiveness between a very high-intensity regimen (INR 7.4 to 10.8) and a lower-intensity regimen (INR 1.9 to 3.6), but the higher-intensity regimen produced more bleeding.

¹ R. Hull, J. Hirsh, R. Jay et al., Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 307 (1982), pp. 1676–1681² A.G.G Turpie, J. Gunstensen, J. Hirsh et al., Randomized comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet 1 (1988), pp. 1242–1245³ J.N. Saour, J.O. Sieck, L.A.R. Mamo et al., Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med 322 (1990), pp. 428–432.

Studies support the use of Warfarin for Prosthetic heart valvesA more recent randomized trial showed that addition of aspirin (100 mg/d) to warfarin (INR 3.0 to 4.5) improved efficacy compared with warfarin alone ¹. This combination of low-dose aspirin and high-intensity warfarin was associated with a reduction in all-cause mortality, cardiovascular mortality, and stroke at the expense of increased minor bleeding.

¹ A.G. Turpie, M. Gent, A. Laupacis et al., A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 329 (1993), pp. 524–529

OPTIMAL ORAL ANTICOAGULANT THERAPY IN PATIENTS WITH MECHANICAL HEARTVALVES

A retrospective study of 16 081 patients with mechanical heart valves in the Netherlands attending 4 regional anticoagulation clinics (target INR 3.6 to 4.8) found a sharp rise in the incidence of embolic events when the INR fell to <2.5, whereas bleeding increased when the INR rose to >5.0².

² S.C. Cannegieter, F.R. Rosendaal, A.R. Wintzen et al., Optimal oral anticoagulant therapy in patients with mechanical heart valve prostheses: the Leiden artificial valve and anticoagulation study. N Engl J Med 333 (1995), pp. 11–17

Warfarin Ischemic Stroke and Intracranial Hemorrhage

One of the physician's most difficult tasks is to decide whether the risk of anticoagulation outweighs the potential benefit of warfarin therapy in an elderly patient.

• Data from the Stroke Prevention in Atrial Fibrillation (SPAF II) trial² suggest that the safety of anticoagulation in the elderly can be maximized through careful monitoring and maintenance of an INR between 2 and 3.

• Another recent study³ investigated the incidence of ischemic stroke in elderly patients with atrial fibrillation who were receiving anticoagulant therapy. This study found that subtherapeutic INRs (i.e., those below 2) have associated risks of thrombotic events.

² Stroke prevention in atrial fibrillation study: final results. Circulation 1991;84:527-39³ Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylacticanticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335:540-6.

Warfarin and Intracranial Haemorrhage

One study¹ found that the risk of intracranial hemorrhage among the elderly is highest in patients with poor control (large variations in INR), patients receiving high-intensity therapy (INR greater than 4) and patients older than 80 years.

Fig: Adjusted Relative risk s for bleeding complications and 95% confidence interval according to age category

¹ Fihn SD, Callahan CM, Martin DC, McDonell MB, Henikoff JG, White RH. The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med 1996;124:970-9.

International GuidelinesGuidelines developed by the European Society of Cardiology¹ called for

anticoagulant intensity in proportion to the thromboembolic risk to specific types of prosthetic heart valves.

• For 1st gen valves, an INR of 3.0 to 4.5 was recommended. An INR of 3.0 to 3.5 was considered sensible for 2nd genvalves in the mitral position, whereas an INR of 2.5 to 3.0 was deemed sufficient for 2nd gen valves in the aortic position.

The American College of Chest Physicians guidelines² of 2001 recommended • an INR of 2.5 to 3.5 for most patients with mechanical prosthetic valves and

of 2.0 to 3.0 for those with bioprosthetic valves and low-risk patients with bileaflet mechanical valves (such as the St Jude Medical device) in the aortic position.

• Similar guidelines have been promulgated conjointly by the American College of Cardiology and the American Heart Association³. In contrast, a higher upper limit of the therapeutic range (INR 4.8 to 5.0) has been recommended by some European investigators.

¹ Gohlke-Barwolf, J. Acar, C. Oakley et al., Guidelines for prevention of thromboembolic events in valvular heart disease: Study Group of the Working Group on Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 16 (1995), pp. 1320–1330.² P.D. Stein, J.S. Alpert, J.E. Dalen et al., Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 114 Suppl (1998), pp. 602S–610S³ ACC/AHA 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 (Committee on Management of Patients with Valvular Heart Disease). J Am Coll Cardiol 32 (1998), pp. 1486–1588.

Conclusion of the studies

Warfarin compared to Aspirin• Increased bleeding incidence with warfarin and increased

thromboembolic complication with aspirin and vice versa.Warfarin alone• Less bleed with moderate regimen (INR 2.0-2.25) as compared to

intense one (INR 2.5-4.0).• Low INR leads to embolic Event and high leads to bleed.• Increased Intracranial bleed in 1. Elderly2. Poor control3. High intensity therapy

Note: All studies suggest that tighter control of therapy at an INR range of 2 to 3 is superior to use of lower level of anticoagulation.

Final Comment

1. Identify the therapeutic goal2. Estimate the chronic maintenance dosage based on the

presence of factors associated with hyperresponsiveness or hyporesponsiveness, such as concomitant drug use, liver disease and poor nutrition.

3. Initiate therapy at the patient's anticipated maintenance dosage.

4. Loading doses are not necessary.5. Make any necessary adjustments by looking at the

cumulative weekly dosage and adding or subtracting 10 to 20 percent evenly over the week.

6. Remain alert to potential warfarin-drug interactions and educate your patients also.

References• Lai MW, Klein-Schwartz W, Rodgers GC, Abrams JY, Haber DA, Bronstein AC. 2005 Annual Report

of the American Association of Poison Control Centers' national poisoning and exposure database. Clin Toxicol (Phila). 2006;44(6-7):803-932.

• Deveras RA, Kessler CM. Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med. Dec 3 2002;137(11):884-8.

• Caravati EM, Erdman AR, Scharman EJ, Woolf AD, Chyka PA, Cobaugh DJ. Long-acting anticoagulant rodenticide poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2007;45(1):1-22.

• Miller MA, Levy PD, Hile D. Rapid identification of surreptitious brodifacoum poisoning by analysis of vitamin K-dependent factor activity. Am J Emerg Med. May 2006;24(3):383.

• Tsutaoka BT, Miller M, Fung SM, et.al. Superwarfarin and glass ingestion with prolonged coagulopathy requiring high-dose vitamin K1 therapy. Pharmacotherapy. Sep 2003;23(9):1186-9.

• Anderson IB. Coumarin and related rodenticides. In: Poisoning and Drug Overdose. 2nd ed. Appleton & Lange; 1994:143-145.

• Chua JD, Friedenberg WR. Superwarfarin poisoning. Arch Intern Med. Sep 28 1998;158(17):1929-32.

• Gitter MJ, Jaeger TM, Petterson TM, et al. Bleeding and thromboembolism during anticoagulant therapy: a population- based study in Rochester, Minnesota. Mayo Clin Proc. Aug 1995;70(8):725-33.

References

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Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 1998;16(5):443-97.

• Mullins ME, Brands CL, Daya MR. Unintentional pediatric superwarfarin exposures: do we really need a prothrombin time?. Pediatrics. Feb 2000;105(2):402-4.

• Smolinske SC, Scherger DL, Kearns PS, et al. Superwarfarin poisoning in children: a prospective study. Pediatrics. Sep 1989;84(3):490-4.

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