Safe Effective Use of Warfarin Joshua Steinberg MD

Topics mechanism of action dosing, indications, tx duration, target INR’s drug & food interactions managing elevated INR’s adverse effects perioperative management patient counseling anticoagulate in first place?

Mechanism of Action VII Warfarin Synthesis of Non- Functional Coagulation Factors * as well as anticoagulant proteins C & S Antagonism of Vitamin K VII IX X II Vitamin K acts as a cofactor for Factors VII, IX, X, and II, which are synthesized in the liver Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity. This activation involves the factors undergoing vitamin K dependent post-translational modification, whereby a number of their glutamic acid residues are carboxylated to form gamma-carboxyglutamic acid residues. The gamma-carboxyglutamyl residues serve an essential role in the activity of these clotting factor during hemostasis Warfarin treatment results in the production of inactive clotting factors, which they lack the gamma-carboxyglutamyl side chains necessary for calcium binding and subsequent activity Reversal by vitamin K takes approximately 24 hours

Mechanism of Action Clotting Cascade The blood coagulation process can be activated by one of two pathways, the tissue Factor pathway (formerly known as the extrinsic pathway) and the contact activation pathway (known as the intrinsic pathway). Tissue Factor binds to and activates Factor VII and the Tissue Factor/VIIa complex then activates Factor X and Factor IX to Xa and Ixa respectively. Factor X can also be converted to Xa by IXa (in the presence of Factor VIII). The intrinsic pathway is activated when Factor XII comes in contact with a foreign surface. The resulting Factor XIIa then activates Factor XI, which in turn activates Factor IX. Factor IXa then activates Factor X. Thus Factor Xa can be generated by activation of the tissue factor or contact activation pathways. Factor Xa then cleves prothrombin and the resulting thrombin converts fibrinogen to fibrin. Four of these clotting factors (Factors IX, VII, X and prothrombin) are Vitamin K dependent and therefore their activity is decreased by the Vitamin K antagonist, warfarin. The half-lives of these four Vitamin K dependent clotting factors are shown on this slide. Factor VII has the shortest half life of the Vitamin K dependent coagulation factors. However, for adequate anticoagulation one needs to reduce the other coagulation factors appropriately, including Factor II (prothrombin) which has a 60 hour half life. It takes several days after initiation of warfarin therapy to reduce Factor II and thus warfarin and heparin need to overlap for approximately 4–5 days when starting therapy.

Mechanism of Action Inhibits synthesis of new Vitamin K-dependent coagulation factors II, VII, IX, and X inhibits anticoagulant proteins C & S too Does not have an effect on already-synthesized coagulation factors, therefore therapeutic effects are not seen until these factors are naturally cleared 3-4 days until overall effect is seen Elimination half-lives of Vit K-dept factors II: 42-72 hours VII: 4-6 hrs IX: 21-30 hrs X: 27-48 hrs

Topics mechanism of action dosing, indications, tx duration, target INR’s drug & food interactions managing elevated INR’s adverse effects perioperative management patient counseling anticoagulate in first place?

Dosing Initiating Warfarin Adjusting Warfarin

Initiating Warfarin Case 23 year old suffers fibular fx skateboarding, casted by ortho. A week later, suddenly has new onset pain and swelling in leg, ortho removes cast and dx’es DVT, sent to you for mgmt before re-casting. After starting LMWH Enoxaparin, how do you get Warfarin started?

Initiation Basic idea: do something to get pt started, then convert from initiation to maintenance/adjustment protocols Two general initiation schemes: 5 mg PO qDay for a few days, then follow INR-based schemes 2 mg qD for elderly, malnourished, liver/heart dz, etc. 10 mg PO qDay x2 days loading doses, then follow INR-based schemes algorithms for each, look ‘em up every time (AFP ‘05) some evidence leans towards former, ACCP 2012 expresses mild preference for latter I used to prefer former, then latter, now ambivalent stop Lovenox when when INR nears 2.0

Maintenance Dosing we all use a single Warfarin mgmt protocol practice-wide no evidence that any one protocol better than another but there IS evidence that using a single protocol improves outcomes (more time in therapeutic range, fewer bleeds & clots) we all use the protocol from American Family Physician May 2005 (Ebell, from Univ. Michigan anticoag clinic) modified slightly for ACCP 2012 guideline update there’s a free iPhone app for that, we’ll get to it…

Maintenance Dosing in general dose 4 to 6 mg qDay but could be as little as 2, as much as 10 or even 15, no one’s personal dose can be predicted, gotta just find out by dosing and adjusting Two strategies of simple Warfarin dosing All pts practice-wide receive multiples or fractions of scored 5 mg tablets for all doses All pts practice-wide receive same strength tablet(s) of any strength every day Less simple: combination(s) of above

Multiples/fractions of single tablet (5 mg scored) 1/2 1 Mon Tue Wed Thu Fri Sat Sun Total Weekly Dose 30 mg Multiples/fractions of single tablet (5 mg scored) Mon Tue Wed Thu Fri Sat Sun 4 Total Weekly Dose 28 mg Every day the same, any strength tablet(s) 5 4 Mon Tue Wed Thu Fri Sat Sun Total Weekly Dose 30 mg Different pills different days

Adjustment Warfarin Case 70 y.o. woman with chronic A-fib takes 5 mg PO qDay, nurse reports lab draw shows INR 1.6. What dose adjustment do you order? A) extra 5 mg now, increase dose to 6 mg qD no extra dose, increase daily dose to 6 mg qD change to 5 mg qD except 6 mg qMon & qThu extra 5 mg now, no change daily 5 mg dose not enough info

waaaait! if INR non-therapeutic, before making dose adjustments, ask if anything else disturbing INR such as… non-compliance confused about pills and doses and variations you raised dose last week but pt never got message, didn’t understand (don’t raise dose again!) just plain forgets pills altered health status (liver failure, heart failure) taking new other med, throwing off INR (more later) altererd diet (finally eating veggies, more later)

Adjust Warfarin if INR non-therapeutic and you decide nothing else disturbing INR, adjust the dose when adjusting dose, always think of WEEKLY overall dose adjust weekly dose by 5-ish%, 10-ish%, or 20-ish% weekly dosing has to be composed of easily produced daily doses have to know the target INR 2.5 or 3.0 (more later)

Adjusting Warfarin ACCP 2012: single INR off by ≤ 0.5 option to observe, no change, recheck 7-14 days

Warfarin Dosing Schedule Total Weekly Dose Mon Tue Wed Thu Fri Sat Sun 3 3 3 3 3 3 3 21 mg 2.5 3 20 mg  5% 2 3 19 mg  10% The half life of warfarin is about 40 hours and the half life of prothrombin is about 60 hours. Therefore there is a delay of 2 to 3 days before the full effects of alterations of warfarin dosing is reflected in the INR This slide provides an example of daily warfarin dosing to achieve weekly dosing of 35mg, 30mg and 27.5mg. Thus if the INR is excessive an a weekly dose of 35mg, the dose of warfarin can be reduced by 5 or 7.5 mg/week by altering the daily dosing as shown in rows two and three of the table. It is recommended to treat most patients with a single strength of warfarin tablet and to use multiples or fractions of that tablet on alternate days of the week for different dosing schemes. 2 3 18 mg  15%

Warfarin Dosing Schedule Total Weekly Dose Mon Tue Wed Thu Fri Sat Sun 5 5 5 5 5 5 5 35 mg 6 5 37 mg  5% 7 5 39 mg  10% The half life of warfarin is about 40 hours and the half life of prothrombin is about 60 hours. Therefore there is a delay of 2 to 3 days before the full effects of alterations of warfarin dosing is reflected in the INR This slide provides an example of daily warfarin dosing to achieve weekly dosing of 35mg, 30mg and 27.5mg. Thus if the INR is excessive an a weekly dose of 35mg, the dose of warfarin can be reduced by 5 or 7.5 mg/week by altering the daily dosing as shown in rows two and three of the table. It is recommended to treat most patients with a single strength of warfarin tablet and to use multiples or fractions of that tablet on alternate days of the week for different dosing schemes. 7.5 5 40 mg  15%

Warfarin Dosing Schedule Total Weekly Dose Mon Tue Wed Thu Fri Sat Sun 3 3 3 3 3 3 3 21 mg 4 3 23 mg  10% The half life of warfarin is about 40 hours and the half life of prothrombin is about 60 hours. Therefore there is a delay of 2 to 3 days before the full effects of alterations of warfarin dosing is reflected in the INR This slide provides an example of daily warfarin dosing to achieve weekly dosing of 35mg, 30mg and 27.5mg. Thus if the INR is excessive an a weekly dose of 35mg, the dose of warfarin can be reduced by 5 or 7.5 mg/week by altering the daily dosing as shown in rows two and three of the table. It is recommended to treat most patients with a single strength of warfarin tablet and to use multiples or fractions of that tablet on alternate days of the week for different dosing schemes. 4 3 24 mg  15%

Monitoring next INR ACCP 2012: single INR off by ≤ 0.5 option to observe, no change, recheck 7-14 days ACCP 2012: can stretch testing interval for stable pts to 12 wks (yikes! no!)

Topics mechanism of action dosing, indications, tx duration, target INR’s drug & food interactions managing elevated INR’s adverse effects perioperative management patient counseling anticoagulate in first place?

Indications & Durations of Tx Durations of Treatment DVT or PE A-fib, A-flutter, Paroxysmal A-fib Valve and Structural Heart Disease After major orthopedic surgery Thrombophilia when clear reason for anticoagulation and that reason is short-lived, generally brief tx 3 mos when reason for anticoag lifelong or has no definite endpoint, generally lifelong tx

INR targets Pretty much all target INR’s are 2.5 (range 2.0-3.0) Rare exceptions when higher level anticoagulation proven beneficial mechanical (non- bioprosthetic) valve in mitral position target 3.0 (range 2.5-3.5)

Indications, Targets, Durations

Topics mechanism of action dosing, indications, tx duration, target INR’s drug & food interactions managing elevated INR’s adverse effects perioperative management patient counseling anticoagulate in first place?

Stuff that Messes with Warfarin/INR Drug interactions Diet Alteration of intestinal flora (increase INR) Fever (increase INR) Hepatic failure (incr INR) Heart failure (incr INR) Thyroid (metab of Vit K) hypo decrease INR hyper increase INR Stress (increase INR) Smoking/tobacco use (tobacco has Vit K, decrease INR) Warfarin compliance

Drug Interactions: Increased INR The Biggies Other important ones Fluoroquinolone antibiotics Alcohol Amiodarone Antibiotics (ceph, flagyl, zith, bactrim, etc.) Antifungals Levothyroxine, etc. Statins Omeprazole Phenytoin Heparin Fibrates Cimetadine Ginko, garlic, ginseng

Drug Interactions: Decreased INR Estrogens Vitamin K itself (multivitamins) Alcohol Carbamazepine Barbiturates Phenytoin Ribabutin, rifampin, rifampicin Ritonavir St. John’s Wort

Drug Interactions: no change INR Aspirin Clopidogrel (Plavix) Dipyridamole (Persantine, Aggrenox) NSAIDs BUT!!!! ... some cause bleeding by direct GI mucosal toxicity all potentiate Warfarin by rendering platelets ineffective indications for aspirin, plavix, and warfarin are few indications for NSAIDs and warfarin none!

Food Interactions asparagus avocado broccoli brussel sprouts kale spinach collard turnip mustard greens cabbage cole slaw watercress liver green tea green beans green onions soybeans cauliflower lettuce peas pickles sauerkraut mayonnaise

Interactions case: which worse? 62 y.o. on Dilantin, Amiodarone, and PremPro (estrogen/progesterone HRT), acute DVT needs Warfarin case 62 y.o. on Warfarin, Amiodarone, and PremPro HRT acute seizure needs Dilantin

Topics mechanism of action dosing, indications, tx duration, target INR’s drug & food interactions managing elevated INR’s adverse effects perioperative management patient counseling anticoagulate in first place?

Seriously elevated INR Old scheme before 2012 INR <9, no signif bleed INR >9, no signif bleed serious bleed any INR life threatening bleed any INR 2012 ACCP scheme INR <10, no signif bleed INR >10, no signif bleed Major bleeding any INR

INR <10 no significant bleed ACCP 2012: no Vit K necessary, no other explicit advice* Previous ACCP recommendations: hold Warfarin for 1-2 days consider Vit K 1.0-2.5 mg PO x1 decrease total weekly dose 10-20% monitor INR frequently * this is why previous ACCP advice remains in iPhone app

INR >10 no significant bleed ACCP 2012: give Vit K, no other explicit advice* discussion cites doses of 2.0-2.5 mg PO from studies Previous ACCP recommendations: hold Warfarin consider Vit K 5-10 mg PO x1 monitor INR frequently resume at lower dose when INR (nears) therapeutic * this is why previous ACCP advice remains in iPhone app

Major bleeding any INR ACCP 2012: Previous ACCP recommendations: rapidly reverse Warfarin with four-factor prothrombin complex concentrate (PCC), fresh frozen plasma (FFP), or recombinant factor VIIa, with preference for PCC over FFP give Vit K 5-10 mg slow IV push to reverse Warfarin still in pt’s system, as above reversal factors are short-lived relatively Previous ACCP recommendations: Serious bleeding: hold Warfarin, give Vit K 10 mg slow IV push plus FFP or PCC depending on urgency, repeat Vit K every 12 hrs as needed Life threatening bleeding: hold Warfarin, give PCC or recombinant factor VIIa, give Vit K 10 mg slow IV push to be repeated as needed

Topics mechanism of action dosing, indications, tx duration, target INR’s drug & food interactions managing elevated INR’s adverse effects perioperative management patient counseling anticoagulate in first place?

Adverse Effects Treatment: stop Warfarin Skin necrosis day 3-7 painful red then necrotic skin lesions mainly in fatty areas (buttocks, breasts, hips) incidence 0.01-0.1% Purple toe syndrome week 3-8 blue/purple toes fingers Allergic dermatitis skin rash, hives, itching Vasculitis fever, itching, skin sores or blisters Excessive prothrombin times and higher international normalized ration (INR) have been reported leading to episodes of minor and major HEMORRHAGE. Mini-dose warfarin decreases the potential for major bleeding (Hylak et al, 2000; Gullov 35 al, 1999)(McMahan et al, 1998; Landefeld et al, 1989; Coon & Willis, 1974; Moseley et al, 1963). Patients who develop BLEEDING complications while on anticoagulant therapy should be evaluated for an organic cause (Baugh, 1965) and for drug interactions The incidence of bleeding episodes in patients treated with anticoagulants has been reported to be from 2% to 48% Anticoagulation may persist for up to 48 hours after withdrawal of warfarin Examples of bleeding complications include EPISTAXIS, HEMOPTYSIS, HEMATURIA, GINGIVAL BLEEDING, HEMATOCHEZIA, GUAIAC-POSITIVE STOOL, BRUISING, VAGINAL BLEEDING, SUBCONJUNCTIVAL HEMORRHAGE, and HEMATOSPERMIA. Hemorrhage leading to death, hospitalization, or transfusion is reported in patients on long-term anticoagulant therapy The purple toe syndrome, characterized as a dark cutaneous lesion with blue discoloration of the feet and lower leg, is a relatively rare complication of warfarin therapy (Prod Info COUMADIN(R), 1999); (Soisson et al, 1994)(Hyman et al, 1987); (Akle & Jouner, 1981)(DiCato, 1975). The onset of symptoms is usually between 3 and 8 weeks and typically involves the fingers or toes. The lesion will generally blanche under pressure and tends not to progress or involve more of the affected extremity. Purple toe syndrome is usually painful and the involved areas may be cool to touch. Elevation of the extremity reduces, but does not eliminate the lesion. Although the tenderness and intensity of the purple lesions usually subside within a few weeks of anticoagulant discontinuation, some discoloration can be noticeable for weeks to months. Laboratory values, including prothrombin time, hemoglobin and platelet count, are typically within normal limits and there is no clinical evidence of hemorrhage. Alopecia due to warfarin-therapy has occurred; incidence range from 5% (Spencer & Callen, 1987) to reports as high as 78%. Alopecia is reported to occur after both acute and chronic use (Umlas et al, 1988). The response is directly related to the highest warfarin dose given and not to the duration of treatment. Hair is shed diffusely two or three months after an adequate dose of the drug (Rook, 1965). Marked hair loss is rare and hair growth resumes once warfarin is discontinued (Criscitiello & Levine, 1992). Alopecia may recur upon warfarin re-challenge (Umlas & Harken, 1988). Two case reports in which ubidecarenone (30 milligrams daily) reversed warfarin-induced alopecia despite continuation of warfarin therapy are available (Nagao et al, 1995). Treatment: stop Warfarin

Topics mechanism of action dosing, indications, tx duration, target INR’s drug & food interactions managing elevated INR’s adverse effects perioperative management patient counseling anticoagulate in first place?

Perioperative Warfarin mgmt case 71 y.o. man on Warfarin 5 mg qDay for chronic A-fib will have elective cholecystectomy for symptomatic gallstones. A) do you stop Warfarin? B) when do you stop Warfarin? C) when do you resume Warfarin? D) what do you do to minimize risk of thromboembolic event while pt off Warfarin?

Warfarin & bridging Heparins WARFARIN +/- Heparin ---> day preop 5 4 3 2 1 surgery 1 2 day postop ACCP guideline recommends you handle this based upon risk of thromboembolism during non-anticoagulated time Basically stop Warfarin 5 days before surgery, resume when surgical wounds hemostatic and clinical situation favorable Depending on level of risk of thromboembolic event, cover pt with a Heparin product up until time of surgery and as soon after surgery as pt deemed safe for anticoagulation Can’t go to surgery on Warfarin anticoagulation. You’re definitely going to stop 5-7 days before surgery. [click for animation] You’re definitely going to resume postop when surgery hemostatic. [click for animation] Question is what to do about this middle time [click], should you provide temporary and effective anticoagulation with a Heparin product like Lovenox? Depends on the risk of thromboembolic event.

Thromboembolic Risk while un-anticoagulated If TE risk high, use bridging Heparin If TE risk low, no bridging Heparin If TE risk moderate, no evidence, ACCP says individualize, leans towards bridging

Periop bridging Heparins the PreOpEval iPhone app has all the details and tells you exactly how to do bridging Heparins

Topics mechanism of action dosing, indications, tx duration, target INR’s drug & food interactions managing elevated INR’s adverse effects perioperative management patient counseling anticoagulate in first place?

Patient Counselling carry alert card or bracelet noting Warfarin use inform physician/dentist of Warfarin before surgery or dental work prescription of new medication (i.e. ABX at walk-in) tell physician or pharmacist before taking OTC’s keep all prescriptions at same pharmacy keep diet consistent Vit K foods fine, just eat them consistently keep alcohol minimal (or zero) and consistent importance of INR monitoring appointments importance of Warfarin compliance, clarity of dosing side effects and signs/symptoms of bleeding

Topics mechanism of action dosing, indications, tx duration, target INR’s drug & food interactions managing elevated INR’s adverse effects perioperative management patient counseling anticoagulate in first place?

Should pt be on Warfarin? case 68 y.o. male former alcoholic dry x3 yrs has A-Fib from alcoholic cardiomyopathy (well preserved EF 55%). After surviving a GI bleed (EtOH ulcer) and cleaning up his life, he has mild COPD from former smoking but otherwise is healthy. A) should he be on Warfarin for A-Fib? B) what is his risk of bleed on Warfarin? C) what is his risk of stroke from non-anticoagulated A-Fib? you can quantify this stuff…

Risk on vs. off Warfarin CHADS2 score ---> 1.9% annual stroke risk OBRI score ---> 2.5% annual major bleeding risk

Anticoagulate? case 87 y.o. woman moderately demented from Alzheimers, well cared for at home by her family, but she does fall from time to time. She has chronic A-Fib. A) should she be on Warfarin for A-Fib? B) what are pros? C) what are cons? D) how would you counsel the family to make this choice?

There’s an App for that… PreOpEval has periop Warfarin & bridging Heparins Warfarin Guide has Indications INR targets Durations of therapy Adjustment protocol Initiation info free at Apple iOS (iPhone) App Store go get ‘em

References American College of Chest Physicians (ACCP) 9th edition Antithrombotic and Thrombolytic Therapy Guidelines, Chest, February 2012 Ebell, “Evidence Based Initiation of Warfarin” and “Evidence Based Adjustment of Warfarin Doses”, American Family Physician, February & May 2005 Qx Calculate iPhone app for CHADS2 Score for A-fib and OBRI Warfarin Bleeding Risk WarfarinGuide iPhone app & PreopEval iPhone app slides on mechanism of action, drug/food interactions, adverse effects adapted from warfarin mgmt presentations available online by Margaret Jin PharmD 2007, Christen Freeman PharmD, and Flavio Guzman MD 2010