Anticoagulants for venous thromboembolic disease- Optimizing the old, ushering in the new. Daniel A. Forman, DO RPS Hematology Oncology daniel.forman@readinghealth.org 610 509 5067 cell
RHS Anticoagulation Clinic Opening in November 2013. Doctors office building. 3 rd floor. Patient will need to be referred by a physician with basic information (EPIC). Pharmacy consult on first visit. Twice year visit. You are still in charge! (holding, discontinuation, etc.) Point of care testing available.
Goals Discuss ways to improve the safety and more convenient administration of warfarin. Review efficacy and pharmacologic issues associated with the newer oral anticoagulants.
Warfarin Basics VII, XI, X, II Protein C & S Inhibits Vitamin K Oxide Reductase ( recycles Vit. K) Lack vitamin K prohibits carboxylation of clotting factors (Inactive clotting factors produced) Genetic factors can predict warfarin sensitivity or resistance VKORC1 genotypes CYP2C9 polymorphism
Warfarin Basics Protein C Anticoagulant 8 hours Protein S Anticoagulant 30 hours Factor VII Procoagulant 7 hours Factor IX Procoagulant 24 hours Factor X Procoagulant 36 hours Factor II Procoagulant 50 hours All factors need to be suppressed for anticoagulant effect (takes two days after INR therapeutic)!
Avoid loading doses. INR reflective of rapid decline in factor VII. Confounds the patient s real dose.
Warfarin Dosing African-American - 6.0-7.0 mg/d European - mean ~ 5 mg/d Asian - lower ~ 3.0-3.5 mg/d Obese 14%/S.D. Age 13%/decade Drugs (100 s interactions) Ex. Amiodarone 24% ~ 6.0-7.0 mg/d Asian - lower ~ 3.0-3.5 mg/d
You are treating a 55 y.o. black male presenting with an acute L. lower extremity DVT with IV Heparin, and warfarin that was started on his first hospital day. His dose of warfarin is 5 mg daily. His day 3 INR was 1.0. What is the next best action? A. Stop IV Heparin, start LMWH at therapeutic dosing. Continue warfarin 5 mg daily. B. Change to LMWH as above; but increase warfarin 10 mg daily. C. Continue IV Heparin. Continue warfarin 5 mg daily. D. Continue IV Heparin. Increase warfarin 10 mg daily.
Newly diagnosed VTE disease case: If the INR = 1.0 on Day 3 then double starting dose. LMWH is better than UFH for VTE Disease! No lab testing, Less risk HIT, more clot regression, lower recurrence, lower bleeding, less deaths One study reported 60% patient on UFH failed to achieve adequate aptt response in 24 hours. ACCP 2B recommendation. Arch Intern Med 1988; 148:1321 Chest 2012; 141: e495s
Patient is a 50 y.o. male with a mechanic AVR and atrial fibrillation with a difficult to control INR. The patient s time in the therapeutic range is less than 40 %. His INR today is 5.0, last week it was 1.5. His dose was changed last week from 5 mg daily to 5 mg alternating with 7.5 mg. The patient has seen a dietician and said that he does not eat any vitamin k containing foods. Which of the following is the most reasonable advice? A. Stop warfarin and start dabigatran (Pradaxa) 150 mg bid. B. Continue warfarin at the current dose and recheck the INR in 4 weeks. C. Stop warfarin and start aspirin therapy. D. Start low dose daily vitamin K.
Low dose vitamin k for erratic patients Multiple studies have suggested that daily low dose vitamin k improves INR control 100-200 Mcg day Increasing dietary intake of vitamin K may suffice Not recommended for routine use. Chest 2012;141:e44S-e88S
Patient is a 70 year old man on warfarin for recurrent DVT. The first DVT was 15 years ago after surgery, and the second one was idiopathic and occurred 3 years ago. The patient s INR has been at goal on 5 mg daily. You received a call that his most recent INR is 1.5. The patient is feeling fine, just got back from a cruise, and reports no health changes. What is the next best action? A. Start enoxaparin 1mg/kg SQ Q12 hours and increase dose of warfarin to 7.5mg. B. Increase dose of warfarin to 6mg daily. C. Continue same dose warfarin and repeat INR in two weeks. D. Send the patient to the ER for a stat INR.
INR out of range?? Stable patients with single outlier INR will often fall back into therapeutic range at time of recheck with NO adjustment (60% time) Guidelines support rechecking 1-2 weeks at same dose (2C) One Observational study suggests only adjusting warfarin dose if INR is less than 1.7 or greater than 3.3. Schuman et al Throm Res 2010; 125:393 Rose et al J Throm Haemost 2009; 7:94 Chest 2012; 141S: e44
Next patient is a 42 year old female with multiple dvt s, a second trimester miscarriage, and laboratory confirmed Anti-phospholipid Antibody Syndrome (APAS). She has to leave work early for INR testing and it is causing conflict with her employer. Her INR s have been therapeutic for 6 months on 3 mg alternating with 4mg warfarin every other day. Which of the following is the best approach for this patient? A. Change to dabigatran 150mg po bid. B. Change to aspirin 81mg daily. C. Change to enoxaparin 1.5 mg/kg/day. D. Check the INR every 3 months.
Give your patient a break! PRINT Study- Randomized Controlled Trial, Concluded: Stable patients can have INR s performed every 12 weeks. Less dose change (2% vs. 18%) no increased bleeding. Accepted by CHEST guidelines (2B). Not for Everyone (CHF, New Disease Development, etc). Schulman et al Ann Intern Med 2011; 155:653-9
What is the best way to determine a patient s warfarin dose if he was previously on this medication? A. Genetic testing for VKOR1 polymorphisms. B. Genetic testing for Cytochrome P450 CYP2C9 polymorphisms. C. Dose based upon age, weight, and sex. D. Find out his/her previous dose.
You receive a call from the lab with an INR of 8.6. You call the 70 y.o. patient with PAF and HTN, and he has no bleeding symptoms. He just started ciprofloxin last week for sinusitis given to him by a provider at an urgent care clinic. What is the risk of major bleeding in this patient over the next month? A. 1% B. 5% C. 10% D. 20%
Supratherapeutic INR s Risk of major bleeding is low (1%) when single INR 5-9. Spurious INR suspected if doesn t make sense. Bleeding risk scoring systems for warfarin are not better than clinicians judgment. Donzé J et al. Am J Med 2012; 125:1095 Ageno et al. Chest 2012; 141S: e44
Reversing warfarin without bleeding Wait it out: INR will fall from 6-10 to < 4 in 2.4 days. Vitamin K1 (phytonadione) given orally takes about 1.4 days to bring INR 6-10 to <4. Follow CHEST Guidelines Ageno et al Chest 2012; 141S: e44
Rapid Correction of warfarin in an unstable patient or ICH Vitamin K1 10 mg iv FFP 15ml/kg (4-8 units) Prothrombin Complex Concentrates 3 Factor (II, IX, X) & 4 Factor (II, VII, IX, X) Effective, but thrombogenic Recommended over FFP by ACCP guidelines. rfactor VIIa- Not FDA approved for reversal Lawrence and Shander Blood 2011; 1182
Your patient is a 50 y.o. male who presented 6 months ago with syncope due to an idiopathic PE. He is afraid of dying and does not want to stop warfarin, but he is an international traveler and is concerned about work related travel due to his INR testing. His INR s have not been stable. He takes no other medications. What is the best option for this patient? A. Stop warfarin and recommend aspirin. B. Check INR every 3 months. C. Change to LMWH. D. Change to Rivaroxaban 20 mg daily.
Idiopathic Clot Risk of recurrence 10% per year ( 50% long term) New paradigm and recommendations are to continue indefinite therapy for idiopathic proximal DVT and PE (ACCP 2B) Big Picture: First 3 months: Vigilant therapeutic anticoagulation After 3 months treatment is prophylactic
Ideal anticoagulant Safe and effective Rapid acting Available p.o. and parenteral Rapid elimination Free of drug interactions Predictable effect and wide therapeutic window No need for monitoring Minimal toxicity and side effects Reversible with an antidote
Warfarin VS. Newer Rxs Features Warfarin Newer Agents Onset Slow (days) Rapid Dosing Variable Fixed Half life Long Short Food effects Yes No Drug Interactions Many Few Monitoring Yes No Antidote Yes No (but short ½ life) Cost Low High
Newer Anticoagulants FDA Approval Drug Dabigatran (Pradaxa) Prophylaxis (ortho) A. Fib ACUTE DVT Prolonged treatment DVT/PE x Rivaroxaban (Xarelto) x x x x Apixaban (Eliquis) X x Edoxaban
Drug CYP 3A4 P-gp Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Yes Yes Yes Yes
Dabigatran (Pradaxa) Direct thrombin inhibitor Renal excretion Not for use with mechanical heart valves (increase CVA and bleeding) NEJM 2013; 369:1206 Slight increase for CAD (0.2%) Circulation 2012; 125:669 Dyspepsia
Rivaroxaban (Xarelto) Once daily with food (BID for acute VTE x 3wk) Avoid with medications that affect both the P-gp and Cytochrome P450 3A4. Cyp3A4 inhibitors: (HIV protease inhibitors, ketoconazole, voriconazole) CYP3A4 inducers: (Rifampin, carbamazepine, or phenytoin) No need for overlapping parenteral Tx (ex. LMWH)
Patient is a 57 y.o. male school teacher recently diagnosed with AIDS while admitted for an acute PE. Which of the following is correct? A. HIV/AIDS is not a risk factor for VTE disease. B. Intravenous unfractionated heparin is preferred in HIV patients with acute VTE disease. C. Rivaroxaban is contraindicated in patient on protease inhibitor therapy due to CYP3A inhibition.
Rivaroxaban (Xarelto) vs. Warfarin for acute PE Symptomatic PE +/- DVT Excluded: Cr clearance < 30, Liver disease, SBP <110 or >180, drugs that affect CYP 3A4 Average age 57 10% treated outpatient 12% ICU Conclusion: Rivaroxaban is non-inferior with similar bleeding risk (less major bleeding) N Engl J Med 2012; 366:1287-1297
Apixaban (Eliquis) Twice daily Less bleeding? AMPLIFY Major bleeding or clinically relevant for acute DVT/PE 4.3% vs. 9.7% (warfarin) AMPLIFY EXT for continued therapy after 6-12 months no higher bleeding then placebo. Risk of DVT 12 mo. 1.7% 2.5mg, 1.7% 5mg, and 8% placebo Risk of Death 12mo 3.8%, 4.2%, 11.6% N Engl J Med 2013; 368:699-70
Edoxaban Once daily (60mg) 30mg/d. Cr.Cl 30-50 or weight less than 60kg. Approx. 10% < 60 kg Approx. 10% > 75 y.o. More effective than warfarin in patients with high risk PE. (RV enlargement, elevated BNP). N Engl J Med 2013; 369:1406-1415
Bleeding Patients Supportive measures Last dose? Renal or hepatic dysfunction? Other anticoagulants? If PT normal, unlikely any effect of rivaroxaban. If PTT is normal, unlikely any effect of dabigatran. Oral Anticoagulants: The old and the new. 2012; American Society of Hematology Webinar King et al Chest 2013; 143;:1362
Control of bleeding Modality Dabigatran Rivaroxaban Apixaban Charcoal X X X Hemodialysis X Prothrombin Complex Concentrates X X avii??? King et al Chest 2013; 143: 1362 Gonsalves et al Mayo Clin Proc. 2013; 88: 495
Future is here: 59 y.o. female with breast cancer. Oct 24 th, 2013 Hi Dr. Dan, I bet you thought I died or something. Just got back from the Italy trip on Monday night - had a wonderful time. Didn't think that I was going to be able to go. About a month ago, I had such bad chest pain that I thought I was having a heart attack - turned out to be a blood clot on my lung. Was in the hospital for a week until they got my INR levels correct. Now I am on Warfarin. Oct 25 th, 2013 Dr. Dan, Just had a chemo. treatment today and they checked my pro-time levels - 3.9 - must have been all that wine I drank in Italy. Dr. Latif told me not to take my warfarin tonight and also tomorrow night, but I am to resume on Sunday, but only 5 mg. not the 7.5 mg. 1950 s- present Future One week in the hospital Numerous tests Exposure to sick patients Discharged on therapeutic warfarin Outpatient labs, risk of over and under dosing. Missed work, bills, etc. Start rivoroxaban BID for three weeks then daily. Discharge from the ED or hospital the next day.
Newer Oral Anticoagulants:
Mayo Clinic Proceedings: Wilson I. Gonsalves, MD, et al. Volume 88, Issue 5, Pages 495-511, May 2013 The New Oral Anticoagulants in Clinical Practice http://www.mayoclinicproceedings.org/article /PIIS002561961300222X/fulltext Good Review on the newer anticoagulants Pragmatic advice about how long to hold these agents prior to surgery, changing to warfarin while on these agents, etc.
Summary Try to avoid unnecessary adjustments when managing warfarin. Stable patients on warfarin need less frequent testing. The newer agents appear to be well tolerated with similar, or less bleeding risk. Be careful with potential serious drug interactions, and watch organ function with the newer agents.
Questions?