08/03/2015. Anticoagulation in the Elderly: Using New Direct Acting Oral Anticoagulants (DOACs) Indications for Anticoagulation

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1 Anticoagulation in the Elderly: Using New Direct Acting Oral Anticoagulants (DOACs) Steven Zweig, MD, MSPH MU School of Medicine MU Interdisciplinary Center on Aging Caring for the Frail Elderly Conference August 2015 Indications for Anticoagulation Prevention of venous embolization Treatment of deep vein thrombosis or pulmonary embolism Surgical prophylaxis of high risk patients Prevention of systemic embolization Atrial fibrillation Valvular heart disease Warfarin in Long term Care Settings Risks are greater because these are the most frail of patients High prevalence of conditions requiring use Age, comorbid conditions, diet, medications affect pharmacodynamics making dosing and monitoring challenge As many as 12% or 200,000 may be affected Gurwitz JH, Field TS, Radford MJ et al. Am J Med 2007;120:

2 Warfarin Challenging in Clinical Practice Narrow therapeutic window Variability in dose response Subject to multiple drug interactions Laboratory control that can be difficult to standardize Problems is dosing as result of miscommunication and patient nonadherence to regimen Ansell J, Hirsch J, Poller L, et al. Chest 2004; s 233s. Warfarin Pharmacology Modulates y carboxylation of Vitamin K dependent proteins (Factors II,VII,IX,X) which reduces binding to phospholipid surfaces Warfarin is rabidly absorbed, max concentration in 90 minutes, hour half life, accumulates in liver where R and S isomers are metabolized by two different pathways S (more potent) cytochrome P450 2C9 reduced by cotrimoxazole, metronidazole, others; R isomer metabolism reduced by cimetadine and omeprazole Impact of thyroid metabolism and drugs affecting platelets (ASA, NSAIDs) First year of warfarin therapy for patients with atrial fibrillation 472 community dwelling patients over 65 years managed by onsite anticoagulation clinic at Mass General Hospital % of time INR 2 3; only 8 of 26 with major hemorrhage INR was >4 7.2 per 100 person years major hemorrhage; patients >80 years 13.1 per 100 person years 26% of >80 stopped warfarin within first year; 81% due to concerns of safety Hyeck EM, Evans Molina C, Shea C, et al. Circulation 2007;115:

3 Use of the new Direct Acting Oral Anticoagulants (DOACs) Pharmacology How do they work How long do they last Indications Risks vs benefits compared with conventional therapies Special considerations in frail elders Dosing guidelines Reversal of DOACs in severe bleeding Cases Special challenges in the nursing home Indications and timelines may be obscure or miscommunicated. Multiple providers may be ordering meds or tests. Ordered tests may be forgotten or unrecorded. Multiple drugs increase risk for interaction. Treated patients also at increased risk if they become ill (fever, dehydration, CHF, diarrhea). Direct anticoagulants: Factor X inhibitors Rivaroxaban, apixaban, edoxaban Rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) are oral direct factor Xa ("ten a") inhibitors. Generic names for these agents include "Xa ban" (eg, rivaroxaban, apixaban, edoxaban) Other anticoagulants inhibit factors Xa and thrombin, but their effects are indirect. Heparins inhibit factor Xa and to a lesser extent thrombin and fondaparinux inhibits factor Xa. Both are mediated through antithrombin. 3

4 Direct anticoagulants: Thrombin inhibitors Direct thrombin inhibitors inactivate clot bound and circulating thrombin (factor IIa). Parenteral versions may be used in persons with coronary thrombosis. Unlike heparin, direct thrombin inhibitors do not bind to platelet factor 4 (PF4), do not induce or react with the anti heparin/pf4 antibodies that cause heparin induced thrombocytopenia. Dabigantrin etexilate (Pradaxa) is an oral drug that is converted in the liver to dabigatran, an active direct thrombin inhibitor that inhibits clot bound and circulating thrombin. Dosing of DOACs Rivaroxaban 15 mg twice daily (for the first three weeks), then 20 mg daily Apixaban 10 mg twice daily (for first seven days), then 5 mg bid Edoxaban 60 mg once daily (and 30 mg once daily in patients with a CrCl 15 to 50 or a body weight below 60 kg) Dabigatran 150 mg twice daily 4

5 Excretion of DOACs Rivaroxaban Excretion is approximately 35 percent renal; severe hepatic impairment could result in bio accumulation. Apixaban Excretion is approximately 25 percent renal; severe hepatic impairment could result in bio accumulation. Edoxaban Excretion is approximately 35 percent renal; severe hepatic impairment could result in bio accumulation. Dabigatran Excretion is approximately 80 to 85 percent renal. Indications for anticoagulation in the elderly Preventing stroke in atrial fibrillation Treating venous thromboembolism (VTE) Deep vein thrombosis Pulmonary embolism Preventing VTE Knee and hip replacement Hip fracture Preventing stroke in atrial fibrillation Using risk estimators: CHA2DS2 VASc score Score of 0 or 1 risk of anticoagulation is greater than risk of stroke All studies have shown that benefits of anticoagulation are greater than risk in most patients with score >1M Warfarin preferred Mitral stenosis, prosthetic heart valves, decompensated valvular dx (no data for DOACs Patients already doing well on warfarin, easy to control, in range >65% Unacceptable cost of DOACs Risky drug interactions (enzyme inducing anticonvulsants, eg phenytoin) and HIV patients on protease inhibitors CrCl <30 ( CrCl > 25, apixaban ok) Dual antiplatelet therapy has reduced benefit and similar risk of bleeding as warfarin 5

6 Why chose DOACs? Compared with warfarin, similar or lower rates of stroke, lower risk of intracranial hemorrhage, and lower risk of major bleeding Convenience (no need for monitoring) No dietary interactions and fewer drug interactions Ntaios G, Papavasileiou V, Diener HC, Makaritsis K, Michel P. Stroke 2012 Dec;43: Salazar CA, del Aguila D, Cordova EG. Cochrane Database Syst Rev 2014 (March 27);3. Transition from warfarin to DOAC No studies have shown optimal approach One study showed no difference in efficacy or safety if transtioned from warfarin to rivaroxaban when INR < 3 Mahaffey KW, Wojdyla D, Hankey GJ, et al. Ann Intern Med 2013;158:861. Anticoagulation in acute pulmonary embolism In acute PE risk of recurrence without optimal anticoagulation is 25% vs. major bleeding 3% IV heparin, low molecular weight heparin, fondaparinux with simultaneous warfarin is traditional approach with IV heparin preferred if hemodynamically unstable, ESRD, or thrombolysis considered DOACs ok in other circumstances (reach peak efficacy in 1 4 hours), thereby not requiring initial heparin best data for rivaroxaban Treat indefinitely in those at low risk or moderate risk of bleeding, for 3 months if high risk. Consider vena cava filters in those at high risk for bleeding 6

7 Anticoagulation in deep vein thrombosis Standard therapies with heparin followed by warfarin Low molecular weight heparin preferred in malignancy DOACs In dabigantrin and endoxaban trials all patients were treated with 5 days of heparin prior to administration Rivaroxaban and apixaban evaluated as effective without prior heparin administration EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, et al. N Engl J Med 2010;363(26):2499 Agnelli G, Buller HR, Cohen A, et al. AMPLIFY Investigators. N Engl J Med 2013;369(9):799. Hokusai VTE Investigators, Büller HR, Décousus H, Grosso MA, et al. N Engl J Med 2013;369(15):1406. Schulman S, Kearon C, Kakkar AK, et al. RE COVER Study Group. N Engl J Med 2009;361(24):2342. Dabigantrin may have higer risk of bleeding in elderly Most recommend 3 months of therapy unless other risk factors suggesting need for indefinite treatment (recurrent unprovoked DVT, active cancer, antiphospholipid syndrome) Prevention of VTE after hip or knee replacement Rivaroxaban and dabigantrin have FDA approved indications; Apixaban is approved for use in Canada for this indication Rivaroxaban, apixaban, and edoxaban were compared with LMWH in metaanalysis of 22 randomized controlled trials and showed reduced rated of symptomatic DVT with no difference for PE or death Neumann I, Rada G, Claro JC, et al. Ann Intern Med 2012;156:710. Another systematic review showed no difference between LMWH and dabigantrin Gómez Outes A, Terleira Fernández AI, Suárez Gea ML, Vargas Castrillón E. BMJ 2012;344:e3675. Duration of most trials 28 to 35 days after surgery There is no data available for use of DOACs in VTE prophylaxis after hip fracture Risk of bleeding with DOACs vs Warfarin The risk of bleeding with DOACs versus vitamin K antagonists reviewed in a meta analysis of 12 randomized trials including 102,607 patients with atrial fibrillation or venous thromboembolism. Compared with vitamin K antagonists, DOACs were associated with lower risks of major bleeding (relative risk [RR] 0.72; 95% CI ), fatal bleeding (RR 0.53; 95% CI ), and intracranial bleeding (0.43; 95% CI ); major GI bleeding was not Increased (RR 0.94; 95% CI ). Chai Adisaksopha C, Crowther M, Isayama T, Lim W. Blood : Epub 2014 Aug 22. 7

8 Risk of death using DOACs vs warfarin Meta analysis of randomized trials in patients with VTE included 10 trials (almost 38,000 patients). In six trials comparing DOAC with vitamin K antagonist, fatal bleeding was less frequent in DOAC treated compared with vitamin K antagonist treated patients (0.09 versus 0.18 percent; RR 0.51; 95% CI ). In three trials of secondary VTE prevention, all cause mortality was lower with DOAC administration compared with placebo (0.41 versus 0.86 percent; RR 0.38; 95% CI ). Kakkos SK, Kirkilesis GI, Tsolakis IA. Eur J Vasc Endovasc Surg 2014;48:565. Risk of death using DOACs vs warfarin Systematic review comparing dabigatran with warfarin in patients with atrial fibrillation included five randomized controlled trials (RCTs with over 27,000 patients). 30 day mortality was lower with dabigatran than warfarin (9.1 versus 13.0; adjusted odds ratio [OR] 0.66; 95% CI ). Dabigatran treated patients had shorter average stays in the intensive care unit compared with warfarin treated patients (1.6 versus 2.6 nights). Majeed A, Hwang HG, Connolly SJ, et al. Circulation. 2013;128: Systematic Analyses of Older Patients Recent meta analyses of 10 RCTs including over 25,000 elderly participants (>74 years) compared DOACs (rivaroxaban, apixaban, and dabigantrin) with conventional therapy No difference in risk of major or clinically relevant bleeding In atrial fibrillation trials, DOACs were more effective than warfarin in preventing stroke In VTE trials, DOACs had significantly lower risk of VTE or VTE related death than conventional therapies Sardar P, Chatterjee S, Chaudhari S, Lip G. JAGS 2014;62:

9 Risk/benefit of aspirin plus anticoagulation Multiple studies in patients with CAD show small but not significant reduction in CAD outcomes but also twice the risk of bleeding No good data comparing ASA + DOACs Most recent guidelines do not recommend adding ASA or other antiplatelet therapy to those receiving anticoagulation You JJ, Singer DE, Howard PA, et al. American College of Chest Physicians. Chest 2012;141(2 Suppl):e531S 75S. Resolving anticoagulation in DOACs Anticoagulation should resolve fully after five half lives since the last dose. Dabigatran 12 to 17 hours; five half lives by day 2.5 to 3.5 after the last dose. Rivaroxaban 7 to 17 hours; five half lives by day 1.5 to 3.5. Apixaban 5 to 9 hours; five half lives by day 1 to 2. Edoxaban 6 to 11 hours; five half lives by day 1.3 to 2. Scaglione F. Clin Pharmacokinet 2013 Feb;52: Approaches to bleeding with DOACs See table describing target specific DOAC reversal strategies Assess hemoglobin, platelet count, kidney and liver functions There are no RCTs to inform best approach. In most cases of major DOAC associated bleeding, use of an antifibrinolytic agent and the removal of excess drug using hemodialysis (for dabigatran) and/or oral activated charcoal (for all agents), especially if the last dose was taken in the previous few hours. Use activated or unactivated prothrombin complex concentrates for the most serious DOAC associated bleeding such as ongoing bleeding likely to lead to death or permanent disability if not stopped immediately. These products should not be considered routine or "standard of care." No data support use of recombinant activated factor VII, Fresh Frozen Plasma or cryoprecipitate in DOAC associated bleeding Garcia DA, Crowther M. Management of bleeding in patients receiving direct oral anticoagulants. UpToDate. Accessed July 10,

10 Antidote for all DOACs Researchers have created a small molecule antidote (PER977; Perosphere) has been shown in preliminary studies to bind directly and specifically to direct thrombin inhibitors, factor Xa inhibitors, and heparins (including LMW heparin), and to reverse their anticoagulant properties within minutes without side effects. Ansell JE, Bakhru SH, Laulicht BE, et al. N Engl J Med. 2014;371:2141 Case 1 76 year old widowed woman with well controlled type 2 diabetes and hypertension has new onset of nonvalvular atrial fibrillation. She takes ASA 81 mg for CAD with stent placement 10 years ago. Her creatinine clearance is 65 ml/min. She lives independently at home but her macular degeneration limits her driving. What is her risk of stroke without treatment? What would you do to prevent stroke? Should aspirin be continued? Solution to Case 1: Older woman with Afib What is her risk of stroke without treatment? She has a CHA2DS2_Vasc Risk score of at least 5 making her estimated risk of stroke at 6.7% annually, clearly making her a candidate for anticoagulation. What would you do to prevent stroke? Warfarin or DOAC would be indicated and we know the risk of intracranial hemorrhage is less with DOAC but the cost is higher. Since she cannot drive the increased cost will likely more than make up for the challenges of regular warfarin monitoring. DOAC is better. Should aspirin be continued? Continuing the ASA increases her risk of bleeding. 10

11 Case 2 84 year old long term nursing home resident develops acute shortness of breath and is found to have a pulmonary embolism in the emergency department of the local hospital. After a brief period he has stabilized and no longer has an oxygen requirement. He has moderate dementia but is generally independent in his ADLs. CrCl= 45. Solution to Case 2: NH resident with PE Where would you care for this patient? The where we will treat him depends a lot on how we will treat him. There is little doubt that admission to the hospital for parenteral heparin therapy will increase his risk of developing delirium and other potential risks of hospitalization such as falls, pressure ulcers, and urinary track infections. How would you treat him? Since he is clinically stable but has a 25% risk of another PE without medical treatment, a DOAC such as rivoroxaban could be initiated in the nursing home without admission or initial heparin. The cost will be covered by his Medicaid insurance. Duration of therapy may be 3 months or long term depending on bleeding risk. Case 3 60 year old disabled male nursing home resident with alcoholic liver disease and frequent prostatitis has developed an acute venous thrombosis following a hospitalization with immobility. His creatinine clearance is 62 ml/min. What would be the most appropriate drug used to treat this patient? 11

12 Solution to Case 3: The liver patient with DVT. What would be the most appropriate drug used to treat this patient? We certainly don t want to send him back to the hospital. In someone with liver disease warfarin is dangerous, plus he is often treated with antibiotics such as ciprofloxacin, increasing the risk of a drug interaction with warfarin. Of the DOACs, dabigantrin is the drug that is the least dependent on hepatic metabolism for clearance so that would be our choice. Three months of therapy would likely be sufficient since this was a first and provoked DVT. Case 4 68 year old woman with ESRD on dialysis with a history of GI bleeding has been diagnosed with a pulmonary embolism in the hospital. How should she be treated? Solution to Case 4: Dialysis patient with PE How should she be treated? This is very challenging situation because of her risks of bleeding with anticoagulation due to renal failure and history of GI bleeding. She is definitely not a candidate for a DOAC due to her renal failure. If she is hemodynamically unstable, thrombolysis may be indicated. If not, initial treatment with closely monitored intravenous heparin is reasonable. The next decision would be venal caval shunt alone vs use of warfarin for long term anticoagulation. 12

13 Case 5 71 year old man must go for outpatient colonoscopy for surveillance after several large polyps were removed 3 years ago. He takes dabigantrin to prevent stroke from atrial fibrillation. He has never had an episode of stroke or TIA and does not have significant valvular disease. How would you prepare him for his colonoscopy (besides making him poop until clear?). Solution to Case 5: DOAC pt getting procedure. How would you prepare him for his colonoscopy? He does not appear to be at high risk for stroke during a brief time of being anticoagulated. Furthermore, he will likely have more polyps requiring biopsy or removal so stopping his dabigantrin without bridging anticoagulation seems reasonable. Since we know that five half lives of dabigantrin should take 2.5 to 3.5 days, stopping his drug 4 days before the procedure and restarting the next day, if no bleeding, should be sufficient. Summary DOACs probably better although more expensive than warfarin in treating patients to prevent stroke in atrial fibrillation and to treat VTE. Warfarin indicated in valvular heart disease or dialysis patients. Despite limited experience with drug reversal DOACs are probably safer than warfarin treatment especially in patients at risk for poor adherence and on multiple medications. Factor Xa inhibitors can be used without the need for bridging with heparin in acute treatment of VTE. Learn the basics of pharmacology for one or two agents as indications are similar. 13