MEDICATION MANAGEMENT IN VTE FROM CONVENTIONAL TO NEW

MEDICATION MANAGEMENT IN VTE FROM CONVENTIONAL TO NEW Presented by: David B. Coriale RPh. Pharm D BCPS Clinical Pharmacy Manger Oneida Healthcare Oneida, NY

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Presentation John is a 75-year-old man with a recent (4 weeks ago) admission to hospital for hip replacement. The procedure was performed under general anaesthetic. During admission John received the following VTE prophylaxis (to be continued until John no longer had significantly reduced mobility): antiembolism stockings pharmacological VTE prophylaxis. John reports that his right leg has been swollen for over 2 weeks. He thought it was healing after the operation, which is why he has not told anyone sooner. He presented to his FP and the FP has referred him to your ER.

John reports that he had a DVT 20 years ago and that he has osteoarthritis. On admission he is apyrexial with a temperature of 37oc and his right calf and ankle are red, blotchy and swollen with pitting edema. His heart rate is 80 beats per minute, respiratory rate 15 breaths per minute, blood pressure is 136/80 mmhg and SpO2 96% in air. Question: You suspect DVT: what medication do you start?

Discuss conventional vs. NOAC dosing, interactions and pharmacology Understand risks and benefits for therapy Make a decision on the type of therapy based on the clinical situation Transition to outpatient

Presentation Jane is a 65-year-old woman with inoperable ovarian cancer and poor functional status. She presents to your ER following a referral from the oncology outpatient clinic. She complains of pain along the length of her left leg with her left calf feeling particularly painful. She also reports that her left calf feels hot. Question You believe Jane has symptoms of a suspected DVT. What s important in her background?

LMWH or fondaparinux suggested if DOAC not possible UFH reserved for: Potential need for invasive procedures Potential for thrombolysis Increased bleeding risk as it has a short ½ life Possible need for reversal Severe renal impairment

LMWH monotherapy for first 3-6 months Superior efficacy and safety DOAC trials only evaluated a small number of patients with active malignancy DOAC or warfarin may be used if patient refuses LMWH

DOAC not studied in thrombophilia Not enough data to conclude efficacy of DOACs LMWH plus warfarin titration until INR 2-3 recommended

Table 6. Effect of Thrombosis and Medications on Thrombophilia Test Results - Laboratory Test for: Factor V Leiden Factor II gene mutation Protein S deficiency Protein C deficiency Antithrombin deficiency Antiphospholipid antibody Lupus anticoagulant 1 LMWH, low-molecular-weight heparin Medications Acute Vitamin K Direct lla Direct Xa Thrombosis Heparin LMWH 1 Antagonist Inhibitor Inhibitor No effect No effect No effect No effect No effect No effect No effect No effect No effect No effect No effect No effect May be low No effect No effect Don t test No effect No effect May be low No effect No effect Don t test No effect No effect May be low Lowered Lowered No effect No effect No effect No effect No effect No effect No effect No effect No effect No effect Don t test Don t test Don t test Don t test Don t test Copyright 2016 by Society of Hospital Medicine. www.hospitalmedicine.org/vtetreatment accessed 4/17/18

DOAC studies for VTE did not adequately evaluate patients below 40 kg or above 120 kg Fixed doses of DOAC may lead to over or under treatment Edoxaban dose is reduced to 30 mg if patient is <60 kg Fondaparinux (Arixtra ) is contraindicated if patient <50kg Extreme low weight may lead to overtreatment and bleeding complications even at prophylactic doses

LMWH, fondaparinux, and DOACs are renally cleared thus not recommended if CrCl < 30 ml/min UFH bridged to warfarin is recommended

Apixaban (Eliquis): Age 80 or above PLUS serum creatinine of 1.5 or above

Active bleeding Severe bleeding diathesis Platelet count <50,000/microL Recent, planned, or emergent high bleeding-risk surgery/procedure Major trauma History of intracranial hemorrhage (ICH) particularly recent ICH

Initial therapy (first 10 days) Weigh risk of bleed vs. benefit of therapy PE or DVT Asymptomatic vs. symptomatic Inpatient or Outpatient

Unfractionated Heparin (UFH) Low molecular weight heparin (LMWH) Fondaparinux (Arixtra ) Addition of Warfarin

Significant shift in treatment Pharmacokinetics similar to LMWH Parenteral lead in needed only for edoxaban and dabigatran Apixaban and rivaroxaban do not need bridging just initial higher dosing Less labor intensive

Protocol Driven Optimal initial dosing of continuous infusion heparin therapy is controversial Route Reference Bolus dose Maintenance dose Continuous infusion Fixed dose Hull et al. [1] 5000 units 1250 1280 units/h a Weight based Raschke et al. [6] 80 units/kg 18 units/kg/h https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4715846/

aptt or heparin anti-xa level monitoring may be used Check every 6 hours until two consecutive therapeutic results are obtained, after which the frequency of monitoring can be extended to once daily

obese/morbidly obese patient either total body weight or adjusted body weight can be used no increased risk of major bleeding has been reported when morbidly obese patients are managed using total body weight studies have not included patients weighing above 270 kg prompt attention to initial laboratory results is warranted to ensure the therapeutic threshold is exceeded in a timely manner

Twice daily dosing Exception severe renal disease all patients, including underweight and obese, LMWH dosing should be based on total body weight For patients <40 kg, UFH may be more appropriate enoxaparin dosing in obese patients, 1 mg/kg BID is preferred over 1.5 mg/kg daily Routine monitoring of peak anti-xa levels is not suggested

Renal function should be estimated using the Cockcroft-Gault method In patients with a CrCl < 30 ml/min the use of UFH may be preferred over LMWH If enoxaparin is used, it should be dosed at 1 mg/kg daily May consider a trough anti-xa measurement in patients with severe renal dysfunction if LMWH used beyond 5 7 days of treatment LMWH should be avoided in patients with CrCl < 20 ml/min and those receiving renal replacement therapy.

An immune-mediated disorder Typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications. Previous exposure to heparin can cause HIT to develop earlier May switch to fondaparinux (Arixtra ) Avoid fondaparinux in weight 50kg or CrCl 30 ml/min Alternatives: Argatroban or bivalirudin(angiomax )

Table 3 History of ACCP recommendations for overlapping parenteral anticoagulants with warfarin for the treatment of VTE Year VTE recommendation Level of evidence 2001 [41] 2004 [10] 2008 [32] 2012 [11] Treat with heparin or LMWH for at least 5 days and overlap with heparin or LMWH for at least 4-5 days Initiate vitamin K antagonist with LMWH or hepahn on day one and discontinue heparin when INR is stable and >2.0 Treat with LMWH, heparin or fondaparinux for at least 5 days and until the INR is 2 for 24 h Recommend early initiation of vitamin K antagonist (same day as parenteral is started) over delayed initiation, and until the INR is 2.0 or above for at least 24 h 1A (in comparison to treatment for 10 days) 1A 1C 1B

Started on the same day with LMW heparin or UFH (day 1) Typical initiating dose of 5 mg/day for the first two days (range 2 to 10 mg/day) Dosing is then adjusted until the INR is within the therapeutic range (2 to 3; target 2.5) for two consecutive days Initial doses at the lower range (2 to 5 mg/day) may be considered for high bleeding risk (eg, older adults) Doses in the higher range (5 to 10 mg/day) may be for low risk for bleed

Premature discontinuation of heparin (prior to therapeutic INR for two days) may result in inadequate protection against recurrent thrombosis Overlap is required because it takes a time for all of the vitamin K-dependent factors to become depleted (factors II, VII, IX, and X) During the first few days of warfarin therapy, prolongation of the prothrombin time mainly reflects the depression of factor VII Takes approximately five days of adequate dosing to reach therapeutic level Reduction of protein C and S occurs shortly after warfarin therapy and potentially renders a procoagulant state.

Suggested protocol for initiating warfarin therapy IN Ft INR Days of warfarin INR INR 1.5 to 2.0 to treatment <1.5 >3.0 1.9 3.0 Suggested initial dose tor days 1 and 2 Normal adult 5 mg* n/a n/a n/a Frail adult, malnourished, elderly, liver disease 2.5 mg* n/a n/a n/a Dosing for day 3 and beyond Day 3 5 to mg 2.5 to mg 0 to mg No dose Day 4 10 mg 5 to 0 to No dose Day 5 10 mg 7.5 to 0 to No dose mg mg 10 mg mg Day 6 7.5 to 5 to 0 to No dose 12.5 mg mg mg In this protocol, which is provided for guidance only, suggested doses of warfarin after day 2 are given as ranges. The clinician must judge the rapidity and magnitude of INR changes for the individual patient and make dosage adjustments accordingly. An algorithm for monitoring and adjustment of maintenance warfarin is presented separately. Refer to UpToDate topics on use of warfarin and table on suggested protocol for adjustment of maintenance warfarin. n/a: not applicable. * This table assumes that the patient has started with an INR in the normal range. Copyrights apply See text for details concerning the source for this protocol and relevant references. UpToDate

Table 4 Transitions from parenteral to oral anticoagulants in the treatment of VTE To warfarin To dabigatran or edoxaban To rivaroxaban or apixaban Initial Required Required Not required parenteral therapy From Start warfarin and Start heparin alone Stop heparin heparin heparin concurrently Continue heparin for a After a minimum of 5 days of Give first dose of rivaroxaban or minimum of 5 days heparin, start dabigatran or apixaban AND until INR > 2.0 edoxaban and stop heparin From Start warfarin and Start LMWH/fondaparinux alone Stop LMWH/fondaparinux LMWH or fondaparinux LMWH foudaparinux concurrently After a minimum of 5 days, stop LMWH fondaparinux Continue Give first dose of dabigatran or Give first dose of rivaroxaban or LMWH' foudaparinux edoxaban at the time the next dose apixaban at the time the next dose of for a minimum of of LMWH/fondaparinux would LMWH/fondaparinux would have 5 days AND until have been given been given rnr>2.g

Free yourself from - conventional thinking

Presentation Gary is a 52-year-old man who is an endurance cyclist. He presents to your ER following referral from his FP. He reports shortness of breath at rest and chest pain. On direct questioning he admits to pain in the right calf for a month, which he put down to muscle sprain. Question You believe Gary has symptoms of a suspected PE and DVT. What DOAC can be used?

Medication Approved Date Dabigatran (Pradaxa ) 2014 Rivaroxaban (Xarelto ) 2010,2011 Apixaban (Eliquis ) 2014 Edoxaban (Savayasa ) 2015

Simple dosing and regimen No dietary restrictions Decreased drug interactions No routine monitoring Less labor for staff Less impact on quality of life Possible improved safety and efficacy

Compliance Review contraindications Health literacy Renal and liver function Drug-interactions Disease interactions

Medication Target Renal Clearance Half-Life Metabolism Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savayasa ) Thrombin 80% 14-17h P-gp Xa 33% 7-11h CYP3A4 & P-gp Xa 25% 8-12h CYP3A4 & P-gp Xa 35% 8-10h CYP3A4 & P-gp

Table 4 Absorption and metabolism of the different NOACs Dabigatran Apixaban Edoxaban a Rivaroxaban Bio-availability 3-7% 50% 62% 17 66% without food Prodrug Yes No No No Clearance non-renal/renal of 20%/80% 73%/27% 13 50%/50% 9 65%/35% absorbed dose (if normal renal function; see also Section 8) Liver metabolism: CYP3A4 involved No Yes (elimination; minor Minimal (<4% of elimination) Yes (elimination) CYP3A4 contribution) 19 Absorption with food Intake with food recommended? Absorption with H2B/PPI Asian ethnicity Gl tolerability Elimination half-life No effect No -12-30% 22-24 +25% 24 Dyspepsia 5-10% No effect No No effect No effect No problem 6-22% more 20 No official recommendation yet No effect No effect 20 No problem +39% more 21 Mandatory Almost 100% with food No effect21, 25 No effect No problem 12-17 h 23 12 h 9-11 h 9 5-9 h (young) 11-13 h (elderly) a No EMA approval yet. Needs update after finalization of SmPC. H2B, H2-blocker; PPI, proton-pump inhibitor; Gl, gastro-intestinal. Europace (2013) 15, 625-651 625 651 doi:10.1093/europace/eut083

Medication Dosing CrCl (Cockcroft-Gault ml/min) Dabigatran (Pradaxa )* 150 mg bid after 5-10 days of parenteral Above 30 15-30 Less than 15 Renal Dose Adjustments for maintenance Normal Dose 75 mg BID Not Recommended Rivaroxaban (Xarelto )* 15 mg bid w/food for 21 days then 20 mg daily with food Above 50 15-50 Normal Dose 15 mg Daily with evening meal Apixaban (Eliquis ) # 10 mg bid for 7 days then 5 mg bid Must meet 2 factors: Age above 80, Scar 1.5 or weight 60kg 2.5 mg twice a day Edoxaban (Savayasa )* Above 60 kg 60 mg daily 60 kg 30 mg daily *End stage CKD with or w/o dialysis Not recommended # End stage CKD with or w/o dialysis No recommendations 15-50 Less than 15 CrCL >95 ml/min 60 mg once a day Do NOT USE Do NOT USE

Dabigatran Rivaroxaban Apixaban Edoxaban Europace (2013) 15, 625 651 doi:10.1093/europace/eut083

Drug-Drug Interaction Effects on NOAC - Plasma Levels, and Recommendations - Atorvastatin via Dabigatran Apixaban Edoxaban Rivaroxaban P-gp weak +18% no data no effect no effect CYP3A4 Digoxin p-gp no effect no data no effect no effect p-gp +12-180% Verapamil weak reduce dose no data CYP3A4 take together Diltiazem Quinidine p-gp weak CYP3A4 p-gp no effect +50% +40% no data +53% (SR) reduce dose no data +80% reduce dose Amiodarone p-gp +12-60% no data no effect Dronedarone p-gp weak CYP3A4 +70-100% no data +88% reduce dose minor effect use with caution if CrCL: 15-50ml/min minor effect use with caution if CrCL: 15-50ml/min +50% minor effect use with caution if CrCL: 15-50ml/min No data yet Heidbuchel H, et al. Europace. 2013;15:625-651. [31] Not recommended/contraindicated Reduce dose if 2 factors or more Reduce dose No data yet

Possible drug-drug interactions - Effect on NOAC plasma levels part 2 Interaction Dabigatran Apixaban Edoxaban Rivaroxaban Fluconazole CYP3A4 no data no data no data +42% Cyclosporin; tacrolimus - Clarithromycin; - erythromycin - HIV protease inhibitors P-gp no data no data no data +50% P-gp/ CYP3A4 P-gp and BCRP/ CYP3A4 +15-20% no data no data +30-54% no data strong increase no data no data up to +153% Rifampicin; - St John's wort; carbamezepine; phenytoin; phenobarbital - P-gp and BCRP/ CYP3A4/CYP2J2-66% -54% -35% up to -50% Antacids GI absorption -12-30% no data no effect no effect Red - contraindicated; orange - reduce dose; yellow - consider dose reduction if another yellow factor present; - hatching - no data available; recommendation made from pharmacokinetic considerations - www.escardio.org/ehra

Care transitions associated with adverse events - of readmissions that occur within one year after a hospitalization are related 20 % to an adverse drug event. 1 60 % of all medication errors times of care transition. 2 occur during 72% of post-discharge medication-related. 2 adverse events are 1 New England Journal of Medicine. Adherence to medication. 2005; 353:487-97. 2 The American Society for Automation in Pharmacy. 2014 Midyear Conference. Transitional Care: How Pharmacies Can Impact Outcomes for Discharged Patients. Jure 26-28, 2014.

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Table 1. Elements of Good Care Transition for Patients Receiving Anticoagulation Accurate and complete information exchange among transferring and receiving provider Medication reconciliation Case management with arrangement for uninterrupted medication supply and laboratory monitoring (e.g., INR for warfarin, renal function) - Education of patient and caregiver(s) about the purpose of the medication, importance of adherence, how to take the medication, signs and symptoms of bleeding, when to seek medical attention and adverse effects Follow-up contact to ensure adherence and continuity of care Copyright 2016 by Society of Hospital Medicine. www.hospitalmedicine.org/vtetreatment accessed 4/17/18

Evaluate the specific patient Understand the need for conventual and new therapies Keep informed