Wm. Semchuk, MSc,PharmD,FCSHP Manager, Pharmacy Practice Regina Qu Appelle Health Region
As always, drug therapy should be assessed on three basic criteria: Efficacy Safety Cost Most importantly though, we need to think of what is best for the patient In an era of understanding what we know, it would be a travesty to extapolate to seems to be a class effect Between trial comparisons are fraught with limitations
Mrs. Smith is a 67 year old female undergoing a TKR and you are going to start her on a DOAC.. Mr. Jones is a 71 year old gentleman with AF who is CHADS 3, HASBLED 2 with good renal function who has been stabilized on dabigatran 150 mg bid for 3 years and is admitted to hospital with pneumonia Mrs. Brown is a 53 year old woman with a history of 2 unprovoked DVTs (most recent 9 months ago) and is admitted to hospital for a non clot, non-surgical admission.
Maslow s Hammer: It is tempting, if the only tool you have is a HAMMER, to treat EVERYTHING as if it were a NAIL Abraham Maslow Mrs. Smith is a 67 year old female undergoing a TKR and you are going to start her on a DOAC.. Mr. Jones is a 71 year old gentleman with AF who is CHADS 3, HASBLED 2 with good renal function who has been stabilized on dabigatran 150 mg bid for 3 years and is admitted to hospital with pneumonia Mrs. Brown is a 53 year old woman with a history of 2 unprovoked DVTs (most recent 9 months ago) and is admitted to hospital for a non clot, non-surgical admission.
Orthopedic Surgery prophylaxis following total hip and knee arthroplasty Atrial Fibrillation Stroke Prevention Treatment of VTE Prevention of Secondary VTE ACS
Weitz J, Semchuk W, Turpie G et al. Accepted for publication 6
Weitz J, Semchuk W, Turpie G et al. Accepted for publication 7
Orthopedic AF Acute VTE Treatment Rivaroxaban Dabigatran Apixaban Efficacy: Safety: Efficacy: Safety: Efficacy: Safety (MB): Efficacy: Enox 40 qd Enox 30 bid Safety: Efficacy: 150 bid 110 bid Safety: 150 bid 100 bid Efficacy: Safety (MB): Efficacy: Enox 40 qd Enox 30 bid Safety: Efficacy: Safety: Efficacy: Safety: VTE Prevention Efficacy: Safety: Efficacy: Safety: Efficacy: Safety:
What happens as you move from clinical evidence to clinical practice? Clinical variables that are always under consideration include but are not limited to: Age, Weight, Excretion, Drug interactions, Clinical Practice variability - What patients do. 9
All of the clinical trials looked at efficacy and safety, however what are some of the other things we look at? Customizing the drug to the patient Excretion, side effects, drug interactions Do we know how to effectively and safely interchange drugs if we only have one agent on formulary? What is the effect of an interchange program on patients?
APIXABAN 1 RIVAROXABAN 2 DABIGATRAN 3 Mild - Moderate renal impairment (CrCl 30-50 ml/min) Yes Generally no dose reduction Dose adjustment only if 2 of ABC* criteria Yes 15mg QD Yes Dose reduction to be considered in elderly or those with other risk factors for bleeding Severe renal impairment (CrCl 25-29 ml/min) No Not recommended No Not recommended (CrCl 15-24 ml/min) no dosing recommendation can be made CrCl <15 ml/min or patients undergoing dialysis No Not recommended ABC criteria: Dose reduction to 2.5 mg BID if at least 2 of the following: Age 80, Body weight 60kg, serum Creatinine 133micromol/L NOAC: novel oral anticoagulant CrCL: estimated creatinine clearance 1. Eliquis PM, 2012. 2. Rivaroxaban PM, 2013. 3. Dabigatran PM, 2013 11
Rivaroxaban Dabigatran Apixaban Bleeding Bleeding Bleeding Rare liver enzyme elevation Dyspepsia/Gastritis Rare liver enzyme elevation
Via Dabigatran Apixaban Edoxaban* Rivaroxaban Atrovastatin Digoxin Verapamil P-gp Competition And CYP3A4 Inhibition P-gp Competition P-gp competition +18% No data yet No effect No effect No effect No data yet No effect No effect +12-180% (reduce dose and take simultaneously) No data yet +53% (SR) (Reduce dose by 50%) Minor effect (use with caution if CrCl 15-50 ml/min) Diltiazem Quinidine Amiodarone P-pg competition and weak CYP3A4 inhibition P-gp Competition P-gp Competiton No effect +40% No data yet Minor effect (use with caution if Crcl 15-50 ml/min) +50% No data yet +80% (Reduce dose by 50%)* +50% +12-60% No data yet No effect Minor effect (use with caution if Crcl 15-50 ml/min) Dronedarone Ketoconazole; Itraconazole; Variconazole posaconazole P-gp and CYP3A4 inhibitor P-gp and BCRP Competition; CYP3A4 inhibition +70-100% (US: 2 x 75mg) +140-150% (US: 2 x 75mg) No dat yet +85% (Reduce dose by 50%)* No data yet +100% No data yet Up to +160% Europace 2013;15:625-651 Red: CI or not recommended, Orange: Reduce dose, Yellow: consider dose reduction
Via Dabigatran Apixaban Edoxaban* Rivaroxaban Fluconazole Cyclosporin; tacrolimus Clarithromycin; erythromycin HIV protease inhibitors (e.g. ritonavir) Rifampicin; St. John s wort; carbamazepine; phenytoin; phenobarbital Antancids (H2B; PPI; Al- Mg-hydroxide) Other factors: Moderate CYP3A4 inhibition P-gp Competition P-gp Competition and CYP3A4 inhibition P-gp/BCRP and CYP3A4/CYP2J2 Inducers P-pg/BCRP and CYP3A4/CYP2J2 Inducers No data yet No data yet No data yet +42% (if systemically administered) No data yet No data yet No data yet +50% +15-20% No data yet No data yet +30-54% No data yet Strong increase no data yet Up to +153% -66% +54% -35% Up to -50% GI absorption -12-30% No data yet No effect No effect Age 80 Years Age 75 years Weight 50 kg Renal Function Other increased bleeding risk Increased plasma level Increased plasma level Increased plasma level Increased plasma level No data yet No data yet Pharmacodynamics interactions (antiplatelet drugs; NSAID; systemic steroid therapy; Other anticoagulants); history or active GI bleeding; recent surgery on critical organ (brain; eye); thrombocytopenia (e.g. chemotherapy); HAS-BLED 3 Europace 2013;15:625-651 Red: CI or not recommended, Orange: Reduce dose, Yellow: consider dose reduct
Dabigatran to Warfarin: CrCl>50 Start warfarin 3 days before stopping dabigatran CrCl 31-50 start dabigatran 2 days before topping dabigatran Rivaroxaban/Apixaban to Warfarin: Give concurrently with warfarin until the INR is 2 or greater and then stop DOAC to DOAC???? best guess
Nonrandomized, prospective evaluation of therapeutic interchange in Regina Intervention: patient given option of using own medication Control: therapeutic intervention occurred Prevalence of interchange related problems post discharge: 3% intervention arm 14% control arm Cost to the hospital, cost to the patient: Cost of medication wasted when patient went home significantly higher for patients in interchange group No cost savings for hospital Eurich D, Semchuk W, et al. CJHP 2001;54:176-183
All 3 products similarly priced (no significant cost advantage) Does a single option create risk of shortages?
Characteristic Drug Choice Rationale GI bleed Dyspepsia or upper GI complaints Elderly with AF Recent ACS CrCl of 30-50 ml/min Recent ischemic stroke on Warfarin Continue therapy after resolution Rivaroxaban or Apixaban Rivaroxaban Rivaroxaban or Apixaban Apixaban or Rivaroxaban Dabigatran Benefit outweighs the risk, reduce other modifiable risk factors for bleeding Dyspepsia in up to 10% of patients given dabigatran Most efficacy and bleeding reduction; dabigatran 150 mg and apixaban need dose reduction compromising efficacy MI signal with dabigatran Oral Xa inhibitors are less affected by impaired renal function than dabigatran Dabigatran (150 mg BID) associated with lowest risk of ischemic stroke vs warfarin Adapted/modified from Weitz & Gross, Hematology 2012:536-40
Its clear that: Need for different drugs for different indications Different clinicians will see different risks/benefits depending on the indication From a safety perspective there are differences in drug interactions, excretion and adverse effects We don t know how to safely switch between these drugs and likely therapeutic interchange may not be a great idea anyway There is no cost advantage to only one and maybe there is a risk
Benefit of pharmacist involvement in management of DOAC therapy Improved appropriateness of medication selection and dose Reduction in adverse events Increased patient adherence Lee P et al. AJHP 2013:70;1154-1161. Larock A et al. Ann Pharmacother 2014;48(0): 1258-1268. Shore S et al JAMA 2015;313(14); 1443-1450. Tedders KM et al. Ann Pharmacother 2013;47(12): 1649-1653
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To serve the patient? To serve as police?