Dabigatran: Medication Use Evaluation Jenna M. Faircloth, PharmD PGY1 Pharmacy Practice Resident Vanderbilt University Medical Center June 22, 2012

Situation SBAR Dabigatran is an oral direct thrombin inhibitor recently added to formulary Of all drugs marketed in US, dabigatran had the highest number of serious adverse events reported to the FDA in 2011 3781 (2367 hemorrhages; 542 deaths) versus 1,106 events with warfarin (72 deaths)

Background SBAR Dabigatran (Pradaxa®) MOA: Competitive, direct and reversible inhibitor of thrombin Works on platelet-derived, clot-bound and free-floating thrombin Absorption/Metabolism: Oral prodrug converted in the liver through esterases to the active compound Elimination: Urine Does not require routine lab monitoring

Background SBAR Key Monitoring Parameters Adjustment for renal function Conversions from anticoagulants to/from Dabigatran Adjustment for drug-interactions Holding prior to surgical procedures

Assessment SBAR Time period evaluated Data Collected January 2011- January 2012 Data Collected Age, weight, gender, BMI Dose and frequency Indication If applicable, CHADS2 score New initiation or home medication Past medical history Diagnosis of cancer Creatinine Clearance (Cockgroft-Gault), Hgb, PCV Acute kidney injury (AKI) events during admission Active medications Invasive procedure during admission Bleeding event during admission Readmission for bleeding event Drug discontinuation due to adverse event

Assessment SBAR Evaluated 103 hospital admissions in 94 patients Baseline Characteristics (n=103) Demographics Gender Male Female 58 (56.3%) 45 (43.7%) Race White Black Other 98 (95.1%) 4 (3.9%) 1 (1%) Mean age 66 ± 13.1 Mean BMI 32 ± 10.1 Obesity (Class 1) Creatinine Clearance (mL/min) < 15 15-29 30-50 > 50 0 (0%) 12 (11.7%) 26 (25.2%) 65 (63.1%) Acute Kidney Injury episodes 7.8% (8/103)

Assessment SBAR Baseline Characteristics (n=103) New initiation Home medication 48 (47.5%) 53(52.5%) Indication Atrial fibrillation Atrial flutter DVT/PE treatment Other 93 (90.3%) 16 (15.5%) 13 (12.6%) 7 (6.8%) CHADS2 Score (n=100) 1 2 3 4 5 14 (14%) 24 (24%) 33 (33%) 19 (19%) 3 (3%) 7 (7%) If 0 or 1, CHA2DS2Vasc Score: 0 =4 1= 10 2= 13 3= 8 4= 2 Diagnosis of Cancer 12 (11.7%) Concomitantly administered medications Aspirin Clopidogrel NSAIDS 49 (79%) 15 (24.2%) 8 (12.9%)

Assessment SBAR

Assessment SBAR Off-label doses (N =17) Low Dose 15 Post ablation procedure* 7 Due to ASA and Clopidogrel 1 Due to high dose ASA & bruising with minimal contact Other 6 High Dose 2 *Post-procedure dose reduction is single 75mg dose, therapy resumed at maintenance the follow day

Acute Kidney Injury 8/103 (7.8%) patients had an AKI event Dose adjusted when AKI occurred: 62.5% Pradaxa Dose Initial Baseline Cr Peak Cr Change in CrCl Drug Held (Y/N) Dose changed (Y/N) Dabigatran adjusted appropriately (Y/N) Cause of AKI Comments 150 mg BID 1.37 2.28 19 (47.5-> 28.5) No Per nephrology note, dehydration due to poor intake; ATN due to intermittent low BP, CIN contrast, or AIN due to ABX Scr not checked for 7 days. Obtained SCr prior to d/c (CrCl 28.5ml/min) and did not adjust to 75mgBID ; admitted to stallworth- Scr improved to with CrCl 35ml/min. Admitted for GI Bleed 5 days later; 0.63 1.3 36 (75-> 39) Yes unknown; had surgery 10 days prior dose reduced to 75mg BID; Scr not rechecked to see if continued to trend up or down; 0.98 1.89 22 (46->24) Y es(24 hrs late) possibly overdiuresis with Furosemide team did not adjust for 24 hours dose until 24hr after patient dropped below 30ml/min.

Drug Interactions Assessment SBAR 7.8% (8/103) concurrently taking Dronedarone

Conversion from anticoagulants to Dabigatran Assessment SBAR Conversion from anticoagulants to Dabigatran 87.4% (90/103) of anticoagulants converted per FDA label Anticoagulant Agent Appropriately Converted Inappropriately Converted Comments Heparin 23 11 7 overlap duration excessive - 3 Heparin infusion - 4 Heparin 5000 units SQ 4 withheld too long - 3 Heparin 5000 units SQ - 1 Heparin infusion Warfarin 4 1 overlap duration excessive Received Warfarin 15mg dose, dbl home dose, evening before first morning dose of Dabigatran Enoxaparin 5 withheld too long Warfarin dose was double home dose (15mg – 7 mg normal home dose)

Evaluation of holding prior to invasive procedures Assessment SBAR Evaluation of holding prior to invasive procedures Invasive procedures in 30.1% (31/103) of population 3 procedures were emergent Procedure Type Ablation 18 LHC/PCI 3 Orthopedic 2 AAA repair 1 AV balloon valvuloplasty Bilateral thoracoscopy Pacemaker implant BiV ICD Thyroid Biopsy

Evaluation of holding prior to invasive procedures Assessment SBAR Evaluation of holding prior to invasive procedures Dabigatran was held per FDA labeling based on CrCl in 19 of 31 procedures (61.3%) In remaining 12 cases, medication was not held per labeling RF ablation= 9* Dual chamber pacemaker implant = 1 PCI with stent = 2 Orthopedic procedure= 1 *routine process for prevention of perioperative stroke

Bleeding Events Assessment SBAR 12.6% (13/103) patients experienced drop in Hgb ≥ 2mg/dL Mean patient age: 73 years old 12 dosed per FDA labeling 1 under dosed Site of bleed 9 Unknown 3 GI bleeds 1 Sub-dural 5 required transfusions 2 invasive procedures

Readmission for bleeding event Assessment SBAR Readmission for bleeding event 3 readmissions (2.9%) for bleeding event Site: GI bleed Age Dose CHADS2 score Renally adjusted (Y/N) Concomitant medications Anticoag Overlap excessive Invasive procedures Comments 63 150mg BID 2 Yes/No Dronedarone No Bilateral Amputee patient –CrCl unclear 69 1 Yes n/a Yes- Heparin infusion 76

Therapy Discontinuation Assessment SBAR Therapy Discontinuation 6.8% (7/103)- discontinuation due to an adverse event Reason for discontinuation Approximate Days of therapy until d/c Inpatient or outpatient d/c Subdural hematoma, recurrent falls 28 days Inpatient Severe joint pain 122 days Outpatient Dyspepsia 50 days GI complaints 210 days GI bleed 91 days Severe epigastric pain and possible GI bleed 16 days Stomach pain and lightheadedness 150 days

Recommendations SBAR Require height and serum creatinine for prior to ordering therapy During order processing, pharmacist to evaluate for drug interactions and renal function Dispense message to provide reminder Dashboard monitoring of appropriate dose for renal function, drug-interactions, Hgb/Hct

Recommendations SBAR Continue patient education prior to discharge Education to providers regarding proper conversion of anticoagulants Education to providers regarding proper holding prior to invasive procedures

Dabigatran: Medication Use Evaluation Jenna M. Faircloth, PharmD PGY1 Pharmacy Practice Resident Vanderbilt University Medical Center June 22, 2012

Appendix A. Key Monitoring Parameters Adjustments for renal function 150mg BID = estCrCl >30mL/min 75mg BID = estCrCl 15-30ml/min Not Recommended = est CrCl <15ml/min and/or HD Conversions from Anticoagulation to/from Dabigatran LMWH/Fondaparinux to Dabigatran = Stop parenteral agent and administer dabigatran 0-2h before next parenteral dose due Continuous parenteral anticoagulant to Dabigatran = Administer first dose of dabigatran at the time of discontinuation of IV anticoagulant Dabigatran to parenteral anticoagulant = CrCl >30mL/min, start parenteral anticoagulant 12 hours after the last dose of dabigatran; CrCl <30mL/min: Start parenteral anticoagulant 24 hours after the last dose  of dabigatran Warfarin to Dabigatran= initiate when INR < 2.0 Dabigatran to warfarin = CrCl >50mL/min, start warfarin 3 days before discontinuing dabigatran                                            CrCl 30-50mL/min, start warfarin 2 days before discontinuing dabigatran                                             CrCl 15-30mL/min, start warfarin 1 day before discontinuing dabigatran                                             CrCl <15mL/min, no recommendations can be made Adjustments for Drug Interactions Ketoconazole: Switch 150mg BID to 75mg BID if estCrCl=30-50mL/min and D/C if estCrCl <30mL/min Dronedarone: Switch 150mg BID to 75mg BID if estCrCl=30-50mL/min and D/C if estCrCl <30mL/min Rifampin: Avoid concomitant use NSAIDs: Use with caution; Increase risk of bleeding Duloxetine: Use with caution; Increase risk of bleeding Holding Prior to Surgical Procedures estCrCl >50mL/min = Hold dabigatran 1 to 2 days estCrCl <50mL/min = Hold dabigatran 3 to 5 days May require doses to be held longer in patients undergoing major surgery, spinal puncture, or placement of a spinal /epidural catheter , port