Dabigatran 101: Community Pharmacists. Peter Thomson Clinical Resource Pharmacist, Medicine Program Winnipeg Regional Health Authority

Objectives At the end of this session, you should be able to: Describe the basic pharmacology of new oral antithrombotic agents Discuss potential drug interactions and adverse effects with dabigatran Field potential questions relating to the use of dabigatran

Disclosures In the past 2 yrs I have either been sponsored to speak at education event, introduced speakers or attended advisory meeting provided advice to the following pharmaceutical companies: AstraZeneca Canada Boehringer Ingelheim Canada Paladin Labs Inc. Pfizer Canada Sanofi Aventis Canada

Mrs. RH 59 yr. diagnosed with pulmonary embolus and discharged from HSC on July 20 Discharge medications include warfarin 5 mg/day, fosinopril, furosemide, iron and insulin Follow up appointment with family MD ordered for July 22 or 23. Assessed prior to discharge by Home Care: had family supports in place

July 16 17 18 19 20 INR 0.9 1.1 1.7 2.5 3.4 Dose 5 5 5 5

Presents to ER on July 29 with numbness of face, now spreading to R arm and leg. First visit to family MD earlier that day with no signs or symptoms CT reveals small hemorrhage. Labs back: INR 8.5 Over next 4 hrs she rapidly deteriorates with enlarging bleed on CT scan Expires a few hrs later despite fresh frozen plasma and 10 mg IV Vitamin K Family states pt took prescribed warfarin with no extra or missed doses

Many Factors Play a Role in Underutilization of Warfarin in AF Perceived Bleeding Risk Concern about risk of hemorrhage, not always balanced against risk of stroke Lifestyle Implications Need for regular monitoring, lifestyle restrictions, compliance and other patient factors Resources Lack of availability of an anticoagulant outpatient monitoring clinic Knowledge and comfort level with anticoagulation therapy in the primary care setting

Avoiding Bleeding and Preventing Stroke: Finding The Balance

Clinical Events Warfarin is as Challenging as it is Effective Under-anticoagulated DVT Recurrence Pulmonary Embolus Valve Thrombosis TIA Ischemic Stroke Therapeutic Window Over-anticoagulated IC Hemorrhage GI Hemorrhage Intensity of Anticoagulation (INR) Warfarin: Complex Pharmacodynamics Delayed, indirect action Concomitant diseases Concomitant medications Diet & lifestyle interactions Inter- and intraindividual variability Bungard et al. Arch Intern Med 2000

Antithrombotic Therapy & 30 d Stroke Mortality Ischemic stroke in cohort of 13,559 patients with NVAF 30-day mortality based on treatment at presentation p=0.002 ASA mortality rate is similar to warfarin at INR < 2.0 Those with INR 2.0 had less severe strokes, lower mortality Hylek et al. N Engl J Med 2003

Desirable Qualities of New Anticoagulants At least as safe as current agents At least as effective as current agents Oral Simple dosing Predictable effect No anticoagulation monitoring Minimal food and drug interactions Rapid onset and offset of action Patient support programs

New Oral Agents Are all small molecules targeted at specific sites in the coagulation system Primary target is either Thrombin; i.e. activated factor II (F IIa) Activated factor X (F Xa)

New Oral Anticoagulants Direct Thrombin Inhibitors: Dabigatran (Pradax ) Direct F Xa Inhibitors: Rivaroxaban (Xarelto ) Apixaban (Pfizer/BMS) Betrixaban (Merck) Edoxaban (Daichi Sankyo)

Coagulation Cascade Intrinsic Pathway (surface contact) Extrinsic Pathway (tissue factor) Warfarin: F II, VII, IX, X XIIa IX XIa Fondaparinux (AT-III dependent Pure Anti-Xa) IXa VIIa Heparin / LMWH (AT-III dependent) TF Pathway Inhibitor Apixaban Betrixaban Rivaroxaban X II Xa Thrombin (IIa) Ximelagatran Dabigatran (direct antithrombin) Thrombin-Fibrin Clot

New Oral Anticoagulants Benefits of new oral agents include: Predictable pharmacokinetics with low interpatient variability: LMW Heparin like Much lower rate of drug interactions than warfarin Much faster onset of action than warfarin - few hrs versus days Generally, much shorter duration of action than warfarin

New Oral Anticoagulants Benefits of new oral agents include a flatter dose response curve than warfarin. Should translate into a lower risk of major bleeding with overshooting the therapeutic range With warfarin increased bleeding incidence becomes exponential once INR > 4.5 A commonly forgotten reason for high INRs is people are sick, not eating yet still take their warfarin as usual Palareti G Thromb Haemost 2009

New Oral Anticoagulants: Clinical Indications Approved for use in Canada Hip and knee orthopedic surgery prophylaxis (dabigatran and rivaroxaban) Atrial fibrillation (dabigatran alone) Likely to see in the future: Venous thromboembolism treatment Possibly see in the future: Following heart attacks and other acute coronary syndromes Venous thromboembolism prophylaxis Anything else that warfarin is used for (except killing rodents)

Dabigatran Pharmacokinetics Pradax is a prodrug: Dabigatran etexilate, Rapidly absorbed and quickly converted to active form: dabigatran by non CYP pathways Bioavailability ~ 6.5 % Capsule contains pellets that are coated in tartaric acid. Makes absorption independent of gastric ph (also dose independent) Despite low bioavailability, is quite consistent Food delays time to peak concentration (normally 1-3 hr) but doesn t affect AUC 25 30% protein bound t 1/2 ~ 15 hrs Ericksson BI, Clin Pharmaockin 2009

Dabigatran Pharmacokinetics Excreted 80% unchanged by the kidneys: plasma concentrations really start to rise CrCl < 50 ml/min In Canada, use is contraindicated if Clcr < 30 ml/min Partially dialyzable (high volume of distribution) 20 % excreted through bile as active glucuronic acid conjugates which are active Smoking and ETOH do not affect clearance Ericksson BI, Clin Pharmacokin 2009 Br J Clin Pharmacol. 64; 3: 292-303 Pradax Product Monograph

Dabigatran Drug Interactions P-glycoprotein dependent clearance. Inhibitors increase exposure to dabi; inducers decrease Inhibitors: Amiodarone Clarithromycin Verapamil Quinidine Inducers: Rifampin St John s Wort Not metabolised nor exhibits effects on the cytochrome P450 systems. Different than most drugs affected by P glycoprotein which rely on cyp 3A4

Dabigatran Dose: Orthopedic Hip Standard Dose and Knee Replacement 110 mg 1-4 hr post op then 220 mg daily X 10 days (knees) X 28-35 d (hips) Special Population Dose Age > 75 yrs 150 mg daily Clcr 30 50 ml/min 75 mg 1-3 hr post op then 150 mg daily No safety data (hence not recommended) pediatrics, pregnancy, lactation Pradax Product Monograph

Dabigatran Dose: Atrial Fibrillation Standard Dose 150 mg twice daily Special Population Dose 110 mg twice daily Pradax Product Monograph

Dabigatran Adverse Effects: RELY Trial Connelly S, NEJM 2009

RELY Adverse Effects Connelly S, NEJM 2009

Case KK is a 63 yr old female who has presented to you pharmacy with a new prescription for dabigatran 150 mg twice daily X 30 days

KK s Patient Profile ASA EC 81 mg daily Pantoprazole 40 mg daily Ramipril 20 mg daily Metoprolol 75 mg bid Zopiclone 7.5 mg qhs prn

Case KL is a 63 yr old female who has presented to you pharmacy with a new prescription for dabigatran 150 mg twice daily X 30 days

KL s Patient Profile ASA EC 81 mg daily digoxin 0.0625 mg od Ramipril 1.25 mg daily furosemide 120 mg bid metolazone 5 mg od Metoprolol 25 mg bid Zopiclone 15 mg qhs prn

Questions Questions and more Questions

Dabigatran in A fib: Questions Shouldn t we be monitoring the anticoagulant response to dabigatran?

Van Ryn J Thromb Haemost 2010

Dabigatran in A fib: Questions She we use it if the person has a mechanical heart valve?

Canada Dabigatran Indications US Pradax and Pradaxa Product Monographs

Dabigatran in A fib: Questions How come they have approved a lower dose of dabigatran for renal dysfunction in the U.S. and in Canada it is contraindicated?

Dabigatran A Fib Dosing Canada (contraindicated Clcr < 30). For others: US 150 mg twice daily Aged > 80 yrs 110 mg bid Geriatric esp. > 75 yrs with at least 1 other risk factor for bleeding 110mg bid may be considered Pradax and Pradaxa Product Monographs

What drug interactions should I worry about?

Dabigatran: Some Example Drug Canada US Interactions Contraindicated: ketoconazole Generally be avoided: rifampin Reduce dose to 150 mg daily: verapamil Give at least 2 hrs before dabigatran: quinidine No dose adjustment generally recommended: amiodarone, clarithromycin, number of others on list Pradax and Pradaxa Product Monographs

Dabigatran Contraindications Canada US Pradax and Pradaxa Product Monographs

Dabigatran in A fib: Questions If someone injures themselves and starts to bleed, what should we tell them to do? Is there an antidote for dabigatran?

Van Ryn J Thromb Haemost 2010

Case BB is a 77 yr old male placed on dabigatran for A Fib 3 weeks ago. He is scheduled for prostate surgery next month. His family doctor has called you to ask how should long should he be off dabigatran before his surgery

Case in Hamilton large amount of bleeding (> 70 transfusions) following major CV surgery. Dabi held 2 days preop. Did have signf dabi in system at time of surgery Van Ryn J Thromb Haemost 2010; verbal report P Wells Oct 2010

Questions Will people already on warfarin stay on it or switch to dabigatran?

Reasons to Stay on Warfarin (with apologies to P. Wells) Compliance: regularly seeing people Frequently checking blood work Get to avoid taking green leafy vegetables Multicolour pills makes taking pills fun Helps keep alcoholism rates down

Putting RE-LY into Perspective Meta-analysis of ischaemic stroke or systemic embolism Favours Warfarin Standard Dose-Adjusted Warfarin versus: Placebo Favours Comparator Low-dose warfarin ASA ASA + clopidogrel Ximelagatran Dabigatran 150 mg 0 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Camm J.: Oral presentation at ESC on Aug 30th 2009

The Near Future I expect a large increase in people with AFib on oral anticoagulation now that there is an alternative to warfarin. More aggressive use in lower stroke risk group; especially CHADs 1 Prescribers will likely become much more comfortable using a drug other than warfarin Recent Danish paper, newly discharged from hospital AF pts 43% on warfarin, 40% on ASA

for the Pharmacist As much as we worry about warfarin, we should not get overly confident with the new oral agents Dabigatran for A Fib will be our first full test to see how we do as health care providers

for the Pharmacist Very important to remind people on the agent: About taking the drug every day to prevent strokes Being aware of signs of major bleeding Being aware of when to see medical assessment Assessing for potential drug interactions Assessing for impact of renal function Assessing for other bleeding risk agents: e.g. NSAIDs, herbals with salicylates

Summary Anticoagulants are very important to prevent strokes in atrial fibrillation Landscape is going to change drastically in very short order in how we prevent strokes

Summary Number of unanswered questions with dabigatran and we will need time, experience to really answer the questions Overall, very exciting times in the field of anticoagulation with lots of opportunity for pharmacists to take an proactive role in patient care