CCPN SPAF Tool. STROKE PREVENTION IN ATRIAL FIBRILLATION (SPAF): POCKET REFERENCE

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1 SEPTEMBER 2012 CCPN SPAF Tool STROKE PREVENTION IN ATRIAL FIBRILLATION (SPAF): POCKET REFERENCE Approximately 20% of all strokes are attributable to Atrial Fibrillation (AF). 1 Of these, 20% will result in death and 60% will result in disability. Given this, it is important to ensure appropriate antithrombotic therapy for those at risk for cardioembolic stroke. This pocket reference summarizes the therapeutic options for the prevention of stroke in patients with non-valvular AF. It does not address patients with rheumatic heart or patients with transient, self-limited AF associated with an acute illness or secondary cause. It is intended only as a general reference to supplement the existing knowledge of healthcare professionals and is NOT a substitute for the sound clinical judgement of the knowledgeable healthcare professional. The authors, editors, or CCPN cannot be held responsible for any harm, direct or indirect, caused as a result of the application of the information contained in this resource.

2 step 1 Determine your patient s risk of stroke using CHADS 2 Score: 2 CHADS 2 Score Finding Points C Congestive Heart Failure 1 point H Hypertension 1 point A Age > 75 years 1 point D Diabetes 1 point S Prior Stroke or TIA 2 points Patients with a CHADS 2 score of 0 could still be at increased risk of stroke and require further risk stratifi cation based on the following characteristics: 3 Age between 65 and 75 years Female sex Known vascular Next, determine your patient s corresponding risk of stroke and recommended stroke prophylaxis: 4 CHADS 2 = 0 Stroke risk is 1.9 per 100 patient years ( ) > 65 years or combination of female sex and vascular Either female sex or vascular No additional risk factors for stroke OAC* ASA No antithrombotic CHADS 2 = 1 or More CHADS 2 Score Stroke Rate per 100 patient years (95% CI) Recommended therapy ( ) OAC* ( ) OAC ( ) OAC ( ) OAC ( ) OAC ( ) OAC * OAC refers to therapeutic (i.e., treatment dose) Oral Anticoagulant Therapy OAC is favoured over ASA, but ASA is reasonable for some 4

3 step 2 step 3 Determine your patient s risk of bleeding On the right is the HAS-BLED risk score 5 (tested in a cohort of European patients with AF). A score > 3 indicates high risk for a patient to experience a bleeding event and hence warrants some caution and regular patient evaluation of antithrombotic therapy. Overlap amongst risk factors for determining risk of stroke and risk of major bleeding is evident, and stroke risk usually exceeds the risk of bleeding. 4 As such, the presence of risk factors for bleeding should not be the sole criteria upon which the decision to anticoagulate or not is made, but may be helpful to stratify in conjunction with other information. The incidence of major bleeding with a HAS-BLED score NOTE: The table provides inter-trial comparative data along with data derived from meta-analyses. Endpoints and defi nitions along with trial populations differ, and caution must be taken in the interpretation. Data presented provides guidance to readers in understanding the comparative benefi ts and risks of therapeutic alternatives. Effi cacy with warfarin is only achieved if patients are appropriately anticoagulated (INR ) at least 60% of the time. 7,8 As time in the therapeutic range falls below 60%, there is an increase in mortality, major bleeding, and stroke severity. 7,8,9 HAS-BLED Score Major Risk %/yr 2 1.9%/yr 3 3.7%/yr 4 8.7%/yr %/yr While certain patient populations may require dual antiplatelet therapy (e.g., ASA + clopidogrel) with anticoagulant therapy (i.e., triple therapy), the risk of bleeding dramatically increases, with population estimates of a 4-fold increased risk compared to warfarin alone 6 * Major bleeding defi ned as a reduction in the hemoglobin level of at least 20 g/l, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ Major bleeding defi ned as a reduction in the hemoglobin level of at least 20g/L, transfusion of at least 2 units of blood, any critical bleeding which was defi ned by bleeding that was intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular (with compartment syndrome) or into the retroperitoneum, or fatal bleeding Balance the benefi ts and risks with available agents Positive Outcomes Comparators Primary endpoint: (95% CI) ASA vs. Placebo 10 All Stroke: (meta-analysis of 5 trials n=2834, 6.86%/yr vs 8.77%/yr; 41% secondary prevention) RRR 22% (2-39) Warfarin vs. Placebo 10 (meta-analysis of 6 trials, n=2900, 20% secondary prevention) All Stroke: 2.21%/yr vs 6.03%/yr; RRR 64% (49-74) Warfarin vs. ASA 10 All Stroke: (meta analysis of 5 trials, n=3647, 2.43%/yr vs 3.81%/yr; 21%secondary prevention) RRR 38% (18-52) Dabigatran 110 mg bid vs warfarin 11 (n=18113) Dabigatran 150 mg bid vs warfarin 11 (n=18113) Rivaroxaban 20 mg daily vs warfarin 12 (n=14264, ITT analysis) Stroke/Systemic Embolism: 1.54%/yr vs 1.71%/yr; RR 0.91 ( ) Stroke/Systemic Embolism: 1.11%/yr vs 1.71%/yr; RR 0.66 ( ) Stroke/Systemic Embolism: 2.1%/yr vs 2.4%/yr; HR 0.88 ( ) Letter Characteristic Score H Hypertension (systolic blood pressure > 160 mmhg) 1 A Abnormal Renal (dialysis, transplant or serum Cr > 200 µmol/l) or Liver function (cirrhosis or bilirubin > 2 x upper limit normal with AST/ALT/Alk Phos > 3 x upper limit normal) (1 point each) 1 or 2 S Stroke 1 B (by history or predisposition, e.g., bleeding diathesis, anemia) 1 L Labile INRs (poor time in INR range [< 60% time in range] or frequent unstable or high INRs) 1 E Elderly (> 65 years) 1 D Drugs (concomitant antiplatelet, NSAIDS) or Alcohol abuse (1 point each) 1 or 2 Maximum Score 9 Safety Endpoints Primary endpoint Primary ARR endpoint Intracranial (NNT) RRR Events/year (95% CI) Hemorrhage Events 1.91%/yr 22% Major Extracranial hemorrhage: 16 vs 15 8 vs 4 (53) 3.82%/yr (26) 1.38%/yr (72) 0.13%/yr (769) 0.56%/yr (177) 0.3%/yr (333) 64% Major Extracranial hemorrhage: 31 vs 17 6 vs 3 38% Major Extracranial hemorrhage: 40 vs vs 7 8% Major bleeding:* 2.71%/yr vs 3.36%/yr; RR 0.80 ( ) 36% Major bleeding:* 3.11%/yr vs 3.36%/yr; RR 0.93 ( ) 12% Major bleeding: 3.6%/yr vs 3.4%/yr; HR 1.04 ( ) 0.23%/yr vs 0.74%/yr; RR 0.31 ( ) 0.30%/yr vs 0.74%/yr; RR 0.40 ( ) 0.5%/yr vs 0.7%/yr; HR 0.67 ( )

4 step 4 Acetylsalicylic Acid (ASA) 13 Dosing for Stroke Prophylaxis mg daily Contraindications Allergy or hypersensitivity, active peptic ulcer, ASA plus methotrexate in doses > 15 mg/wk (majority occurs within GI tract) Dyspepsia Hold Prior to Surgery 5-7 days Drug-Drug Interactions May decrease the effi cacy of antihypertenisives Ibuprofen may reduce cardioprotective effects of ASA May increase methothrexate levels/ toxicity particularly at high methotrexate doses Warfarin (Coumadin ) 14 Mechanism of Action Inhibits vitamin K dependent coagulation factors (factors II, VII, IX and X) Pharmacokinetics t max : hrs t 1/2 : 40 hrs (range hrs) (highly variable in patients) Dosing for Stroke Prophylaxis and Dose Adjustment Target INR 2.5 (range ) for nonvalvular AF Warfarin initiation doses of 5-10 mg for 1-2 days, with subsequent dosing based on INRs. 15 Choice of initial warfarin dose may be < 5mg for those with liver, taking medications likely to pronounce warfarin s effects, are malnourished, debilitated, have heart failure, acutely ill or had recent surgery Select, implement & monitor stroke prophylaxis Dosing alteration in the maintenance phase of therapy should typically be on the order of 5-15% of the weekly dosage (or average daily dose) Maintenance Dosing Adjustments for INR of * INR Action < 1.5 Reload 0 2 doses, dose by 5 15% weekly Reload 0 1 dose, by 0 10% weekly dose No Change Hold 0 1 dose, by 0 10% weekly dose Hold 0 2 doses, by 5 15% weekly dose Hold warfarin, consider Vitamin K mg PO > 9 Hold warfarin and Vitamin K mg PO * Guidelines are to be used as a general framework for dosage adjustment to be modifi ed as individual needs dictate Reload refers to giving the patient up to twice the daily maintenance dose Appropriate in patients with no signifi cant bleeding Contraindications Hepatic impairment: monitor INR closely as may potentiate response Active bleeding Hold Prior to Surgery Amongst stable patients it is likely that the INR will be < 2 after 2 days of withholding warfarin, and < 1.3 with 5 days of holding warfarin. If warfarin is held greater than 2 days, consider bridging if patient is at high thromboembolic risk Drug-Drug Interactions Numerous drug interactions are evident with warfarin, and are beyond the scope of this tool. Clinicians should note some of these interactions are delayed, and management of warfarin doses will vary. For a detailed list of drug interactions with management tips, please refer to a published practice tool (www. cpjournal.ca/doi/pdf/ / x ) 16 Dabigatran (Pradax ) 17 Mechanism of Action Direct thrombin inhibitor that binds to both free and clot-bound thrombin and prevents thrombus formation Pharmacokinetics t max : 2 hrs t 1/2 : hrs (t 1/2 ~ 27 hrs if CrCl < 30 ml/min) 18 Elimination: primarily renal (80%) Dosing for Stroke Prophylaxis Establish baseline renal function 150 mg BID OR 110 mg BID for patients greater than 80 yrs of age; consider this dose for those > 75 years with at least one risk factor for bleeding Do not chew, break or open capsules as this may result in increased exposure Take with or without food Dosage Adjustment Renal: renal function should be assessed at initiation (to ensure CrCl > 30 ml/min), during clinical situations when renal function may decline, and at least annually in those > 75 years or with moderate renal function (CrCl ml/min) 19 Hepatic: not studied in moderate to severe impairment Contraindications 17 CrCl < 30 ml/min Active bleeding Lesions at risk of clinically signifi cant bleeding (eg., hemorrhagic or ischemic stroke within 6 months, active peptic ulcer with recent bleeding) Treatment with strong P-glycoprotien inhibitors/inducers (e.g., ketoconazole, rifampin) Hypersensitivity or allergy Use in pregnancy and nursing is not recommended Converting From or To Warfarin* From warfarin to dabigatran discontinue warfarin and start dabigatran once INR less than From dabigatran to warfarin, based on CrCl 20 - CrCl > 50 ml/min start warfarin 3 days before stopping dabigatran - CrCl ml/min start warfarin 2 days before stopping dabigatran - CrCl ml/min start warfarin 1 day before stopping dabigatran * because dabigatran can contribute to an elevated INR, venipuncture INR will better refl ect warfarin effect once dabigatran has been stopped for at least 2 days Anticoagulation Testing and Assessment Routine anticoagulant monitoring is not required. 17,18,20 INR and aptt testing should not be used for routine monitoring or dose adjustment. A normal TT rules out the presence of clinically important dabigatran levels. In absence of TT availability, aptt may be used although a minority of patients (<2%) may have a normal aptt just prior to their next dose, while chronically taking dabigatran. 21 Monitor CBC at baseline and with any change in health status that may impact hemoglobin, red blood cell count or platelets Monitor CrCl to assess stability of renal function and ongoing dabigatran dose / use Dabigatran (Pradax ) continued

5 step 4 Rivaroxaban (Xarelto ) 22 Mechanism of Action Direct Factor Xa inhibitor Pharmacokinetics t max : 2 4 hrs t 1/2 : 7-11 hrs Elimination: renal elimination of unchanged drug (33%) continued Select, implement & monitor stroke prophylaxis Dabigatran (Pradax ) continued Dyspepsia (including abdominal pain) in 11% of patients Hold Prior to Surgery 17* Timing of discontinuation after first dose of CrCl dabigatran before surgery (Prod Monog) Standard risk of bleeding High risk of bleeding > 80 ml/min 24 hours 2 days > 50 < 80 ml/min 1 2 days 2 3 days > 30 < 50 ml/min 2-3 days (>48 hours) 4 days * To minimize the risk of ischemic stroke, therapy should be restarted once hemostasis is achieved, and this should be also guided by the risk of bleeding due to the procedure If CrCl < 30mL/min (dabigatran is contraindicated), hold at least 5 days 17 Such as cardiac catheterization, ablation therapy, or uncomplicated laparoscopic procedures 20 Such as neurosurgery, major cancer/cardiac/urologic/vascular surgery 20 Antidote No specifi c antidote In case of life-threatening bleed consult local specialist. Limited clinical data is available; options may include activated prothrombin complex concentrates (PCCs), inactivated PCCs or rfviia 18,20 Dialysis may be considered, but may not be practical Drug-Drug Interactions 17 Limited drug interaction data is currently available and data below refl ects those studied/reported to date * No empiric dosage adjustment required however use with caution Recommend to give 2 hours after dabigatran Contraindicated Dabigatran concentration is not affected by digxoin Potential in Dabigatran Amiodarone* Clarithromycin* Dronedarone Ketoconazole Quinidine* Verapamil* Strong P-glycoprotein inhibitors Potential in Dabigatran Antacids Carbamazepine Pantoprazole* Rifampin St John s Wort Tenofovir Strong P-glycoprotein inducers Dosing for Stroke Prophylaxis 20 mg daily with food (for CrCl > 50 ml/min) 15 mg daily with food (for CrCl ml/min) Administration with food enables complete absorption of the 15 mg and 20 mg doses Establish baseline renal function Dosage Adjustment Adjusted based on renal function (per above) Assess CrCl routinely to ensure stability Not recommended if CrCl < 30 ml/min Hepatic: not studied in moderate to severe impairment Contraindications 22 Active bleeding Lesions at risk of clinically signifi cant bleeding (eg., hemorrhagic or ischemic stroke within 6 months, active peptic ulcer with recent bleeding) Concomitant treatment with strong inhibitors of both CYP 3A4 and P-glycoprotein Hepatic (including Child-Pugh Class B and C) associated with coagulopathy and have clinically high bleeding risk Pregnancy or Nursing Hypersensitivity (product contains lactose) or allergy Use in patients with CrCl < 30 ml/min is not recommended Converting From or To Warfarin 22 From warfarin to rivaroxaban discontinue warfarin and start rivaroxaban once INR is less than 2.5 From rivaroxaban to warfarin give rivaroxaban concurrently with warfarin until Hold Prior to Surgery 22* CrCl Timing of discontinuation after first dose of rivaroxaban before surgery Standard risk of bleeding High risk of bleeding > 30 ml/min 24 hours 2-4 days * To minimize the risk of ischemic stroke, therapy should be restarted once hemostasis is achieved, and this should be also guided by the risk of bleeding due to the procedure If CrCl < 30mL/min (rivaroxaban is not recommended), hold at least 2 days for standard bleeding risk and 4 days for high risk of bleeding 20 Such as cardiac catheterization, ablation therapy, or uncomplicated laparoscopic procedures 20 Such as neurosurgery, major cancer/cardiac/urologic/vascular surgery 20 Antidote No specifi c antidote In case of life-threatening bleeding, consult local specialist. Limited clinical data is available, consider use of prothrombin complex concentrates (PCC) or activated PCCs 18,20,23 Drug-Drug Interactions 22 Limited drug interaction data is currently available and data below refl ects those studied/reported to date * No empiric dosage adjustment required however use with caution Contraindicated in combination with strong inhibitors of both CYP 3A4 and P-glycoprotein Should be avoided in combination with rivaroxaban the INR is > 2.0. Rivaroxaban will increase the INR and testing should be done 24 hours after rivaroxaban dosing to better refl ect the impact of warfarin. Rivaroxaban can be discontinued once the INR is > 2.0 Anticoagulation Testing and Assessment Routine anticoagulant monitoring is not required, and INR or aptt testing should not be used as a measure of the anticoagulant effect. Rivaroxaban-calibrated anti-xa levels refl ect the pharmacodynamic effect in a dose dependent fashion. In the absence of anti-xa levels, the PT (Neoplastin reagent) may be useful to refl ect presence of drug Monitor CBC at baseline and with any change in health status that may impact hemoglobin, red blood cell count or platelets Monitor CrCl to assess stability of renal function and ongoing rivaroxaban dose/use Potential in Potential in Rivaroxaban Rivaroxaban Clarithromycin* Fluconazole* Ketoconazole Ritonavir Strong inhibitors of both P-glycoprotein and 3A4 Carbamazepine Phenytoin Rifampin St. Johns Wort Strong inducers of both P-glycoprotein and 3A4

6 overview step 1 CHADS 2 Congestive heart failure Hypertension > 65 years or combination of female sex and vascular step 2 High SBP >160 mmhg CHADS 2 1 or More CHADS 2 Score Stroke Rate per 100 patient years (95% CI) Recommended therapy ( ) OAC* ( ) OAC ( ) OAC ( ) OAC ( ) OAC ( ) OAC Abnormal renal or liver function Determine your patient s risk of stroke using CHADS 2 : 2 Age (>75 years) Determine your patient s risk of bleeding using the HAS-BLED Score: 5 Stroke Diabetes Mellitus Either female sex or vascular history Labile INR Elderly age >65 years Drugs or ETOH MAX. SCORE 1 1 or or 2 9 Score > 3 indicates high risk & warrants some caution/regular patient evaluation of antithrombotic therapy No additional risk factors for stroke OAC* ASA No antithrombotic * OAC refers to therapeutic (i.e., treatment dose) Oral Anticoagulant Therapy OAC is favoured over ASA, but ASA is reasonable for some 4 Stroke/TIA 2 MAX.SCORE If CHADS 2 Score = 0, further risk stratify in accordance with: 3 Age 65 to 75 years Vascular Disease Female Sex CHADS 2 = 0 Stroke risk is 1.9 per 100 patient years ( ) step 3 Stroke Prevention Major Comments Compared to warfarin, dabigatran 150 mg BID is superior in preventing stroke, while dabigatran 110 mg BID has similar effi cacy 11 Compared to warfarin, rivaroxaban 20 mg once daily is at least as good at preventing strokes 12 Warfarin is superior to ASA 10 (Effi cacy based on achieving a time in therapeutic range (INR 2-3) at least 60% of the time) 7, Canadian AF Guidelines recommend dabigatran and rivaroxaban over warfarin 4 step 4 Agent ASA Dose mg daily Dabigatran 150 mg BID 110 mg BID* Rivaroxaban 20 mg daily, 15 mg daily with food Warfarin As per INR target of 2.5 Balance the benefi t and risk with available agents Compared with warfarin, dabigatran 150 mg BID and rivaroxaban 20 mg once daily are associated with similar rates of major bleeding but more GI bleeds 11,12 Compared with warfarin, dabigatran 110 mg BID is associated with less major bleeding 11 and is the preferred dose for patients over 80 years or over 75 years with risk factors for bleeding 17 Both dabigatran and rivaroxaban are associated with less intracranial hemorrhage (ICH) than warfarin 11,12 No clinical trials directly comparing dabigatran to rivaroxaban therapy are available Dabigatran and rivaroxaban should be avoided in signifi cant renal dysfunction (i.e., CrCl < 30 ml/ min) 17, Canadian AF Guidelines suggest dialysis patients should not routinely receive OAC or ASA 4 Dabigatran is contraindicated in combination with drugs that are strong P-glycoprotein (gp) inhibitors/inducers. 17 Rivaroxaban is contraindicated in combination with drugs that are strong inhibitors/inducers of both P-gp and CYP 3A4 22 Discuss cost and coverage of new OACs with patient Select, implement & monitor stroke prophylaxis 13,14,17,22 Routine Monitoring DI/Food Interactions Offset Antidote No Dyspepsia No No 5 7 days No Yes/No 1-4 days No Yes/Yes 1-4 days Yes * Should use Dabigatran 110 mg BID if > 80 years of age and consider for those > 75 years with at least one additional risk factor for bleeding Dependent upon renal function Extensive/ Extensive 3-5 days For a complete list of References, go to No No Yes Dyspepsia Major bleeding occurs with all antithrombotic agents Effi cacy based on achieving a time in therapeutic range of at least 60% of the time 7,8 Rivaroxaban 15mg daily if CrCl 30-49mL/min Must be taken with food for complete absorption