An Overview of Non Vitamin-K Antagonist Oral Anticoagulants Helen Williams Consultant Pharmacist for CV Disease South London
Contents Drugs and drug classes Licensed indications and NICE recommendations Pharmacological characteristics Contraindications and cautions Drug interactions Practical Issues Dosing Side effects Bleeding, Dyspepsia, CNS effects Switching Adherence
3 Desirable qualities of a new anticoagulant As effective or more effective than current agents As safe or safer than current agents Oral Fixed dosing Minimal food and drug interactions Predictable anticoagulant response (no monitoring) Rapid onset and offset of action Reversible
Drugs and Drug Classes Direct Thrombin Inhibitor Dabigatran Factor Xa inhibitors Rivaroxaban Apixaban
The Clotting Cascade Initiation X TF VIIa VII IX Propagation Xa IXa Apixaban Rivaroxaban X II Prothrombin Transformation Catalysis IIa X Thrombin Dabigatran Clot formation Fibrinogen Fibrin
NOAC Licensed Indications AF stroke prevention - All NICE approved Dabigatran, rivaroxaban and apixaban Acute VTE treatment and secondary prevention Rivaroxaban NICE approved Rivaroxaban, dabigatran, apixaban VTE prophylaxis - Post-hip and knee surgery All NICE approved All licensed full course should be supplied by acute trust Acute Coronary Syndromes Rivaroxaban only (not yet launched)
AF is the leading - and most preventable - cause of embolic stroke Risk increases with age Without preventive treatment, approximately 1 in 20 patients (5%) with AF will have a stroke each year % of strokes attributable to AF 25 20 15 % 10 5 0 50-59 60-69 70-79 80-89 Age (years) Kannel WB et al. Am J Cardiol 1998; 82 (8A): 2N 9N.
Warfarin better Placebo better AFASAK SPAF BAATAF CAFA SPINAF EAFT All trials RRR 64% *, ARR 2.7% (95% CI: 49 74%) 100 50 0 50 RRR (%) 100 Hart RG et al. Ann Intern Med 2007; 146: 857 867. Random effects model; Error bars = 95% CI; *p>0.2 for homogeneity; Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)
RE-LY 2009
Cumulative event rate (%) ROCKET- AF 2011 6 5 4 3 2 1 Event Rate Primary Efficacy Outcome Stroke and non-cns Embolism Rivaroxaban Warfarin 1.71 2.16 Warfarin Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 0 0 120 240 360 480 600 720 840 960 Days from Randomization No. at risk: Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655 Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population NEJM, Patel et al, 2010;
ARISTOTLE Main Trial Results Stroke or systemic embolism ISTH major bleeding International Society of Thrombosis and Hemostasis 21% RRR 31% RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66 0.95); P=0.011 ARR 0.33% NNT 303 Median TTR 66% Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60 0.80); P<0.001 ARR 0.96% NNT 105 N Engl J Med 2011;365:981-92.
Venous thromboembolism - Treatment and secondary prevention September 2012 UK.PH.GM.XAR.2012.220n DVT PE Deep vein insufficiency Pulmonary hypertension Death Post-thrombotic syndrome Chronic PE Venous Ulcers Impact UK is organised and funded by Bayer HealthCare. This meeting includes promotional content
Rivaroxaban EINSTEIN phase III: study designs 30-day observation after treatment cessation 30-day observation after treatment cessation Confirmed acute symptomatic DVT without symptomatic PE Confirmed acute symptomatic PE with or without symptomatic DVT N=3,449 R N=4,833 EINSTEIN DVT 1 and EINSTEIN PE 2 (non-inferiority studies) Treatment period of 3, 6 or 12 months Rivaroxaban 15 mg bid Enoxaparin 1.0 mg/kg bid for at least 5 days, followed by VKA to start 48 hours, target INR range 2.0 3.0 Day 1 Day 21 Rivaroxaban 20 mg od Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA N=1,197 R Day 1 EINSTEIN Extension 1 (superiority study) Treatment period of 6 or 12 months Rivaroxaban 20 mg od Placebo The EINSTEIN investigators, 1. N Eng J Med 2010;363:2499-2510 & 2. N Eng J Med 2012;366:1287-1297 L.GB.01.2013.1379 Jan 2013
EINSTEIN DVT: primary efficacy outcome - Time to first event Cumulative event rate (%) September 2012 UK.PH.GM.XAR.2012.220n 4.0 3.0 2.0 1.0 Enoxaparin/VKA (n=1,718) Rivaroxaban (n=1,731) HR=0.68; p<0.001 0 Number of subjects at risk Rivaroxaban 1,731 1,668 1,648 1,621 1,424 1,412 1,220 400 369 363 345 309 266 Enoxaparin/ VKA 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) 1,718 1,616 1,581 1,553 1,368 1,358 1,186 380 362 337 325 297 264 The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510 Impact UK is organised and funded by Bayer HealthCare. This meeting includes promotional content
EINSTEIN DVT: principal safety outcome analysis September 2012 UK.PH.GM.XAR.2012.220n First major or non-major clinically relevant bleeding Rivaroxaban (n=1,718) Enox/VKA (n=1,711) n (%) n (%) 139 (8.1) 138 (8.1) HR (95% CI) p-value 0.97 (0.76 1.22) p=0.77 Major bleeding 14 (0.8) 20 (1.2) 0.65 (0.33 1.30) p=0.21 Contributing to death 1 (<0.1) 5 (0.3) In a critical site 3 (0.2) 3 (0.2) Associated with fall in haemoglobin 2 g/dl and/or transfusion of 2 units 10 (0.6) 12 (0.7) Non-major clinically relevant bleeding 126 (7.3) 119 (7.0) Safety population The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510 Impact UK is organised and funded by Bayer HealthCare. This meeting includes promotional content
September 2012 UK.PH.GM.XAR.2012.220n Impact UK is organised and funded by Bayer HealthCare. This meeting includes promotional content N Engl J Med 2012; 366:1287-129
RE-MEDY Study 1.8% 1.3% Dabigatran Warfarin Schulman S, et al NEJM 2013;368:709-718
RE-MEDY Study Any Bleeding 26.2% 19.4% Warfarin Dabigatran Major Bleeding Dabigatran 0.9% Warfarin 1.3% Schulman S, et al NEJM 2013;368:709-718
AMPLIFY (Apixaban)
Advantages of NOACs in VTE treatment No need for LMWH bridging (for some agents!) Cost, patient training, risks Immediate efficacy no waiting for INR control Facilitates fast-track treatment in acute care, or management in community settings Short-term treatment first 3 months is most onerous in managing warfarin Reduced inconvenience - VTE effects a younger patient group, often working = a first-line option?
Pharmacologic Characteristics Characteristics Dabigatran Rivaroxaban Apixaban Target IIa Xa Xa Bioavailability 7% 60%-80% 80% Half-Life 12-17 hrs 7-11 hrs 12 hrs Twice daily dose One daily dose Twice daily dose Clearance 80% renal 60% renal 33% biliary 25% renal 75% biliary Metabolism Conjugation to active glucuronides CYP3A4 CYP2J2 CYP3A4 P-GP interaction Yes Yes Yes minimal Adapted from Galanis T et al Thromb Thrombolysis 2011;31:310-320
Contraindications Known hypersensitivity to ingredients Clinically significant active bleeding Mechanical valve in situ Renal impairment (drug specific) Hepatic disease Recent high risk bleeding lesion (e.g ICH < 6 months) Pregnancy and breast-feeding Recent stroke, surgery, GI bleed, ulcers Recent fibrinolytic surgery (< 10 days) Concomitant warfarin therapy
Drug Interactions Strong P-gp inhibitors ketoconazole, itraconazole, cyclosporin, dronedarone, ritonavir, indinavir, clarithromycin Other P-gp inhibitors verapamil, amiodarone, quinidine, pozaconazole Inducers of CYP3A4 and P-gp rifampicin, carbamazepine, phenytoin, St Johns Wort
PRACTICAL ISSUES
Dosing Affected mainly by: INCREASING AGE REDUCING RENAL FUNCTION LOW BODYWEIGHT
Importance of calculating CrCl Patient: AF1 92 year old female started rivaroxaban 20mg daily by local cardiologist at private hospital Bodyweight only 46kg Prescribing responsibility passed to GP at 3 months no transfer of care paperwork sent Practice recorded egfr = 49ml/min Calculated CrCl - 23.3ml/min Required rivaroxaban dose reduction
Balancing benefits vs. risks Are all bleeds equal? All bleeding events Hb drop of 2g/dl Transfusion of 2 U Symptomatic bleeding in critical organ Major bleeding Life threatening bleeding Fatal haemorrhage Intracranial haemorrhage Hb drop of 5g/dl Transfusion of 4 U Inotropic agent support Surgery
Major bleeding rates RE-LY: Connolly NEJM2009 3.36% warfarin versus 3.11% dabigatran 150mg bd (NS) / 2.71% dabigatran 110mg bd (p=0.003) Less life threatening bleeds and ICH More GI bleeds ROCKET-AF: Patel NEJM 2011 3.4% warfarin versus 3.6% rivaroxaban (NS) Reduced ICH and fatal bleeds Increased transfusions and more GI bleeds ARISTOTLE Granger NEJM 2011 3.09% warfarin versus 2.13% apixaban (p<0.001) Less ICH No increased risk of GI bleeds
Reducing risk of bleeding 1. Control BP 2. Review benefit/risk of concomitant aspirin: Hypertensives, diabetics, CHD and no acute ischemic event or intervention in the last year Stop aspirin when INR in therapeutic range 3. Risk of bleeding is greatest in first 90 days of OAC therapy Caution : drug interactions and new drugs Close or more frequent monitoring 4. Review concomitant use of NSAIDS, SSRIs, steroids 5. Consider a PPI Hylek, E.M., Evans-Molina, C, Shea, C. et al. (2007), Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation, Circulation, 115, 2689-2696.
Recommendations for Major Bleeds Dabigatran FFP, Prothrombin Complex Concentrate (PCC) Activated Factor VII Dialysis Rivaroxaban & Apixaban Prothrombin Complex Concentrate Four Factor PCC FFP
Bleeding and referral? 1. Where is the source of the bleeding? 2. Intermittent or continuous? Continuous bleeding Haematemesis Haemoptysis Severe headache/dizziness Malaena Heavy menstrual bleeding Continuous bleeding from cut/graze Continuous haematuria CLINICAL JUDGEMENT Minor bruising Intermittent epistaxis Intermittent gum bleeding Transient haematuria A&E GP/Anticoag clinic - INR
MONITORING Laboratory Testing New Oral Agents Lab Tests Useful Lab Test Dabigatran Rivaroxaban Apixaban Strong ECT Chromogenic Anti-Xa Chromogenic Anti -Xa TT aptt, PT aptt Weak PT / INR Palladino M et al A J Hem 2012;87 Suppl:S127-S132
Other Adverse Effects Minor bleeding - reassure Dabigatran dyspepsia Try PPI, consider alternative NOAC Rivaroxaban / Abixaban dizziness, wooziness, headache Consider alternative agent
Medicines Compliance Aids Dabigatran Cannot use in standard MCAs moisture sensitive Use companies own MCA Rivaroxaban and Apixaban Suitable for use in MCAs no special storage requirements
Adherence Shorter-acting than warfarin therefore efficacy reduced of patient is not fully compliant Impact of missed doses? BD vs OD dosing No routine monitoring How to identify non-adherence? Use NMS / MUR service to support
An Overview of Non Vitamin-K Antagonist Oral Anticoagulants Helen Williams Consultant Pharmacist for CV Disease South London