Cardiology Protected Learning Time Event 16th June 2015 Welcome

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Presentation transcript:

Cardiology Protected Learning Time Event 16th June 2015 Welcome Dr Manik Arora General Practitioner and LTC Executive Lead

New Chest Pain Pathway Dr John Walsh Consultant Cardiologist

Haematology Issues / Novel Anticoagulants Dr Gerry Dolan Consultant Haematologist

Properties of an ideal anticoagulant versus currently available agents Oral Fewer drug interactions Predictable response No routine coagulation monitoring Fixed dosing No risk of HIT IDEAL  LMWH UFH Fondaparinux VKAs Rivaroxaban Dabigatran Apixaban Edoxaban

Targets of new oral anticoagulants Xll Xl lX TF VIIIa VII Direct factor Xa inhibitors Rivaroxaban Apixaban Xa Va Targets of Oral Anticoagulant Therapies in Phase 3 Development Three oral anticoagulant therapies are currently in phase 3 development. Two of these therapies directly target factor Xa: rivaroxaban and apixaban One of these therapies directly targets thrombin: dabigatran etexilate Phase 3 trials for these anticoagulants are focused on the following treatment areas: VTE prevention and treatment Stroke prevention in atrial fibrillation Secondary prevention of acute coronary syndrome References Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemost. 2007;5(suppl1):60-64. Turpie AGG. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler Thromb Vasc Biol. 2007;27:1238-1247. National Institutes of Health. ClinicalTrials.gov. www.clinicaltrials.gov/ct2/results?term=apixaban. Accessed July 16, 2008. National Institutes of Health. ClinicalTrials.gov. www.clinicaltrials.gov/ct2/results?term=rivaroxaban. Accessed July 16, 2008. National Institutes of Health. ClinicalTrials.gov. www.clinicaltrials.gov/ct2/results?term=dabigatran. Accessed July 16, 2008. Direct thrombin inhibitors Dabigatran IIa I Fibrin Clot Adapted from Ansell J. J Thromb Haemost 2007;5(suppl 1):60-64. Turpie AGG. Arterioscler Thromb Vasc Biol 2007;27:1238-1247.

Meta-analysis of Efficacy and Safety of New Oral Anticoagulants Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients All cause stroke/SEE Ischemic and unspecified stroke Am J Cardiol. 2012 Aug 1;110(3):453-60. Epub 2012 Apr 24. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Source Division of Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Abstract New oral anticoagulants, including apixaban, dabigatran, and rivaroxaban, have been developed as alternatives to warfarin, the standard oral anticoagulation therapy for patients with atrial fibrillation (AF). A systematic review and meta-analysis of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants to those of warfarin in patients with AF. The published research was systematically searched for randomized controlled trials of >1 year in duration that compared new oral anticoagulants to warfarin in patients with AF. Random-effects models were used to pool efficacy and safety data across randomized controlled trials. Three studies, including 44,563 patients, were identified. Patients randomized to new oral anticoagulants had a decreased risk for all-cause stroke and systemic embolism (relative risk [RR] 0.78, 95% confidence interval [CI] 0.67 to 0.92), ischemic and unidentified stroke (RR 0.87, 95% CI 0.77 to 0.99), hemorrhagic stroke (RR 0.45, 95% CI 0.31 to 0.68), all-cause mortality (RR 0.88, 95% CI 0.82 to 0.95), and vascular mortality (RR 0.87, 95% CI 0.77 to 0.98). Randomization to a new oral anticoagulant was associated with a lower risk for intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66). Data regarding the risks for major bleeding (RR 0.88, 95% CI 0.71 to 1.09) and gastrointestinal bleeding (RR 1.25, 95% CI 0.91 to 1.72) were inconclusive. In conclusion, the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favorable safety profile, making them promising alternatives to warfarin. Copyright © 2012 Elsevier Inc. All rights reserved. Hemorrhagic stroke Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354..

Meta-analysis of Efficacy and Safety of New Oral Anticoagulants Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients Major bleeding Intracranial bleeding Figure 3. Forest plot for (A) major bleeding, (B) intracranial bleeding, and (C) gastrointestinal bleeding, new oral anticoagulants (NOA) versus warfarin in patients with AF. Am J Cardiol. 2012 Aug 1;110(3):453-60. Epub 2012 Apr 24. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Source Division of Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Abstract New oral anticoagulants, including apixaban, dabigatran, and rivaroxaban, have been developed as alternatives to warfarin, the standard oral anticoagulation therapy for patients with atrial fibrillation (AF). A systematic review and meta-analysis of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants to those of warfarin in patients with AF. The published research was systematically searched for randomized controlled trials of >1 year in duration that compared new oral anticoagulants to warfarin in patients with AF. Random-effects models were used to pool efficacy and safety data across randomized controlled trials. Three studies, including 44,563 patients, were identified. Patients randomized to new oral anticoagulants had a decreased risk for all-cause stroke and systemic embolism (relative risk [RR] 0.78, 95% confidence interval [CI] 0.67 to 0.92), ischemic and unidentified stroke (RR 0.87, 95% CI 0.77 to 0.99), hemorrhagic stroke (RR 0.45, 95% CI 0.31 to 0.68), all-cause mortality (RR 0.88, 95% CI 0.82 to 0.95), and vascular mortality (RR 0.87, 95% CI 0.77 to 0.98). Randomization to a new oral anticoagulant was associated with a lower risk for intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66). Data regarding the risks for major bleeding (RR 0.88, 95% CI 0.71 to 1.09) and gastrointestinal bleeding (RR 1.25, 95% CI 0.91 to 1.72) were inconclusive. In conclusion, the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favorable safety profile, making them promising alternatives to warfarin. Copyright © 2012 Elsevier Inc. All rights reserved. GI Bleeding Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354.

Pharmacokinetics of NOACs   Apixaban Dabigatran Rivaroxaban Direct factor inhibition Xa IIa Bioavailability (Frel) 80% 6% Peak action (tmax) 1–3 hr Protein binding 84% 35% 92–95% Renal clearance 25% 33% Elimination half life with creatinine clearance > 80 ml/min 15.1 hr 13.8 hr 8.3 hr Elimination half life with creatinine clearance 50–79 ml/min 14.6 hr 16.6 hr 8.7 hr Elimination half life with creatinine clearance 30–49 ml/min 17.6 hr 18.7 hr 9.0 hr Elimination half life with creatinine clearance < 30 ml/min 17.3 hr 27.5 hr 9.5 hr Am J Hematol. 2012 May;87 Suppl 1:S141-5. doi: 10.1002/ajh.23202. Epub 2012 Apr 4. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J. Source Department of Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA. skaatz1@hfhs.org. Abstract The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug-drug interactions and less food-drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed. Copyright © 2012 Wiley Periodicals, Inc. PMID: 22473649 Kaatz S, et al. Am J Hematol. 2012 May;87 Suppl 1:S141-5. Pub Med PMID: 22473649.

Measuring the Effect of NOACs Coagulation Assays Apixaban Rivaroxaban Dabigatran PT -dilute PT -modified PT Not useful Data n/a Qualitative Data n/a  aPTT TT   -dTT/HEMOCLOT No effect  No effect Qualitative  Quantitative Chromogenic Assays -Anti-Xa -Anti-IIa No Effect Table 3: A summary of different assays and their utility with apixaban, rivaroxaban and dabigatran. aPTT, activated partial thromboplastin time; dPT, dilute prothrombin time; dTT, dilute thrombin time; INR, international normalized ratio; mPT, modified prothrombin time; NOAC, novel oral anticoagulants; PT, prothrombin time; TT, thrombin. NB: any assay intended for quantitative assessment must be calibrated for the specific drug measured (e.g. a chromogenic anti-Xa assay calibrated for enoxaparin cannot be used – without calibration - interchangeably to measure rivaroxaban). Most assays used for “qualitative” assessment exclude the presence of clinically important drug effect when COMPLETELY NORMAL – when abnormal, these assays can be interpreted only as showing that anticoagulant effect is present. n/a = not available Garcia DA, et al. In review. 10

Human volunteers and rat model Reversal of NOACs Types of Studies Evaluating Reversal of New Oral Anticoagulants Apixaban Dabigatran Rivaroxaban Oral activated charcoal No data In vitro Hemodialysis Human volunteers Hemoperfusion with activated charcoal Fresh frozen plasma Mouse model Activated factor VIIa Rat model Rat and baboon model 3-factor PCC 4-factor PCC Human volunteers and rat model Table II. Types of Studies Evaluating Reversal of New Oral Anticoagulants Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J. Am J Hematol. 2012 May;87 Suppl 1:S141-5. doi: 10.1002/ajh.23202. Epub 2012 Apr 4. Review. PMID: 22473649 Am J Hematol. 2012 May;87 Suppl 1:S141-5. doi: 10.1002/ajh.23202. Epub 2012 Apr 4. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J. Source Department of Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA. skaatz1@hfhs.org. Abstract The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug-drug interactions and less food-drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed. Copyright © 2012 Wiley Periodicals, Inc. Kaatz S, et al. Am J Hematol. 2012 May;87 Suppl 1:S141-5. Pub Med PMID: 22473649.

NOACs approved or under evaluation for prevention of systemic embolism or stroke in patients with non-valvular AF Dabigatran Apixaban Edoxaban * Rivaroxaban Action Direct thrombin inhibitor Activated factor Xa (FXa) inhibitor Dose 150 mg BID 110 mg BID 5 mg BID 2.5 mg BID 60 mg QD 30 mg QD 15 mg QD 20 mg QD Phase III clinical trial RE-LY 1 ARISTOTLE 2 AVERROES 3 ENGAGE-AF 4 ROCKET-AF 5 * not yet approved by EMA 1. Connolly et al, N Engl J Med 2009; 361:1139-51 4. Ruff et al, Am Heart J 2010; 160:635-41 2. Granger et al, N Engl J Med 2011; 365:981-92 5. Patel et al, N Engl J Med 2011;365:883-91 3. Connolly et al , N Engl J Med 2011; 364:806-17 www.escardio.org/EHRA

Practical start-up and follow-up scheme for patients on NOACs Risk/benefit analysis: is a NOAC indicated? When choosing a NOAC, consider co-medications taken by patient. Consider co-medications such as PPI to reduce risk for gastro-intestinal bleeding. Carry information card: generic card could serve for all NOACs. Need to educate patient on importance of strict adherence to regimen – discontinuation is dangerous. www.escardio.org/EHA 4

EHRA proposal for a universal NOAC anticoagulation card Card can be downloaded in a printer-ready form or in a ppt format that can be configured to the local language from www.NOACforAF.eu

Need for structured follow-up All NOACs are anticoagulants and hence can cause serious bleeding. All NOACs have some drug-drug interactions (DDIs). AF population is a fragile patient population. Patients should return for ongoing review according to a predetermined schedule. Follow-up can be undertaken by specialist or GP with experience in the field and/or appropriate secondary care physicians. Nurse co-ordinated AF clinics may be used. 1 1. Berti et al, Eur Heart J, 2013 (Epub ahead of print) www.escardio.org/EHRA 6

Checklist during follow-up of AF patients on NOACs Interval Comments Compliance Each visit Inspect remaining medication Stress importance of compliance Inform about compliance aids Thrombo-embolism Cerebral, systemic and pulmonary circulation Bleeding “Nuisance” bleeding – prevention possible? Bleeding with risk or impact on QoL – prevention possible? Need to revise dose? Side effects Continuation? Temporary cessation with bridging? Change of anticoagulant drug? Co-medications Prescription or over-the counter drugs? Even temporary use can be risky Blood sampling Yearly 6-monthly 3-monthly on indication Haemoglobin, renal, liver function Renal function if CrCl 30-60 ml/min or if on dabigatran and aged >75 years or fragile If CrCl 15-30 ml/min If intercurring condition may impact renal or hepatic function. www.escardio.org/EHRA