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

2. New Chest Pain Pathway
Dr John Walsh
Consultant Cardiologist

3. Haematology Issues / Novel Anticoagulants
Dr Gerry Dolan
Consultant Haematologist

5. 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

6. 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:
National Institutes of Health. ClinicalTrials.gov. Accessed July 16, 2008.
National Institutes of Health. ClinicalTrials.gov. Accessed July 16, 2008.
National Institutes of Health. ClinicalTrials.gov. Accessed July 16, 2008.
Direct thrombin inhibitors
Dabigatran
IIa I
Fibrin Clot
Adapted from Ansell J. J Thromb Haemost 2007;5(suppl 1): Turpie AGG. Arterioscler Thromb Vasc Biol 2007;27:

7. 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): 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): Pub Med PMID:

8. 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): 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): Pub Med PMID:

9. 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:S doi: /ajh 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.
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: 
Kaatz S, et al. Am J Hematol May;87 Suppl 1:S Pub Med PMID:

10. 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

11. 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 May;87 Suppl 1:S doi: /ajh Epub 2012 Apr 4. Review.
PMID:
Am J Hematol. 2012 May;87 Suppl 1:S doi: /ajh 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.
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 May;87 Suppl 1:S Pub Med PMID:

12. 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: Ruff et al, Am Heart J 2010; 160:635-41
2. Granger et al, N Engl J Med 2011; 365: Patel et al, N Engl J Med 2011;365:883-91
3. Connolly et al , N Engl J Med 2011; 364:806-17

13. 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. 4

14. 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

15. 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) 6

16. 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 ml/min or if on dabigatran and aged >75 years or fragile
If CrCl ml/min
If intercurring condition may impact renal or hepatic function.