1. Anticoagulation Update
Rhona Maclean

2. By the end of this session you will know:
What anticoagulant therapies are currently available
What anticoagulants can be used in particular clinical situations
Practical tips in using anticoagulants
Starting/ switching/ procedures
Current STH pathway for management DVT/PE

3. Available Anticoagulant Therapies
Heparins
Vitamin K Antagonists
NOACs
Unfractionated Heparin
Warfarin
Dabigatran
Low molecular weight heparin
Sinthrome (Acenocoumarol)
Rivaroxaban
Fondaparinux
Phenindione
Apixaban

4. Heparin and Fondaparinux
Immediate onset of anticoagulation

5. Warfarin Mode of Action
Prothrombin
Prothrombin
precursor
Carboxylase
Reduced vitamin K
Oxidised vitamin K
Vitamin K epoxide reductase -
Vit K dependent
Coagulation factors
FII
FVII
FIX FX
Warfarin
Onset of action- >5 days; not until INR >2 for 24hrs

6. Mode of Action NOACs

7. Novel Oral Anticoagulants (NOACs)
Dabigatran
Rivaroxaban
Apixaban
Half life
12-17h
5-13h
9-12h
Administration
Oral
Renally excreted?
+++
+/-
Heparin Induced Thrombocytopenia -
Osteoporosis
Side effects
Dyspepsia in 8-10%
Monitoring? No
Dietary/ drug interactions +
Reversal agent? ?

8. Drug Interactions with NOACs
Dabigatran
Rivaroxaban
Apixaban
Increase anticoagulant effect
Amiodarone (caution)
Verapamil (caution)
Azole antimycotics
Tacrolimus
Cyclosporin
HIV protease inhibitors
Dronaderone
Azole Antimycotics
HIV Protease Inhibitors
Reduce anticoagulant effect
Rifampicin
Carbamazepine
Phenytoin
Phenobarbital
St John’s wort

9. Licensed and NICE approved indications for NOACs
Dabigatran:
VTE prevention after elective hip or knee replacement surgery
Stroke prevention in Atrial Fibrillation
Rivaroxaban:
Deep Vein Thrombosis treatment and secondary prevention
Pulmonary Embolism treatment and secondary prevention
Acute coronary syndromes
Apixaban:

10. Risk of adverse events in patients with atrial fibrillation taking warfarin : Warfarin is an effective drug
Background: Oral anticoagulant therapy is effective for
the prevention of arterial thromboembolism in variouspatient groups. The increased risk of hemorrhage remains
the major drawback to this therapy and is associated
with the intensity of anticoagulation. Finding the
optimal intensity at which the overall incidence rate of
both bleeding and thromboembolic events is minimized
represents a way to improve the safety of oral anticoagulant
treatment.
Methods: We evaluated all patients visiting the Leiden
Anticoagulation Clinic with mechanical heart valve
prostheses, atrial fibrillation, or myocardial infarction
from 1994 to Untoward events were major thromboembolism
and major hemorrhage. We calculated
intensity-specific incidence rates of untoward events to
assess the optimal intensity per indication of treatment.
We enrolled 4202 patients for a total of 7788 patientyears.
Results: A total of 3226 hospital admissions were reported,
306 owing to an untoward event. Incidence rates
of untoward events were around 4% per year for all indications:
4.3 (95% confidence interval [CI], ) for patients
with mechanical heart valve prostheses, 4.3 (95% CI,
) for patients with atrial fibrillation, and 3.6 per year
(95% CI, ) for patients treated after a myocardial infarction.
The optimal intensity of anticoagulation for patients
with mechanical heart valve prostheses was an international
normalized ratio (INR) of 2.5 to 2.9; for patients
with atrial fibrillation, an INR of 3.0 to 3.4; and for patients
after myocardial infarction, an INR of 3.5 to 3.9.
Conclusion: Our study suggests target INRs of 3.0 for
patients with mechanical heart valve prostheses and atrial
fibrillation
Optimal level of oral anticoagulant therapy
Torn M et al, Arch Int Med 2009; 169:

11. Tips for achieving good warfarin control and avoid complications
Patient education and engagement
Encourage stable lifestyle
Minimise other drug changes/ choose drugs less likely to interact with warfarin
Use standardised induction regimen
Adjust warfarin dose cautiously (+/- 10% of weekly dose) when outside therapeutic range
Consider patient’s previous response
Don’t blindly follow CCDS (INR star)
Do INR if change of medication likely to interact or if unwell/ bleeding

12. Unstable Warfarin Anticoagulation
INR Results 4 8 12 16 20
09/09/2006
08/10/2006
06/11/2006
05/12/2006
03/01/2007
01/02/2007
Dosage 40 60 80
100
68 year old woman on warfarin for recurrent VTE INR 3.5

13. Rivaroxaban
Warfarin
Event rate/100 patient years
Major and non major clinically relevant bleeding
14.9
14.5
Major bleeding
3.6
3.4
Critical bleeding
0.8
1.2
Intracranial bleeding
0.5
0.7

15. Clinical Benefit of Anticoagulants in AF
Banerjee et al, T&H 2012

16. What anticoagulant to use in AF?
Warfarin
Pros
Experience
Efficacious
Long half life
Reversal agent
Use in renal failure
Cons
Requirement for monitoring
Variable dosing requirements
Not immediate onset of action
Drug interactions/ lifestyle issues
Bleeding Risk

17. What anticoagulant to use in AF
NOACs
Pros
Immediate onset of action
Once or twice daily medication- dosette boxes
No (little) monitoring required
Few drug interactions
Risk major bleeding reduced, particularly intracranial
Cons
New- as yet relatively unfamiliar
Shorter half life- compliance issues?
Lack of specific reversal agent- as yet…
Cannot use in renal failure

18. How to start NOAC in patient with AF
Counsel patient- it is an anticoagulant
Check baseline bloods (FBC, renal and liver biochem)
Start NOAC (Rivaroxaban with food- in morning?)
See patient for review in 3-4 weeks- any problems?
Check FBC, biochemistry, 3-12 monthly dependent on patient factors
Reinforce compliance whenever possible

19. Which anticoagulant to use for VTE?
After a first VTE event, patients require minimum 3 months anticoagulation
If idiopathic or ongoing risk factors, consider longer term anticoagulant treatment (NICE)
Patients require immediate anticoagulation
If start warfarin, usually entails 8-15 anticoagulation visits in first 3 months of treatment

20. EINSTEIN DVT and EINSTEIN PE pooled analysis: primary efficacy outcome
Methods of VTE treatment
EINSTEIN DVT and EINSTEIN PE pooled analysis: primary efficacy outcome
0.5
3.0
2.5
2.0
1.5
1.0
0.0
Rivaroxaban
N = 4150
Enoxaparin/VKA
N = 4131 30 60 90
120
150
180
210
240
270
300
330
360
Time to event (days)
Cumulative event rate (%)
HR=0.89; p non-inferiority <0.0001
Mean time in therapeutic range = 61.7%
EINSTEIN DVT and EINSTEIN PE pooled analysis: primary efficacy outcome
Among patients with acute symptomatic DVT without PE or PE with or without DVT treated for 3, 6 or 12 months, the single-drug approach with oral rivaroxaban showed non-inferiority for the primary efficacy outcome of symptomatic recurrent VTE, compared with the current standard therapy (86 events [2.1%] vs 95 events [2.3%], respectively; HR=0.89; 95% CI 0.66–1.19; p< for non-inferiority).
Number of patients at risk
Rivaroxaban
4150
4018
3969
3924
3604
3579
3283
1237
1163
1148
1102
1034
938
Enoxaparin/VKA
4131
3932
3876
3826
3523
3504
3236
1215
1149
1109
1071
1019
939
ITT population

21. EINSTEIN DVT and EINSTEIN PE pooled analysis: major bleeding
Methods of VTE treatment
EINSTEIN DVT and EINSTEIN PE pooled analysis: major bleeding
First major bleeding
0.5
3.0
2.5
2.0
1.5
1.0
0.0
Rivaroxaban
N=4130
Enoxaparin/VKA
N=4116 30 60 90
120
150
180
210
240
270
300
330
360
Time to event (days)
Cumulative event rate (%)
Rivaroxaban n/N (%)
Enoxaparin/VKA n/N (%)
HR (95% CI) p-value
40/4130 (1.0)
72/4116 (1.7)
0.54 (0.37–0.79) p=0.002
EINSTEIN DVT and EINSTEIN PE pooled analysis: major bleeding
Major bleeding, a prespecified secondary outcome, was significantly lower in the rivaroxaban group compared with standard therapy (40 events [1.0%] vs 72 events [1.7%], respectively; HR=0.54; 95% CI 0.37–0.79; p=0.002). This included fewer critical-site bleeding events in the rivaroxaban compared with standard therapy group (9 vs 26, respectively) and fewer fatal major bleeding events (3 vs 8, respectively).
Number of patients at risk
Rivaroxaban
4130
3921
3862
3611
3479
3433
2074
1135
1095
1025
969
947
499
Enoxaparin/VKA
4116
3868
3784
3525
3394
3348
1835
1109
1065
990
950
916
409
Safety population

22. Rivaroxaban for VTE
Currently in patients with a first DVT without contraindications
Eg pregnancy, breastfeeding, renal failure, interacting drugs
15mg bd for 3 weeks then
20mg od for 10 weeks
?Reduce dose in renal impairment
A reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patient's assessed risk for bleeding outweighs the risk for recurrent DVT and PE
Consider duration of treatment
Reassess after 3 months
Idiopathic/ recurrent events
Long term rivaroxaban?
Renal impairment
Limited clinical data for patients with severe renal impairment (creatinine clearance ml/min) indicate that rivaroxaban plasma concentrations are significantly increased therefore, Xarelto is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.4 and 5.2).
In patients with moderate (creatinine clearance ml/min) or severe (creatinine clearance ml/min) renal impairment the following dosage recommendations apply:
- For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section 5.2).
- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: Patients should be treated with 15 mg twice daily for the first 3 weeks.
Thereafter, the recommended dose is 20 mg once daily. A reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patient's assessed risk for bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg is based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2).
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance ml/min) (see section 5.2).

23. LMWH for patients with VTE and cancer
Lee A et al, NEJM 2003

24. LMWH for treatment VTE Dalteparin 200iu/kg once daily
In pregnancy currently use bd dosing.
SPC caps dose at 18,000iu od if >83kg- good evidence that need to increase dose in those with high body weight- STH guideline
After 30 days reduce dose (as per BNF/ STH guideline)
Patients with cancer- watch weight and renal function- may need to adjust dose

25. Summary: Anticoagulation for VTE
Patient choice
Rivaroxaban after a first VTE event (unless contraindicated), if unstable, side effects or contraindications to warfarin
LMWH if cancer, pregnant, interacting drugs with rivaroxaban
Once chemotherapy finished, consider switching from LMWH to alternative anticoagulant
Warfarin if renal failure, if recurrent events

26. Mechanical Heart Valves
Do not use NOACs
Study of dabigatran terminated as excess bleeding and thrombosis in dabigatran groups compared with warfarin.
No other studies underway at present

27. Converting from Warfarin to Rivaroxaban
Discuss with patient
Check that patient is not on interacting drugs
Baseline bloods- FBC, renal and liver biochemistry, INR
Make switch
Review in a couple of weeks for side-effects and to reinforce compliance
FBC and biochemistry every 3-12 months

28. Converting from Warfarin to Rivaroxaban
VTE treatment
INR < 2.5
Stop VKA
VKA
Monitor INR
Commence Xarelto at appropriate dose
SPAF
INR < 3.0
VTE
INR ≤ 2.5
Xarelto SmPC
SmPC for rivaroxaban
L.GB Date of preparation Jan 2013 28 28 28

29. (dose according to indication)
Converting from Rivaroxaban to Warfarin
Standard VKA dose
INR adapted VKA dose
Xarelto
(dose according to indication)
Xarelto can be stopped once INR > 2.0
INR testing before Xarelto administration
Days
Once Rivaroxaban is discontinued, INR testing may be done reliably at least 24hrs after the last dose
Xarelto SmPC 29

30. Preoperative management of Rivaroxaban anticoagulation
Major surgery
Minor surgery

31. Postoperative Management of Rivaroxaban Anticoagulation
Major surgery
Surgery
D +1
D+2
D+3
D+4
D+5
D + 6
Prophylactic dalteparin once daily starting 6 – 8 hrs post op
Stop dalteparin the day before restarting therapeutic rivaroxaban (at day 3 – 5, at earliest on day 3, depending on bleeding tendency). Check U&E/LFT. Do not restart therapeutic anticoagulation with epidural in situ.
Minor surgery
Start Rivaroxaban 24 hours after the procedure.
Patients admitted on prophylactic doses of rivaroxaban (10 mg OD) may be re-started hours post op.

32. Patient pathway for VTE
Diagnosed in A&E or as an inpatient
Seen by thrombosis nurse specialist for
assessment
MDT
Malignancy suspected
2 weeks O.P.A
with consultant
Unprovoked DVT
4 to 6 weeks O.P.A
with consultant
Provoked DVT
Nurse-led pathway

33. Conclusion
Warfarin and NOACs both efficacious in prevention stroke in AF and treatment VTE
Most important issue is patients who require anticoagulation have access to anticoagulant treatment