1. What’s new in AF and VTE guidelines?
Rapid Clinical updates since last EPCCS, Part 2
What’s new in AF and VTE guidelines?
Prof David Fitzmaurice
Birmingham, United Kingdom

2. Declarations
I have received honoraria from BI, Roche Diagnostics, Bayer, BMS-Pfizer I went to the same primary school as Matt Fay

3. VTE Comprises DVT and PE 3rd leading cause of cardiovascular mortality
1 million deaths per year in Europe
At least 50% due to hospital admission
VTE causes more deaths than MRSA, AIDS, Breast Cancer and RTAs combined
1/20 lifetime incidence

4. Aims of treatment To prevent extension To prevent embolisation
To allow stabilisation and recanalisation
To prevent recurrence
To prevent long term effects (PTS, PH)

5. Current Treatment Initial treatment with UFH, LMWH, SP
No placebo controlled trials
Minimum 5 days (average 7)
LMWH drug of choice for cancer patients

6. Current Treatment Combined with warfarin (VKA)
Treatment phase 3-12 months
One placebo controlled trial (PE pts, Barritt and Jordan 1960)
Duration of therapy?

7. Current Treatment – What’s the problem?
INR monitoring
Which LMWH – HIT??
Bleeding versus recurrence
Duration of therapy

8. Rivaroxaban EINSTEIN phase III: study designs
Methods of VTE treatment
Rivaroxaban EINSTEIN phase III: study designs
EINSTEIN DVT1 and EINSTEIN PE2 (non-inferiority studies)
Treatment period of 3, 6 or 12 months
Confirmed acute symptomatic DVT without symptomatic PE
Rivaroxaban
Rivaroxaban
N=3,449
15 mg bid
20 mg od
30-day observation after treatment cessation R
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
Confirmed acute symptomatic PE with or without symptomatic DVT
N=4,833
Day 1
Day 21
Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA
Rivaroxaban 20 mg od
Placebo
Day 1
N=1,197
EINSTEIN Extension1 (superiority study)
Treatment period of 6 or 12 months R
30-day observation after treatment cessation
Rivaroxaban EINSTEIN phase III: study designs
The EINSTEIN phase III study programme consisted of three phase III clinical studies assessing the effect of rivaroxaban in the treatment of VTE.
EINSTEIN DVT and EINSTEIN PE1,2
Randomised, open-label, active-controlled, parallel-group, non-inferiority, event-driven studies. EINSTEIN DVT has been completed. EINSTEIN PE is still on going.
Patients had confirmed acute symptomatic DVT without symptomatic PE (EINSTEIN DVT), or confirmed acute symptomatic PE with or without symptomatic DVT (EINSTEIN PE)
Patients were randomized to receive oral rivaroxaban 15 mg bid for 3 weeks then 20 mg od or subcutaneous enoxaparin (1 mg/kg bid for at least 5 days) then VKA (INR 2.0–3.0 started within 48 hours) for 3, 6 or 12 months1,2
Treatment duration (3, 6 or 12 months) was decided by the investigator prior to randomization according to the patient’s risk profile and local standards
EINSTEIN Extension1
A randomised, double-blind, placebo-controlled, parallel-group, superiority study in patients with confirmed symptomatic DVT or PE.
Patients with confirmed symptomatic DVT or PE were treated for 6 or 12 months with rivaroxaban or a VKA before the decision for continued treatment was made. At this point, where there was no clear decision for stopping or continuing anticoagulation therapy, patients were randomized to receive rivaroxaban 20 mg od or placebo for 6 or 12 months.
References
The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
EINSTEIN PE. Available at: Trial ID: NCT Accessed August 2011
The EINSTEIN investigators, 1. N Eng J Med 2010;363: & 2. N Eng J Med 2012;366:
L.GB Jan 2013

9. Einstein - Conclusion Rivaroxaban
Non-inferior acutely compared with standard therapy
Superior in terms of secondary prevention compared with placebo but some excess bleeding
Pre-specified joint analysis suggest superiority of rivaroxaban

10. Einstein
A new era?

11. Length of Treatment
1st episode of idiopathic VTE should be treated with warfarin at an INR of 2.0 to 3.0 at least three months
the optimal length of time and optimal degree of anticoagulation are not known
Baglin Tet al. JTH 2012 Duration of anticoagulant therapy after a first episode of unprovoked pulmonary embolus or deep vein thrombosis: guidance from the scientific and standardization committee of the international society on thrombosis and haemostasis.
Boutitie Fet al. BMJ 2011; 342:d3036 Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials.

12. Length of Treatment – balance of risks Thrombosis vs bleeding
Risk benefit analysis
Patients values and preferences in regard to such risks and benefits
The potential benefit of extending anticoagulation to six (or more) months may be offset by a higher risk of bleeding and the greater cost and inconvenience of the longer duration of treatment

13. 2012 ACCP Guidelines
Recommendations based upon the perceived balance between
the number of deaths from recurrent VTE prevented by continued anticoagulation
versus
the number of fatal bleeding episodes associated with continued anticoagulation

14. Risk of rVTE after discontinuation of anticoagulation
Risk or rVTE
1st year
Thereafter
1st VTE provoked by surgery 1%
0.5%
1st VTE provoked by a nonsurgical factor 5%
2.5%
1st unprovoked VTE
10%
2nd episode unprovoked VTE
15%
7.5%

15. Risk of major bleeding if anticoagulation is continued
Risk factors
Risk category
During 1st 3 months
Thereafter/yr
None
LOW
1.9%
0.9% 1
INTERMEDIATE
3.2%
1.6% 2
HIGH
12.8%
> 6.5%

16. BLEEDING
Warfarin in top 10 drugs largest number of serious adverse event reports submitted to the United FDA
Anticoagulants also ranked first in 2003 and 2004 in the number of total mentions of death for drugs "causing adverse effects in therapeutic use"
a common cause of emergency department visits
"black box" warning re warfarin's bleeding risk
Related to the degree of anticoagulation as well as the presence in the patient of pre-existing risk factors for bleeding.

17. Thrombotic recurrence risk group
LOW bleeding risk group
INTERMEDIATE bleeding risk group
HIGH bleeding risk group
1st VTE provoked by surgery
Discontinue
(strong)
1st VTE provoked by a nonsurgical factor or 1st unprovoked distal DVT
(weak)
1st unprovoked proximal DVT or PE
Continue
2nd episode unprovoked VTE

18. ISTH guidance 2012
1st provoked episode VTE or unprovoked calf DVT – a/c no greater than 3 months
1st unprovoked episode VTE – initial treatment 3-6 months
Continue provided perceived risk a/c related bleeding not so high to preclude continued treatment

19. ISTH guidance 2012 – unprovoked VTE
In favour of long term a/c (>3-6 months)
Male
Moderate to severe PTS
Ongoing dyspnoea
Satisfactory a/c control
Elevated D-dimer 3-4 weeks after stopping (using study validated assay)

20. ISTH guidance 2012 – unprovoked VTE
In favour of stopping a/c at 3-6 months
female
Absent or mild PTS
Unsatisfactory a/c control
Low D-dimer 3-4 weeks after stopping (using study validated assay)

21. Issues to consider Patient information and counselling
Estimated risk of recurrence
Bleeding risk
Patient values and preferences
Age, comorbidities, quality of life issues

22. Length of Treatment
Who is truly low risk of recurrence? Who is truly high risk of bleeding?

23. Aspirin Warfasa and Aspire trials
40% reduction compared to placebo following standard treatment

24. VTE Conclusion New agents now available
Optimal length of time of anticoagulation are not known (low risk of recurrence)
Cost?
New care pathways
Warfarin here for a while yet

25. AF Most common heart rhythm disorder 25% risk of AF for those over 40
5-fold increase in risk of stroke with non-valvular AF
Worsens stroke outcomes
15% of all strokes caused by AF

26. AF 3 new agents All good All reduce ICH Headline data
Issues: cost, monitoring, reversal

27. New anticoagulants (1) Dabigatran RE-LY trial NEJM 2009; 361:1139
150mg v warfarin
stroke: 1.0% vs 1.6%, RR 0.64 ( )
death: 3.6% v 4.1%, RR 0.88 ( )
major bleed: 3.3% v 3.6%, RR 0.93 ( )
110mg v warfarin
stroke: 1.4% vs 1.6%, RR 0.92 ( )
death: 3.7% v 4.1%, RR 0.91 ( )
major bleed: 2.9% vs 3.6%, RR 0.80 ( )

28. New anticoagulants (2) Rivaroxaban ROCKET-AF NEJM 2011
stroke 2.1% vs 2.4%, RR 0.88 ( )
death 1.9% vs 2.2%, RR 0.85 ( ) on treatment
major bleeding 3.6% vs 3.4%, RR 1.04 ( ) on treatment

29. New anticoagulants (3) Apixaban: ARISTOTLE NEJM 2011
stroke 1.3% vs 1.6%, RR 0.79 ( )
death 3.5% vs 3.9%, RR 0.89 ( )
major bleeding 2.1% vs 3.1%, RR 0.69 ( ) on treatment

30. Who to anticoagulate? NICE dabigatran guidance (March 2012)
Previous stroke or TIA
Age 75 or over
Left ventricular ejection fraction < 40%
Age 65 or over with a risk factor (diabetes; CHD; hypertension)
Who not to anticoagulate?
Age under 65 (unless 2 risk factors)
Age 65-74?
Role of aspirin (ESC guidelines)

31. Stroke risk stratification
CHADS2
CHA2DS2VASc2
Risk factor
Score
CHF 1
Hypertension
Age >75
Diabetes
Stroke / TIA 2
Risk factor
Score
CHF OR LVEF ≤ 40 % 1
Hypertension
Age ≥ 75 2
Diabetes
Stroke / TIA
Thromboembolism Vascular Disease
Age
Female
Low risk = 0
Moderate risk = 1
High risk ≥ 2

32. Guidelines for antithrombotic therapy in AF
NICE guidelines (2006)
Stroke risk
Recommended antithrombotic therapy
High risk
Anticoagulation with warfarin
Moderate risk
Consider OAC or aspirin
Low risk
Aspirin mg if no contraindications
European Society of Cardiology (2010)
CHA2DS2VASc score
Recommended antithrombotic therapy
CHA2DS2VASc ≥ 2
Oral anticoagulant (OAC)
CHA2DS2VASc = 1
Either OAC or aspirin 75–325 mg daily. Preferred: OAC rather than aspirin
CHA2DS2VASc = 0
Either aspirin 75–325 mg daily or no antithrombotic therapy. Preferred: no antithrombotic therapy rather than aspirin

33. HAS-BLED Score for bleeding risk on oral anticoagulation in AF
Feature Score if present
Hypertension (systolic > 160mmHg 1
Abnormal renal function 1
Abnormal liver function 1
Age > 65 years 1
Stroke in past 1
Bleeding
Labile INRs 1
Taking other drugs as well 1
Alcohol intake at same time 1
Increased 1-year bleed risk with score of 3 or more on anticoagulant.
Is this sufficient to justify caution or more regular review?

35. Conclusions New agents More emphasis on risk:benefit
Individual versus population
Warfarin?