DABIGATRAN

(Evidence from RELY & RELYABLE Trial) & Novel Oral Anticoagulants (NOAC)

Dr. Surinder Hansra MD, DNB (Card) FSCAI

AF & Stroke
AF increases the risk of ischaemic stroke up to 7 times AF is responsible for 15% of all strokes Strokes associated with AF tend to be particularly severe, with increased likelihood of death or disability Two out of three strokes due to AF can be prevented with appropriate anticoagulation

Limitations of VKA (Warfarin)

New Oral Anticoagulant

RE-LY Efficacy endpoints favor 150 mg BID dose

Decrease in incidence (RRR) In percent compared to warfarin
Statistically significant Statistically non significant

RE-LY DABIGATRAN 150 mg bid Stroke / Systemic Embolism - Ischemic Stroke - Hemorrhagic Stroke Death from a Vascular Cause
35% 24% 74%

RE-LY DABIGATRAN 110 mg bid

10% 11%

69 %

15%

10%

DABIGATRAN 150 MG IS THE ONLY OAC THAT REDUCES ISCHEMIC STROKE SIGNIFICANTLY
Connolly SJ, et al. N Engl J Med. 2010;363:1875-1876.
Source: BI Medical, NEJM RELY

RE-LY Safety end points largely favor 110 mg BID dose

Decrease in incidence (RRR) In percent compared to warfarin
Statistically significant

Statistically non significant

RE-LY PRADAXA 150 mg bid Intracranial Bleeding

59% 20% 7%

RE-LY PRADAXA 110 mg bid

70% 32%

Life Threatening Bleeding

Major Bleeding

20%

Connolly SJ, et al. N Engl J Med. 2010;363:1875-1876.

22% of the patients had mild-to-moderate valve disease with AF

RELY excluded patients with severe heart valve disease (Mechanical Heart Valves & Rheumatic HD). Patients with valvular heart disease where valvular disease was not considered the proximate cause of AF (haemodynamically stable) were included in RELY.
DE 110 mg BID n (%) DE 150 mg BID n (%) Warfarin n (%) Total n (%)

Valvular heart disease

Aortic stenosis Aortic regurgitation Mitral stenosis Mitral regurgitation Other

1288 (100.0)
152 (11.8) 264 (20.4) 77 (5.9) 1035 (80.3) 470 (36.4)

1353 (100.0)
163 (12.0) 281 (20.7) 62 (4.5) 1050 (77.6) 496 (36.6)

1303 (100.0)
156 (11.9) 272 (20.8) 54 (4.1) 1016 (77.9) 492 (37.7)

3944 (100.0)
471 (11.9) 817 (20.7) 193 (4.8) 3101 (78.6) 1458 (36.9)

Data on file * : Per Re-LY definition, they were still considered non-valvular; therefore eligible

Patients who are not eligible for Dabigatran

Boehringer-Ingelheim , Pradaxa India Prescribing Information , 2011

Monitoring Dabigatran?

1. Stangier J et al. Br J Clin Pharmacol 2007; 64:292303. 2. Stangier J et al. J Clin Pharmacol 2005; 45:555563.

Emergency Monitoring with Dabigatran?

aPTT >80 seconds at trough (when the next dose is due) Higher risk of bleed1,2

Other test for Emergency Monitoring 3 - Thrombin time (TT)

1. Boehringer Ingelheim. dabigatranProduct Monograph (Canada). 2010. 2. Boehringer Ingelheim. dabigatranPackage Insert (US). 2010. 3. van Ryn J et al. Thromb Haemost 2010; 103:11161127.

Algorithm for bleeding management on Dabigatran

Bleeding Management for Dabigatran is similar as that of Warfarin with exception of use of Vit K

Adequate diuresis to be maintained

PCC = prothrombin complex concentrates; rFVIIa = recombinant Factor VIIa; Rx =treatment *Recommendation based only on limited non-clinical data; there is no experience in volunteers or patients; van Ryn J, et al. Thromb Haemost. 2010;103:1116-1127.

Protocol for discontinuation before surgery

Boehringer-Ingelheim , Pradaxa India Prescribing Information , 2011

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Use of Dabigatran in patients undergoing PCI

In patients with IHD/CAD and AF, who require PCI stenting,

current guidelines advocate the use of bare metal stents rather than drug-eluting stents due to the shorter duration of triple oral therapy after the procedure (four weeks vs. 6 months; additional 6 months with a single antiplatelet) In such patients, triple therapy with aspirin, clopidogrel and dabigatran (110 mg mg BID dose may be considered) after revascularisation can be given for a short period but requires close observation for bleeding events.

Huisman MV et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: Resolving uncertainties in routine practice Thrombosis and Haemostasis 107.5/2012

Consider using Dabigatran 110 mg in such patients

Huisman MV et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: Resolving uncertainties in routine practice Thrombosis and Haemostasis 107.5/2012

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Use of Dabigatran in patients post Stroke

Depends on Stroke Severity TIA

Restart As soon as imaging has excluded a cerebral haemorrhage 35 days after symptom onset

Mild stroke

Moderate stroke
Severe stroke

57 days after stroke onset

2 weeks after stroke onset

Huisman MV et al. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: Resolving uncertainties in routine practice Thrombosis and Haemostasis 107.5/2012

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Efficacy and safety of dabigatran versus warfarin in patients with atrial fibrillation: Analysis in Asian population in RE-LY trial

Masatsugu Hori, Stuart J. Connolly, Jun Zhu, Li Sheng Liu, Chu-Pak Lau, Prem Pais, Denis Xavier, Sung Soon Kim, Razali Omar, Antonio L. Dans, Ru San Tan, Jyh-Hong Chen, Supachai Tanomsup, Mitsunori Watanabe, Masahide Koyanagi, Michael D. Ezekowitz, Paul A. Reilly, Lars Wallentin, Salim Yusuf, and the RE-LY Investigators

Background
Incidence of ischemic stroke and bleeding including intracranial hemorrhage (ICH) may not be identical among different ethnic groups.

The rate of ICH is reported to be higher in Asians than in whites1,2.

In RE-LY (randomized control trial, consisting of 18,113 patients) 2,782 patients are from Asian countries3,4 (15%). Since RE-LY includes a large number of Asian patients, this control trial is suitable for analyzing the ethnic difference between Asian and non-Asian countries.

1. Shen AY, et al.: J Am Coll Cardiol 50, 309-315, 2007 2. van Asch CJ, et al.: Lancet Neurol 9, 167-176, 2010 3. Connolly SJ, et al.: N Engl J Med 361, 1139-1151, 2009 4. Connolly SJ, et al.: N Engl J Med 363, 1875-1876, 2010

Asia Pacific Stroke Conference 2012

Primary Endpoint (Stroke or Systemic Embolism)

Asia
HR 0.45
(95% CI: 0.280.72)

HR 0.81

4.0 3.0 % / year 2.0 1.0 0 1.39

(95% CI: 0.541.21)

3.06 2.50

The reduction in stroke and systemic in ASIAN subgroup consistent to RE-LY

Dabigatran 150mg bid (25/933)

Dabigatran 110mg bid (44/923)

Warfarin (53/926)

Asia Pacific Stroke Conference 2012

Ischemic & Hemorrhagic Stroke

Asia Ischemic Stroke
HR 0.55
(95% CI: 0.320.95)

Asia Hemorrhagic Stroke

HR 1.01

3.0

(95% CI: 0.631.61)

2.0 % / year

2.05

2.02

1.0

1.12

The

Dabigatran 150mg bid reduction (20/933) in both

Dabigatran 110mg bid Ischemic (36/923) &

Hemorrhagic stroke in ASIAN subgroup consistent to RE-LY

Asia Pacific Stroke Conference 2012

Warfarin (35/926)

Major Bleeding
Asia
HR 0.57
(95% CI: 0.380.84)

HR 0.57

4.0 3.0 % / year 2.0 1.0 0

(95% CI: 0.380.85)

3.82

Major bleeding rates were lower in both the doses Dabigatran arm as compared to Warfarin in the RELY Asian population. Benefits of Pradaxa are more pronounced at lower levels of INR control.

2.17

2.22

Dabigatran 150mg bid (39/933)

Dabigatran 110mg bid (39/923)

Warfarin (66/926)

Asia Pacific Stroke Conference 2012

Intracranial Bleeding
Asia
HR 0.40
(95% CI: 0.180.92)

HR 0.20

2.0

(95% CI: 0.070.60)

The reduction in life threatening bleeding in ASIAN subgroup consistent to RE-LY Both doses of Dabigatran were significantly better as compared to well controlled warfarin in reducing Intracranial bleeding.

% / year

1.0

1.10

0.45 0 0.23
Dabigatran 150mg bid (8/933) Dabigatran 110mg bid (4/923) Warfarin (19/926)

Asia Pacific Stroke Conference 2012

Life Threatening Bleeding

Asia
HR 0.58
(95% CI: 0.340.97)

HR 0.41

3.0

(95% CI: 0.230.73)

The reduction in life threatening bleeding in ASIAN subgroup consistent to RE-LY

2.0 % / year

2.20

1.0

1.28 0.91

Both doses of Dabigatran were significantly better as compared to well controlled warfarin in reducing life threatening bleeding.
Warfarin (38/926)

Dabigatran 150mg bid (23/933)

Dabigatran 110mg bid (16/923)

Asia Pacific Stroke Conference 2012

GI Major Bleeding
Asia
HR 0.68
(95% CI: 0.371.27)

HR 0.82

2.0

(95% CI: 0.451.49)

% / year

1.41 1.0 0.96 1.15

GI bleeding was lower in both doses of Dabigatran 150 mg & 110mg in Asian sub group patient

Dabigatran 150mg bid (17/933)

Dabigatran 110mg bid (20/923)

Warfarin (24/926)

Asia Pacific Stroke Conference 2012

Summary
The effects of dabigatran against stroke or systemic embolism are comparable in Asian and non-Asian patients for both doses of dabigatran compared to warfarin.

Dabigatran reduced the risk of bleeding in Asians more than in RE-LY.

Accordingly, this analysis suggests that dabigatran is more beneficial compared to warfarin in Asians.

Asia Pacific Stroke Conference 2012

RE-LYABLE Long term data of 4.3 yrs mean follow up of RE-LY Dabigatran patients

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Major bleeding: RE-LY + RELY-ABLE periods

RELY-ABLE patients only
5851 patients, mean FU 4.25 yr
0.20
D150: 2.50 %/yr D110: 2.13 %/yr HR: 1.18 95% CI: 1.001.38 Dabigatran 150 mg BID

All dabigatran patients

12 091 patients, mean FU 3 yr
0.20
D150: 3.38 %/yr D110: 2.83 %/yr HR: 1.20 95% CI: 1.071.35

0.15

0.15

Cumulative risk

0.10

Dabigatran 110 mg BID

0.10

0.05

0.05

0 0
No. at risk D110 D150

0 1 2 3 4 0 1 2 3 4

Years
2937 2892 2815 2617 1831 6076 5627

Years
4152 2644 1846

2914 2867 2796 2634 broadly 1852 6015 over 5622 4092 of 2661 1868 Rates of major bleeding consistent a period 4.25 years.

Lower rate ofand major bleeding with mg BID dose in the secondary BID = twice daily; D150 D110 = dabigatran 150 and110 110 mg BID, respectively; FU = follow -up; HR = hazard ratio covering both RE-LY and RELY-ABLE
Results presented at the AHA congress on 3rd Nov 2012

analysis
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Bleeding events: RELY-ABLE

RELY-ABLE only

Event
Major bleeding Life-threatening GI Intra-cranial Extra-cranial

D150 (%/yr)
3.74 1.79 1.54

D110 (%/yr)
2.99 1.57 1.56

HR
1.26 1.14 0.99

95% CI
1.041.53 0.871.49 0.751.31

1.31 0.682.51 In contrast 0.33 to RE-LY, 0.25 rates of GI bleeding stabilized over time and in RELYABLE were comparable with both doses 3.43 2.82 1.23 1.011.49 of dabigatran 0.24 9.70 0.25 8.19 0.94 1.21 0.461.89 1.071.36

Fatal
Minor bleeding

5851 patients followed for mean of 2.3 years D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio
Results presented at the AHA congress on 3rd Nov 2012

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RE-LY + RELY-ABLE: all dabigatran patients

All intra-cranial haemorrhage Intra-cerebral haemorrhage

0.020

0.015

D150: 0.33 %/yr D110: 0.22 %/yr HR: 1.45 95% CI: 0.982.16

0.020

0.015

D150: 0.11 %/yr D110: 0.13 %/yr HR: 0.91 95% CI: 0.501.64 Dabigatran 150 mg BID Dabigatran 110 mg BID

Cumulative risk

0.010

0.010

1%

0.005

0.005

0 0
No. at risk D110 D150 6015 6076

0 1
5771 5814

3
2794 2785

4
1974 1975

0
6015 6076

1
5774 5825

3
2799 2790

4
1979 1980

Years
4277 4350

Years
4282 4360

Rates of intracranial haemorrhage and cerebral haemorrhage were low for both doses of dabigatran in the 12 091 patients, mean FU 3 yr; BID = twice daily; D150 and D110 = dabigatran 150 and 110 mg BID, respectively; secondary analysis FU = follow -up; HR = hazard ratio
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Results presented at the AHA congress on 3rd Nov 2012

Stroke/systemic embolism: RE-LY + RELY-ABLE

RELY-ABLE patients only
5851 patients, mean FU 4.25 yr
0.10
D150: 0.89 %/yr D110: 1.05 %/yr HR: 0.84 95% CI: 0.651.09

All dabigatran patients

12 091 patients, mean FU 3 yr
0.10
D150: 1.25 %/yr D110: 1.54 %/yr HR: 0.81 95% CI: 0.660.96

0.08

0.08

Cumulative risk

0.06

Dabigatran 150 mg BID Dabigatran 110 mg BID

0.06

0.04

0.04

0.02

0.02

0 0
No. at risk D110 D150 2914 2937

0 1
2902 2931

Years

3
2711 2729

4
1905 1929

0
6015 6076

1
5709 5777

Years

3
2740 2757

4
1921 1943

In the secondary analysis of RE-LY and RELYABLE , dabigatran 150 mg BID was associated with a lower rate of BID = twice daily; D150 and D110 = dabigatran 150 and 110 mg BID, respectively; FU= follow -up; HR = hazard ratio stroke and systemic embolism than the 110 mg BID dose

2860 2882

4208 4298

Results presented at the AHA congress on 3rd Nov 2012

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Stroke and ischaemic events: RELY-ABLE

D150 Event Stroke or SEE All stroke Ischaemic Haemorrhagic (%/yr) 1.46 1.24 1.15 0.13

D110 (%/yr) 1.60 1.38 1.24 0.14

HR 0.91 0.89 0.92 0.89

95% CI 0.691.20 0.661.21 0.671.27 0.342.30

Rates of ischemic stroke were consistent with those in RE-LY Myocardial 0.69 0.72 with 110 0.96mg BID 0.63 1.45 infarction lower with 150 mg BID dose compared dose
Pulmonary embolism 0.13 0.11 1.14 0.413.15

5851 patients followed for mean of 2.3 years D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio SEE = systemic embolic event
Results presented at the AHA congress on 3rd Nov 2012

32

RE-LYABLE Summary

In patients who continued treatment on dabigatran after RE-LY, the rates of stroke and major bleeding remain low. There were no new safety signal observed during this extended follow up period

The results from RELY-ABLE are highly consistent with those observed in RE-LY

Results presented at the AHA congress on 3rd Nov 2012

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Practical Considerations for NOAC

No Head to head Trials major bleeding appears lower with dabigatran 110mg b.i.d. and apixaban dabigatran appears to be most cost-effective When switching from a VKA to a NOAC, the INR should be allowed to fall to about 2.0 When changing from a NOAC to a VKA, the VKA should be started with a overlap of 23 days

Compliance and adherence to treatment is crucial since these drugs have a short half-life, such that patients would be left without any anticoagulation protection if more than one dose were missed.
Assessment of renal function (by CrCl) is mandatory for all NOACs (especially dabigatran). Renal function should be assessed annually in patients with normal or mild renal impairment, and 23 times per year in patients with moderate renal impairment.

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The NOACs do not require dose adjustment on the basis of a specific coagulation test . There are non-specific coagulation tests that can be used to check for the presence of an anticoagulation effect For dabigatran, the ecarin clotting time and thrombin clotting time are useful tests, however, an aPTT can also be used (in emergency) Rivaroxaban prolongs the PT but a better estimate is an anti-Xa assay. NOACs do not have specific antidotes and management of bleeding is supportive because of short (5 to 17 hours) half-life. Perioperative management is another important consideration. Given the rapid onset and offset of action of dabigatran, no bridging therapy with LMWH is required. Following surgery, NOACs can be restarted as soon as effective haemostasis has been achieved.

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Choosing Anticoagulants

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THANK YOU

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