Pradaxa

DABIGATRAN

(Evidence from RELY & RELYABLE Trial)

&

Novel Oral Anticoagulants (NOAC)

Dr. Surinder HansraMD, DNB (Card)

FSCAI

• 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

AF & StrokeAF & Stroke

2

Limitations of VKA (Warfarin)Limitations of VKA (Warfarin)

3

New Oral AnticoagulantNew Oral Anticoagulant

4

74%

Source: BI Medical, NEJM RELY

RE-LY Efficacy endpoints favor 150 mg BID dose RE-LY Efficacy endpoints favor 150 mg BID dose

Decrease in incidence (RRR) In percent compared to warfarin

Stroke / Systemic Embolism

RE-LYDABIGATRAN

150 mg bid

- Ischemic Stroke

RE-LYDABIGATRAN

110 mg bid

35%

24% 11%

69 %

10%

Death from a Vascular Cause

- Hemorrhagic Stroke

15% 10%

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

Statistically significant Statistically non significant

DABIGATRAN 150 MG IS THE ONLY OAC THAT REDUCES ISCHEMIC STROKE SIGNIFICANTLY

7%

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

Decrease in incidence (RRR) In percent compared to warfarin

Intracranial Bleeding

RE-LYPRADAXA150 mg bid

RE-LYPRADAXA110 mg bid

59%

20% 32%

20%

70%

Life Threatening Bleeding

Major Bleeding

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

Statistically significant Statistically non significant

7

22% of the patients had mild-to-moderate valve disease with AF22% of the patients had mild-to-moderate valve disease with AF

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

DE 110 mg BID

n (%)

DE 150 mg BIDn (%)

Warfarinn (%)

Totaln (%)

Valvular heart disease

1288 (100.0) 1353 (100.0) 1303 (100.0) 3944 (100.0)

Aortic stenosis 152 (11.8) 163 (12.0) 156 (11.9) 471 (11.9)

Aortic regurgitation 264 (20.4) 281 (20.7) 272 (20.8) 817 (20.7)

Mitral stenosis 77 (5.9) 62 (4.5) 54 (4.1) 193 (4.8)

Mitral regurgitation 1035 (80.3) 1050 (77.6) 1016 (77.9) 3101 (78.6)

Other 470 (36.4) 496 (36.6) 492 (37.7) 1458 (36.9)

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.

Patients who are not eligible for DabigatranPatients who are not eligible for Dabigatran

9Boehringer-Ingelheim , Pradaxa® India Prescribing Information , 2011

Monitoring Dabigatran?Monitoring Dabigatran?

1. Stangier J et al. Br J Clin Pharmacol 2007; 64:292–303. 2. Stangier J et al. J Clin Pharmacol 2005; 45:555–563.

Emergency Monitoring with Dabigatran?Emergency Monitoring with Dabigatran?

1. Boehringer Ingelheim. dabigatranProduct Monograph (Canada). 2010. 2. Boehringer Ingelheim. dabigatranPackage Insert (US). 2010. 3. van Ryn J et al. Thromb Haemost 2010; 103:1116–1127.

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)

Algorithm for bleeding management on DabigatranAlgorithm for bleeding management on Dabigatran

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.

Adequate diuresis to be maintained

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

Protocol for discontinuation before surgery Protocol for discontinuation before surgery

Boehringer-Ingelheim , Pradaxa® India Prescribing Information , 2011 13

Use of Dabigatran in patients undergoing PCIUse 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 patientsConsider 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 15

Use of Dabigatran in patients post StrokeUse of Dabigatran in patients post Stroke

17

Depends on Stroke Severity

Restart

TIAAs soon as imaging has excluded a cerebral haemorrhage

Mild stroke 3–5 days after symptom onset

Moderate stroke 5–7 days after stroke onset

Severe stroke 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

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

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

BackgroundBackground

• 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, 20072. van Asch CJ, et al.: Lancet Neurol 9, 167-176, 20103. Connolly SJ, et al.: N Engl J Med 361, 1139-1151, 20094. Connolly SJ, et al.: N Engl J Med 363, 1875-1876, 2010

Asia Pacific Stroke Conference 2012

Dabigatran150mg bid(25/933)


Warfarin(53/926)

0

4.0

HR 0.45(95% CI: 0.28–0.72)

2.0

1.0

% /

year

AsiaAsia

1.391.39

3.063.063.0

2.502.50

Primary EndpointPrimary Endpoint(Stroke or Systemic Embolism)(Stroke or Systemic Embolism)

HR 0.81(95% CI: 0.54–1.21)


The reduction in stroke and systemic in ASIAN subgroup

consistent to RE-LY

0

3.0

HR 0.55(95% CI: 0.32–0.95)

1.0

% /

year

Asia – Ischemic StrokeAsia – Ischemic Stroke

2.0



Warfarin(35/926)

2.052.05

1.121.12

2.022.02

Ischemic & Hemorrhagic StrokeIschemic & Hemorrhagic Stroke

HR 1.01(95% CI: 0.63–1.61)


Asia – Hemorrhagic StrokeAsia – Hemorrhagic Stroke

The reduction in both Ischemic & Hemorrhagic stroke in ASIAN subgroup consistent to RE-LY

0

4.0

HR 0.57(95% CI: 0.38–0.84)

2.0

% /

year

AsiaAsia

3.0



Warfarin(66/926)

2.222.222.172.17

3.823.82

1.0

Major BleedingMajor Bleeding

HR 0.57(95% CI: 0.38–0.85)


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.

0

2.0

HR 0.40(95% CI: 0.18–0.92)

% /

year

AsiaAsia

0.450.45

1.101.101.0

0.230.23Dabigatran150mg bid

(8/933)

Dabigatran110mg bid

(4/923)

Warfarin(19/926)

Intracranial BleedingIntracranial Bleeding

HR 0.20(95% CI: 0.07–0.60)


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.

0

HR 0.58(95% CI: 0.34–0.97)

% /

year

AsiaAsia

2.0

1.0

3.0

1.281.28

2.202.20

0.910.91



Warfarin(38/926)

Life Threatening BleedingLife Threatening Bleeding

HR 0.41(95% CI: 0.23–0.73)


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 life threatening bleeding.

0

2.0

HR 0.68(95% CI: 0.37–1.27)

% /

year

AsiaAsia

0.960.96

1.411.41

1.0 1.151.15



Warfarin(24/926)

GI Major BleedingGI Major Bleeding

HR 0.82(95% CI: 0.45–1.49)


GI bleeding was lower in both doses of Dabigatran - 150 mg & 110mg in Asian

sub group patient

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.


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

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

27

Major bleeding: RE-LY® + RELY-ABLE® periodsMajor bleeding: RE-LY® + RELY-ABLE® periods

Results presented at the AHA congress on 3rd Nov 2012 28

BID = twice daily; D150 and D110 = dabigatran 150 and 110 mg BID, respectively; FU = follow -up; HR = hazard ratio

0

Years

1 2

0.05

0.10

0.15

0.20

0

Cum

ula

tive r

isk

No. at risk

D110

D150

D150: 2.50 %/yrD110: 2.13 %/yrHR: 1.1895% CI: 1.00–1.38

RELY-ABLE® patients only5851 patients, mean FU 4.25 yr

3 4 0

Years

1 20

D150: 3.38 %/yrD110: 2.83 %/yrHR: 1.2095% CI: 1.07–1.35

All dabigatran patients12 091 patients, mean FU 3 yr

3 4

0.05

0.10

0.15

0.20

2914 2867 2796 2634 1852 6015 5622 4092 2661 1868

2937 2892 2815 2617 1831 6076 5627 4152 2644 1846

Dabigatran 150 mg BID


Rates of major bleeding broadly consistent over a period of 4.25 years.

Lower rate of major bleeding with 110 mg BID dose in the secondary analysis covering both RE-LY® and RELY-ABLE®

Bleeding events: RELY-ABLE®Bleeding events: RELY-ABLE®


5851 patients followed for mean of 2.3 yearsD150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio

Event

RELY-ABLE® only

D150 (%/yr)

D110 (%/yr)

HR 95% CI

Major bleeding 3.74 2.99 1.26 1.04–1.53

Life-threatening 1.79 1.57 1.14 0.87–1.49

GI 1.54 1.56 0.99 0.75–1.31

Intra-cranial 0.33 0.25 1.31 0.68–2.51

Extra-cranial 3.43 2.82 1.23 1.01–1.49

Fatal 0.24 0.25 0.94 0.46–1.89

Minor bleeding 9.70 8.19 1.21 1.07–1.36

In contrast to RE-LY®, rates of GI bleeding stabilized over time and in RELYABLE® were comparable with both doses

of dabigatran

RE-LY® + RELY-ABLE®: all dabigatran patients RE-LY® + RELY-ABLE®: all dabigatran patients


12 091 patients, mean FU 3 yr; BID = twice daily; D150 and D110 = dabigatran 150 and 110 mg BID, respectively; FU = follow -up; HR = hazard ratio

0

Years

1 2

0.005

0.010

0.015

0.020

0

Cum

ula

tive r

isk

No. at risk

D110

D150

D150: 0.33 %/yrD110: 0.22 %/yrHR: 1.4595% CI: 0.98–2.16

All intra-cranial haemorrhage

3 4 0

Years

1 20

D150: 0.11 %/yrD110: 0.13 %/yrHR: 0.9195% CI: 0.50–1.64

Intra-cerebral haemorrhage

3 4

0.005

0.010

0.015

0.020

1%

6015 5771 4277 2794 1974 6015 5774 4282 2799 1979

6076 5814 4350 2785 1975 6076 5825 4360 2790 1980



Rates of intracranial haemorrhage and cerebral haemorrhage were low for both doses of dabigatran

in the secondary analysis

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


BID = twice daily; D150 and D110 = dabigatran 150 and 110 mg BID, respectively; FU= follow -up; HR = hazard ratio

0Years

1 2

0.04

0.06

0.08

0.10

0

0.02

Cum

ula

tive r

isk

No. at risk

D110

D150

D150: 0.89 %/yrD110: 1.05 %/yrHR: 0.8495% CI: 0.65–1.09

RELY-ABLE® patients only5851 patients, mean FU 4.25 yr

3 4 0Years

1 2

0.04

0.06

0.08

0.10

0

0.02

D150: 1.25 %/yrD110: 1.54 %/yrHR: 0.8195% CI: 0.66–0.96

All dabigatran patients12 091 patients, mean FU 3 yr

3 4

2914 2902 2860 2711 1905 6015 5709 4208 2740 1921

2937 2931 2882 2729 1929 6076 5777 4298 2757 1943



In the secondary analysis of RE-LY® and RELYABLE®, dabigatran 150 mg BID was associated with a lower rate of stroke and systemic embolism than the 110 mg

BID dose

Stroke and ischaemic events: RELY-ABLE®Stroke and ischaemic events: RELY-ABLE®


5851 patients followed for mean of 2.3 yearsD150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratioSEE = systemic embolic event

Event

D150

(%/yr)

D110

(%/yr)HR 95% CI

Stroke or SEE 1.46 1.60 0.91 0.69–1.20

All stroke 1.24 1.38 0.89 0.66–1.21

Ischaemic 1.15 1.24 0.92 0.67–1.27

Haemorrhagic 0.13 0.14 0.89 0.34–2.30

Myocardial infarction 0.69 0.72 0.96 0.63–1.45

Pulmonary embolism 0.13 0.11 1.14 0.41–3.15

Rates of ischemic stroke were consistent with those in RE-LY® – lower with 150 mg BID dose compared with 110 mg BID dose

RE-LYABLE – SummaryRE-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

33

34

35

Practical Considerations for NOACPractical 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 2–3

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 2–3 times per year in patients with moderate renal impairment.

36

• 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.

37

Choosing AnticoagulantsChoosing Anticoagulants

38

39

THANK YOU

40

Pradaxa

Documents

routine practice

asian subgroup

life threatening

dabigatran

ly rely

dabigatran

patients only5851

110 mg bid