c. michael gibson, m.s., m.d. atrial fibrillation management past, present and future harvard...

C. Michael Gibson, M.S., M.D.C. Michael Gibson, M.S., M.D.

Atrial Fibrillation Management Atrial Fibrillation Management Past, Present and FuturePast, Present and Future

Harvard Medical School

Dr. Gibson has received research grant support and Dr. Gibson has received research grant support and

consulting monies from all major manufacturers of consulting monies from all major manufacturers of

antithrombin and antiplatelet agents including all antithrombin and antiplatelet agents including all

sponsors of Factor Xa inhibitors (BMS, Pfizer, sponsors of Factor Xa inhibitors (BMS, Pfizer,

Johnson and Johnson, Portola, DSI) and Factor II Johnson and Johnson, Portola, DSI) and Factor II

inhibitors (Boehringer Ingelheim)inhibitors (Boehringer Ingelheim)

C. Michael Gibson, M.S., M.D.

Conflict of Interest Statement

• AF responsible for 1/6 of all strokesAF responsible for 1/6 of all strokes

• Warfarin reduces stroke in AF by 64%Warfarin reduces stroke in AF by 64%

－－ significant increase in intracranial and other significant increase in intracranial and other hemorrhagehemorrhage

－－ Difficult to useDifficult to use

• Only 50% of eligible patients receive warfarinOnly 50% of eligible patients receive warfarin

• An alternative treatment is neededAn alternative treatment is needed

Atrial Fibrillation and Stroke


Dabigatran Apixaban RivaroxabanEdoxaban

(DU-176b)

Betrixaban

(PRT054021)

TargetIIa

(thrombin)Xa Xa Xa Xa

Hrs to Cmax 2 1-3 2-4 1-2 NR

CYP Metabolism None 15% 32% NR None

Half-Life 12-14h 8-15h 9-13h 8-10h 19-20h

Renal Elimination 80% 25% 66% 35% <5%

Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010; 4: 7-14Ericksson BI et al. Clin Pharmacokinet 2009; 48: 1-22

Ruff CR et al. Am Heart J 2010; 160: 635-41

CYP = cytochrome P450; NR = not reported

PK/PD of 5 Novel Oral Agents

RE-LY ROCKET AF ARISTOTLEENGAGE AF-TIMI

48

Drug Dabigatran Rivaroxaban Apixaban Edoxaban

Dose (mg)Freq

150, 110BID

20 (15*)QD

5 (2.5*)BID

60*, 30*QD

N 18,113 14,266 18,206 >21,000

Design PROBE 2 x blind 2 x blind 2 x blind

AF criteriaAF x 1

<6 mthsAF x 2

(≥ 1 in <30d)AF or AFI x 2

<12 mthsAF x 1

<12 mths

% VKA naive 50% 38% 43% 40% goal

Phase III AF trials

*Dose adjusted in patients with ↓drug clearance. **Max of 10% with CHADS-2 score = 2 and no stroke/TIA/SEE

PROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist

RE-LY Dabigatran110 mg

Dabigatran150 mg Warfarin

CHADS2 Mean 0-1 (%) 2 (%) 3+ (%)

2.132.634.732.7

2.232.235.232.6

2.130.937.032.1

ROCKET AF Rivaroxaban Warfarin

CHADS2 Mean 2 (%) 3 (%) 4 (%) 5 (%) 6 (%)

3.5134329132

3.5134428122

ARISTOTLE Rivaroxaban Warfarin

CHADS2 Mean 0-1 (%) 2 (%) 3+ (%)

2.134

35.830.2

2.134

35.830.2

Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Med; 2011Med; 2011

3+87%


Comparison of Trial Metrics

Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Med; 2011Med; 2011


RE-LY ROCKET AF ARISTOTLE

Time in Therapeutic Range (TTR)

64%67% warfarin-experienced

61% warfarin-naïve

Mean 55%Median 58%

62%

Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis

　 Dabigatran 110 mg 1.53% / yr 0.91 <0.001　 Dabigatran 150 mg 1.11% / yr 0.66 <0.001

　 Warfarin 1.69% / yr

　 Rivaroxaban 20 mg 1.7% / yr 0.79 <0.001


ROCKETROCKET AFAF

RE-LYRE-LY

　 Apixaban 5 mg 1.27% / yr 0.79 <0.001


ARISTOTLEARISTOTLE

Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009; 361: 1139-1151; Granger C et al, N Eng J Med; 2011

HR

(Modified ITT)


Non Inferiorityp vs warfarin

(ITT)

(ITT)

No ITT analysis is available for non-inferiority in ROCKET AF. An on treatment or per-protocol analysis is generally No ITT analysis is available for non-inferiority in ROCKET AF. An on treatment or per-protocol analysis is generally performed in the assessment of non-inferiority. If numerous patients come off of study drug, this biases the trial towards a performed in the assessment of non-inferiority. If numerous patients come off of study drug, this biases the trial towards a non-inferior result in an ITT analysis. This is the basis for performing a per-protocol analysis in a non-inferiority non-inferior result in an ITT analysis. This is the basis for performing a per-protocol analysis in a non-inferiority assessment.assessment.

Hemorrhagic Stroke



　 Dabigatran 110 mg 0.12% / yr 0.31 <0.001　 Dabigatran 150 mg 0.10% / yr 0.26 <0.001


　 Rivaroxaban 20 mg 0.26% / yr 0.59 0.012*


ROCKETROCKET AFAF

RE-LYRE-LY

　 Apixaban 5 mg 0.24% / yr 0.51 <0.001


ARISTOTLEARISTOTLE

HRITT

p vs warfarin

*In an on treatment analysis in ROCKET AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr for *In an on treatment analysis in ROCKET AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr for warfarin, p=0.024. No on treatment analysis is available from RE-LY.warfarin, p=0.024. No on treatment analysis is available from RE-LY.

Ischemic Stroke



　 Dabigatran 110 mg 1.34% / yr 1.20 0.35　 Dabigatran 150 mg 0.92% / yr 0.76 0.03




ROCKETROCKET AFAF

RE-LYRE-LY

　 Apixaban 5 mg 0.97% / yr 0.92 0.42


ARISTOTLEARISTOTLE

HRITT

p vs warfarin

*In an on treatment analysis in ROCKET AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and 1.42% / yr for *In an on treatment analysis in ROCKET AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and 1.42% / yr for warfarin, p=0.58. No on treatment analysis is available from RE-LY.warfarin, p=0.58. No on treatment analysis is available from RE-LY.

Dabigatran now has a superiority labeling for stroke in the US

Dabigatran 110 mgvs. Warfarin

Dabigatran 150 mgvs. Warfarin

RR =1.1195% CI = 0.89-1.40P = 0.35

RR = 0.7695% CI = 0.60-0.98P = 0.03

Years of Follow-up

0.0

0.02

0.04

0.06

0.08

0 0.5 1.0 1.5 2.0 2.5

Dabigatran110mg

Dabigatran150mg

Warfarin

Ischemic/Unspecified Stroke

Dabigatran now has a superiority labeling for stroke in the US

Cu

mu

lati

ve H

azar

d R

ates

The contributions of components of the composite endpoint, including stroke by subtype, are shown in Table 5. The treatment effect was primarily a reduction in stroke. PRADAXA 150 mg twice daily was superior in reducing ischemic and hemorrhagic stroked relative to warfarin.

PRADAXA 150 mg twice daily

WarfarinHazard ratio vs. warfarin

(95% CI)

Patients randomized 6076 6022

Stroke 122 186 0.64 (0.51, 0.81)

Ischemic stroke 103 134 0.75 (0.58, 0.97)

Hemorrhagic stroke 12 45 0.26 (0.14, 0.49)

Systemic embolism 13 21 0.61 (0.30, 1,21)

Revised US Label

• Dabigatran 150 mg BID preferable to dose-adjusted VKA* for: – patients at intermediate or high risk of stroke

(CHADS2 ≥1)

– secondary prevention of cardioembolic stroke

• Dabigatran as an alternative to dose-adjusted VKA or LMWH in patients undergoing elective cardioversion

2012 ACCP guidelines for antithrombotic therapy in AF: recommendations for dabigatran

You JY et al. Chest 2012;141;e531S–e575S

*Target range for international normalized ratio: 2.0–3.0

LMWH = low-molecular-weight heparin; VKA = vitamin K antagonist

You JY et al. Chest 2012;141;e531S–e575S

2012 ACCP guidelines for antithrombotic therapy in patients with AF

BID = twice daily; TIA = transient ischaemic attack; VKA = vitamin K antagonist *Target range for international normalized ratio: 2.0–3.0

Major Bleeding







ROCKETROCKET AFAF

RE-LYRE-LY

　 Apixaban 5 mg 2.13% / yr 0.69 <0.001


ARISTOTLEARISTOTLE

HRITT

p vs warfarin

2 g drop in 24 hours2 g drop in 24 hours

2 g drop2 g drop(On Treatment)(On Treatment)

150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052

*There is no ITT analysis of safety in ROCKET AF. There is no on treatment analysis of safety from RE-LY.*There is no ITT analysis of safety in ROCKET AF. There is no on treatment analysis of safety from RE-LY.

• Excess bleeding reported in some countries for Dabigatran compared to coumadin.

• Most likely this is due to the fact that bleeding with warfarin was expected, and it was not expected with Dabigatran.

Post Marketing Surveillance

• The EMA found that “the frequency of occurrence of fatal bleedings with Pradaxa seen in post-marketing data was significantly lower than what was observed in the clinical trials that supported the authorisation of the medicine”

• “On the basis of the available evidence, the Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of Pradaxa continue to outweigh its risks and that it remains an important alternative to other blood-thinning agents.”

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/05/news_detail_001518.jsp&mid=WC0b01ac058004d5c1

Post Marketing Surveillance

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/05/news_detail_001518.jsp&mid=WC0b01ac058004d5c1

All Cause Mortality







ROCKETROCKET AFAF

RE-LYRE-LY

　 Apixaban 5 mg 3.52% / yr 0.89 0.01


ARISTOTLEARISTOTLE

HRITT

p vs warfarin

*In an on treatment analysis in ROCKET AF mortality rates were 1.87% / yr for rivaroxaban and 2.21% / yr for warfarin, *In an on treatment analysis in ROCKET AF mortality rates were 1.87% / yr for rivaroxaban and 2.21% / yr for warfarin, p=0.073. No on treatment analysis is available from RE-LY.p=0.073. No on treatment analysis is available from RE-LY.

95% CI 0.89 (0.80, 0.998)N=448 events planned, 480 in trial

Characteristic Overall Japan

Randomized 18,113 326

Mean age (years) 71.5 71.2

Male (%) 63.6 76.7

CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%)

2.131.935.632.5

2.231.334.034.7

Prior stroke / SEE / TIA(%) 21.8 33.1

Prior MI (%) 16.6 5.5

CHF (%) 32.0 31.0

Baseline ASA (%) 39.8 35.9

VKA naive (%) 50.4 56.1

Japanese RE-LY Data: Baseline Characteristics

Hori M, et al: Circ J 75: 800–805, 2011Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009

Region n INR ＜ 2.0INR2.0-3.0

INR ＞ 3.0

Overall 5,789 22.2％ 64.4％ 13.5％

Japan 108 36.8％ 57.6％ 5.6％

Hori M, et al: Circ J 75: 800–805, 2011Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009

For Age >=70 in Japan: INR 2.0-2.6

INR control 　 / Time in Therapeutic Range

Stroke or Systemic Embolism

Dabigatran150mg bid

(n=134/6,076)

Dabigatran110mg bid

(n=183/6,015)

Warfarin

(n=202/6,022)

1.111.111.541.54 1.711.71

0.0.6767

1.381.38

2.652.65

Dabigatran150mg bid(n=1/111)

Dabigatran110mg bid(n=2/107)

Warfarin

(n=4/108)

Connolly SJ, et al: N Engl J Med 361: 1139-1151, 2009 Connolly SJ, et al: N Engl J Med 363: 1875-1876, 2010

Hori M, et al: Circ J 75: 800–805, 2011

RR 0.90 (95 ％　 CI: 0.74-

1.10)

RR 0.65 (95 ％　 CI: 0.52-0.81)

RR 0.52 (95% CI: 0.10-2.84)

RR 0.25 (95% CI: 0.03-2.27)

0

3.0

2.0

1.0

4.0

5.0

0

3.0

2.0

1.0

4.0

5.0Overall Japan

% p

er y

ear

% p

er y

ear

Event (yearly rate)

110 mg bid (N=107)

150 mg bid (N=111)

Warfarin(N=108)

Major bleeding8 (5.53)*(2.87)

5 (3.33)*(3.32)

5(3.31)*(3.57)

Life threatening 1 (0.69) 3 (2.00) 2 (1.33)

Gastrointestinal 3 (2.11) 1 (0.67) 1 (0.67)

Intracranial 1 (0.69) 1 ( 0.67) 1 (0.66)

Minor bleeding 35 (24.19)*(13.16)

50 (33.26)*(14.85)

50 (33.14)*(16.37)

Any bleeding (major or minor)

40 (27.64)*(14.74)

52 (34.59)*(16.56)

51 (33.81)*(18.37)

* Overall

Hori M, et al: Circ J 75: 800–805, 2011

Bleeding Events in Japanese Subjects

• The demographics of the Japanese subgroup differ from the overall population in prior stroke and MI of RE-LY but the overall risk score is similar.

• The stroke and systemic embolism frequencies in the Japanese subgroup are comparable with the overall RE-LY results.

• The major bleeding rates of 150mg bid in the Japanese subgroups, are generally consistent with the overall population.

• The minor bleeding rates of Japanese subgroups, are higher than the overall population.

Summary / Japanese patients

Hori M, et al: Circ J 75: 800–805, 2011

c. michael gibson, m.s., m.d. atrial fibrillation management past, present and future harvard...

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