Кристенсен

Current options of anticoagulation in acute coronary syndromes Steen D. Kristensen, MD, DMSc, FESC Professor of Cardiology Aarhus Denmark

UNIVERSITY OF AARHUS

1

COI Steen Dalby Kristensen: lecture fees • • • • • • • •

AZ Bayer Boehringer-Ingelheim BMS Eli Lilly Merck Pfizer The Medicines Company

Acute myocardial infarction: coronary thrombus Coagulation Platelets

E Falk 1983 and 1985

Heart attack: Symptoms • Chest pain

What to do? • Call 112

The ambulance arrives • Acute electrocardiogram

STsegment Elevation

If transfer for Primary PCI: which anti-coagulant?

• • • •

Unfractionated heparin?

Enoxaparin?

Bivalirudin?

None?

If transfer for Primary PCI: which anti-coagulant?

• • • •

Unfractionated heparin?

Enoxaparin? ATOLL trial Bivalirudin? EUROMAX (ongoing) None?

If prehospital thrombolysis: which anti-coagulant?

• • • •

Unfractionated heparin?

Enoxaparin?

Bivalirudin?

None?

If there is no ST-elevation: which anti-coagulant?

• • • •

Unfractionated heparin?

Enoxaparin?

Bivalrudin?

None?

Pocket Guidelines

www.escardio.org/guidelines

European Heart Journal 2012 doi:10.1093/eurheartj/ehs215

Periprocedural anti thrombotic medication in primary PCI, con’t

www.escardio.org/guidelines

European Heart Journal 2012 doi:10.1093/eurheartj/ehs215

HORIZONS - bivalirudin: 30-day net adverse clinical events Heparin + GP IIb/IIIa inhibitor (n=1802) Net adverse clinical events (%)*

Primary Endpoint

Bivalirudin (n=1800) 12.2%

9.3%

HR [95%CI] = 0.75 [0.62, 0.92]

P=0.006

Time in Days *MACE or major bleeding (non- CABG)

Stone et al. N Engl J Med. 2008;358:2218-30

1-Year all-cause mortality Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802)

5

4.8% Δ = 1.4%

Mortality (%)

4

3.4% 3.1%

3

2

Diff [95%CI] = -1.5% [-2.8,-0.1] HR [95%CI] =

2.1% Δ = 1.0%

1

0.69 [0.50, 0.97]

P=0.049

P=0.029

0 0 Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months 1800 1802

1705 1678

1684 1663

1669 1646

1520 1486

Mehran, TCT 2008

European Heart Journal Advance Access published August 26, 2011

JD124857 Kristensen Slides 13/04/16 07:28 16

Antithrombins: Mechanisms of Action direct inhibition

indirect inhibition

Rivaroxaban Apixaban Otamixaban (i.v.)

LY517717,YM150 DU-176b, DX-9045 AZD-4927

FXa

AT-Pentasaccharid Fondaparinux Idraparinux

Hirudin

AT-LMWH Enoxaparin

Bivalirudin

AT-UFH

Argatroban Ximelagatran Dabigatran SCH 539348 (TRA)

Thrombin

Study Design Randomized, Double Blind Patients with NSTE ACS, Chest discomfort < 24 hours 2 of 3: 3: Age>60, Age>60, ST ST Segment Segment Δ, ↑↑ cardiac cardiac markers markers

Exclude Age < 21 Any contra-ind to Enox Hem stroke< 12 mo.

Creat> 3 mg/dL/265 umol/L

Randomize

ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per local practice

Enoxaparin Fondaparinux N=20,000 1 mg/kg sc twice daily 2.5 mg sc once daily PCI< 6 h, No additional UFH PCI >6 h, IV UFH With IIb/IIIa 65 U/kg Without IIb/IIIa 100 U/kg

PCI <6 h: IV Fonda 2.5 mg without IIb/IIIa, 0 with IIb/IIIa PCI> 6 h: IV Fonda 2.5 mg with and 5.0 mg without IIb/IIIa

Outcomes Primary: Primary:

Efficacy Efficacy:

Death, Death, MI, MI, refractory refractory ischemia ischemia at at 9 days

Safety Major bleeding Safety: bleeding at at 99 days days Risk Risk benefit benefit: Death, Death, MI, MI, refractory ischemia, major major bleeds bleeds 99 days days Secondary Secondary:: Above & each component separately separately at at day day 30 30 & & 66 months months Hypothesis Hypothesis:: First First test test non-inferiority, non-inferiority, then test superiority

OASIS-5 bleeding

0.01 0.02 0.03 0.04 0.05 0.06

HR 1.01 95% CI 0.90-1.13 Enoxaparin Fondaparinux

0.0

Cumulative Hazard

Death/MI/RI: Day 9

0

1

2

3

4

5 Days

6

7

8

9

OASIS-5 bleeding

Enoxaparin

0.02

0.03

HR 0.52 95% CI 0.44-0.61 P<0.00001

0.01

Fondaparinux

0.0

Cumulative Hazard

0.04

Major Bleeding: 9 Days

0

1

2

3

4

5 Days

6

7

8

9

OASIS-5 bleeding

Mortality: Day 30

0.02

Fondaparinux

0.01

HR 0.83 95% CI 0.71-0.97 P=0.022

0.0

Cumulative Hazard

0.03

Enoxaparin

0

3

6

9

12

15

Days

18

21

24

27

30

Recommendations for anticoagulation:

JD124857 Kristensen Slides 13/04/16 07:28 21

 Anticoagulation is recommended for all patients in addition to antiplatelet therapy (I-A)  Anticoagulation should be selected according to the risk of both ischaemic and bleeding events (IB)  Several anticoagulants are available, namely UFH, LMWH, fondaparinux, bivalirudin. The choice depends on the initial strategy (I-B)  In an urgent invasive strategy UFH (I-C), or enoxaparin (IIa-B) or bivalirudin (I-B) should be immediately started.

Recommendations for anticoagulation:

JD124857 Kristensen Slides 13/04/16 07:28 22

 In an non-urgent situation, as long as decision between early invasive or conservative strategy is pending:  Fondaparinux is recommended on the basis of the most favorable efficacy/safety profile. (I-A) – Enoxaparin with a less favourable efficacy/safety profile than fondaparinux should be used only if the bleeding risk is low (IIa-B) – As efficacy/safety profile of LMWH (other than enoxaparin) or UFH relative to fondaparinux is unknown; these anticoagulants cannot be recommended over fondaparinux (IIa-B)

Bivalirudin vs GPIIb/IIIa antagonists Class

23

Level

Individualising combinations

24

Class

Level

Class

Level

ISAR REACT 4

ISAR REACT 4

ISAR REACT 4

ORAL ANTICOAGULATION IN ACS

Thrombin in ACS • There is excess thrombin generation that persists for 6 months following an index ACS event.1 • Thrombin is the most potent stimulant of platelet aggregation.2 • Reduction of thrombin generation by warfarin reduces recurrent MI by 44% in a meta-analysis of 10 ACS trials.3 1. Merlini PA et al. Circulation. 1994;90:61-68. 2. Coughlin S. Thrombin signaling and protease-activated receptors. Nature 2000;407(6801):258-64. 3. Rothberg MB et al Ann Intern Med. 2005 Aug 16;143(4):241-50.

WARIS-2

New oral AC: ACS • APPRAISE and -2 apixaban • ATLAS and -2 rivaroxiban

APPRAISE-2 Publication

APPRAISE-1 Trial Phase 2, 1715 patients, recent acute coronary syndrome Apixaban 2.5 mg BID, 10 mg QD, 10 mg BID, 20 mg QD, placebo Apixaban 10 mg BID & 20 mg QD stopped due to excess bleeding ISTH Major or CRNM Bleeding HR 2.45 (1.31-4.61) p=0.005

HR 1.78 (0.91-3.48) p=0.09

CV Death, MI, Stroke, Sev Recurrent Ischemia HR: 0.73 (0.44-1.19) p=0.21

HR: 0.61 (0.35-1.04) p=0.07

Alexander JH. Circulation 2009;119:2877â&#x20AC;&#x201C;85.

Risk Factors • Age ≥65 years • Diabetes mellitus Recent (≤7days) Acute Coronary Syndrome • Prior MI within 5 years (STEMI or NSTE-ACS) • At Least 2 Additional Cerebrovascular Risk-Factors disease N=10,800 • Aspirin • Other antiplatelet therapy

• Peripheral vascular disease Randomize 1:1 • Clinical heart failure or LV EF <40% Double blind • Renal dysfunction (CrCl <60 mL/min) • No revascularization for ACS event

Projected event rate: 8%5/ year, median f/u 1.25 years Apixaban mg BID

Placebo Event driven: 938 patients with the primary outcome CrCl<40 ml/min 2.5 mg BID • 80% power to detect a 20% risk reduction at a one-sided α of 0.005 • 93% power to detect a 20% risk reduction at a one-sided α of 0.025 Outcome: Death, Stroke Analysis: time to Primary first event (stratified:CV single vs. MI, dualIschemic antiplatelet therapy) Safety: TIMI Major Bleeding Key subgroups: single / dual antiplatelet therapy, revascularized / not revascularized

Objective

To determine whether apixaban 5mg twice daily reduces the composite of cardiovascular death, MI or stroke at an acceptable risk of bleeding in patients at high-risk for recurrent ischemic events receiving contemporary antiplatelet therapy following an acute coronary syndrome

Trial Stopped Prematurely

On November 15, 2010 the Data Monitoring Committee recommended that the trial be stopped due to an excess of clinically important bleeding in the apixaban arm without a counterbalancing reduction in ischemic events. â&#x20AC;˘ Patients = 7048 â&#x20AC;˘ Primary Events = 412 (44%)

Primary Outcome CV Death, MI, Ischemic Stroke Apixaban 279 (7.5%) Placebo 293 (7.9%) HR 0.95; 95% CI 0.80-1.11; p=0.509

TIMI Major Bleeding Apixaban 48 (1.3%) Placebo 18 (0.5%) HR 2.59; 95% CI 1.50â&#x20AC;&#x201C;4.46; p=0.001

Other Efficacy Outcomes Apixaban N=3705

Placebo N=3687

p-value

CV death, MI, ischemic stroke

7.5

7.9

0.509

CV death, MI, ischemic stroke, UA

9.5

10

0.430

Death

4.2

3.9

0.514

CV death

2.8

2.9

0.754

Myocardial infarction

4.9

5.3

0.509

Ischemic stroke

0.6

0.9

0.145

Unstable angina

2.3

2.4

0.670

Definite stent thrombosis

0.9

1.3

0.150

Primary Outcome CV Death, MI, Stroke — Subgroups

*HR not calculated for subgroups with ≤10 events

TIMI Major Bleeding Subgroups

*HR not calculated for subgroups with â&#x2030;¤10 events

Conclusions

• APPRAISE-2 Summary: The addition of apixaban to contemporary antiplatelet therapy increases major bleeding without any significant reduction in ischemic events in high-risk patients following an ACS.

• Limitations: Because of the early termination of the trial, with accrual of two-thirds of the expected events and a median follow-up of 8 months, some uncertainty regarding efficacy remains.

• Clinical Implications: The addition of an anticoagulant to currently recommended anti-platelet treatment post-ACS should be used cautiously and only in patients with clear indications for both an anticoagulant and antiplatelet therapy.

• Future Directions: Further research is needed to explore different antithrombotic combinations and doses that might have a different risk-benefit balance.

ATLAS ACS TIMI 46: trial profile N=3491 N=3491 Physician's decision to add thienopyridine or not

ASA ASA alone alone

ASA ASA ++ thienopyridine thienopyridine

n=761 n=761

n=2730 n=2730

Placebo Placebo n=253 n=253

Rivaroxaban Rivaroxaban od od n=254 n=254

Rivaroxaban Rivaroxaban bid bid n=254 n=254

Placebo Placebo n=907 n=907

Rivaroxaban Rivaroxaban od od n=912 n=912

Rivaroxaban Rivaroxaban bid bid n=911 n=911

55 mg mg (n=77) (n=77) 10 10 mg mg (n=98) (n=98) 20 mg (n=78) 20 mg (n=78)

55 mg mg (n=77) (n=77) 10 10 mg mg (n=99) (n=99) 20 mg (n=78) 20 mg (n=78)

2.5 2.5 mg mg (n=77) (n=77) 55 mg mg (n=97) (n=97) 10 10 mg mg (n=80) (n=80)

55 mg mg (n=74) (n=74) 10 10 mg mg (n=428) (n=428) 15 15 mg mg (n=178) (n=178) 20 20 mg mg (n=227) (n=227)

55 mg mg (n=78) (n=78) 10 10 mg mg (n=430) (n=430) 15 15 mg mg (n=178) (n=178) 20 20 mg mg (n=226) (n=226)

2.5 2.5 mg mg (n=76) (n=76) 55 mg mg (n=430) (n=430) 7.5 7.5 mg mg (n=178) (n=178) 10 10 mg mg (n=227) (n=227)

Treatment Treatment for for 66 months months ASA dose: 75â&#x20AC;&#x201C;100 mg Mega et al, 2009

Clinically significant bleeding (%)

Primary safety endpoint: dose-dependent increases in clinically significant bleeding rates Total daily dose: Rivaroxaban 20 mg Rivaroxaban 15 mg Rivaroxaban 10 mg Rivaroxaban 5 mg Placebo

15

10

KM HR (rates) (95% CI) 15.3% 5.06 (3.45–7.42) 12.7% 3.60 (2.32–5.68) 10.9% 3.35 (2.31–4.87)

6.1%

5

2.21 (1.25–3.91)

3.3% p<0.0001

0 0

60 90 120 150 30 Time after start of treatment (days)

180

Cumulative Kaplan–Meier estimates of bleeding rates and HR; one fatal intracranial haemorrhage in the ASA-only arm Mega et al, 2009

ATLAS ACS TIMI 46: primary efficacy endpoint

Incidence of primary endpoint (%)

 A trend towards reduction of death, MI, stroke and severe recurrent ischaemia with rivaroxaban versus placebo 8 7.0% (79/1,160) HR=0.79 (0.60–1.05); p=0.10 5.6% (126/2,331)

Placebo 6

4 Rivaroxaban 2

0 0

30

60

90

120

150

180

Time from randomization (days) Cumulative Kaplan–Meier estimates of rate of composite primary efficacy endpoint (death, MI, stroke, severe recurrent ischaemia requiring revascularization) Mega et al, 2009

Recent ACS: STEMI, NSTEMI, UA No increased bleeding risk, No warfarin, No ICH, No prior stroke if on ASA + Thienopyridine Stabilized 1-7 Days Post-Index Event

Stratified by Thienopyridine use at MD Discretion

Placebo N=5,176 ASA + Thieno, n=4,821 ASA, n=355

+ ASA 75 to 100 mg/day

RIVAROXABAN

RIVAROXABAN

2.5 mg BID

5.0 mg BID

n=5,174

N=5,176

ASA + Thieno, n=4,825 ASA, n=349

ASA + Thieno, n=4,827 ASA, n=349

PRIMARY ENDPOINT: EFFICACY: CV Death, MI, Stroke* (Ischemic + Hemg.)

SAFETY: TIMI major bleeding not associated with CABG Event driven trial of 1,002 events in 15,342 patients**

* Stroke includes ischemic stroke, hemorrhagic stroke, and uncertain stroke ** 184 subjects were excluded from the efficacy analyses prior to unblinding

BASELINE CHARACTERISTICS Placebo

Rivaroxaban Rivaroxaban 2.5 mg BID 5.0 mg BID

Age, mean (SD)

61.5 (± 9.4)

61.8 (± 9.2)

61.9 (± 9.0)

Sex, male n (%)

75.0%

74.9%

74.2%

Prior MI, n (%)

27.3%

26.3%

27.1%

Diabetes, n (%)

31.8%

32.3%

31.8%

STEMI, n (%)

50.9%

50.3%

49.9%

NSTEMI, n (%)

25.6%

25.5%

25.8%

UA, n (%)

23.6%

24.2%

24.3%

PCI at Index Hosp, n (%)

59.9%

60.2%

60.0%

PRIMARY EFFICACY ENDPOINT: CV Death / MI / Stroke* (Ischemic + Hemg.)

2 Yr KM Estimate

Estimated Cumulative Rate (%)

Placebo

No. at Risk Placebo Rivaroxaban

10.7% 8.9% HR 0.84 (0.74-0.96) ARR 1.7%

Rivaroxaban (both doses)

mITT p = 0.008 ITT p = 0.002

NNT = 59

5113 10229

4307 8502

Months After Randomization 3470 6753

2664 5137

1831 3554

1079 2084

421 831

*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; ARR=Absolute Relative Reduction; NNT=Number needed to treat; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.

PRIMARY EFFICACY ENDPOINT*: 2.5 mg PO BID CV Death / MI / Stroke* Estimated Cumulative incidence (%)

12%

HR 0.84

5%

10.7%

5%

Placebo

4.1%

mITT p=0.002

9.1%

ITT p=0.007

0

HR 0.66

Placebo

mITT p=0.020

All Cause Death

Cardiovascular Death

HR 0.68

Placebo

mITT p=0.002

4.5%

ITT p=0.004

ITT p=0.005

2.9%

2.7%

Rivaroxaban 2.5 mg BID

Rivaroxaban 2.5 mg BID

Rivaroxaban 2.5 mg BID

NNT = 63

NNT = 71

NNT = 63

12 Months

24

0

12 Months

24

0

12 Months

24

* First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; NNT=Number needed to treat.

PRIMARY EFFICACY ENDPOINTS: 2.5 mg PO BID In Patients Treated with ASA + Thienopyridine

CV Death / MI / Stroke* Estimated Cumulative incidence (%)

12%

HR 0.85

Placebo

mITT p=0.039

Cardiovascular Death

5%

HR 0.62

Placebo

mITT p<0.001

10.4%

5%

4.2%

All Cause Death HR 0.64

Placebo

mITT p<0.001

4.5%

9.0%

ITT p=0.011

ITT p<0.001

ITT p<0.001 2.7%

2.5%

0

Rivaroxaban 2.5 mg BID

Rivaroxaban 2.5 mg BID

Rivaroxaban 2.5 mg BID

NNT = 71

NNT = 59

NNT = 56

12 Months

24

0

12 Months

24

0

12 Months

*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; NNT=Number needed to treat.

24

STENT THROMBOSIS* ARC Definite, Probable, Possible

Estimated Cumulative incidence (%)

2 Yr KM Estimate

Placebo

2.9% 2.3%

HR 0.69 Rivaroxaban (both doses) ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012

(0.51- 0.93) mITT p = 0.016 ITT p = 0.008

Months After Randomization * End point events are as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.

SAFETY ENDPOINTS Treatment-Emergent Non CABG TIMI Major Bleeding* Analysis

2 Yr KM Estimate

Placebo

2.5 mg Rivaroxaban

5.0 mg Rivaroxaban

0.6%

1.8%

2.4%

HR 3.46

HR 4.47 p<0.001

p<0.001

Post-Treatment Ischemic Events# 1-10 Days After Last Dose

1.8%

1.4% p=NS

2.2% p=NS

Liver Function Test (ALT > 3xULN) ## Treatment-Emergent

1.6%

1.3% p=NS

1.4% p=NS

There was no excess of either combined ALT > 3x ULN and Total Bilirubin > 2x ULN cases among patients treated with Rivaroxaban, or SAEs. *: First occurrence of Non-CABG TIMI major bleeding events occurred between first dose to 2 days post last dose as adjudicated by the CEC across thienopyridine use strata; Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine are provided; Stratified log-rank p-values are provided; #: Raw percentage for CV death/MI/stroke (ischemic, hemorrhagic, uncertain) ; ##: Raw percentage of subjects with abnormal value measured between first dose to 2 days post last dose among subjects with normal baseline measurement.

TREATMENT-EMERGENT FATAL BLEEDS AND ICH 1.2 1 0.8 0.6

p=NS for Riva vs Placebo

0

0.7

p=0.044 for 2.5 mg vs 5.0 mg

0.4

0.4 0.2

p=0.009 Riva Vs Placebo

0.2

0.1*

Placebo 2.5 mg Rivaroxaban 5.0 mg Rivaroxaban

0.4

p=NS for Riva vs Placebo

0.2

0.2 0.1 0.1

n=9 n=6 n=15

n=5 n=14 n=18

n=4 n=5 n=8

Fatal

ICH

Fatal ICH

*Among patients treated with aspirin + thienopyridine, there was an increase in fatal bleeding among patients treated with 5.0 mg of Rivaroxaban (15/5110) vs 2.5 mg of Rivaroxaban (5/5115) (p=0.02)

New oral AC in ACS â&#x20AC;˘ Differences between the drugs and dosing?

New oral AC in ACS â&#x20AC;˘ Diffferences in study design?

New oral AC in ACS â&#x20AC;˘ Differences in study design? â&#x20AC;˘ Patients: comorbidity

New oral AC in ACS • Differences in study design?

• Patients: comorbidity • Duration of therapy

Lessons from ATLAS-2/APPRAISE-2 â&#x20AC;˘ Rivaroxiban inhibits late stent-thrombosis?!

STENT THROMBOSIS* ARC Definite, Probable, Possible

Estimated Cumulative incidence (%)

2 Yr KM Estimate

Placebo

2.9% 2.3%

HR 0.69 Rivaroxaban (both doses) ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012

(0.51- 0.93) mITT p = 0.016 ITT p = 0.008

Months After Randomization * End point events are as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.

PRIMARY EFFICACY ENDPOINT: 5.0 mg BID

Estimated Cumulative incidence (%)

CV Death / MI / Stroke* (Ischemic + Hemg.)

Placebo

10.7%

10

8.8% HR 0.85 mITT p=0.028

5

Rivaroxaban 5 mg BID

0 0

12 Months

ITT P=0.010

24

Rivaroxaban at 5 mg PO BID was associated with a numerical but not statistically significant reduction in mortality.

* First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches.

Lessons from ATLAS-2/APPRAISE-2 • Rivaroxiban inhibits late stent-thrombosis?!

• Much of the benefit appears at around 12-15 months (stopping clopidogrel)?!

• Maybe we should avoid to treat/randomize very ill ACS patients (potential bleeders?)?!

• Maybe very low dose of anticoagulant is the key.

New oral AC in ACS â&#x20AC;˘ We are now using ticagrelor/prasugrel instead of clopidogrel. â&#x20AC;˘ Will there be a place for new oral AC in this context?

Thank you

Thank you

ESC myocardial revascularization

Wijns et al. Eur Heart J. 2010;31:2501-55

Impact on DEATH

HR (95% CI) MI

OASIS-5 bleeding

RISK of death at 180 days

5.7 (4.7-6.9)

Refractory ischemia 2.7 (2.0-3.6) Major bleeding

4.2 (3.5-5.1)

Minor bleeding

2.2 (1.7-3.0) 1

3

6

Major Bleeding and MI in the First 30 Days Risk of Death Over 1 Year 524 (3.8%) died within 1 year Cox model adjusted for 36 baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates HR Âą 95% CI

HR (95% CI) P-value

Myocardial infarction

2.51 (1.95-3.25) <0.0001

Major bleeding without or before transfusion

2.00 (1.30-3.06) <0.0001

Major bleeding after transfusion

3.93 (2.95-5.24) <0.0001

Mehran RM et al. In press EHJ

Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 1 year Estimate Both MI and Major Bleed (N=94) Major Bleed only (without MI) (N=551) MI only (without Major Bleed) (N=611) No MI or Major Bleed (N=12,557)

30

28.9% 12.5% 8.6% 3.4%

Mortality (%)

25 20 15 10 5 0 0

30

60

90

120 150

180 210 240 270

Days from Randomization Stone GW. ACC 2007

300 330 360

390

Other Bleeding Scales Apixaban N=3705

Placebo N=3687

p-value

TIMI major

1.3

0.5

0.001

TIMI major or minor

2.2

0.8

<0.001

ISTH major

2.7

1.1

<0.001

ISTH major or clinically relevant non-major

3.2

1.2

<0.001

GUSTO severe

1.0

0.3

0.001

Intracranial

0.3

0.1

0.030

Fatal bleeding: Apixaban = 5 vs. Placebo = 0 ISTH major bleeding = bleeding leading to death, occurring in a critical location, or associated with a â&#x2030;Ľ2 g/dL drop in hemoglobin or transfusion of 2 or more units of PRBC.