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;119:2877–85.
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. • Patients = 7048 • 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 1.50–4.46; 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 ≤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: 75–100 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 • Differences between the drugs and dosing?
New oral AC in ACS • Diffferences in study design?
New oral AC in ACS • Differences in study design? • Patients: comorbidity
New oral AC in ACS • Differences in study design? • Patients: comorbidity • Duration of therapy
Lessons from ATLAS-2/APPRAISE-2 • 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 • We are now using ticagrelor/prasugrel instead of clopidogrel. • 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 ≼2 g/dL drop in hemoglobin or transfusion of 2 or more units of PRBC.