Walking The Tight Rope In ACS: Balancing Safety And Efficacy Stefan - - PowerPoint PPT Presentation

UCR

Uppsala Clinical Research Center

Walking The Tight Rope In ACS: Balancing Safety And Efficacy

Stefan James, MD, PhD

Associate Professor Head of Interventional Cardiology Uppsala Clinical Research Center University Hospital Uppsala, Sweden

Grant/Research Support Consulting Fees/Honoraria Astra Zeneca, Daiichi Sankyo, Eli Lilly, BMS, Terumo, Merck, Medtronic, Boston Scientific

Risk for bleeding

Risk for ischemic events

Bleeding Thrombosis

Reversible Transfusion Irreversible Tissue Injury

… is bleeding the inevitable cost of improved antithrombotic efficacy? Do we have a balance between thrombosis and bleeding in ACS or…

Important issues in ACS and antithrombotic treatment:

1.

How common is bleeding?

2.

What are the outcomes after bleeding complications?

3.

How to identify patients with increased risk?

4.

Treatment of bleeding complications?

1 2 3 4 5 6

GRACE Registry

% "Major" Bleeding

Overall Unstable angina NSTEMI STEMI

Frequency of Major Bleeding in ACS GRACE Registry: Worldwide

Moscucci M, et al. Eur Heart J 2003; 24: 1815-1823.

N=24,045

Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Italy, New Zealand, Poland, Spain, United Kingdom, United States 1999-2002

Transfusion ≥2 units PRBC Decrease in hct of ≥10% Death or hemorrhagic stroke

• r SDH

Incidence of Major Bleeding in Randomised ACS Trials

2 4 6 8 10 12

GUSTO IIb OASIS-2 PRISM- PLUS PURSUIT PRISM CURE SYNERGY

%

PLATO

Comparison of incidence of Major Bleeding across the trials

Differences in:

 Timing of Bleeds  Definitions

– TIMI, GUSTO, OASIS, ISTH

 Co-interventions

– Combination of antithrombotic drugs – Procedures (PCI, CABG)

 Transfusion strategies

PLATO Bleedings

Wallentin et al. NEJM Aug 30, 2009

2 4 6 8 10 12 14 PLATO Major TIMI Major Fatal/Life- threatening

p=NS p=NS p=NS Ticagrelor Clopidogrel

%

PLATO Bleedings

Wallentin et al. NEJM Aug 30, 2009

2 4 6 8 10 12 14 PLATO Major TIMI Major Fatal/Life- threatening

p=NS p=NS p=NS p=0.03 p=0.03

PLATO Major

Non-CABG

TIMI Major

Non-CABG Ticagrelor Clopidogrel

%

Is bleeding dangerous?

GRACE Registry Bleeding Predicts In-hospital Deaths

n = 24 045

Moscucci M, et al. Eur Heart J 2003; 24: 1815-1823.

patients who developed (open bars) or did not develop major bleeding (closed bars)

OASIS Registry, OASIS-2, CURE “Dose-related” association with mortality

Eikelboom JW, et al. Circulation 2006

N = 34,126

PURSUIT, PARAGON, GUSTO IIb Dose-related Association

Kaplan Meier Curves for 30 Day Death, Stratified by Bleed Severity

0.7 0.75 0.8 0.85 0.9 0.95 1 5 10 15 20 25 30

Days to Death

None Mild Moderate Severe

Rao SV, et.al. AJC 2005

N = 26,452

GUSTO

Why is bleeding dangerous?

Transfusion in Acute Coronary Syndromes and 30-day mortality

1.0 10

• 4.0

Adjusted for transfusion propensity Adjusted for baseline characteristics Adjusted for baseline characteristics, bleeding propensity, transfusion propensity & nadir HCT

3.77 (3.14, 4.52) 3.54 (2.96, 4.23) 3.94 (3.26, 4.75)

Rao SV, et. al., JAMA 2004;292:1555-1562

OASIS Registry, OASIS-2, CURE

Outcome Major Bleed No Major Bleed Hazard (Adjusted) P- Value Death 60/470 (128%) 833/33676 (25%) 537 <00001 MI 46/436 (106%) 1375/33710 (41%) 444 <00001 Stroke 12/469 (2.6%) 187/33677 (0.6%) 6.46 <0.0001

Eikelboom JW et al, Circulation 2006

N = 34,126

Risk stratification

GRACE Risk Score and 1 year Mortality/MI

GRACE Risk Score (Death / MI) Age Killip class Heart rate SBP Female gender Creatinine Diabetes mellitus Positive biomarkers ST-segment deviation Cardiac arrest

CRUSADE = Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines, GRACE = Global Resgistry of Acute Coronary Events, MI = myocardial infarction, SBP = systolic blood pressure. Subherwal S, et al. Circulation. 2009;119:1873-82. Granger CB, et al. Arch Intern Med. 2003;163:2345-53. Eagle KA, et al. JAMA. 2004;291:2727-33.

Risk Assessment

Age Killip class Heart rate SBP (U-shape) Female gender Creatinine clearance Diabetes mellitus CRUSADE Bleeding Score Hematocrit Previous vascular disease

18

Implications?

Optimal therapeutic window for antiplatelet drugs?

Becker & Gurbel. Thromb Haemost 2010

OASIS-5

Fondaparinux vs Enoxaparin

(2/3 on ASA + Clopidogrel)

Death/MI/RI: Day 9

Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0.05 0.06 1 2 3 4 5 6 7 8 9 Enoxaparin Fondaparinux HR 1.01 95% CI 0.90-1.13

OASIS-5 Investigators NEJM 2006

N = 20,078

OASIS-5 Less Bleeding = Less Deaths

Days Cumulative Hazard

0.0 0.01 0.02 0.03 0.04 1 2 3 4 5 6 7 8 9

HR: 0.52 95% CI: 0.44-0.61 p<0.001 Enoxaparin Fondaparinux Days Cumulative Hazard

0.0 0.01 0.02 0.03 0.04 1 2 3 4 5 6 7 8 9

HR: 0.52 95% CI: 0.44-0.61 p<0.001 Enoxaparin Fondaparinux

OASIS-5 Investigators NEJM 2006

Days Cumulative Hazard

0.0 0.01 0.02 0.03 3 6 9 12 15 18 21 24 27 30

HR: 0.83 95% CI: 0.71-0.97 p=0.02 Enoxaparin Fondaparinux Days Cumulative Hazard

0.0 0.01 0.02 0.03 3 6 9 12 15 18 21 24 27 30

HR: 0.83 95% CI: 0.71-0.97 p=0.02 Enoxaparin Fondaparinux

Bleeding Reduced by 50% Deaths Reduced by 17%

OASIS-5 Less Bleeding = Less Deaths

Days Cumulative Hazard

0.0 0.01 0.02 0.03 0.04 1 2 3 4 5 6 7 8 9

HR: 0.52 95% CI: 0.44-0.61 p<0.001 Enoxaparin Fondaparinux Days Cumulative Hazard

0.0 0.01 0.02 0.03 0.04 1 2 3 4 5 6 7 8 9

HR: 0.52 95% CI: 0.44-0.61 p<0.001 Enoxaparin Fondaparinux

OASIS-5 Investigators NEJM 2006

Days Cumulative Hazard

0.0 0.01 0.02 0.03 3 6 9 12 15 18 21 24 27 30

HR: 0.83 95% CI: 0.71-0.97 p=0.02 Enoxaparin Fondaparinux Days Cumulative Hazard

0.0 0.01 0.02 0.03 3 6 9 12 15 18 21 24 27 30

HR: 0.83 95% CI: 0.71-0.97 p=0.02 Enoxaparin Fondaparinux

Bleeding Reduced by 50% Deaths Reduced by 17%

30-Day Major Adverse CV Events

Time, Days 5.5% 5.5% Bivalirudin Should Probably Always Be Combined with UFH

CV = cardiovascular. Stone GW, et al. N Engl J Med. 2008;358:2218-30.

Major Adverse CV Events, %*

HR=1.00 (95% CI, 0.75, 1.32) P=0.98 Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800)

Bivalirudin

24

1 2 3 4 5 6 7 8 5 10 15 20 25 30

Number at risk Bivalirudin 1800 1697 1675 1668 1664 1653 1590 Heparin + GPIIb/IIIa 1802 1651 1617 1606 1598 1581 1511

Primary Endpoint Major Bleeding (%)

Time in Days

8.4% 5.0%

HR [95%CI] = 0.59 [0.45, 0.76]

P<0.0001

Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800)

30 Day Major Bleeding (non-CABG)

30 Day Mortality

Number at risk Bivalirudin 1800 1758 1751 1746 1742 1729 1666 Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630

Death (%)

Time in Days

3.1% 2.1%

HR [95%CI] = 0.66 [0.44, 1.00]

P=0.048

Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800)

HR 0.84 (0.77–0.92) p=0.0003 NNT = 54

Days after randomization

60 120 180 12 11 10 9 8 7 6 5 4 3 2 1

Cumulative incidence (%)

9.8 11.7

Clopidogrel Ticagrelor

Wallentin L, et al. N Engl J Med. 2009;361:1045-57.

Primary Endpoint (CV death, MI, Stroke) CV death

Clopidogrel Ticagrelor

4.0 5.1

HR 0.79 (0.69–0.91) p=0.001 NNT = 90

Ticagrelor vs. Clopidogrel

360

Primary safety event: Major bleeding*

• No. at risk

Clopidogrel Ticagrelor 6,585 6,651 5,215 5,235 4,984 4,947 4,786 Days after randomization 3,753 3,726 2,754 2,741 2,496 2,503 60 120 180 240 300 360 10 5 15 Clopidogrel Ticagrelor 11.6 11.5 4,755 K-M estimated rate (% per year) HR 0.99 (95% CI = 0.89–1.10), p=0.88

* PLATO definitions

Total Patients KM % at Month 12 HR (95% CI) Hazard Ratio (95% CI) Characteristic P Value (Interaction) Ti. Cl.

Ticagrelor better Clopidogrel better

0.5 1.0 2.0 5185 11.9 10.3 1.17 (0.98, 1.39) 13236 11.5 11.6 0.99 (0.89, 1.10) 0.2 0.12 1136 14.6 14.9 0.99 (0.71, 1.37) 17284 11.4 11.0 1.04 (0.95, 1.14) 4621 14.1 14.8 0.95 (0.81, 1.12) 13800 10.8 10.0 1.08 (0.97, 1.20) 0.77 0.21 2846 14.2 13.3 1.04 (0.84, 1.29) 15574 11.1 10.8 1.04 (0.94, 1.15) 1.00 17086 11.5 10.9 1.06 (0.96, 1.16) 1296 12.6 15.2 0.82 (0.60, 1.12) 0.12 5237 10.7 10.5 1.01 (0.85, 1.21) 13184 11.9 11.4 1.05 (0.94, 1.16) 0.76 7471 9.0 9.2 0.98 (0.83, 1.14) 10949 13.4 12.6 1.07 (0.95, 1.19) Planned Treatment Approach Medically managed Invasive Yes No Previous TIA / Non-hemorrhagic Stroke Yes No Medical History of DM ≥75 Years <75 Years Age Group Weight Group ≥60 kg <60 kg Sex Female Male New ST elevation / LBBB at rand. Yes No 0.30

Wallentin L, et al. N Engl J Med. 2009;361:1045-57. (suppl. material)

Consistency Across Subgroups

Major Bleeding

PLATO: CABG and Non-CABG Major Bleeding*

11.6 4.5 7.4 11.2 3.8 7.9

P=NS P=0.03

K-M estimated rate (% per year) 1 2 3 4 5 6 7 8 9 10 12 11 13 TIMI Major Bleeding PLATO Major Bleeding Non-CABG CABG 7.9 7.7 5.3 2.8 5.8 2.2

P=0.03 P=NS

Non-CABG CABG NS PLATO Major Bleeding NS

*Both groups included aspirin; patients may be counted in more than 1 bleeding event category. The graded areas in the middle of the columns represent patients with both a CABG bleed and a non-CABG bleed, or both a procedural bleed and a nonprocedural bleed; NS, not significant; CABG, coronary artery bypass graft; K-M, Kaplan Meier Wallentin L, et al. N Engl J Med. 2009;361:1045-1057; AstraZeneca Data on file: G, I, J.

Clopidogrel Ticagrelor

Time from CABG to CV Death (CABG Population)

130 119 Clopidogrel

• No. at Risk

Ticagrelor 629 629 565 583 539 557 472 404 415 269 291 491

8 7 6 5 4 3 2 1 1 2 3 4 5 6 7 8 9 10 11 12

Months from CABG procedure

HR 0.52 (95% CI, 0.32-0.85) P<0.01

7.9 4.1 Clopidogrel Ticagrelor K-M estimated rate, %

Held C, et al. J Am Coll Cardiol. 2011;57:672-84.

CABG

CABG, coronary artery bypass graft; NNH, number needed to harm; NNT, number needed to treat; TRITON-TIMI 38, Trial to Assess Improvement in Therapeutic Outcomes by Optimising Platelet Inhibition with Prasugrel−Thrombolysis in Myocardial Infarction 38. Wiviott SD, et al. N Engl J Med. 2007;357:2001-15.

TRITON-TIMI 38: Primary Endpoint: CV Death / MI / Stroke; TIMI Non-CABG Bleeding

HR 0.81 (95% CI, 0.73-0.90) P<0.001 NNT=46

138 Events Days Endpoint, % 5 10 15 12.1 9.9 1.8 2.4 CV Death / MI / Stroke TIMI Major Non-CABG Bleeds 0 30 60 90 180 270 360 450 Clopidogrel Prasugrel

HR 1.32 (95% CI, 1.03-1.68) P=0.03 NNH=167

35 Events

Prasugrel vs Clopidogrel

Net Clinical Benefit: Post-hoc Analysis

OVERALL ≥60 kg <60 kg <75 ≥75 No Yes 0.5 1 2 Prior Stroke / TIA Age Weight Risk, % + 37

• 16
• 1
• 16

+3

• 14
• 13

Prasugrel Better Clopidogrel Better HR

PInt=0.006 PInt=0.18 PInt=0.36

Adapted from Wiviott SD, et al. Presented at: American Heart Association Scientific Sessions 2007; 4-7 November, 2007; Orlando, FL. Wiviott SD, et al. N Engl J Med. 2007;357:2001-15.

Prasugrel

33

Triple therapy with novel anticoagulants

Clopidogrel

* In combination with standard therapy ASA, aspirin; RRR, relative risk reduction. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Clopidogrel + ASA* 3 6 9 Placebo + ASA*

11.4% 9.3%

20% RRR P<0.001 N=12,562

12 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14

Cumulative Hazard Rate Months of Follow-Up

Primary Endpoint – MI / Stroke / CV Death

Unmet need

36

Vitamin K antagonist combined with aspirin in MI patients

36

WARIS II, NEJM 2002; 347; 969-74

Target INR 2-2.5 in the combination arm Target INR 2-3 in the combination arm

ASPECT 2, Lancet 2002;360 109:-13

Triple therapy

Retrospective registry study, first time MI, mean FU 1.3 y, N=40 812

Sörensen et al. Lancet 2009; 374: 1967–74

N=18763 N=7250 N=1320 N=12219 N=749 N=196 N=315

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

APPRAISE-2 and ATLAS-ACS-2 Primary Efficacy outcome (CV Death, MI, Stroke)

APPRAISE-2 HR 0.95 (95% CI 0.80-1.11; p=0.51) ATLAS-ACS 2 TIMI 51 HR 0.84 (95% CI 0.74-0.96; p=0.008) Months since randomization Estimated cumulative rate (%)

Alexander et al. N Engl J Med 2011., Mega et al. N Engl J Med 2011.

Placebo Apixaban Rivaroxaban Placebo

*Ischemic stroke only in APPRAISE-2 Ischemic and hemorrhagic stroke in ATLAS-ACS-2

2 4 6 8 10 12 4 8 12 16 20 24

STENT THROMBOSIS

ARC Definite / Probable / Possible Months After Randomization

Rivaroxaban

(both doses)

HR 0.69

(0.51- 0.93) p = 0.008

2.9% 2.3%

Estimated Cumulative Incidence (%)

Placebo

2 Yr KM Estimate

Apixaban Placebo HR 0.73

(0.47- 1.12)

p = 0.15

1.3% 0.9%

HR 3.46 (95% CI 2.08- 5.77; p<0.001) No of patients (%)

Apixaban (n=3673) Placebo (n=3642)

HR 2.59 (95% CI 1.50-4.46; p=0.001) 1.8% 0.6% HR 4.47 (95% CI 2.71- 7.36; p<0.001)

Rivaroxaban 5 mg (n=5115)

2.4%

Rivaroxaban 2.5 mg (n=5114) Placebo (n=5113)

APPRAISE-2 TIMI major ATLAS-ACS 2 TIMI major non-CABG

1.3% 0.5%

1.5 0.5 1.0

ICH: 12 (0.3%) with apixaban vs 3 (0.1%) with placebo: p=0.03 ICH: 32 (0.6%) with rivaroxaban vs 5 (0.2%) with placebo

2.0 2.5

Alexander et al. N Engl J Med 2011, Mega et al. N Engl J Med 2011.

APPRAISE-2 and ATLAS-ACS-2 Primary Safety Outcome (Major bleeding)

Months After Randomization

PRIMARY EFFICACY ENDPOINT:

CV Death / MI / Stroke

Rivaroxaban

(both doses) HR 0.84 (0.74-0.96) 10.7% 8.9%

Estimated Cumulative Incidence (%)

Placebo

5113 4307 3470 2664 1831 1079 421 10229 8502 6753 5137 3554 2084 831 Placebo Rivaroxaban

2 Yr KM Estimate

• No. at Risk

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.

HR 0.94 p=0.57 4.0% 4.1%

Placebo Rivaroxaban

(5 mg)

CV Death

Months After Randomization

PRIMARY EFFICACY ENDPOINT:

CV Death / MI / Stroke

Rivaroxaban

(both doses)

Estimated Cumulative Incidence (%)

Placebo

5113 4307 3470 2664 1831 1079 421 10229 8502 6753 5137 3554 2084 831 Placebo Rivaroxaban

• No. at Risk

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.

HR 0.68 p=0.04 2.9% 4.5%

Placebo Rivaroxaban

(2.5 mg) HR 0.84 (0.74-0.96) 10.7% 8.9% 2 Yr KM Estimate

CV Death

Conclusion

The forthcoming challenges in antithrombotic treatment are

 To improve patient selection concerning both the risk of

new ischemic events and bleeding

 To develop new drugs and/or combinations of

antiplatelets and anticoagulants that improve efficacy, with acceptable bleeding risk

–

preferably evaluated with standardized bleeding definitions

 To refine treatment of bleeding complications including

appropriate transfusion strategies and re-commenced antithrombotic therapy after bleeding