Practical Application Of New Developments In Antithrombotic And - - PowerPoint PPT Presentation

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UCR Uppsala Clinical Research Center Practical Application Of New Developments In Antithrombotic And Antiplatelet Therapy In ACS Stefan James, MD, PhD Associate Professor Head of Interventional Cardiology Uppsala Clinical Research Center

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UCR

Uppsala Clinical Research Center

Practical Application Of New Developments In Antithrombotic And Antiplatelet Therapy In ACS

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

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STE- / NSTE-ACS

Clopidogrel 300 mg Pre / post cath Ticagrelora Pre / post cath Bivalirudin 11 anti-thrombotic agents with 384 possible treatment combinations

Parenteral anticoagulant

UFH Bolus / infusion LMWH Fondaparinux Primary PCI / Lytics

Early Invasive/ Early Conservative Aspirin loading Parenteral antiplatelet

Abciximab Pre / post cath Eptifibatide Pre / post cath Tirofiban Pre / post cath Clopidogrel 600 mg Pre / post cath Prasugrel Pre / post cath

Oral antiplatelet

aTicagrelor is not currently approved for use in any market.

ESC = European Society of Cardiology, LMWH = low-molecular-weight heparin, UFH = unfractionated heparin. Bassand JP, et al. Eur Heart J. 2007;28:1598-660. Van de Werf F, et al. Eur Heart J. 2008;29:2909-45

ESC guidelines NSTE-ACS I-A, STE-ACS I-B

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Targets for Antithrombotic Treatment

Fibrin Thrombus Platelet aggregation Conformational activation of GPIIb/IIIa Collagen Thrombin Tx A2 ADP Aspirin Clopidogrel Prasugrel Ticagrelor Cangrelor Elinogrel GPIIb/IIIa inhibitors PAR1 PAR1-inhib Vorapaxar Atopaxar

ADP = adenosine diphosphate, AT = antithrombin , GP = glycoprotein, inhib = inhibitor, PAR1 = protease activated receptor, TxA2 = thromboxane A2.

Platelet activation Tissue factor Plasma clotting cascade Prothrombin Thrombin Fibrinogen AT AT Bivalirudin Dabigatran Factor Xa Fondaparinux LMWH Heparin Rivaroxaban Apixaban Edoxaban Coagulation Warfarin

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Targets for Antithrombotic Treatment

Fibrin Thrombus Platelet aggregation Conformational activation of GPIIb/IIIa Collagen Thrombin Tx A2 ADP Aspirin Clopidogrel Prasugrel Ticagrelor Cangrelor Elinogrel GPIIb/IIIa inhibitors PAR1 PAR1-inhib Vorapaxar Atopaxar

ADP = adenosine diphosphate, AT = antithrombin , GP = glycoprotein, inhib = inhibitor, PAR1 = protease activated receptor, TxA2 = thromboxane A2.

Platelet activation Tissue factor Plasma clotting cascade Prothrombin Thrombin Fibrinogen AT AT Bivalirudin Dabigatran Factor Xa Fondaparinux LMWH Heparin Rivaroxaban Apixaban Edoxaban Coagulation Warfarin

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Variability in Inter-Individual Clopidogrel Response

ADP, adenosine diphosphate. Hochholzer W, et al. Circulation. 2005;111:2560-4.

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Clopidogrel

Mehta SR, et al. NEJM 2010 and Lancet 2010

0.14 0.95

  • 1.44

1.17 4.9 4.2 No PCI (2N=7855) 0.74

  • 0.99

0.85 3.9 4.5 PCI (2N=17,232) CV Death / MI / Stroke Int P P 95% CI HR Double Standard 0.14 0.95

  • 1.44

1.17 4.2 No PCI (2N=7855) 0.016 0.74

  • 0.99

0.86 4.5 PCI (2N=17,232) CV Death / MI / Stroke P P 95% CI HR Double Standard 0.04

300 (-600) mg

5 Days Cumulative Hazard

0.0 0.01 0.02 0.03 0.04 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard Clopidogrel Double

HR= 0.86 (95% CI, 0.74-0.99) P=0.039

CV Death / MI / Stroke in PCI Patients

0.37 0.84

  • 1.07

0.95 4.2 4.4 Overall (2N=25,087) 0.84

  • 1.07

0.95 4.4 Overall (2N=25,087)

Days Cumulative Hazard

0.0 0.01 0.02 0.03 0.04 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard Clopidogrel Double

HR= 0.85 (95% CI, 0.74-0.99) P=0.036

CV Death / MI / Stroke

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Clopidogrel dosing

Class Level

www.escardio.org/guidelines

Class Level Class Level

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PRINCIPLE-TIMI44

(Wiviott SD et al. Circulation 2007) (Gurbel PA et al. Circulation 2009)

ONSET-OFFSET

Prasugrel 60 mg

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TRITON-TIMI 38: study design

ASA N=13,608

Wiviott S, et al. N Engl J Med 2007;357:2001–15 UTVR = urgent target vessel revascularisation

Clopidogrel 300mg loading dose/75mg maintenance (N=6,795) ACS (STEMI or UA/NSTEMI) and planned PCI

Double-blind randomisation

Prasugrel 60mg loading dose/10mg maintenance (N=6,813)

Median duration of therapy: 12 months

1o endpoint: CV death, MI, stroke 2o endpoints: CV death, MI, stroke, recurrent ischaemia with rehospitalisation CV death, MI, UTVR stent thrombosis (ARC definite/probable) Safety endpoints: TIMI major bleeds, life-threatening bleeds Key substudies: pharmacokinetic, genomic

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Efficacy endpoints

Prasugrel Clopidogrel Days

12.1 9.9 1.8 2.4

CV death/MI/stroke TIMI major non-CABG bleeds CV death, MI, stroke and major non-CABG bleeding

HR=0.41 (0.29–0.59) p<0.0001 HR=0.60 (0.37–0.97) p=0.03

Early Late

Wiviott S, et al. N Engl J Med 2007;357:2001–15; Wiviott S, et al. Lancet 2008;371:1353–1363

15 10 5 90 180 270 360 450 Endpoint (%) 5 10 15 20 25 30 2.5 2.0 1.5 1.0 0.5

1.56 0.64 40% 0.82 0.49 CABG = coronary artery bypass grafting

Early and late stent thrombosis Days

59%

2.5 2.0 1.5 1.0 0.5 Endpoint (%) Endpoint (%) 0 90 270 450 Days

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Montalescot G, et al. Lancet 2009;373:723–31.

STEMI cohort

10 Days 15 10 5 50 100 150 200 250 300 350 400 450 Proportion of patients, % 9.5 6.5 12.4 10.0 HR = 0.79 (0.65–0.97); NNT = 42 P = 0.02 RRR = 21% P = 0.002 RRR = 32% 2.1 2.4 HR = 1.11 (0.70–1.77); NNH = 333 P = 0.65 Clopidogrel Prasugrel CV Death / MI / stroke TIMI major non-CABG bleeds

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Montalescot et al. Lancet 2009; 373, 723-31

Prasugrel

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Conclusions on Prasugrel in ACS

In patients with ACS and planned PCI Prasugrel 60/10mg vs Clopidogrel 300/75mg for 15 months

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reduces the composite: CV death + MI + stroke

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reduces MI (especially produre related MI)

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reduces stent thrombosis

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raises the risk of major (including fatal) bleeding

with

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higher risk of bleedings at age >75 years, <65 kg, history of stroke or TIA and at CABG

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net clinical benefit larger at STEMI and DM

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Prasugrel

www.escardio.org/guidelines

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PLATO study design

Primary endpoint : • Composite of CV death, MI or stroke Key secondary • CV death, MI, or stroke in patients intended for invasive management

  • Total mortality, MI or stroke
  • CV death, MI, stroke, recurrent ischemia, TIA, or arterial thrombosis
  • Components of primary endpoint - CV death; MI; stroke
  • Death from any cause

Primary safety: • Total Major bleeding

6–12 month exposure

Clopidogrel If pretreated, no additional loading dose; if naive, standard 300mg loading dose, then 75mg q.d maintenance; (additional 300mg allowed pre PCI) Ticagrelor 180mg loading dose, then 90mg b.i.d maintenance; (additional 90mg prePCI) NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624)

James S, et al. Am Heart J 2009;157:599–605

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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)

Ticagrelor vs. Clopidogrel

Clopidogrel Ticagrelor

2.3 2.8 HR 1.25 (1.03–1.53) p=0.03 NNH=167

TIMI Major Non CABG bleeds

N=18,624

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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

N=18,624

Ticagrelor vs. Clopidogrel

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Cannon CP, et al. Lancet. 2010;375:283-293.

Definite Stent Thrombosis

Days Since PCI

Invasive

Ticagrelor

Definite stent thrombosis, % 5 10 15 20 25 30 2 1

1.41 1.42 0.87 0.96

Clopidogrel, <600 mg Ticagrelor, <600 mg clopidogrel Clopidogrel, ≥600 mg Ticagrelor, ≥600 mg clopidogrel

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James S et al. ESC abstract 2010

Mortality reduction in invasive and non- invasive treatment strategies

Invasive HR, 0.81, 95% CI: (0.68–0.95)

Number at risk Invasive Ticagrelor 6732 6439 6375 6241 5141 3951 3233 Clopidogrel 6676 6376 6331 6209 5114 3917 3164

Days after randomization All-cause mortality (%)

3.9% 5.0%

2 4 6 8 10 60 120 180 240 300 360

Non- Invasive N=13408

Non-invasive HR, 0.75, 95% CI: (0.61–0.93)

6.1% 8.2%

N=5216

Non-invasive Ticagrelor 2601 2485 2447 2385 1978 1531 1186 Clopidogrel 2615 2488 2448 2380 1965 1524 1200

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2 4 6 8 10 12 14 60 120 180 240 300 360

Clopidogrel Ticagrelor Clopidogrel Ticagrelor

588 542 530 507 397 314 246 564 534 525 511 411 332 254 8699 8318 8245 8078 6679 5124 4115 8761 8382 8289 8107 6701 5143 4162

Prior stroke No prior stroke Patient at risk Clopidogrel Clopidogrel Ticagrelor Ticagrelor

Prior stroke No prior stroke

James, S et al, ESC 2011

Prior stroke or TIA

N=1052 HR, 0.62 (0.42, 0.91) All cause death Stroke

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Primary endpoint in ONSET/OFFSET study: Onset: IPA (20 M ADP, final extent) at 2 h after the first dose of study drug. Offset: Slope of IPA between 4 and 72 h after the last dose of study drug. Ticagrelor (180 mg load, 90 mg bd maintenance dose), clopidogrel (600 mg load, 75 mg/day maintenance dose) or placebo on top of aspirin 75-100 mg/day. *P<0.001; †P<0.005; ‡P<0.05 ticagrelor vs clopidogrel. Gurbel PA, et al. Circulation. 2009;120:2577-85.

20 M ADP (Final Extent)

6 Weeks

IPA, %

Onset Maintenance Offset

Time, h

0.5 1 2 4 8 24 2 4 8 24 48 120 168 240

10 20 30 40 50 60 70 80 90 100

Clopidogrel (n=50) Ticagrelor (n=54) Placebo (n=12)

* * * * * * * * *

† ‡ †

Loading Dose Last Maintenance Dose 72

IPA in the ONSET/OFFSET Study Following Last Maintenance Dose

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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

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PLATO dyspnoea

AE, adverse event; CI, confidence interval; HR, hazard ratio. Storey RF, et al. Eur Heart J 2011;108:1542–1546.

Ticagrelor Clopidogrel Onset of any dyspnoea AE (%) p for interaction <0.001 Days from first dose First 30 days 10 8 6 4 2 10 20 30 8.29 3.84 HR(95% CI) = 2.24(1.97–2.54) Days from randomisation All-cause mortality (%) p for interaction <0.001 Days from randomisation 20 15 10 5 31 90 150 210 270 330 8.51 3.39 All-cause mortality (%) p for interaction =0.659 20 15 10 5 31 90 150 210 270 330 3.04 2.54 HR(95% CI) = 1.11(0.69–1.78) HR(95% CI) = 2.73(1.82–4.09)

Dyspnoea No dyspnoea

Ticagrelor mortality Clopidogrel mortality

Dyspnoea No dyspnoea

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Ticagrelor

www.escardio.org/guidelines

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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

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

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Days After PCI Percent

SCAAR

30 25 20 15 10 5 0.12 0.10 0.08 0.06 0.04 0.02 0.00

Bivalirudin Plus UFH, N=1068 Bivalirudin, N=1928 Adjusted N=2996 OR; 0.63, 95% CI (0.42-0.94), P=0.025

Koutouzis M, et al. Presented at: EuroPCR 2010; 25-28 May 2010; Paris, France.

Death or Target Lesion Stent Thrombosis

Bivalirudin

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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)

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Bivalirudin

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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)

All Cause Death

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

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

1.5 0.5 1.0

ICH: 32 (0.6%) with rivaroxaban vs 5 (0.2%) with placebo

2.0 2.5

Mega et al. N Engl J Med 2011.

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

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ASA ASA+(Plavix eller Ticlid)

Andel Blodproppshämmande (%)

10 20 30 40 50 60 70 80 90 100 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 ASA ASA+(Clopidogrel)

Proportion inhibitors (%)

10 20 30 40 50 60 70 80 90 100 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Uppsala Clinical Research Centre 2006

Antithrombotic treatment at discharge

2009 Proportion treated % Clopidogrel + ASA

ASA

Warfarin Proportion treated %

Uppsala Clinical Research Centre 2009

Clopidogrel + ASA

ASA

Warfarin

STEMI NSTEMI

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Alteplase Tenecteplase Reteplase

Proportion acute reperfusion therapy (%)

10 20 30 40 50 60 70 80 90 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Uppsala Clinical Research Centre 2006

2009

Reperfusion treatment in STEMI < 80 yrs

Primary PCI Streptokinase Actilyse-tPA rPA TNK

Uppsala Clinical Research Centre 2009

Proportion reperfusion treatment %

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Mortality in STEMI

In Hospital 30-days 1 year Observed Standardized according to baseline data 2007 5 10 15 20 25

%

  • JAMA. 2011;305(16):1677-1684
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Long-term mortality in STEMI

2.6 years

  • JAMA. 2011;305(16):1677-1684
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Long-term mortality in NSTEMI

1.7 years

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Conclusions

  • Outcome has improved considerably and

mortality has been reduced by almost 50% the last decade

  • With the introduction of new more potent anti

thrombotic agents with a favourable balance between efficacy and safety mortality can be reduced further

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