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Kenneth W. Mahaffey, MD, on behalf of the TRACER Investigators and Committees . Vorapaxar, a Platelet Thrombin Receptor Antagonist, in Acute Coronary Syndromes. Trial funded by Merck Complete financial disclosures: www.DCRI.org. Background. Platelet. Vorapaxar : First-in-class - PowerPoint PPT Presentation
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Kenneth W. Mahaffey, MD, on behalf of the TRACER Investigators and Committees
Vorapaxar, a Platelet Thrombin Receptor Antagonist, in Acute Coronary Syndromes
Trial funded by MerckComplete financial disclosures: www.DCRI.org
• Vorapaxar: First-in-class Oral PAR-1
inhibitor• Metabolism:
Primarily hepatic via CYP 3A4
Terminal half-life:
~126–269 hrs• Prior trials:
No increase in bleeding and fewer MIs
Background
Chackalamannil S, J Med Chem, 2006
Platelet
PAR-4
TBX A2TBXA2-R
Thrombin
Anionicphospholipidsurfaces
GP IIb/IIIa
ADP P2Y12
PAR-1
ClopidogrelPrasugrelTicagrelorCangrelor
ASA
Vorapaxar
Trial Design
1:1RandomizedDouble-blind
NSTE Acute Coronary Syndromes
Vorapaxar Loading: 40 mg
Maintenance: 2.5 mg daily
Placebo
Follow-up: 1, 4, 8, 12 months, then every 6 monthsStandard of care based on practice guidelines
Key inclusion criteria• Within 24 hrs of symptoms• biomarkers or ECG changes• 1 other high-risk feature
Efficacy Endpoints Primary: CV death, MI, stroke, hospitalization for ischemia, urgent revascularization Key Secondary: CV death, MI, strokeBleeding Endpoints: GUSTO moderate or severe and clinically significant TIMI bleeding
Statistical Considerations
• Sample size Event-driven with estimated 15% reduction Power:
• 1900 primary endpoint events >95% • 1457 key secondary endpoint events ≥90%
12,500 patients• Analysis
Efficacy analyses: intention-to-treat Bleeding analyses: all subjects with ≥1 dose and on drug Hierarchical testing procedure to control overall
type 1 error• January 8, 2011: DSMB recommended to stop follow-up
in the trial
Enrollment37 countries, 818 sites, 12,944 patients
Canada: 591
United States: 2772
Finland: 119
Denmark: 205
Hungary: 266
Netherlands: 471
Sweden: 346Norway: 251
U.K.: 463
Belgium: 153
France: 441Spain: 379
Austria: 319Italy: 764
Israel: 410
Poland: 561
Czech Rep: 496
Chile: 148
Peru: 11
Colombia: 275
Brazil: 284
Argentina: 130
South Africa: 207
China: 219South Korea: 127
Taiwan: 219
Malaysia: 52Singapore: 26
Australia: 235
Germany: 911Japan: 276
Turkey: 164
Hong Kong: 17
New Zealand: 195
Portugal: 189
Switzerland: 211
Puerto Rico: 41
Study Conduct
Placebo(N=6471)
Vorapaxar(N=6473)
Did not receive treatment (%) 30 (0.5) 27 (0.4)
Discontinued treatment (%) 1726 (27) 1818 (28)
Treatment duration (days) 393 (236, 588) 379 (231, 585)
Follow-up duration (days) 503 (348, 667) 500 (349, 668)
Lost to follow-up (%) 8 (0.1) 7 (0.1)
Median (IQR)
Baseline Demographics
Placebo(N=6471)
Vorapaxar(N=6473)
Age, yrs 64 (58, 72) 64 (58, 71)
Female sex, % 28 28
Region of enrollment, %North AmericaSouth AmericaWestern EuropeEastern EuropeAsiaAustralia/New Zealand
267451273
267
451273
Diabetes mellitus, % 31 32
Prior MI, % 29 29
Positive troponin or CK-MB, % 94 94
Antiplatelet agents, %AspirinThienopyridine
9787
9688
Median (IQR)
Index Hospitalization Procedures
Placebo(N=6471)
Vorapaxar(N=6473)
Hospital presentation to randomization (hrs) 21 (12, 41) 21 (12, 41)
Symptom onset to randomization (hrs) 27 (8, 50) 27 (18, 49)
Cardiac catheterization, % 88 88
PCI, %Loading dose of study drug to PCI (hrs)
Drug-eluting stent, %Bare metal stent, %
574 (2, 21)
5846
584 (2, 21)
5649
CABG, % 10 10
Median (IQR)
Primary EndpointCV Death, MI, Stroke, Hospitalization for Ischemia, Urgent Revascularization
No. at riskPlacebo 6471 5844 5468 5121 3794 2291 795Vorapaxar 6473 5897 5570 5199 3881 2318 832
HR (95% CI): 0.92 (0.85, 1.01)P-value= 0.072
Placebo Vorapaxar2-year KM rate 19.9% 18.5%
Key Secondary EndpointCV Death, MI, Stroke
No. at riskPlacebo 6471 5895 5575 5263 3922 2383 830Vorapaxar 6473 5949 5684 5356 4023 2427 868
HR (95% CI): 0.89 (0.81, 0.98)P-value= 0.018
Placebo Vorapaxar2-year KM rate 16.4% 14.7%
Selected Efficacy Outcomes Placebo
(N=6471)Vorapaxar(N=6473)
2-yrKM rate (%)
2-yrKM rate (%) HR (95% CI) P-value
Primary endpoint 19.9 18.5 0.92 (0.85–1.01) 0.072
CV death 3.8 3.8 1.00 (0.83–1.22) 0.96
MI 12.5 11.1 0.88 (0.79–0.98) 0.021
Stroke 2.1 1.9 0.93 (0.70–1.23) 0.61
Hospitalization for ischemia
1.5 1.6 1.14 (0.83–1.58) 0.42
Urgent revascularization
3.5 3.8 1.07 (0.88–1.31) 0.49
Stent Thrombosis* 1.5 1.7 1.12 (0.78–1.62) 0.54
All-cause mortality 6.1 6.5 1.05 (0.90–1.23) 0.52
*ARC definite or probable; data are proportions of patients
Bleeding Endpoints Placebo
(N=6441) Vorapaxar(N=6446)
2-yr KM rate (%)
2-yr KM rate (%) HR (95% CI) P-value
GUSTO moderate or severe
5.2 7.2 1.35 (1.16–1.58) <0.001
Clinically significant TIMI
14.6 20.2 1.43 (1.31–1.57) <0.001
GUSTO severe 1.6 2.9 1.66 (1.27–2.16) <0.001
TIMI major 2.5 4.0 1.53 (1.24–1.90) <0.001
Fatal 0.15 0.35 1.89 (0.80–4.45) 0.15
Intracranial hemorrhage 0.24 1.07 3.39 (1.78–6.45) <0.001
CABG-related TIMI major*
7.3 9.7 1.34 (0.92–1.95) 0.13
* data are proportions of patients
ICH
Bleeding OutcomesGUSTO Moderate/Severe
No. at risk6441 5536 5137 4674 3393 1972 6506446 5529 5108 4598 3278 1883 625
HR (95% CI): 1.35 (1.16, 1.58)P-value <0.001
Placebo Vorapaxar
2-year KM rate 5.2% 7.2%
No. at risk6441 5673 5281 4823 3511 2038 6786446 5694 5272 4760 3411 1965 657
HR (95% CI): 3.39 (1.78, 6.45)P-value <0.001
Placebo Vorapaxar
2-year KM rate 0.24% 1.07%
SubgroupsGUSTO Moderate/Severe
Placebo better
Vorapaxar better
Primary Endpoint
Placebo better
Vorapaxar better
Summary
When added to standard of care in patients with NSTE ACS and high use of aspirin and P2Y12 inhibition, vorapaxar:
• Did not significantly reduce the composite of CV death, MI, stroke, hospitalization for ischemia, or urgent revascularization
• Reduced CV death, MI, or stroke
• Significantly increased bleeding, including major bleeding and intracranial hemorrhage
Whether PAR-1 blockade improves outcomes with different medication strategies or in other patient populations with coronary artery disease requires further study.
Executive CommitteeR Harrington (Chair), P Armstrong, P Aylward,
E Chen, K Mahaffey, D Moliterno, J Strony, F Van de Werf, L Wallentin, H White
Data & Safety Monitoring BoardF Verheugt (Chair), R Frye, J Hochman,
P Steg, K Bailey, J Easton
CECA Johnson J O’ BriantM Smith P Tricoci
Academic Research Organizations
DCRI: P Tricoci, T Rorick, S Leonardi, D Underwood, J Wrestler
CVC: P Armstrong, C SorochuckC5: A Lincoff, D Mason
Henry Ford: M Hudson, D SydlowskiThomas Jefferson: D Whellan,
B Gallagher Flinders: P Aylward, J Garrett
Green Lane: H White, S DouglasLeuven: P Sinnaeve, A Beernaert
SponsorMerck: E Chen, R Harmelin–Kadouri,
A Kilian, S Petrauskas, J Strony
Core LabECG: P Armstrong, H Siha
Platelets: L Jennings, E HordAngio: M Gibson, A Chirlin
Study Organization
Steering CommitteeG Ambrosio, A Betriu, C Bode, A Cequier,
T Cheem, M Chen, J Cornel, A Dalby, R Diaz, A Erkan, P Grande, C Held, K Huber,
M Hudson, Y Huo, D Isaza, J Jukema, M Laine, B Lewis, A Lincoff, J Lixin, G Montalescot,
J Nicolau, J Nordrehaug, P Ofner, H Ogawa,S Park, M Pfisterer, J Prieto, L Providencia,W Ruzyllo, P Sinnaeve, R Storey, P Tricoci,
M Valgimigli, D Whellan, P Widimsky, L Wong, T Yamaguchi
The full article is now available online at www.nejm.org
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