TRITON-TIMI 38

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Wiviott ST, et al. "Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes". The New England Journal of Medicine. 2007. 357(20):2001-2015.
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Clinical Question

In patients with ACS and scheduled PCI, does prasugrel reduce CV morbidity and mortality when compared to clopidogrel?

Bottom Line

In patients with ACS and scheduled PCI, prasugrel reduces CV morbidity and mortality but increases bleeding when compared to clopidogrel.

Major Points

Clopidogrel's use in ACS was evaluated in CURE (2001), CLARITY-TIMI 28 (2005),[1] and ARMYDA-2 (2005),[2] and remains the standard of care in ACS. Prasugrel, a newer thienopyridine, is thought to have more potent and rapid platelet inhibition with less variability.[3]

TRITON-TIMI 38 randomized 13,608 patients with ACS who were awaiting PCI to usual care plus either prasugrel or clopidogrel. At a mean follow-up of 15 months, the prasugrel group had less CV mortality, non-fatal MI, or non-fatal stroke than the clopidogrel group (9.9% vs. 12.1%). This came at the expense of more non-CABG-related TIMI major bleeding (2.4% vs. 1.8%) and CABG-related TIMI major bleeding (13.4% vs. 3.2%). There was no difference in either CV or all-cause mortality. The authors published a subgroup analysis of STEMI patients that demonstrated a greater relative risk reduction for the same primary outcome (6.5% vs. 9.5%; HR 0.68; 95% CI 0.54-0.87; P=0.0017) without an increased risk of bleeding except for CABG-related TIMI major bleeding.[4]

In contrast to the positive endpoint of TRITON-TIMI 38, TRILOGY ACS (2012)[5] did not demonstrate a risk reduction of a similar primary endpoint with prasugrel in patients with UA/NSTEMI not scheduled for revascularization.

The FDA approved generic versions of clopidogrel in May 2012[6] while prasugrel is sold as a name-brand without a generic alternative.

Guidelines

ACCF/AHA NSTE-ACS (2014, adapted)[7]

  • Aspirin 162-325 mg without enteric coating at presentation then ASA 81-162 mg PO qday continuously, unless aspirin is contraindicated (class I, level A)
    • If aspirin is contraindicated, treat with clopidogrel with a loading dose then a maintenance dose continually (class I, level B)
  • If treated with an early invasive strategy or an ischemia-guided strategy, treat for ≤12 months with clopidogrel or ticagrelor (class I, level B)
    • In this instance, it's reasonable to use ticagrelor over clopidogrel (class IIa, level B)

ACCF/AHA STEMI (2013, adapted)[8]

  • Aspirin 162-325 mg without enteric coating before PCI (class I, level B) then daily (class I, level A) continuously
    • It's reasonable to use aspirin 81 mg as a daily maintenance dose (class IIa, level B)
  • Clopidogrel, prasugrel, or ticagrelor (class I, level B) as early as possible or at time of primary PCI
  • If DES or BMS stent placed during PCI, one year of therapy with clopidogrel, prasugrel, or ticagrelor (class I, level B)

Design

  • Multicenter, double-blind, controlled trial
  • N=13,608
    • Prasugrel (n=6,813)
    • Clopidogrel (n=6,795)
  • Setting: 707 sites in 30 countries
  • Enrollment: 2004-2007
  • Median therapy duration: 14.5 months
  • Analysis: Intention-to-treat
  • Primary outcome: CV mortality, non-fatal MI, or non-fatal CVA

Population

Inclusion Criteria

  • UA or NSTEMI:
    • Ischemic symptoms lasting ≥10 minutes in prior 72 hours
    • TIMI risk score ≥ 3
    • ST deviation ≥1 mm or elevated cardiac enzymes
  • STEMI:
    • Symptoms in prior 12 hours if PCI planned or if within 14 days after PCI if it already occurred
  • Coronary anatomy amenble to PCI

Exclusion Criteria

  • Increased bleeding risk
  • Anemia or thrombocytopenia
  • Intracranial pathology
  • Thienopyridine in prior 5 days

Baseline Characteristics

From the prasugrel group.

  • Demographics: Age 61, female 25%, white race 92%
  • Location: North America 32%, Western Europe 26%, Eastern Europe 24%
  • Health data: BMI 28 kg/m2
  • PMH: HTN 64%, HLD 56%, DM 23%, tobacco use 38%, MI 18%, CABG 8%
  • Procedure performed: PCI 99%, CABG 1%
    • PCI-specific: BMS 48%, DES 47%, multivessel PCI 14%
  • PCI medications: Heparin 66%, LMWH 9%, bivalirudin 3%, other 22%
  • Meds during hospitalization: ACE/ARB 76%, beta-blocker 88%, statin 92%, CCB 18%, ASA 99%, GP IIb/IIIa inhibitor 54%

Interventions

  • Assessment of coronary anatomy if not previously completed
  • Randomization to prasugrel (60 mg loading dose then 10 mg daily) or clopidogrel (300 mg loading dose then 75 mg daily)

Outcomes

Comparisons are prasugrel vs. clopidogrel at 15 months follow-up.

Primary Outcome

CV mortality, non-fatal MI, or non-fatal CVA
9.9% vs. 12.1% (HR 0.81; 95% CI 0.73-0.90; P<0.001; NNT=46)
CV mortality: 2.1% vs. 2.4% (HR 0.89; 95% CI 0.70-1.12; P=0.31)
Nonfatal MI: 7.3% vs. 9.5% (HR 0.76; 95% CI 0.67-0.85; P<0.001)
Nonfatal CVA: 1% vs. 1% (NS)

Secondary Outcomes

All-cause mortality
3.0% vs. 3.2% (HR 0.95; 95% CI 0.78-1.16; P=0.64)
CV mortality, non-fatal MI, urgent target vessel revascularization
10.0% vs. 12.3% (HR 0.81; 95% CI 0.73-0.89; P<0.001)
Definite or probable stent thrombosis in PCI patients
1.1% v.s 2.4% (HR 0.48; 95% CI 0.36-0.64; P<0.001)

Subgroup Analysis

There was no difference in the primary endpoint for UA/NSTEMI vs. STEMI, sex, age, DM, BMS vs. DES, GPIIb/IIIa use, or creatinine clearance.

Adverse Events

Non-CABG-related TIMI major bleeding
2.4% vs. 1.8% (HR 1.32; 95% CI 1.03-1.68; P=0.03; NNH=167)
Spontaneous: 1.6% vs. 1.1% (HR 1.51; 95% CI 1.09-2.08; P=0.01)
Life-threatening: 1.4% vs. 0.9% (HR 1.52; 95% CI 1.08-2.13; P=0.01)
Spontaneous: 0.9% vs. 0.5% (HR 1.78; 95% CI 1.12-2.83; P=0.01)
Fatal: 0.4% vs. 0.1% (HR 4.19; 95% CI 1.58-11.11; P=0.002)
Nonfatal: 1.1% vs. 0.9% (HR 1.23; 95% CI 0.87-1.81; P=0.23)
Intracranial: 0.3% vs. 0.3% (HR 1.12; 95% CI 0.58-2.15; P=0.74)
Major or minor TIMI bleeding
5.0% vs. 3.8% (HR 1.31; 95% CI 1.11-1.56; P=0.002; NNH=84)
Transfusion needed for bleeding
4.0% vs. 3.0% (HR 1.34; 95% CI 1.11-1.63; P<0.001)
CABG-related TIMI major bleeding
13.4% vs. 3.2% (HR 4.73; 95% CI 1.90-11.82; P<0.001; NNH=10)

Criticisms

  • No report of documented stent thrombosis[9]
  • Definition of MI included CKMB ≥2x ULN and may have resulted in more small myocardial infarctions being included in the study[9]
  • More enrollment of elderly patients and those with renal dysfunction may have resulted in increased bleeding rates[10]

Funding

  • Daiichi Sankyo and Eli Lilly, the makers of Effient (prasugrel)
  • Authors with multiple financial ties

Further Reading

  1. Sabatine MS, et al. "Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation." The New England Journal of Medicine. 2005. 352;12:1179-1189.
  2. Patti G, et al. "Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention results from the ARMYDA-2 Study." Circulation. (2005):111;16:2099-2106.
  3. Oprea, AD and Popescu, WM. "P2Y12 Receptor Inhibitors in Acute Coronary Syndromes: What Is New on the Horizon?" Cardiology Research and Practice (2013): 195456.
  4. Montalescot G et al. "Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): Double-blind, randomised controlled trial." The Lancet. 2009;373(9665):60441-60444.
  5. Roe MT et al. "Prasugrel versus clopidogrel for acute coronary syndromes without revascularization." The New England Journal of Medicine. 2012;367:1297-1309.
  6. FDA press release for generic clopidogrel. Accessed 2013-04-28.
  7. Amsterdam EA, et al. "2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes." Journal of the American College of Cardiology. 2014;epublished 2014-09-23. Accessed 2014-09-24.
  8. O'Gara PT, et al. "2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines." Circulation. 2013;127(4):e362-e425.
  9. 9.0 9.1 NEJM letters to the editor
  10. Concurrent editorial