PLATO

From Wiki Journal Club
Jump to: navigation, search
Wallentin L, et al. "Ticagrelor versus clopidogrel in patients with acute coronary syndromes". The New England Journal of Medicine. 2009. 361(11):1045-1057.
PubMedFull textPDF

Clinical Question

In patients with acute coronary syndrome, does ticagrelor have an advantage over clopidogrel preventing major CV events?

Bottom Line

Compared to clopidogrel, ticagrelor significantly reduced the rate of CV death, MI, or stroke without an increase in the rate of overall major bleeding.

Major Points

The thienopyridines clopidogrel (CURE; 2001) and prasugrel (TRITON-TIMI 38; 2007) irreversibly inhibit platelets through P2Y12 ADP receptor blockade and reduce CV outcomes in ACS. The irreversible effects of both thienopyridines is thought to account for the increased bleeding from major surgical procedures including CABG,[1] and thus investigators sought an antiplatelet agent with different pharmacokinetics. Ticagrelor is a nucleoside analogue acts via reversible inhibition of ADP receptors. It has a more rapid onset, more potent platelet inhibition, and more predictable pharmacodynamics,[1] although its clinical utility had not yet been established.

The 2009 Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18,624 patients with ACS (37.5% with STEMI) to ticagrelor or clopidogrel, in addition to standard care. At 12 months, the ticagrelor group had lower rates of CV death, MI, or stroke than clopidogrel (9.8% vs. 11.7%) and all-cause mortality (4.5% vs. 5.9%). While there was no difference in major bleeding, ticagrelor was associated with more non-CABG-related bleeding (4.5% vs. 3.8%). The ticagrelor group experienced a higher rate of dyspnea (13.8% vs. 7.8%) and a trend towards more bradycardia (4.4% vs. 4.0%), likely due to ticagrelor's close resemblance to adenosine.[2]

Guidelines

ACCF/AHA NSTE-ACS (2014, adapted)[3]

  • 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)[4]

  • 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, randomized trial
  • N=18,624 patients admitted to the hospital with ACS
    • Clopidogrel (n=5,128)
    • Ticagrelor (n=5,123)
  • Setting: 862 centers in 43 countries
  • Enrollment: 2001-2005
  • Mean follow-up: 3.5 years
  • Analysis: Intention-to-treat
  • Primary outcome: Composite of CV death, MI, or stroke

Population

Inclusion Criteria

ACS hospitalization with symptom onset <24 hours prior If ST-elevations on EKG, must have both of the following:

  • ST-segment elevations ≥0.1 mV in ≥2 contiguous leads or new LBBB
  • Plan for primary PCI

If no ST-elevations on EKG, at least 2 of 3 of the following:

  • ST changes on EKG indicative of ischemia
  • Elevated cardiac biomarkers indicating necrosis
  • One of several risk factors:
    • ≥60 years
    • previous MI or CABG
    • CAD with ≥50% stenosis in ≥2 vessels
    • previous ischemic stroke, TIA, carotid stenosis of ≥50%, or cerebral revascularization
    • diabetes mellitus
    • peripheral arterial disease
    • CrCl <60 ml/min/1.73 m2

Exclusion Criteria

  • Contraindication for clopidogrel
  • Fibrinolysis in prior 24 hours
  • Need for oral anticoagulation
  • Risk of bradycardia
  • CYP3A inhibitor or inducer use

Baseline Characteristics

  • Demographics: Age 62 years, female 28.4%
    • Race: White 91.8%, Black 1.2%, Asian 5.8%
  • Health data: BMI 27 kg/m2
  • CV risk factor: Smoker 36.0%, HTN 65.8%, HLD 46.6%, DM 24.9%
  • PMH: MI 20.4%, HF 5.5%, non-hemorrhagic stroke 3.8%, PAD 6.1%, CKD 4.1%, dyspnea 15.1%, COPD 5.9%, asthma 2.9%, gout 2.9%
  • PSH: PCI 13.6%, CABG 5.7%
  • EKG findings: Persistent ST-elevations 37.5%, ST depression 50.7%, TWI 31.8%
  • ACS type: STEMI 37.5%, NSTEMI 42.9%, UA 16.6%
  • STEMI risk: Kilip class >2: 0.7%, TIMI risk ≥3
  • NSTEMI risk: Positive troponin I 79.5%, ST depression >0.1 mV 56.6%, TIMI risk ≥5
  • Positive troponins 85.3%

Interventions

  • Randomization to a group:
    • Ticagrelor - Ticagrelor 180 mg loading dose then 90 mg bid
    • Clopidogrel - Clopidogrel 300 mg loading dose then 75 mg daily (no loading dose if already on the medication)
  • If PCI then an additional dose of their study drug during the procedure (clopidogrel 300 mg at the discretion of the investigator or ticagrelor 90 mg if >24 hours after randomization)
  • If planning CABG, study medication withheld for 5 days if clopidogrel or 24-72 hours if ticagrelor
  • All patients received ASA 325 mg loading dose then 75-100 mg daily (no loading dose if already on the medication, 325 mg daily for 6 months optional choice after stent placement)

Outcomes

Presented as ticagrelor vs. clopidogrel.

Primary Outcomes

Vascular mortality, MI, or CVA
9.8% vs. 11.7% (HR 0.77-0.92; P<0.001)
Major bleeding (study criteria)
11.6% vs. 11.2% (HR 1.04; 95% CI 0.95-1.13; P=0.43)

Secondary Outcomes

All-cause mortality, MI, or CVA
10.2% vs. 12.3% (HR 0.84; 95% CI 0.77-0.92; P<0.001)
Vascular mortality, MI, stroke, recurrent severe ischemia, recurrent ischemia, TIA, or other arterial thrombotic event
14.6% vs. 16.7% (HR 0.88; 95% CI 0.81-0.95; P<0.001)
Components of the primary outcome
MI: 5.8% vs. 6.9% (HR 0.84; 95% CI 0.75-0.95; P<0.005)
Vascular mortality: 4.0% vs. 5.1% (HR 0.79; 95% CI 0.69-0.91; P<0.001)
CVA: 1.5% vs. 1.3% (HR 1.17; 95% CI 0.91-1.52; P=0.22)
Ischemic CVA: 1.1% vs. 1.1% (P=0.74)
Hemorrhagic CVA: 0.2% vs. 0.1% (P=0.10)
Unknown CVA type: 0.1% vs. 0.02% (P=0.04)
Planned invasive treatment: 8.9% vs. 10.6% (HR 0.84; 95% CI 0.75-0.94; P=0.003)
First 30 days: 4.8% vs. 5.4% (HR 0.88; 95% CI 0.77-1.00; P=0.045)
Days 31-360: 5.3% vs. 6.6% (HR 0.80; 95% CI 0.70-0.91; P<0.001)
All-cause mortality
4.5% vs. 5.9% (HR 0.78; 95% CI 0.69-0.89; P<0.001)
Non-vascular mortality
0.5% vs. 0.8% (HR 0.71; 95% CI 0.49-1.04; P=0.08)
Recurrent ischemia
Severe: 3.5% vs. 4.0% (HR 0.87; 95% CI 0.74-1.01; P=0.08)
Any: 5.8% vs. 6.2% (HR 0.93; 95% CI 0.82-1.05; P=0.22)
Other arterial thrombotic event
0.2% vs. 0.4% (HR 0.61; 95% CI 0.34-1.08; P=0.09)
Stent thrombosis (those who received a stent)
Definite: 1.3% vs. 1.9% (HR 0.67; 95% CI 0.50-0.91; P=0.009)
Probable or definite: 2.2% vs. 2.9% (HR 0.75; 95% CI 0.59-0.95; P=0.02)
Possible, probable, or definite: 2.9% vs. 3.8% (95% CI 0.77; 95% CI 0.62-0.95; P=0.01)

Adverse Events

Bleeding
Major Bleeding (TIMI criteria): 7.9% vs. 7.7% (HR 1.03; 95% CI 0.93-1.15; P=0.57)
Major bleeding (study criteria): 11.6% vs 11.2% (HR 1.04; 95% CI 0.95-1.13; P=0.43)
Requiring RBC transfusion: 8.9% vs. 8.9% (HR 1.00; 95% CI 0.91-1.11; P=0.96)
Life-threatening or fatal: 5.8% vs. 5.8% (HR 1.03; 95% CI 0.90-1.16; P=0.70)
Fatal: 0.3% vs. 0.3% (HR 0.87; 95% CI 0.48-1.59; P=0.66)
Non-intracranial fatal: 0.1% vs. 0.3% (HR and CI not given; P=0.03)
Intracranial: 0.3% vs. 0.2% (HR 1.87; 95% CI 0.98-3.58; P=0.06)
Fatal: 0.1% vs. 0.01% (HR and CI not given; P=0.02)
Non-fatal: 0.2% vs. 0.2% (HR and CI not given; P=0.69)
CABG vs non-CABG related
CABG (TIMI Criteria): 5.3% vs 5.8% (HR 0.94; 95% CI 0.82-1.07; P=0.32)
CABG (Study Criteria): 7.4% vs 7.9% (HR 0.95; 95% CI 0.85-1.06; P=0.32)
non-CABG (TIMI Criteria): 2.8% vs 2.2% (HR 1.25; 95% CI 1.03-1.53; P=0.03)
non-CABG (Study Criteria): 4.5% vs 3.8% (HR 1.19; 95% CI 1.02-1.38; P=0.03)
Dyspnea
13.8% vs. 7.8% (HR 1.84; 95% CI 1.68-2.02; P<0.001)
Requiring discontinuation: 0.9% vs. 0.1% (P<0.001)
Bradycardia
4.4% vs. 4.0% (P=0.21)
Syncope: 1.1% vs. 0.8% (P=0.08)
PPM placement: 0.9% vs. 0.9% (P=0.87)
Heart block: 0.7% vs. 0.7% (P=1.00)
Ventricular pauses on holter monitoring
Week 1, ≥3 seconds: 5.8% vs. 3.6% (P=0.01)
Week 1, ≥5 seconds: 2.0% vs. 1.2% (P=0.10)
Day 30, ≥3 seconds: 2.1% vs. 1.7% (P=0.52)
Day 30, ≥5 seconds: 0.8% vs. 0.6% (P=0.60)
Serum uric acid
Month 1: +14% vs. +7% (P<0.001)
Year 1: +15% vs. +7% (P<0.001)
Creatinine
Month 1: +10% vs. +8% (P<0.001)
Year 1: +11% vs +9% (P<0.001)

Criticisms

  • Lower rate of bolusing with the intervention medication in PCI with the clopidogrel group may have introduced bias to the results[2]
  • Since almost half of the patients were on clopidogrel at baseline, this trial may have involved clopidogrel non-responders[2]
  • High rate of CABG-related major bleeding[2]
  • High rate of transfusion in the clopidogrel group[2]

Funding

Supported by AstraZeneca, manufacturers of Brilinta, the brand name of ticagrelor.

Further Reading

  1. 1.0 1.1 Schomig A. "Editorial: Ticagrelor -- Is there a need for a new player in the antiplatelet-therapy field?" The New England Journal of Medicine. 2009;361:1108-1111.
  2. 2.0 2.1 2.2 2.3 2.4 Tomoda H. "Correspondence: Ticagrelor versus clopidogrel in acute coronary syndromes." The New England Journal of Medicine. 2009;361(24):2385.
  3. 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.
  4. 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.