P2Y12 INHIBITORS



















TRITON TIMI 38 Trial - Clopidogrel vs Prasugrel in Patients with ACS, NEJM (2007) [PubMed abstract]
  • The TRITON TIMI 38 trial enrolled 13,608 patients with an acute coronary syndrome who were scheduled for PCI
Main inclusion criteria
  • Acute coronary syndrome
  • Scheduled for PCI
Main exclusion criteria
  • Increased risk of bleeding
  • Anemia
  • Thrombocytopenia
  • History of pathologic intracranial findings
Baseline characteristics
  • Median age 61 years
  • Unstable angina or NSTEMI - 74% | STEMI - 26%
  • Index procedure: PCI - 99% | CABG - 1%
  • BMS only - 48%, DES - 47%
Randomized treatment groups
  • Group 1 (6813 patients) - Prasugrel 60 mg loading dose followed by 10 mg once daily
  • Group 2 (6795 patients) - Clopidogrel 300 mg loading dose followed by 75 mg once daily
  • All patients also received aspirin 75 - 162 mg once daily throughout the trial
  • Clopidogrel or prasugrel were given for 6 - 15 months
  • Loading dose was given anytime between randomization and 1 hour after PCI
Primary outcome: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
Results

Duration: 15 months
Outcome Prasugrel Clopidogrel Comparisons
Primary outcome 9.9% 12.1% HR 0.81, 95%CI [0.73 - 0.90], p<0.001
Death from cardiovascular causes 2.1% 2.4% HR 0.89, 95%CI [0.70 - 1.12], p=0.31
Nonfatal MI 7.3% 9.5% HR 0.76, 95%CI [0.67 - 0.85], p<0.001
Nonfatal stroke 1.0% 1.0% HR 1.02, 95%CI [0.71 - 1.45], p=0.93
Overall mortality 3.0% 3.2% HR 0.95, 95%CI [0.78 - 1.16], p=0.64
Non-CABG TIMI major bleeding 2.4% 1.8% HR 1.32, 95%CI [1.03 - 1.68], p=0.03
Bleeding requiring transfusion 4.0% 3.0% HR 1.34, 95%CI [1.11 - 1.63], p<0.001
  • The median duration of study drug treatment was 14.5 months
  • In a post-hoc analysis, three subgroups of patients were identified that did not have a net clinical benefit with prasugrel - patients with a history of stroke or TIA, patients ≥ 75 years old, and patients weighing < 60 kg

Findings: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups.
PLATO Trial - Clopidogrel vs Ticagrelor in Patients with ACS, NEJM (2009) [PubMed abstract]
  • The PLATO trial enrolled 18,624 patients with an acute coronary syndrome
Main inclusion criteria
  • Acute coronary syndrome starting within past 24 hours
Main exclusion criteria
  • Fibrinolytic therapy within past 24 hours
  • Need for anticoagulation
  • Increased risk of bradycardia
  • Taking CYP3A4 strong inducer or inhibitor
Baseline characteristics
  • Median age 62 years
  • Qualifying event: STEMI - 38% | NSTEMI - 42% | Unstable angina - 17%
  • Index procedure: PCI - 64% | CABG - 10%
  • Stent type: BMS only - 42% | DES - 18%
Randomized treatment groups
  • Group 1 (9333 patients) - Ticagrelor 180 mg loading dose followed by 90 mg twice a day
  • Group 2 (9291 patients) - Clopidogrel 300 mg loading dose followed by 75 mg once daily
  • All patients also received aspirin 75 - 100 mg once daily throughout the study
Primary outcome: Composite of death from cardiovascular causes, heart attack, or stroke
Results

Duration: 12 months
Outcome Ticagrelor Clopidogrel Comparisons
Primary outcome 9.8% 11.7% HR 0.84, 95%CI [0.77 - 0.92], p<0.001
Death from cardiovascular causes 4.0% 5.1% HR 0.79, 95%CI [0.69 - 0.91], p=0.001
Myocardial infarction 5.8% 6.9% HR 0.84, 95%CI [0.75 - 0.95], p=0.005
Stroke 1.5% 1.3% HR 1.17, 95%CI [0.91 - 1.52], p=0.22
Overall mortality 4.5% 5.9% HR 0.78, 95%CI [0.69 - 0.89], p<0.001
Major bleeding 11.6% 11.2% HR 1.04, 95%CI [0.95 - 1.13], p=0.43
Bleeding requiring transfusion 8.9% 8.9% HR 1.00, 95%CI [0.91 - 1.11], p=0.96
Dyspnea 13.8% 7.8% HR 1.84, 95%CI [1.68 - 2.02], p<0.001
  • The median duration of study drug treatment was 277 days

Findings: In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding.














































  • NOTE: Information on metabolic pathways presented here is from the manufacurer's PI, FDA website, and a handful of published reviews. Other metabolic pathways may exist; therefore, the information is not meant to be all-inclusive.
Metabolism and clearance
Enzyme Clopidogrel Prasugrel Ticagrelor Ticlopidine
CYP1A2 Substrate - - Weak inhibitor
CYP2B6 Substrate
Weak inhibitor
Substrate (primary)
Weak inhibitor
- Weak inhibitor
CYP2C8 Strong inhibitor - - -
CYP2C19 Substrate (primary) Substrate - Strong inhibitor
CYP2C9 Substrate Substrate - -
CYP2D6 - - - Inhibitor
CYP3A4 Substrate Substrate (primary) Substrate (primary) -
P-glycoprotein - - Weak substrate
Inhibitor
-




COGENT trial - Clopidogrel + Omeprazole vs Clopidogrel alone for Secondary Prevention of CVD, NEJM (2010) [PubMed abstract]
  • The COGENT trial enrolled 3873 patients who had an indication for 12 months of clopidogrel therapy
Main inclusion criteria
  • Anticipated therapy with aspirin and clopidogrel for 12 months including patients with acute coronary syndrome and/or stent placement
Main exclusion criteria
  • Medical need for PPI, H₂ antagonist, sucralfate, or misoprostol
  • Erosive esophagitis
  • Previous gastric surgery
  • Recent fibrinolysis
Baseline characteristics
  • Median age 68 years
  • Positive for H. Pylori - 48%
  • Using NSAIDs - 8.6%
  • PCI - 71%
  • MI - 29%
  • Stroke - 7.8%
  • History of GI bleed or ulcer - 4.1%
Randomized treatment groups
  • Group 1 (1876 patients) - Omeprazole 20 mg once daily + clopidogrel 75 mg once daily
  • Group 2 (1885 patients) - Placebo + clopidogrel 75 mg once daily
  • All patients also received enteric coated aspirin 75 - 325 mg once daily
Primary outcomes: The primary cardiovascular endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization (PCI or CABG), or ischemic stroke. The primary gastrointestinal (GI) outcome was a composite of upper GI clinical events (defined as bleeding, ulcer, pain with erosions, obstruction, or perforation)
Results

Duration: Median of 106 days. The trial was stopped early due to loss of funding.
Outcome Omeprazole + clopidogrel Clopidogrel Comparisons
Primary outcome (CV events) 4.9% 5.7% p=0.96
Primary outcome (GI events) 1.1% 2.9% p<0.001

Findings: Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI.