P2Y12 INHIBITORS














Overview
  • Patients with acute coronary syndrome (myocardial infarction or unstable angina) may be treated in 4 different ways: medical therapy, fibrinolysis, PCI, or CABG
  • After acute treatment, it is recommended that patients receive DAPT (P2Y12 inhibitor + ASA) for a period of time. The ideal length of DAPT is controversial (see antiplatelet therapy in CAD for more)
  • In the two studies detailed below, clopidogrel was compared to prasugrel (TRITON TIMI) and ticagrelor (PLATO) in DAPT after ACS
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.
AHA recommendations
Summary
  • In the TRITON TIMI trial, prasugrel prevented more CVD events than clopidogrel, but it provoked more bleeding events. There was no significant difference in overall mortality.
  • In the PLATO trial, ticagrelor was superior to clopidogrel for CVD events and overall mortality, and there was no difference in major bleeding. Another trial that compared ticagrelor to clopidogrel in patients with STEMI who were treated with fibrinolysis found no difference between the two [PMID 30898608].












Clopidogrel (Plavix®)
Bleeding
  • The therapeutic effect of all P2Y12 inhibitors is their ability to prevent blood clotting
  • By this mechanism, they will also increase the risk of unwanted bleeding
  • A person's risk of bleeding on clopidogrel will depend on a number of variables including medical problems, concomitant medications, activity level, and more
  • In the CAPRIE trial, the risk of any bleeding disorder with clopidogrel was 9.3% which was similar to aspirin

Prasugrel (Effient®)
Bleeding
  • The therapeutic effect of all P2Y12 inhibitors is their ability to prevent blood clotting
  • By this mechanism, they will also increase the risk of unwanted bleeding
  • A person's risk of bleeding on prasugrel will depend on a number of variables including medical problems, medications, medical history, activity level, etc.
  • In the TRITON TIMI 38 trial, prasugrel had a significantly higher rate of major bleeding (2.4% vs 1.8%) when compared to clopidogrel [13, 14]

Ticagrelor (Brilinta®)
Bleeding
  • The therapeutic effect of all P2Y12 inhibitors is their ability to prevent blood clotting
  • By this mechanism, they will also increase the risk of unwanted bleeding
  • A person's risk of bleeding on prasugrel will depend on a number of variables including medical problems, medications, medical history, activity level, etc.
  • In the PLATO trial, there was no significant difference in major bleeding events between ticagrelor and clopidogrel (11.6% vs 11.2%) [16]
Shortness of breath (dyspnea)
  • Some patients taking ticagrelor will experience shortness of breath
  • Shortness of breath often resolves with continued treatment
  • In the PLATO trial, 13.8% of patients on ticagrelor experienced shortness of breath compared to 7.8% taking clopidogrel [16]
  • In the PEGASUS trial, 19% of patients taking ticagrelor 90 mg complained of shortness of breath compared to 6.4% of patients taking placebo [31]
Ventricular pause
  • Ventricular pause is a condition where there is a longer than normal amount of time between ventricular contractions
  • Ticagrelor increases the incidence of these pauses. The effect appears to be from an undefined action on the sinoatrial node. [17]
  • The effect appears to diminish after 30 days
  • The pauses do not typically cause symptoms [16]
  • Patients with certain heart conditions (see bradyarrhythmias below) should use caution when taking ticagrelor
Increase in serum uric acid
  • Ticagrelor causes a slight increase in uric acid levels
  • In the PLATO study, uric acid levels increased by 0.6 mg/dl from baseline in the ticagrelor group (clopidogrel group increase 0.2 mg/dl)
  • There was no difference in reports of gout between the two groups [15]
Increase in serum creatinine
  • Ticagrelor may cause an increase in serum creatinine levels
  • In the PLATO study, 7.4% of patients had an increase of > 50% in their serum creatinine level compared to 5.9% of patients taking clopidogrel [15]
  • There was no difference in renal outcomes between the two groups

Ticlopidine (Ticlid®)
Bleeding
  • The therapeutic effect of all P2Y12 inhibitors is their ability to prevent blood clotting
  • By this mechanism, they will also increase the risk of unwanted bleeding
  • A person's risk of bleeding on ticlopidine will depend on a number of variables including medical problems, concomitant medications, activity level, and more
Neutropenia
  • One of the main reasons ticlopidine is no longer widely used is because of the risk of neutropenia (decreased neutrophils in blood)
  • Neutropenia may occur in 2-3% of patients taking ticlopidine
  • The manufacturer recommends monitoring blood counts every 2 weeks through the first 3 months of therapy [18]
Thrombotic Thrombocytopenic Purpura (TTP)
  • Ticlopidine has been associated with TTP, a serious condition that causes a decrease in platelets
  • The incidence of ticlopidine-induced TTP is unknown
  • The manufacturer recommends monitoring blood counts every 2 weeks through the first 3 months of therapy [18]
Diarrhea
  • Ticlopidine may cause diarrhea (12.5% of patients on ticlopidine vs 4.5% on placebo) [18]
Stomach upset
  • Ticlopidine may cause stomach upset (7.0% of patients) [18]
Rash
  • Ticlopidine may cause a rash (5.1% of patients) [18]





Kidney disease
Clopidogrel (Plavix®)
  • Severe kidney disease (CrCl 5 - 15 ml/min): drug effect is reduced. Manufacturer makes no specific dosage recommendation
  • Moderate kidney disease (CrCl 30 - 60 ml/min): drug effect is reduced. Manufacturer makes no specific dosage recommendation [12]
Prasugrel (Effient®)
  • No dose adjustment is necessary in kidney disease [13]
Ticagrelor (Brilinta®)
  • No dose adjustment is necessary in kidney disease
  • Has not been studied in dialysis patients [15]
Ticlopidine (Ticlid®)
  • Mild kidney disease (CrCl 60 - 89 ml/min): No dose adjustment necessary
  • Moderate-to-severe kidney disease: Ticlopidine has not been studied extensively. Manufacturer makes no specific dosage recommendations [18]

Liver disease
Clopidogrel (Plavix®)
  • No dosage adjustment is necessary in patients with liver disease
  • NOTE: Patients with significant liver disease may be at increased risk of bleeding. See coagulopathy of liver disease. [12]
Prasugrel (Effient®)
  • Child-Pugh A/B: No dosage adjustment necessary
  • Child-Pugh C: Has not been studied
  • NOTE: Patients with significant liver disease may be at increased risk of bleeding. See coagulopathy of liver disease. [12]
Ticagrelor (Brilinta®)
  • No dosage adjustment is necessary in patients with mild liver disease
  • Ticagrelor has not been studied in patients with moderate-to-severe liver disease
  • Ticagrelor should not be used in severe liver disease
  • NOTE: Patients with significant liver disease may be at increased risk of bleeding. See coagulopathy of liver disease. [15]
Ticlopidine (Ticlid®)
  • Ticlopidine should not be used by patients with severe liver disease
  • In mild-to-moderate liver disease, drug dose may need to be adjusted
  • The manufacturer makes no specific dosage recommendations [18]
  • NOTE: Patients with significant liver disease may be at increased risk of bleeding. See coagulopathy of liver disease.

History of stroke or TIA (prasugrel)

Geriatric (prasugrel)

Low body weight (prasugrel)

Bradyarrhythmias (ticagrelor)

HIT lab interference (ticagrelor)








All P2Y12 Inhibitors

Clopidogrel (Plavix®)

  • Bupropion (Wellbutrin®) - clopidogrel inhibits CYP2B6 which can lead to elevated bupropion levels. When taken together, doses of bupropion may need to be decreased.
  • CYP2C19 inhibitors - see clopidogrel and CYP2C19 below
  • CYP2C8 substrates - the acyl-β-glucuronide metabolite of clopidogrel is a CYP2C8 strong inhibitor. Clopidogrel may increase exposure to CYP2C8 substrates.
  • Omeprazole (Prilosec®) and esomeprazole (Nexium®) - DO NOT COMBINE with clopidogrel. See clopidogrel and PPIs below
  • Repaglinide (Prandin®) - repaglinide is a sensitive CYP2C8 substrate. Clopidogrel increases repaglinide exposure by 4 - 5 fold. Repaglinide should not be given with clopidogrel. If concomitant use cannot be avoided, initiate repaglinide at a dose of 0.5 mg before each meal and titrate based on blood sugars. Do not exceed 4 mg/day. When clopidogrel is added to repaglinide, repaglinide doses should be reduced to no more than 4 mg/day.

Ticagrelor (Brilinta®)

  • CYP3A strong inhibitors and inducers - ticagrelor should not be taken with strong CYP3A4 inhibitors or inducers
  • Digoxin - ticagrelor may increase digoxin levels. Monitor levels when starting concurrent therapy.
  • Lovastatin (Mevacor®) - ticagrelor may cause higher blood levels of lovastatin. The manufacturer recommends the lovastatin dose not exceed 40 mg when taken with Ticagrelor
  • Simvastatin (Zocor®) - ticagrelor may cause higher blood levels of simvastatin. The manufacturer recommends the simvastatin dose not exceed 40 mg when taken with Ticagrelor

Ticlopidine (Ticlid®)

  • Bupropion (Wellbutrin®) - ticlopidine inhibits CYP2B6 which can lead to elevated bupropion levels. When taken together, doses of bupropion may need to be decreased.
  • Phenytoin (Dilantin®) - ticlopidine may raise phenytoin levels. Monitor levels when starting concurrent therapy.

  • 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		 -


Overview
  • Clopidogrel (Plavix®) is a prodrug which means it must be metabolized by the body before it becomes active. The enzyme that converts clopidogrel to its active metabolite is CYP2C19.
  • If CYP2C19 is inhibited by another drug, or if a person has weak CYP2C19 enzymes (poor metabolizer), then clopidogrel may not be metabolized extensively, and its effectiveness may be attenuated
  • Some widely prescribed medications, namely proton pump inhibitors (Prilosec®, Nexium®), inhibit CYP2C19
  • PPIs are often prescribed with clopidogrel because they decrease the risk of bleeding from aspirin and/or clopidogrel
  • The COGENT trial detailed below looked at the effect of taking omeprazole (Prilosec®) with clopidogrel on clinical outcomes. Omeprazole is a moderate CYP2C19 inhibitor that is widely used.
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, Hâ‚‚ 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.
Professional recommendations
  • The clopidogrel PI states that clopidogrel should not be taken with omeprazole or esomeprazole. It goes on to state that dexlansoprazole (Dexilant®), lansoprazole (Prevacid®), and pantoprazole (Protonix®) had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole.
StraightHealthcare analysis
  • The clopidogrel PI recommends against using omeprazole or esomeprazole with clopidogrel, although the only randomized controlled trial to look at the issue found no effect of omeprazole on the efficacy of clopidogrel
  • Since there are a number of cheap PPIs now available, it seems prudent to avoid omeprazole and esomeprazole when taking clopidogrel