P2Y12 INHIBITORS

• ACRONYMS AND DEFINITIONS

• ACC - American College of Cardiology
• ACS - Acute coronary syndrome (myocardial infarction or unstable angina)
• A fib - Atrial fibrillation
• AHA - American Heart Association
• ASA - Acetylsalicylic acid (aspirin)
• CABG - Coronary artery bypass graft
• CAD - Coronary artery disease
• CVD - Cardiovascular disease (heart attack and stroke)
• DAPT - Dual antiplatelet therapy (aspirin + P2Y12 inhibitor)
• HIT - Heparin induced thrombocytopenia
• MI - Myocardial infarction
• NSTEMI - Non-ST-Elevation Myocardial Infarction
• PAD - Peripheral artery disease
• PPI - Proton pump inhibitor (ex. Prilosec®, Protonix®, Nexium®, Prevacid®, etc.)
• PCI - Percutaneous coronary intervention. Heart cath and associated procedures - stents, angioplasty, etc.
• RCT - Randomized controlled trial
• STEMI - ST-elevation myocardial infarction
• TIA - Transient ischemic attack

• DRUGS IN CLASS

• Thienopyridines
• Clopidogrel (Plavix®)
• Prasugrel (Effient®)
• Ticlopidine (Ticlid®)


• Other
• Ticagrelor (Brilinta®)

• MECHANISM OF ACTION

• Platelets form blood clots when activated
• ADP (adenosine diphosphate) is a chemical released by activated platelets in response to inflammation
• ADP stimulates "P2Y12 receptors" on the surface of other platelets which causes them to become activated and join in the clotting process
• P2Y12 inhibitors block P2Y12 stimulation by ADP and inhibit platelet activation
• Clopidogrel, prasugrel, and ticlopidine irreversibly inhibit P2Y12 receptors, and ticagrelor is a reversible inhibitor
• Illustration of platelet activation

• FDA-APPROVED INDICATIONS

• Clopidogrel (Plavix®)
• Acute Coronary Syndrome (ACS)
• Plavix is indicated to reduce the rate of myocardial infarction and stroke (MI) in patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], including patients who are to be managed medically and those who are to be managed with coronary revascularization. Plavix should be administered in conjunction with aspirin.
• Plavix is indicated to reduce the rate of myocardial infarction and stroke in patients with acute ST-elevation myocardial infarction (STEMI) who are to be managed medically. Plavix should be administered in conjunction with aspirin.
• Recent MI, Recent Stroke, or Established Peripheral Arterial Disease - In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke, Plavix is indicated to reduce the rate of MI and stroke.


• Prasugrel (Effient®)
• Acute Coronary Syndrome (ACS) - to reduce the rate of thrombotic cardiovascular events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention


• Ticagrelor (Brilinta®)
• Acute coronary syndrome or a history of myocardial infarction - ticagrelor is indicated to reduce the risk of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel.
• Coronary artery disease but no prior stroke or myocardial infarction - ticagrelor is indicated to reduce the risk of a first MI or stroke in patients with coronary artery disease at high risk for such events. While use is not limited to this setting, the efficacy of ticagrelor was established in a population with type 2 diabetes mellitus. See THEMIS trial for more.
• Acute ischemic stroke or transient ischemic attack (TIA) - ticagrelor is indicated to reduce the risk of stroke in patients with acute ischemic stroke (NIH Stroke Scale score ≤ 5) or high-risk transient ischemic attack (TIA). See THALES trial for more.


• Ticlopidine (Ticlid®)
• Stroke and TIA - to reduce the risk of thrombotic stroke (fatal or nonfatal) in patients who have experienced stroke precursors, and in patients who have had a completed thrombotic stroke
• Acute coronary syndrome - as adjunctive therapy with aspirin to reduce the incidence of subacute stent thrombosis in patients undergoing successful coronary stent implantation

• ACUTE CORONARY SYNDROME

• 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

• AHA recommendations
• See dosing and drug recommendations for DAPT

• 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].

• SECONDARY PREVENTION OF CVD

• See antiplatelet therapy for the secondary prevention of CVD

• SECONDARY PREVENTION OF STROKE

• See antiplatelet therapy for the secondary prevention of stroke and TIA

• ATRIAL FIBRILLATION

• See antiplatelet therapy in atrial fibrillation

• PERIPHERAL ARTERY DISEASE

• Overview
• Peripheral artery disease is atherosclerotic vessel disease that affects the arteries of the legs and pelvis
• Antiplatelet therapy with either aspirin or clopidogrel is recommended in patients with PAD to help reduce the risk of MI, stroke and vascular death
• The EUCLID trial summarized below compared the effects of ticagrelor to clopidogrel in symptomatic PAD

• STUDY
  EUCLID trial - Clopidogrel vs Ticagrelor in Patients with Symptomatic PAD, NEJM (2017) [PubMed abstract]
• Design: Randomized, controlled trial (N=13,885, length= median 30 months) in patients with symptomatic PAD
• Treatment: Ticagrelor 90 mg twice daily vs Clopidogrel 75 mg once daily. Aspirin was not allowed.
• Primary outcome: First occurrence of any event in the composite of cardiovascular death, myocardial infarction, or ischemic stroke (defined as any stroke not shown to be primarily hemorrhagic)
• Results:
• Primary outcome: Ticagrelor - 10.8%, Clopidogrel 10.6% (p=0.65)
• Major bleeding: Ticagrelor - 1.6%, Clopidogrel 1.6% (p=0.49)
• Findings: In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups.

• 2016 AHA recommendations
• Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD
• In asymptomatic patients with PAD (ABI ≤ 0.90), antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death
• In asymptomatic patients with borderline ABI (0.91 – 0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain
• The effectiveness of dual-antiplatelet therapy (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established
• Dual-antiplatelet therapy (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization [33]

• SIDE EFFECTS

• 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 ticagrelor 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 is typically mild to moderate and 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]

• Central sleep apnea
• Central sleep apnea including Cheyne-Stokes respirations has been reported in the post-marketing setting in patients taking ticagrelor. Symptoms have been shown to recur after stopping and then restarting ticagrelor. Use caution in susceptible patients and consider alternatives if symptoms persist.

• 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 pauses are typically asymptomatic and appear to diminish after 30 days. In a study that compared ticagrelor to clopidogrel, ventricular pauses were seen in 6% of ticagrelor-treated patients and 3.5% of clopidogrel-treated patients during the first month of therapy; after 1 month, rates were 2.2% and 1.6%, respectively. [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 platelet loss and hemolytic anemia. 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]

• CONTRAINDICATIONS

• Clopidogrel (Plavix®)
• Active bleeding
• Known hypersensitivity


• Prasugrel (Effient®)
• Active bleeding
• Prior TIA or stroke (see precautions below)
• Known hypersensitivity


• Ticagrelor (Brilinta®)
• History of intracranial hemorrhage
• Active bleeding
• Known hypersensitivity
• Severe liver disease


• Ticlopidine (Ticlid®)
• Presence of a hemostatic disorder or active pathological bleeding (such as bleeding peptic ulcer or intracranial bleeding)
• Presence of hematopoietic disorders such as neutropenia and thrombocytopenia or a past history of either TTP or aplastic anemia
• Known hypersensitivity
• Severe liver disease

• PRECAUTIONS

• 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)
• Prasugrel is contraindicated in patients with a prior history of stroke or TIA
• In the TRITON TIMI 38 trial, patients with a history of stroke or TIA had a higher rate of stroke on prasugrel when compared to clopidogrel (6.5% vs 1.2%) [13]

• Geriatric (prasugrel)
• Prasugrel is not recommended in patients ≥ 75 years old
• In the TRITON TIMI 38 trial, patients ≥ 75 years old had a higher risk of bleeding compared to those taking clopidogrel [13]

• Low body weight (prasugrel)
• For patients weighing ≤ 60 kg (132 pounds), exposure to prasugrel's active metabolite is increased
• In the TRITON TIMI 38 trial, patients weighing ≤ 60 kg had an increased risk of bleeding
• Consider lowering the maintenance dose to 5 mg a day
• The efficacy and safety of the 5 mg dose has not been studied [13]

• Bradyarrhythmias (ticagrelor)
• Ticagrelor can cause ventricular pauses (see side effects above)
• Patients with sick sinus syndrome, second or third degree AV block, or bradycardia-related syncope may be at increased risk of bradyarrhythmias when taking ticagrelor. Use caution. [18]

• HIT lab interference (ticagrelor)
• Ticagrelor has been reported to cause false negative results on labs used to diagnose heparin induced thrombocytopenia, particularly the heparin-induced platelet aggregation (HIPA) assay
• Ticagrelor should not affect PF4 antibody testing [15]

• STOPPING BEFORE PROCEDURES

• Manufacturer recommendations for stopping P2Y12 inhibitors before surgery or procedures that have a high risk of bleeding:
• Clopidogrel (Plavix®) - stop for at least 5 days
• Prasugrel (Effient®) - stop for at least 7 days
• Ticagrelor (Brilinta®) - stop for at least 5 days
• NOTE: stopping therapy may increase the risk of cardiovascular events


• Professional recommendations
• See periprocedural antithrombotic recommendations

• REVERSING P2Y12 INHIBITORS

• There is no therapy that has been proven to reverse the antiplatelet effects of P2Y12 inhibitors in a clinical trial
• Clopidogrel and prasugrel irreversibly inhibit platelets while ticagrelor is a reversible inhibitor
• Platelet transfusions are often given to patients on clopidogrel and prasugrel because it is plausible that replacing the inactivated platelets with new platelets will restore normal coagulation. Ticagrelor on the other hand, may unbind itself from native platelets and bind the transfused platelets. The ticagrelor PI states that platelet transfusions did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding. [15,28,29,30]
• A monoclonal antibody fragment has been developed that binds ticagrelor. In a phase 1 study of healthy volunteers published in 2019, it immediately and completely reversed the effects of ticagrelor. [PMID 30883047]

• PLATELET FUNCTION MONITORING

• The effects of P2Y12 inhibitors and aspirin on platelet reactivity can vary between individuals
• Assays are available that can measure platelet reactivity (e.g. VerifyNow®) in patients taking P2Y12 inhibitors and/or aspirin
• Theoretically, monitoring platelet reactivity and adjusting the dosage of P2Y12 inhibitors and aspirin based on the results should improve the effectiveness of antiplatelet therapy
• Two large studies have evaluated the effect of platelet function monitoring on outcomes in patients with CAD receiving coronary stents
• The ARCTIC study compared platelet function monitoring to no monitoring in patients (n=2440) undergoing coronary stenting. Patients were treated with aspirin + clopidogrel or prasugrel. Platelet-function monitoring was performed during the first month of treatment and patients with high reactivity received additional doses of medication. The study found no benefit of platelet function monitoring for the composite outcome of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization at one year after stent implantation. [PMID 23121439]
• The ANTARCTIC study compared platelet function monitoring to no monitoring in patients (n=877) aged ≥ 75 years who underwent coronary stenting for acute coronary syndrome. Patients were treated with aspirin + clopidogrel or prasugrel. Platelet-function monitoring was performed during the first month of therapy, and patients with high reactivity had their prasugrel dose increased while patients with low reactivity were switched to clopidogrel. The study found no benefit of platelet function monitoring for the composite outcome of cardiovascular death, myocardial infarction, stroke, stent thrombosis, urgent revascularization, and bleeding after one year of follow-up. [PMID 27581531]
• SUMMARY: There is no evidence that platelet function monitoring improves outcomes in patients receiving antiplatelet therapy for coronary stents

• DRUG INTERACTIONS

• NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.


• All P2Y12 Inhibitors
• Drugs that slow gastric emptying (e.g. opiates, GLP-1 analogs) - drugs that slow gastric emptying may delay the absorption of P2Y12 inhibitors. Consider parenteral antiplatelet agents in acute coronary syndrome.
• Drugs that increase the risk of bleeding - drugs that inhibit coagulation may increase the risk of bleeding when taken with P2Y12 inhibitors
• Drugs that may increase the risk of bleeding include:
• Anagrelide (Agrylin®)
• Aspirin
• Direct thrombin inhibitors (dabigatran)
• Factor Xa inhibitors (e.g. rivaroxaban, apixaban)
• Fish oil (e.g. Vascepa®)
• NSAIDs (e.g. ibuprofen, naproxen)
• SSRIs and SNRIs (e.g. fluoxetine, venlafaxine)
• Vorapaxar (Zontivity®)
• Warfarin (Coumadin®)


• 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
• CYP2C19 inducers - inducers of CYP2C19 may increase exposure to the active metabolite of clopidogrel and increase the risk of bleeding. Clopidogrel should not be given with CYP2C19 strong inducers (e.g. rifampin) and caution should be used when combining with other inducers.
• 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®)
• Aspirin - in the management of patients with ACS, the use of ticagrelor with maintenance doses of aspirin > 100 mg/day decreased the effectiveness of ticagrelor. Aspirin maintenance doses should be 75 - 100 mg/day when taken with ticagrelor.
• 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.

• CLOPIDOGREL AND PPIs

• 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.

• 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.

• Summary
• 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

• CLOPIDOGREL AND POOR CYP2C19 METABOLIZERS

• Overview
• Clopidogrel is a prodrug that must be metabolized by CYP2C19 to become active. The genes that code for the CYP2C19 enzyme (CYP2C19 alleles) can vary between individuals and races (see below). Some alleles decrease the activity of the enzyme (loss-of-function alleles), while others increase its activity (gain-of-function alleles). Theoretically, clopidogrel may not be as effective in patients with loss-of-function alleles.
• Three post-hoc analyses of clopidogrel trials looked at the difference in outcomes between subjects based on their CYP2C19 metabolizer status. Those studies are reviewed below along with a randomized controlled trial that tested patients for a loss-of-function allele and adjusted therapy based on those results.

• Race and metabolizer status
• The most common CYP2C19 loss-of-function alleles are the *2 and *3 variants. One loss-of-function allele leads to a 47% reduction in CYP2C19 activity, and two loss-of-function alleles lead to a 65% reduction. People with one loss-of-function allele are considered "intermediate metabolizers," and people with two loss-of-function alleles are considered "poor metabolizers."
• The prevalence of CYP2C19 alleles among different races is given below
• Prevalence of at least one loss-of-function allele by ethnicity:
• Asians: 51 - 55%
• African-Americans: 33 - 40%
• Caucasians: 24 - 30%
• Mexican-Americans: 18% [22]
• Prevalence of two loss-of-function alleles by ethnicity (poor metabolizers):
• Chinese: 14%
• African-Americans: 4%
• Caucasians: 2% [12]

• STUDY
  TRITON TIMI 38 - Post-hoc Analysis of CYP2C19 Metabolizer Status, NEJM (2009) [PubMed abstract]
• In TRITON TIMI 38 trial, patients with acute coronary syndrome who were to undergo PCI were randomized to clopidogrel or prasugrel
• In the post-hoc analysis, investigators took 1477 patients treated with clopidogrel and tested their blood to see if they were normal CYP2C19 metabolizers or poor CYP2C19 metabolizers
• Differences in the study outcomes were then compared between the two groups
• Results:
• The primary outcome in the TRITON TIMI 38 trial was a composite of death from cardiovascular causes, heart attack, or stroke
• CYP2C19 poor metabolizers had an absolute increase in the primary outcome of 4.1% when compared to normal metabolizers (p=0.01)
• CYP2C19 poor metabolizers had an absolute increase in stent thrombosis of 1.8% when compared to normal metabolizers (p=0.02) [20]
• Findings: Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.

• STUDY
  CURE and ACTIVE A trials - Post-hoc Analysis of CYP2C19 Metabolizer status, NEJM (2010) [PubMed abstract]
• In the CURE trial, patients with acute coronary syndrome were randomized to clopidogrel or placebo
• In the ACTIVE A trial, patients with atrial fibrillation were randomized to clopidogrel or placebo in addition to aspirin
• In the post-hoc analysis, investigators took a total of 5059 patients from CURE and 1156 patients from ACTIVE-A who were treated with clopidogrel and tested their blood to see if they were normal CYP2C19 metabolizers or poor CYP2C19 metabolizers
• The study also compared patients who were "strong metabolizers" of CYP2C19 to normal and poor metabolizers
• Differences in the study outcomes were then compared between the two groups
• Results from CURE trial
• The primary outcome in the CURE trial was a composite of death from cardiovascular causes, heart attack, or stroke
• The effect of clopidogrel in reducing the primary outcome was the same for poor metabolizers and normal metabolizers when compared to placebo
• CYP2C19 strong metabolizers derived more benefit from clopidogrel than patients who were not strong metabolizers [21]
• Results from ACTIVE A trial
• The primary outcome in the ACTIVE-A trial was a composite of stroke, blood clot, heart attack, or vascular death
• The effect of clopidogrel in reducing the primary outcome was the same for poor metabolizers and normal metabolizers when compared to placebo
• CYP2C19 strong metabolizers did not derive more benefit from clopidogrel than patients who were not strong metabolizers [21]
• Findings: Among patients with acute coronary syndromes or atrial fibrillation, the effect of clopidogrel as compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status.

• STUDY
  CHANCE Trial - Post-hoc Analysis of CYP2C19 Metabolizer Status, JAMA (2016) [PubMed abstract]
• In the CHANCE trial, patients with a TIA or minor stroke were randomized to aspirin + clopidogrel or aspirin only for 90 days. The primary outcome was recurrent stroke within 90 days. The study was performed in China where CYP2C19 loss-of-function alleles are more prevalent.
• In the post-hoc analysis, researchers compared outcomes between carriers (n=1726) of loss-of-function alleles and noncarriers (n=1207). Patients were considered carriers if they had ≥ 1 loss-of-function allele.
• Results
• Primary outcome in carriers: Aspirin - 10.8%, Aspirin + clopidogrel - 9.4% (HR 0.93, 95%CI [0.69 - 1.26], p=0.64)
• Primary outcome in noncarriers: Aspirin - 12.4%, Aspirin + clopidogrel - 6.7% (HR 0.51, 95%CI [0.35 - 0.75], p<0.01)
• A significant interaction (p=0.02) was found between carrier status and the primary outcome
• Findings: Among patients with minor ischemic stroke or transient ischemic attack, the use of clopidogrel plus aspirin compared with aspirin alone reduced the risk of a new stroke only in the subgroup of patients who were not carriers of the CYP2C19 loss-of-function alleles. These findings support a role of CYP2C19 genotype in the efficacy of this treatment.

• STUDY
  TAILOR-PCI study - Genotype-guided Therapy vs Clopidogrel in Patients Undergoing PCI, JAMA (2020) [PubMed abstract]
• Design: Randomized, open-label trial (N=5302 | length = 12 months) in patients with ACS or stable CAD who were undergoing PCI
• Treatment: Genotype-guided (patients with CYP2C19*2 or *3 loss of function alleles received ticagrelor, otherwise, they received clopidogrel) vs Clopidorel. All patients received daily aspirin (81 mg).
• Primary outcome: Composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months
• Results:
• Primary outcome: Genotype-guided - 4%, Clopidogrel - 5.9% (p=0.06)
• Stent thrombosis: Genotype-guided - 0.2%, Clopidogrel - 0.9% (p=0.05)
• 29% of patients in genotype-guided group received ticagrelor
• Findings: Among CYP2C19 loss of function carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months.

• Professional recommendations
• FDA
• The FDA placed a "boxed warning" on clopidogrel stating that the effectiveness of clopidogrel is diminished in poor metabolizers. It states that "tests are available to identify patients who are CYP2C19 poor metabolizers" and one should "consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers."
• AHA/ACC
• The AHA/ACC issued a statement in 2010 in regards to clopidogrel and CYP2C19 metabolism (PPI use and poor metabolizers)
• The statement is mostly a review of the available evidence (much of which is contradictory), and offers no real guidance [22]

• Summary
• Results from the three post-hoc analyses above are conflicting while the TAILOR-PCI randomized trial showed a trend towards significantly better outcomes (p=0.06) with genotype-guided therapy. The ethnic makeup in this study was 68% White, 28% Asian, and 3% Black.
• Based on the available evidence, clopidogrel appears to be slightly less effective in CYP2C19 poor metabolizers. Genotype-guided therapy may help improve outcomes, but the effect is likely small, and it is unclear if it is cost-effective.

• LONG TERM SAFETY

• Clopidogrel was approved for use in the U.S. in 1997. Prasugrel was approved in 2009 and ticagrelor in 2011.
• Clopidogrel has been widely prescribed and has a proven safety record. Prasugrel and ticagrelor have less data, but they have been studied in a number of large trials and appear to be safe when used appropriately.

• DOSING

• P2Y12 inhibitor dosing chart

• BIBLIOGRAPHY

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