Clopidogrel (Plavix)

Clopidogrel is an oral antiplatelet agent which selectively and irreversibly inhibits the platelet ADP receptor.

It inhibits platelet adenosine diphosphate P2Y12 receptor.

Metabolite directly inhibits P2Y12 on of the two types of ADP receptors found on platelets.

Most widely prescribed P2Y12 platelet receptor inhibitor.

An oral thienopyridine derivative.

An irreversible thienopyridine prodrug inhibiting the P2Y12 subtype of adenosine diphosphate receptors critical for platelet activation.

A prodrug that must be metabolized to 2-oxoclopidrogrel, its active form.

It is transformed into its active metabolite by hepatic cytochrome P450 enzymes.

It is an inactive prodrug that partially depends on CYP2C19 for conversion to its active form; inhibition of CYP2C19 blocks the activation of clopidogrel, thus reducing its effects.

The active metabolite irreversibly inhibits the P2Y12 receptors on platelets which results in inhibition of platelet aggregation.

The main pathway for activation is through the cytochrome P4 50 (CYP) pathway mainly through CYP 2C19.

Caution is  used when employed with poor metabolizes of hepatic cytochrome P450 enzyme because it is a pro drug and needs to be biotransformed to an active metabolite by CYPC19.
Clopidogrel is less effective with the secondary prevention of stroke in carriers of the CYP2C19 loss of function alleles.

Optimum use requires a loading dose about 2 hours before PCI.

Loading doses, however, have problems: PCI may not be needed after coronary angiogram, possible delay in surgery until platelet function returns to baseline and exposing patients to increased bleeding risks.

In a meta-analysis among patients scheduled for PCI, clopidogrel pretreatment was not associated with a lower risk of mortality but was associated with a low risk of major coronary events (Bellemain-Appaix A et al).

Approximately 30% of white patients have an in adequate response to clopidogrel as measured with platelet function tests.

With this variation results to genetic variations in the CYP2C19-2 or 3 loss of function alleles.

Without these variations clopidogrel shows similar efficacy to that of ticagrelor (Brilinta) and Prasugrel (Effient).

In the above study there was no significant association between pretreatment and major bleeding overall.

In the above study of more than 37,000 patients there was no significant association between clopidogrel pretreatment and survival nor between clopidogrel pretreatment and major bleeding.

The above meta-analysis demonstrated a significant association between clopidogrel pretreatment in the reduction of major coronary events or myocardial infarction in the primary analysis.

Has a delayed onset of action, even after a loading dose, and it does not provide complete ADP receptor inhibition and has substantial variability of effectiveness among patients.

In many instances this agent is not given before angiographic definition of coronary anatomy, since it is an irreversible platelet inhibitor associated with increased risk of perioperative bleeding if coronary artery bypass graft is required rather than PCI.

In the Gauging Responsiveness with A Verify Now assay-Impact on Thrombosis And Safety (GRAVITAS) trial a double-blind study of 2214 patients with high on-treatment platelet reactivity 12-24 hours after PCI with the drug eluting stents: high dose clopidogral versus standard dose clopidogrel (Price MJ et al).

In the GRAVITAS trial the primary endpoint was the six-month incidence of death from cardiovascular causes, nonfatal myocardial infarction or stent thrombosis: the primary endpoint. In 2.3% of the patients receiving high dose clopidogrel vs 2.3% in the standard dose group suggesting that among patients with high on-treatment reactivity of platelets after PCI with drug eluting stains the dose of clopidogrel did not matter.

Combined with aspirin considered essential for intracoronary stent thrombosis prophylaxis.

Blocks activation of adenosine diphosphate by irreversibly binding to the ADP receptors of platelets and prevents the ADP-dependent activation of glycoprotein IIb/IIIa complex.

Wide individual variability exists in the concentration of the active metabolite and in the magnitude of platelet inhibition achieved by loading and maintenance doses.

Variability to the platelet inhibition effect is due somewhat to genetic polymorphisms that affect the activity of the CYP2C19 enzyme, but most is not explained by genotype or other clinical characteristics.

This may result in a loss of function of the CYP2C19 enzyme resulting in higher platelet reactivity with clopidogrel and associated higher incidence of major adverse cardiovascular and several vascular events.

Use of aspirin or clopidogrel as first-line treatment after an initial TIA or stroke.

Preferred in patients with aspirin intolerance.

Reduces ischemic events in patients with recent myocardial infarction, stroke and peripheral arterial disease.

CAPRIE study of 19, 185 patients demonstrated that this drug is as good as aspirin in preventing cerebrovascular and cardiovascular events in patients with known atherosclerosis.

In the CAPRIE study patients in the nonsmoking group had no reduction in incidence of primary outcome of ischemic stroke, myocardial infarction, or vascular death compared to aspirin treated nonsmoking group, whereas patients in the clopidogrel treated current smoker group had a significantly lower incidence of primary outcome compared to the aspirin treated current smoker group.

Slightly more beneficial than aspirin in decreasing vascular death, myocardial infarction, and stroke in high-risk patients.

TTP can occur after the initiation of clopidrogel therapy, often within the first two weeks of treatment.

Incidence of TTP 11 per 3 million cases.

Pretreatment with clopidrogel in addition to aspirin in patients with acute coronary syndrome undergoing percutaneous coronary intervention is beneficial in reducing major ischemic events up to 30 days after the procedure.

Pre treatment with clopidogrel in the PCI-CURE substudy, with 300 mg loading dose in the median of 10 days before catheterization was associated with a 30% reduction of the composite endpoint of cardiovascular death, myocardial infarction, and urgent vessel revascularization at 30 days, without significant difference in bleeding.

Recommended to be used with aspirin in patients with bare metal stents or drug eluting stents since dual antiplatelet regimen reduces stent thrombosis and in patients undergoing percutaneous coronary intervention for non-ST-Elevation acute coronary syndromes, reduces rate of death from cardiovascular causes, myocardial infartction, or stroke.

CREDO trial found that patients loaded with 300 mg of clopidogrel at least six hours before PCI experienced a 38.6% decrease in major coronary events that reached significance among those pretreated at least 15 hours before the procedure.

Recommendations are for pretreatment with 300 mg loading dose for more than six hours before elective PCI, or greater than 600 mg greater than two hours before the procedure, and 600 mg loading dose as soon as possible for primary PCI patients with us STEMI.

Guidelines recommend use before patients undergo percutaneous coronary intervention and continue to receive the drug for at least 1 month for bare-metal stents, for 3 months for sirolimus stents, and for 6 months for paclitaxel stents.

In a dual antiplatelet study (ASA vs. ASA + clopidogrel) of greater than 12 months in patients with drug eluting stents dual treatment was not significantly more effective than aspirin monotherapy in reducing rate of myocardial infarction or death from cardiac causes (Park Seung-Jung).

Recent studies suggest clopidogrel should be continued for a minimum of 1 year in drug eluting stents to prevent late stent thrombosis.

At least 6 hours is required for the maximal antiplatelet effect of a loading dose of 300 mg.

A 600 mg loading dose results in maximal antiplatelet effect within 2 hours.

The efficacy of 75 mg of daily clopidrogel is marginally better compared to 325 mg of aspirin in the prevention of thromboembolic vascular events and gastrointestinal bleeding occurred in 0.5% and 0.7% patients , respectively.

One week of clopidrogel compared to aspirin results in less gastroduodenal damage on endoscopic examination.

Adverse reactions include TTP, leukopenia, aplastic anemia and serum sickness.

Rarely associated with a hypersensitivity syndrome with fever, rash, tachycardia, nausea and vomiting.

Duration of use of the drug is 4 weeks for bare metal stents and 3-6 months for drug-eluting stents.

CHARISMA trial compared 15,603 patients with cardiovascular disease or multiple atherthrombotic risk factors randomized to low dose aspirin along with clopidrogel or placebo for an average of 28 months: combined incidence of myocardial infarctions, strokes, and cardiovascular deaths not statistically different from combined modality and those treated with aspirin alone.

It is suggested to stop this agent 7-10 days before anticipated surgery.

The withdrawal of clopidogrel is associated with increased thromboembolic events and coronary artery stent thrombosis.

Prompt surgical treatment of acute hip fractures in patients taking clopidogrel does not compromise perioperative outcomes (Feely MA et al).

In the above study it was no difference in perioperative bleeding complications or mortality in patients who undergoing prompt operative treatment of hip fracture while taking clopidogrel compared with patients not taking such a drug.

When used within 7 days of surgery significantly increases the risk of postoperative bleeding, and most bleeding episodes are successsfully managed by transfusions without an increase in mortality or necessity of reoperation (Chernoguz A et al).

Adding clopidogrel to aspirin increases the relative risk of major bleeding perioperatively by 30 to 50% compared to aspirin alone.

Dual antiplatelet therapy does not increase operative mortality, except for intracranial neurosurgery, but is associated with a slight increase in the need for re-operation and a 30% increase in the need for transfusions (Douketis JD).

Most surgical procedures, with the exception of intracranial neurosurgery, can be performed while the patient is receiving dual antiplatelet therapy without significantly increasing morbidity or mortality.

Other surgical procedures that should be avoided, while on antiplatelet therapy, include operations on the spinal cord or posterior chamber of the eye.

Proton pump inhibitors often utilized prophylactically with clopidogrel to reduce gastrointestinal bleeding risk.

Protein pump inhibitors (PPIs) may decrease effects of clopidogrel on platelet aggregation inhibition.

In vitro all PPI’s inhibit CYP 2C19 to variable degrees but omperazole has the strongest affect.

Protein pump inhibitors (PPIs)-when utilized with clopidogrel after hospital discharge for acute coronary artery syndrome associated with increased risk of adverse outcomes compared to the use of clopidogrel alone.

In in a randomized study of clopidogrel with aspirin, dual therapy, with either omperazole or placebo drug use of a proton pump inhibitor reduced the rate of upper gastrointestinal bleeding without apparent cardiovascular interaction with clopidogrel and omperazole (Bhatt DL et al).

Concomitant PPI medications can be used for patients with a history of prior upper G.I. bleeding, advanced age, use of steroids, or nonsteroidal anti-inflammatory drugs, and infection with Helicobacter pylori.

Therapeutic response is variable among patients and low or incomplete platelet inhibition is associated with increased cardiovascular risk (Sweeny JM et al).

In the Omeprazole Clopidogrel Aspirin Study patients undergoing coronary stent placement receiving clopidogrel and aspirin combined with omeprazole had a higher platelet reactivity index value at the end of a 7 day treatment period than did patients taking clopidogrel and aspirin with placebo (Gilard M).

Reduced action of clopidogrel may be due to the competitive metabolic effects of PPIs on CYP2C19.

Clopidogrel resistance is frequent in acute coronary syndromes reaching a prevalence of 25 to 30% and is even more likely in show acute corner syndrome patients with type II diabetes.

Hepatic cytochrome 2C19 enzyme (CYP219) is partially responsible for bilateral activation of this drug.

Carriers of allele variant CYP2C19 have lower levels of clopidogrel metabolite, decreased platelet inhibition, and higher rates of cardiovascular events in a non-carriers (Mega JL et al).

CYP2C19 genotyping is available in patients with genetic polymorphisms alternative treatment strategies or higher doses of this drug were the use of other antiplatelet agents, should be considered.

CYP2C19*2 and CYP2C19*2 and CYP2C19*3 are reduced function alleles and account for the majority of reduced function in poor metabolizers.

The relative risk of major cardiovascular events is increased by a factor of 1.53-3.69 among carriers of loss of function alleles as compared to non carriers.

Estimated that clopidogrel efficacy is genetically altered in about 30% of white patients with suboptimal platelet inhibition, causing subsequent increase thrombotic events after coronary stenting.

In a systemic review and meta-analysis evaluating the association of clopidogrel pretreatment versus no treatment with mortality and major bleeding after PCI: there was no significant association between pretreatment and major bleeding overall, and was not associated with a lower risk of mortality, but was associated with a low risk of major coronary events (Bellemain A et al).

CYP2C19 allele 17 carriers have increased platelet response to this drug and increased the risk of bleeding as this allele is a gain of function one.

Among 5059 patients genotyped for CYP2C19 alleles 2, 3, and 17 treated for acute coronary syndromes randomized to clpoidogrel or placebo: the effect of clopidogrel in reducing the rate of cardiovascular events in acute coronary syndromes was similar in patients who were heterozygous or homozygous for loss of function alleles and those who were not carriers of the alleles and, in contrast gain of function carriers had more benefit from clopidogrel as compared with placebo than did non-carriers (Pare G et al).

Among 1156 patients with atrial fibrillation genotyped for CYP2C19 alleles 2,3,17 and randomized to clopidogrel and placebo there was no evidence of interaction with respect to the efficacy or bleeding between the study drugs and the metabolizes phenotype, loss of function carrier status or gain of function carries status (Pare G et al).

After temporary cessation of therapy, it is recommended to resume treatment approximately 24 hours after surgery when there is adequate hemostasis.

To have an antiplatelet effect it must be converted to an active thiol metabolite by hepatic cytochrome P450 (CYP) isoenzymes, which inhibit ADP stimulated platelet activation by irreversibly binding to platelet P2V12 receptors.

Patients vary in their response to clopidogrel based on its association with statins, calcium channel blockers, proton pump inhibitors smoking, and St. John’s wort.

Clopidogrel for Reduction of Events During Observation trial found that clopidogrel therapy reduced adverse events to a similar degree regardless of PPI use.

In contrast to the above study retrospective studies suggested higher rates of cardiovascular events in patients on clopidogrel and PPIs compared to patients on clopidogrel alone (Perzalla E, Aubert, RE, Ho PM, Juurlinik DN).

In a double-blind, randomized trial, of 7243 patients under the age of 75 years receiving aspirin, with unstable angina or myocardial infarction without a ST segment elevation who did not undergo revascularization were treated with prasugrel10 mg daily versus clopidogrel 75 mg a day: pasugrel did not significantly reduce the frequency of the primary endpoint, as compared with Clopidogrel and similar risks of bleeding were observed (Roe MT et al).

In a VA study of patients with ACS and on clopidogrel the use of PPIs was associated with an increased risk of death and rehospitalization (Ho PM).

Loss of function of the CYP2C19-2 allele associated with decreased activation of clopidogrel and antiplatelet effect with increased cardiovascular events.

5% to 30% of patients do not respond adequately to standard doses of clopidogrel.

Some of the risk for increased ischemic adverse events and death in diabetes may be related to platelet hyperactivity and altered platelet receptor and intracellular signaling pathways, including an up regulation of the P2Y12 pathway.

Patients with diabetes often have persistently high platelet reactivity in the presence of clopidogrel therapy. therapy.

Clopidogrel treatment after MI is associated with a lower reduction in the risk of all cause death and cardiovascular death in diabetics compared with patients without diabetes (Anderson C et al).

Response as defined by ADP-stimulated platelet aggregation is a normally distributed trait with no clear cutoff to define resistance.

Response influenced by cardiovascular burden, medications, concurrent illnesses, and compliance, increased age, BMI, triglyceride levels, decreased levels of high density lipoproteins levels all predict for lowered clopidogrel response.

In a retrospective study evaluating clinical outcomes in patients using clopidogrel alone or with PPIs after myocardial infarction or coronary artery stent placement: patients who received clopidogrel and a proton pump inhibitor, had a significant higher risk of rehospitalization or myocardial infarction or coronary artery stent placement than did patients receivng clopidogrel alone (Sockl KM).

Response is highly heritable with the major locus of influences on chromosome 10q24.

This locus extends across the CYP2C18-CYP2C19-CYP2C9-CYP2C8 gene cluster.

Loss of function CYP2C19*2 variant genotype accounts for approximately 12% of variation of clopidogrel response.

Age, BMI,  and lipid levels, approximately  22%of the variation in clopidrogrel response.

Majority of variation in response to clopidrogrel is unexplained.

CYP2C19*2 Genotype associated with poor clinical outcomes in coronary artery disease treated with clopidrogrel and aspirin (Mega).

CYP2C19*2 genotype carriers with prior myocardial infarction treated with clopidogrel and aspirin, more likely to have a second cardiovascular event than those with other genotypes (Collet).

Broad variation in interindividual response antiplatelet effect.

Patients with high residual platelet reactivity vs low have increased risks of ischemic and bleeding complications, respectively.

In the RECLOSE 2-ACS (Responsiveness to Clopidogrel and stent thrombosis 2-ACS) study evaluating the prognostic implications of HRPR (high residual platelet reactivity) after clopidogrel loading in 1789 patients with ACS who underwent PCI and assessed the effects of adjusting antiplatelet treatment regimens based on platelet function tests: HRPR was noted in 14% of patients, and despite intensification of antiplatelet treatment HR PR persisted in nearly 40% of patients (Parodi G et al).

In the above study the primary endpoint of cardiac death, myocardial infarction, stroke, and any urgent coronary revascularization at two years was 6% higher in patients with HRPR compared with patients with low residual platelet reactivity (LRPR): cardiac mortality was increased by more than twofold in patients with HRPR and stent thrombosis doubled in patients with HRPR.

Recent trials suggest either a reduced or complete lack of clinical benefit from Clopidogrel therapy in non-smokers.

Cigarette smoking induces activity of cytochrome P450 an isoenzyme involved in metabolic activation of Clopidogrel.

Non-smokers have greater platelet reactivity than smokers during clopidogrel treatment.

Aspirin and clopidogrel reduce cancer risk compared with aspirin only or no treatment.

Dualtreatment with aspirin is associated with an 8% reduction in cancer incidence in comparison with aspirin alone (Leader A).

Among all the patients with acute coronary syndrome, platelet inhibition with clopidogrel significantly reduce bleeding risk without increasing thrombotic events compared with ticagrelor.

Dose 75 mg/day.

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