Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so that a loading-dose of 300-600 mg is usually administered.

Mechanism of Action -

Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established cardiovascular atherosclerotic disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, unstable angina or the need for vascular bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting platelet function can reduce the event rate.⁴

Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.⁵

Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.

Indications-

Clopidogrel is indicated for: ⁶

· Prevention of vascular ischaemic events in patients with symptomatic atherosclerosis

· Acute coronary syndrome without ST-segment elevation (NSTEMI),

· ST elevation MI (STEMI)

It is also used, along with aspirin, for the prevention of thrombosis after placement of intracoronary stent.⁶

International guidelines granted the highest grade of recommendation for NSTE-ACS, PCI and stent,for Clopidogrel in addition to Aspirin. Consensus-based therapeutic guidelines recommend also the use of clopidogrel, instead of aspirin, in patients requiring antiplatelet therapy but with a history of gastric ulceration, as inhibition of the synthesis of prostaglandins by aspirin (acetylsalicylic acid) can exacerbate this condition. A study has shown that in patients with healed aspirin-induced ulcers, however, patients receiving aspirin plus the proton pump inhibitor esomeprazole had a lower incidence of recurrent ulcer bleeding than patients receiving clopidogrel.⁷However, a more recent study suggested that prophylaxis with proton pump inhibitors along with clopidogrel following acute coronary syndrome may increase adverse outcomes, possibly due to inhibition of CYP2C19 which is required for activation of clopidogrel, itself a pro-drug.⁸

Pharmacokinetics and metabolism-

After repeated 75-mg oral doses of clopidogrel (base), plasma concentrations of the parent compound, which has no platelet inhibiting effect, are very low and are generally below the quantification limit (0.000258 mg/L) beyond 2 hours after dosing.

Clopidogrel is a pro-drug activated in the liver by cytochrome P450 enzymes, including CYP2C19. The active metabolite has an elimination half-life of about 8 hours and acts by forming a disulfide bridge with the platelet ADP receptor. Patients with a variant allele of CYP2C19 are 1.5 to 3.5 times more likely to die or have complications than patients with the high-functioning allele. ^9,10,11Following an oral dose of ¹⁴C-labeled clopidogrel in humans, approximately 50% was excreted in the urine and approximately 46% in the feces in the 5 days after dosing.

Effect of Food- Administration of clopidogrel bisulfate with meals did not significantly modify the bioavailability of clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite. The effect of food on the bioavailability of the parent compound or active metabolite is currently not known.¹²

Absorption and Distribution- Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg clopidogrel (base), with peak plasma levels (appx. 3 mg/L) of the main circulating metabolite occurring approximately 1 hour after dosing. The pharmacokinetics of the main circulating metabolite are linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150 mg of clopidogrel. Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites. Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 110 μg/mL. After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/mL after a single 75-mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites. Clopidogrel and the main circulating inactive metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively).¹³ The binding is nonsaturable in vitro up to a concentration of 100 mcg/mL.

Metabolism -In vitro and in vivo, clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed. Clopidogrel is extensively metabolized by the liver. In vitro and in vivo, clopidogrel is metabolized according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.¹⁴

Elimination-

Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg,¹⁵clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the inactive acid metabolite was 8 hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.

Note: Coronary artery stents: Duration of clopidogrel (in combination with aspirin): According to the ACC/AHA/SCAI guidelines, ideally 12 months following drug-eluting stent (DES) placement in patients not at high risk for bleeding; at a minimum, 1, 3, and 6 months for bare metal (BMS), sirolimus eluting, and paclitaxel eluting stents, respectively, for uninterrupted therapy (Smith, 2005). The 2008 Chest guidelines recommend for patients who undergo PCI and receive a BMS (with ongoing ACS) or a DES (with or without ongoing ACS) that clopidogrel be continued for at least 12 months. In patients receiving a BMS without ongoing ACS, clopidogrel may be continued for at least 1 month. In patients receiving a DES, therapy with clopidogrel beyond 12 months may be considered in patients without bleeding or tolerability issues (Becker, 2008). Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal myocardial infarction.¹⁷

Prevention of coronary artery bypass graft closure (saphenous vein) [Chest guidelines, 2008]: Aspirin-allergic patients (unlabeled use): Loading dose: 300 mg 6 hours following procedure; maintenance: 75 mg/day

Pharmacogenetics-

CYP2C19 is an important drug-metabolizing enzyme that catalyzes the biotransformation of many clinically useful drugs including antidepressants, barbituates, proton pump inhibitors, antimalarial and antitumor drugs. Clopidogrel is one of the drugs metabolized by this enzyme.

Several recent landmark studies have proven the importance of 2C19 genotyping in treatment using clopidogrel or Plavix. Researchers have found that patients with variants in cytochrome P-450 2C19 (CYP2C19) have lower levels of the active metabolite of clopidogrel, less inhibition of platelets, and a 3.58 times greater risk for major adverse cardiovascular events such as death, heart attack, and stroke; the risk was greatest in CYP2C19 poor metabolizers. ¹⁸

Adverse effects-

Serious adverse drug reactions associated with clopidogrel therapy include:

· Severe neutropenia

· Thrombotic thrombocytopenic purpura (TTP)

· Hemorrhage - The annual incidence of hemorrhage may be increased by the co-administration of aspirin.¹⁹

o Gastrointestinal Hemorrhage

o Cerebral Hemorrhage

o Use of non-steroidal anti-inflammatory drugs is discouraged in those taking clopidogrel due to increased risk of digestive tract hemorrhage

Most-Frequent:²⁰
Abdominal Pain with Cramps, Arthralgia, Back Pain, Chest Pain, Dizziness, Dyspepsia, Flu-Like Symptoms, Headache Disorder, Pain, Purpura, Upper Respiratory. Infection

Less-Frequent:²⁰
Anemia, Anxiety, Atrial Fibrillation, Bronchitis, Cataracts, Constipation, Cough, Cramps in Legs, Depression, Diarrhea, Dyspnea, Eczema, Edema, Epistaxis, Fainting, Fatigue, Gastrointestinal Hemorrhage, General Weakness, Gout, Hypertension, Hypesthesia, Insomnia, Nausea, Palpitations, Paresthesia, Pruritus of Skin, Rhinitis, Skin Rash.

Rare:²⁰
Abnormal Hepatic Function Tests, Acute Hepatic Failure, Acute Pancreatitis, Agranulocytosis, Anaphylaxis, Angioedema, Aplastic Anemia, Bronchospastic Pulmonary Disease, Bullous Dermatitis, Colitis, Conjunctival Hemorrhage, Duodenal Ulcer, Dysgeusia, Erythema Multiforme, Fever, Gastric Ulcer, Glomerulonephritis, Hallucinations, Hematoma, Hepatitis, Hypersensitivity Drug Reactions, Hypotension, Impaired Cognition, Interstitial Pneumonitis, Intracranial Bleeding, Leukopenia, Lichen Planus, Menorrhagia, Myalgia, Neutropenic Disorder, Ocular Bleeding, Pancreatitis, Pancytopenia, Peptic Ulcer, Renal Disease, Retinal Hemorrhage, Serum Sickness, Stevens-Johnson Syndrome, Stomatitis, Thrombocytopenic Disorder, Thrombotic Thrombocytopenic Purpura, Toxic Epidermal Necrolysis.

Clopidogrel worldwide-

Clopidogrel is marketed worldwide in nearly 110 countries, with sales of US$5.9 billion in 2005. ²¹ It had been the 2nd top selling drug in the world for a few years as of 2007 ²² and was still growing by over 20% in 2010.In 2006, generic clopidogrel was briefly marketed by Apotex, a Canadian generic pharmaceutical company before a court order halted further production until resolution of a patent infringement case brought by Bristol-Myers Squibb. ²³ The court ruled that Bristol-Myers Squibb's patent was valid and provided protection until November 2011. ²⁴Generic clopidogrel is also produced by several pharmaceutical companies in India at significantly lower retail prices, up to 1/30th of the price.

Side Effects-²⁵

General-Clopidogrel has been evaluated for safety in more than 17,500 patients, including over 9,000 patients treated for 1 year or more. The overall tolerability of clopidogrel in CAPRIE was similar to that of aspirin regardless of age, gender and race, with an approximately equal incidence (13%) of patients withdrawing from treatment because of adverse reactions.General complaints among at least 2.5% of treated patients in controlled trials have included chest pain, influenza-like syndrome, general body pain, or fatigue. A causal relationship has not been clearly demonstrated.

Cardiovascular-Cardiovascular side effects have included chest pain (8.3%), edema (4.1%), and hypertension (4.3%) in treated patients during controlled trials (compared with 8.3%, 4.5% and 5.1%, respectively, in patients who were given aspirin). Cardiovascular adverse events that have occurred in 1.0% to 2.5% of patients included syncope, palpitations, atrial fibrillation, and heart failure. Generalized edema has been reported in less than 1% of treated patients. A relationship between these adverse events and clopidogrel administration has not been clearly defined. Similar rates were observed among patients treated with aspirin in controlled trials.

Rarely, heart failure has been associated with the use of clopidogrel. Vasculitis, angioedema, and hypotension have also been reported during postmarketing experience.

Drug Interactions -²⁷

Anticoagulants: Antiplatelet Agents may enhance the anticoagulant effect of Anticoagulants.

Antiplatelet Agents: May enhance the anticoagulant effect of other Antiplatelet Agents.

Calcium Channel Blockers: May diminish the therapeutic effect of Clopidogrel.

Dasatinib: May enhance the anticoagulant effect of Antiplatelet Agents.

Drotrecogin Alfa: Antiplatelet Agents may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur.

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Antiplatelet Agents. Bleeding may occur.

Ibritumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding.

Macrolide Antibiotics: May diminish the therapeutic effect of Clopidogrel. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin.

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents.

Omega-3-Acid Ethyl Esters: May enhance the antiplatelet effect of Antiplatelet Agents.

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Antiplatelet Agents. Specifically, the risk of bleeding may be increased by concurrent use of these agents.

Prostacyclin Analogues: May enhance the antiplatelet effect of Antiplatelet Agents.

Proton Pump Inhibitors: May diminish the therapeutic effect of Clopidogrel. This appears to be due to reduced formation of the active clopidogrel metabolite.

Rifamycin Derivatives: May enhance the therapeutic effect of Clopidogrel.

Salicylates: Antiplatelet Agents may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result.

Thrombolytic Agents: Antiplatelet Agents may enhance the anticoagulant effect of Thrombolytic Agents.

Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased.

Warfarin: Clopidogrel may enhance the anticoagulant effect of Warfarin.

Moderate Interaction with drugs:²⁶
Clopidogrel/ Atorvastatin - Decreased effect of the former drug
Platelet Aggregation Inhibitors/ Anticoagulants - Additive side effects from both drugs

Ethanol/ Nutrition/ Herb Interactions-Herb/Nutraceutical: Avoid alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, chamomile, coleus, cordyceps, dong quai, evening primrose oil, fenugreek, feverfew, garlic, ginger, ginkgo biloba, ginseng (American), ginseng (Panax), ginseng (Siberian), grape seed, green tea, guggul, horse chestnut seed, horseradish, licorice, prickly ash, red clover, reishi, SAMe (S-adenosylmethionine), sweet clover, turmeric, white willow (all have additional antiplatelet activity). ²⁶

Drug-Disease Contraindications-²⁷

Most Significant –

Gastrointestinal Hemorrhage, Hemorrhage, Intracranial Bleeding

Significant –

Blood Coagulation Disorder, Gastrointestinal Ulcer, Poor Metabolizer due to Cytochrome p450 CYP2C19 Variant, Retinal Hemorrhage, Thrombotic Thrombocytopenic Purpura

Possibly Significant –

Severe Hepatic Disease, Severe Renal Disease, Surgical Procedure, Trauma

Anesthesia and Critical Care Concerns/Other Considerations-

Perioperative Management of Clopidogrel: ^28-31

In patients with coronary stents, the risk of stent thrombosis becomes elevated depending on the type of stent deployed (bare metal vs drug-eluting stent) and the time from implantation. According to the American College of Chest Physicians (Becker, 2008), the recommended length of therapy for clopidogrel is at least 12 months in patients with ACS who undergo PCI with a bare metal stent (BMS) or drug-eluting stent (DES). In patients receiving a BMS without ongoing ACS, clopidogrel may be continued for at least 1 month. Early discontinuation of clopidogrel may result in stent thrombosis leading to nonfatal and fatal myocardial infarction. The perioperative recommendations for clopidogrel are below (Douketis, 2008):

Patients undergoing noncardiac surgery (low risk of cardiac event without coronary stent): Clopidogrel and other antiplatelet agents should be temporarily discontinued 5-10 days prior to surgery and resumed ~24 hours (or the next morning) after the procedure when adequate hemostasis is achieved.

Patients without coronary stent undergoing cardiac surgery (eg, CABG) or noncardiac surgery (high risk of cardiac event):^32,33 Discontinue clopidogrel at least 5 days and, preferably, 10 days prior to surgery while continuing aspirin up to and beyond the time of surgery. If aspirin is interrupted, it should be reinitiated 6-48 hours after surgery; may resume clopidogrel ~24 hours (or the next morning) after the procedure when adequate hemostasis is achieved.

Patients undergoing cardiac surgery (eg, CABG) or noncardiac surgery (with coronary stent): Based on the risk of stent thrombosis, patients with a BMS who require surgery within 6 weeks of implantation or with a DES who require surgery within 12 months of implantation should continue on both aspirin and clopidogrel during the perioperative period.

The AHA/ACC/SCAI/ACS/ADA Science Advisory (2007) published recommendations (Circulation, February 13, 2007) to prevent premature discontinuation of dual antiplatelet therapy (clopidogrel and aspirin) in patients with coronary artery stents. The advisory panel agreed with the 2004 ACC/AHA guidelines stressing the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent (DES) in patients who are not at high risk of bleeding. The advisory panel included these recommendations. Minor surgery, teeth cleaning, and tooth extraction can usually be performed without increased bleeding on the dual antiplatelet regimen. If increased bleeding is anticipated, then the procedure should be delayed until the antiplatelet regimen is completed. Elective procedures with a significant risk of bleeding should be postponed until the antiplatelet regimen is completed. The advisory panel recommends healthcare providers who perform invasive or surgical procedures contact the patient's cardiologist before discontinuing antiplatelet therapy. For patients with drug-eluting stents who must undergo a procedure that requires discontinuation of thienopyridine therapy, aspirin should be continued if possible and the thienopyridine restarted as soon as possible after the procedure. “Bridging” stent patients with warfarin, other antithrombins, or glycoprotein IIb/IIIa agents is not supported by the Advisory Committee.^32,33

Cardiovascular Considerations-

Acute Coronary Syndrome (ACS): The 2007 ACC/AHA guidelines for unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) recommend administration of clopidogrel to hospitalized patients who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance (Class I; level of evidence: A). In certain situations, patients may even be desensitized to aspirin so that they may receive aspirin and clopidogrel concurrently. The CURE trial demonstrated that clopidogrel reduced major cardiovascular events in patients with ACS without ST-segment elevation (Yusuf S, 2001). In this trial, the risk of major bleeding was significantly increased in the clopidogrel group although life-threatening bleeding and hemorrhagic strokes were similar in both groups. In hospitalized UA/NSTEMI patients in whom an early noninvasive strategy is planned, clopidogrel should be added to aspirin and anticoagulant therapy as soon as possible (Class I, Level of evidence A).

In UA/NSTEMI patients in whom an invasive strategy will be employed, antiplatelet therapy should be initiated prior to diagnostic angiography. This can be done with either clopidogrel or a glycoprotein IIb/IIIa inhibitor (eg, eptifibatide) (Class I, Level of evidence A). The PCI-CURE trial, a substudy of the CURE trial, suggested that in patients with ACS undergoing PCI receiving aspirin, a strategy of clopidogrel pretreatment followed by long-term therapy (9 months) is beneficial in reducing major cardiovascular events, compared with placebo (Mehta SR, 2001). In the CREDO trial, long-term (1 year) clopidogrel treatment (75 mg daily) following PCI, significantly reduced the risk of adverse ischemic events (Steinhubl SR, 2002). In CREDO, the issue of timing was evaluated and a 300 mg loading dose of clopidogrel must be given at least 6 hours before PCI. More recently, however, a 600 mg loading dose of clopidogrel was shown to result in maximal platelet inhibition at 2 hours (Hochholzer W, 2005).

In patients taking clopidogrel in whom elective CABG is planned, clopidogrel should be withheld for 5-7 days before elective CABG. If urgent CABG is required, the benefits of surgery should outweigh the risks of incremental bleeding.

ST-Segment Elevation Myocardial Infarction (STEMI):^34,35 The COMMIT trial (Chen ZM, 2005), randomized 45,852 patients with an acute MI (supporting ECG abnormalities), presenting within 24 hours of onset of symptoms, to clopidogrel 75 mg daily or placebo. All patients received aspirin and standard medical care (eg, thrombolytics if appropriate, ACEI). Clopidogrel was continued for 28 days or until hospital discharge whichever came first. The primary outcome measure was a composite of death, MI, or stroke. Patients in the clopidogrel arm had a significantly lower death rate (7.5% clopidogrel, 8.1% placebo; p=0.002).The CLARITY trial (Scirica BM, 2006) evaluated clopidogrel in the setting of thrombolysis and its relationship to ST-segment resolution. The randomized, double blind, placebo controlled trial included 3491 patients within 12 hours of the onset of STEMI who were candidates for thrombolytic therapy. Patients were randomized to receive clopidogrel (300 mg loading dose, then 75 mg daily) or placebo until angioplasty, discharge, or Day 8. Patients also received aspirin (loading dose followed by 75-162 mg/day). The ECG was monitored at baseline, and 90- and 180 minutes after thrombolysis. There was no difference in ECG resolution (none, partial, complete) between the groups at 90 minutes. Patients with partial (30% to 70%) and complete (>70%) ST-segment resolution on clopidogrel had significantly improved patency on discharge angiogram over placebo patients with similar ST-segment resolution. The clopidogrel group with partial ST segment resolution had a significantly lower rate of in-hospital death and MI than their placebo counterparts. The clopidogrel group with complete resolution of ST-segments showed a trend toward a reduction of in-hospital death and MI but it was not statistically significant (p=0.056). Mortality was followed for 30 days; the clopidogrel group with complete resolution of ST-segment abnormalities had a significant reduction in the rate of death compared to its placebo counterpart.

Percutaneous Coronary Intervention (PCI)- The 2004 ACC/AHA guidelines for ST-elevation myocardial infarction (STEMI) suggests that clopidogrel be continued for at least 1 month after bare-metal stent implantation, for several months after drug-eluting stent implantation (3 months for sirolimus, 6 months for paclitaxel), and ideally for up to 12 months in patients who are not at high risk for bleeding.

Coronary Artery Stents ¹⁶- The 2005 ACC/AHA/SCAI guidelines for PCI recommends that along with aspirin, clopidogrel be continued for at least 1 month after bare-metal stent implantation, for several months after drug-eluting stent implantation (3 months for sirolimus, 6 months for paclitaxel), and ideally for up to 12 months in patients who are not at high risk for bleeding. Clopidogrel is the preferred thienopyridine due to its lower incidence of serious side effects (eg, neutropenia) as compared to ticlopidine.

The 2008 Chest guidelines recommend for patients who undergo PCI and receive a BMS (with ongoing ACS) or a DES (with or without ongoing ACS) that clopidogrel be continued for at least 12 months. In patients receiving a BMS without ongoing ACS, clopidogrel may be continued for at least 1 month. In patients receiving a DES, therapy with clopidogrel beyond 12 months may be considered in patients without bleeding or tolerability issues (Becker, 2008).

The AHA/ACC/SCAI/ACS/ADA Science Advisory (2007) published recommendations (Circulation, February 13, 2007) to prevent premature discontinuation of dual antiplatelet therapy (clopidogrel, aspirin) in patients with coronary artery stents. This advisory panel agreed with the 2004 ACC/AHA guidelines stressing the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent (DES) in patients who are not at high risk of bleeding. The advisory panel included these recommendations. Minor surgery, teeth cleaning, and tooth extraction can usually be performed without increased bleeding on the dual antiplatelet regimen. If increased bleeding is anticipated, then the procedure should be delayed until the antiplatelet regimen is completed. Elective procedures with a significant risk of bleeding should be postponed until the antiplatelet regimen is completed. The Advisory panel recommends healthcare providers who perform invasive or surgical procedures contact the patient's cardiologist before discontinuing antiplatelet therapy. For patients with drug-eluting stents who must undergo a procedure that requires discontinuation of thienopyridine therapy, aspirin should be continued if possible and the thienopyridine restarted as soon as possible after the procedure. “Bridging” stent patients with warfarin, other antithrombins, or glycoprotein IIb/IIIa agents is not supported by the Advisory Committee.

High Cardiovascular-Event Risk Patients- The CHARISMA trial (Bhatt DL, 2006) evaluated the use of clopidogrel compared to placebo in 15,603 patients receiving low-dose aspirin (75-162 mg/day) who were at high risk of future cardiovascular events. This patient group included those with multiple atherothrombotic risk factors, documented coronary, cerebrovascular, or peripheral vascular disease. The primary outcome measure was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The primary outcome measure occurred in 6.8% of patients receiving clopidogrel and aspirin vs. 7.3% with placebo and aspirin (p=0.22). The rates of the secondary endpoints which included hospitalizations for ischemic events, was 16.7% and 17.9% (p=0.04). The rate of GUSTO-defined severe bleeding was 1.7% and 1.3% (p=0.09). A prespecified subgroup analysis divided patients into a “symptomatic” group (with documented cardiovascular disease) and an “asymptomatic” group (without documented cardiovascular disease). In the patients considered symptomatic, the primary event rate was lower in the clopidogrel group compared to placebo (6.9% vs 7.9%, p=0.046). In patients considered asymptomatic, there was a 20% relative increase in the primary event rate (6.6% vs 5.5%; p=0.20) if receiving clopidogrel. The rate of death from cardiovascular causes was also higher in this group (3.9% vs 2.2%, p=0.01). In summary, clopidogrel in addition to low-dose aspirin is not significantly more effective than low-dose aspirin alone in reducing the rate of MI, stroke, or death from cardiovascular causes. Use of clopidogrel in addition to low-dose aspirin may be harmful in patients with multiple atherothrombotic risk factors without cardiovascular disease. The American College of Chest Physicians recommends against the routine use of clopidogrel (in addition to aspirin) for primary prevention unless the patient has an aspirin allergy and is at moderate-to-high risk for a cardiovascular event (Becker, 2008).

Clopidogrel: Ongoing Safety Review - January 2009

Special Alerts- ^36-42

The U.S. Food and Drug Administration (FDA) is communicating important information regarding an ongoing safety review of clopidogrel and its effectiveness when used with proton pump inhibitors (PPIs).

Clopidogrel is a prodrug requiring hepatic conversion via CYP3A4 and/or CYP2C19 to its active metabolite. Impaired clopidogrel conversion to its active metabolite may be due to either CYP450 polymorphisms or drug-drug interactions resulting in suboptimal antiplatelet activity.

A PPI is often prescribed with the combination of aspirin and clopidogrel to prevent gastrointestinal bleeding. A number of PPIs are available and include dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole. Several studies have reported greater clinical event rates (eg, myocardial infarction, death) or greater platelet reactivity associated with concurrent use of clopidogrel and a PPI (Ho, 2008; Pezella, 2008; Gilard, 2006). Similarly, a prospective, randomized, double-blind trial demonstrated a reduction in antiplatelet activity when omeprazole and clopidogrel are used concurrently (Gilard, 2008). Another controlled trial with the PPI lansoprazole also found evidence of a possible interaction resulting in less antiplatelet activity (Small, 2008). This interaction is thought to result from competitive inhibition of the CYP2C19-mediated activation of clopidogrel by omeprazole and other PPIs, which are all metabolized to at least some degree by CYP2C19. In contrast, one study with esomeprazole and pantoprazole did not find evidence of reduced antiplatelet activity when administered with clopidogrel (Siller-Matula, 2009), highlighting the need for additional studies to determine the degree to which individual PPIs may differ in their potential for interacting with clopidogrel.

The manufacturer of Plavix® has agreed to conduct further studies to better understand the effect of other drugs (including PPIs) and genetic factors on the effectiveness of clopidogrel. The FDA is recommending that healthcare providers continue to prescribe clopidogrel while reevaluating the need for prescription or over-the-counter (OTC) PPIs in patients taking clopidogrel. Patients should continue taking clopidogrel as directed. If taking a PPI with clopidogrel, patients should consult with their healthcare provider.

International Brand Names -⁴³

· Ateplax (PE)

· Ceruvin (MY)

· Cloart (KP)

· Clopilet (IN)

· Clopivaz (PH)

· Deplat (TW)

· Iscover (AR, AT, AU, BE, BG, CH, CO, CZ, DE, DK, ES, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)

· Kovix (KP)

· Maxgrel (KP)

· Noclot (PK)

· Plagerine (PH)

· Plamed (KP)

· Plavitor (KP)

· Plavix (AR, AT, AU, BB, BD, BE, BF, BG, BJ, BM, BO, BR, BS, BZ, CH, CI, CL, CN, CO, CR, CZ, DE, DK, DO, EC, ES, ET, FI, FR, GB, GH, GM, GN, GR, GT, GY, HK, HN, ID, IE, IL, IN, IT, JM, JP, KE, KP, LR, MA, ML, MR, MU, MW, MX, MY, NE, NG, NI, NL, NO, PA, PE, PH, PK, PL, PR, PT, PY, RU, SC, SD, SE, SG, SL, SN, SR, SV, TH, TN, TR, TT, TW, TZ, UG, UY, VE, ZA, ZM, ZW)

· Q.O.L. (KP)

SIMILAR RESEARCH ARTICLES

1- Late Clinical Events After Clopidogrel Discontinuation May Limit the Benefit of Drug-Eluting Stents ⁴⁵

Method: A consecutive series of 746 nonselected patients with 1,133 stented lesions surviving 6 months without major events were followed for 1 year after the discontinuation of clopidogrel. Patients were assigned randomly 2:1 to DES versus BMS in BASKET (Basel Stent Kosten Effektivitäts Trial). The primary focus of this observation was cardiac death/MI.

Result: Rates of 18-month cardiac death/MI were not different between DES and BMS patients. However, after the discontinuation of clopidogrel (between months 7 and 18), these events occurred in 4.9% after DES versus 1.3% after BMS implantation. Target vessel revascularization remained lower after DES, resulting in similar rates of all clinical events for this time period (DES 9.3%, BMS 7.9%). Documented late stent thrombosis and related death/target vessel MI were twice as frequent after DES versus BMS (2.6% vs. 1.3%). Thrombosis-related events occurred between 15 and 362 days after the discontinuation of clopidogrel, presenting as MI or death in 88%.

Conclusion: After the discontinuation of clopidogrel, the benefit of DES in reducing target vessel revascularization is maintained but has to be balanced against an increase in late cardiac death or nonfatal MI, possibly related to late stent thrombosis.

2- BASKET-LATE: Late Clinical Events Related to Late Stent Thrombosis After Stopping Clopidogrel: Drug-Eluting vs Bare-Metal Stenting ⁴⁷

Between May 2003 and May 2004, patients treated with percutaneous coronary intervention and stenting were enrolled in the BASKET⁴⁸ trial and randomized in a 2:1 fashion to receive DES or BMS. Patients who remained event-free at 6-month follow-up were subsequently enrolled in the BASKET-LATE trial. Patients were followed for an additional 12 months to determine the incidence of cardiac death or nonfatal myocardial infarction (MI) (primary endpoint) and clinically driven restenosis-related target vessel revascularization. Dual antiplatelet therapy was administered for 6 months in all patients regardless of stent type, and clopidogrel was discontinued in all patients after 6 months.

Results: After clopidogrel discontinuation, late-stent thrombosis-related events were 2-3 times more frequent among those who had received DES than among those who had received BMS,carried 4 times higher risk of cardiac death/MI vs non-thrombosis-related events, occurred up to 1 year after clopidogrel discontinuation, and were more frequent in patients with prior MI, those who needed glycoprotein IIb/IIIa inhibitors initially, or those who had received DES. From these results, the authors calculated that real-world DES use in 100 patients avoids 5 target vessel revascularization events at 6 months but leads to 3.3 late deaths or MI.

3- To Assess The Rates of Adverse Events After Stopping Treatment With Clopidogrel in a National Sample of Patients With Acute Coronary Syndrome (ACS)^.46

Design, Setting, and Patients: Retrospective cohort study of 3137 patients with ACS discharged from 127 Veterans Affairs hospitals between October 1, 2003, and March 31,2005,with,posthospital.treatment,with.clopidogrel.

Main Outcome Measure: Rate of all-cause mortality or acute myocardial infarction (AMI) after stopping treatment with clopidogrel.

Results: Mean (SD) follow-up after stopping treatment with clopidogrel was 196 (152) days for medically treated patients with ACS without stents (n = 1568) and 203 (148) days for patients with ACS treated with percutaneous coronary intervention (PCI) (n = 1569). Among medically treated patients, mean (SD) duration of clopidogrel treatment was 302 (151) days and death or AMI occurred in 17.1% (n = 268) of patients, with 60.8% (n = 163) of events occurring during 0 to 90 days, 21.3% (n = 57) during 91 to 180 days, and 9.7% (n = 26) during 181 to 270 days after stopping treatment with clopidogrel. In multivariable analysis including adjustment for duration of clopidogrel treatment, the first 90-day interval after stopping treatment with clopidogrel was associated with a significantly higher risk of adverse events (incidence rate ratio [IRR], 1.98; 95% confidence interval [CI], 1.46-2.69 vs the interval of 91-180 days). Similarly, among PCI-treated patients with ACS, mean (SD) duration of clopidogrel treatment was 278 (169) days and death or AMI occurred in 7.9% (n = 124) of patients, with 58.9% (n = 73) of events occurring during 0 to 90 days, 23.4% (n = 29) during 91 to 180 days, and 6.5% (n = 8) during 181 to 270 days after stopping clopidogrel treatment.

Conclusions: We observed a clustering of adverse events in the initial 90 days after stopping clopidogrel among both medically treated and PCI-treated patients with ACS, supporting the possibility of a clopidogrel rebound effect. Additional studies are needed to confirm the clustering of events after stopping clopidogrel, including associations with cardiovascular mortality and reasons for stopping clopidogrel, as well as to determine the mechanism of this phenomenon, and to identify strategies to reduce early events after clopidogrel cessation.

DISCUSSION:

Here we found a clustering of death and MI events in the initial 90-day period after clopidogrel cessation, compared with subsequent follow-up intervals. Findings were consistent among subgroups of patients who received shorter or longer durations of clopidogrel therapy, patients with or without diabetes, and ACS patients who underwent PCI. The rate of adverse events in the initial 90-day interval after stopping clopidogrel was higher than the rate of adverse events following hospital discharge while patients were still taking clopidogrel. These findings support the hypothesis of a rebound hyperthrombotic period after clopidogrel cessation. They also highlight the need for additional studies to confirm these findings and to gain a deeper understanding of the pathophysiology of this phenomenon as well as allowing identification of strategies to attenuate this effect. The results of this study add to the literature supporting the hypothesis of a rebound phenomenon following antiplatelet agent withdrawal In vitro and physiologic evidence exist that support the notion of a short-term increase in platelet activation and corresponding thrombotic risk immediately after stopping antiplatelet therapy.''" Previous studies have shown that discontinuation of aspirin therapy is associated with an increased short-term risk of cerebrovascuiar and cardiac events compared with continuous aspirin use. The STRATEGY (Single High- Dose Bolus Tirofiban and Sirolimus Eluting Stem versus Abciximab and Bare Metal Stent in Acute Myocardial Infarction) study reported a clustering of death or nonfatal MI within 30 days of stopping thienopyridine therapy among patients treated with DES or BMS for ST-segment elevation MF; however, a stent-related mechanism was identified as the likely etiology for these events. We observed an increase in the incidence of adverse events in nonstented, medically treated ACS patients following clopidogrel cessation, implicating a mechanism unrelated to stenting. this study has several potential implications. First, while the absolute rate of adverse events was low, the relative increase in adverse events seen in the early period after clopidogrel cessation was nearly twofold higher than in later periods. The absolute number of adverse events attributable to this event clustering is significant when extrapolated to a population level.These findings do not necessarily offset the benefits of clopidogrel therapy for patients with ACS. They do indicate, however, that additional studies are urgently needed to confirm event clustering and understand the pathophysiology of this phenomenon. Should these findings be confirmed, guideline recommendations may need to be reconsidered regarding the duration of clopidogrel therapy and possibly the means of clopidogrel cessation. Possibilities include continuing clopidogrel for an extended period or indefinitely, although before implementing this recommendation, the increased risk of bleeding with prolonged dual antiplatelet therapy and the cost-effectiveness of such a strategy would need to be considered tapering clopidogrel therapy; bridging clopidogrel cessation with higher-dose aspirin for a given period; or using alternative antiplatelet regimens. All these approaches would require formal study before making a specific recommendation

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Received on 29.01.2013

Modified on 10.02.2013

Accepted on 24.02.2013

Research J. Pharmacology and Pharmacodynamics. 5(1): January –February 2013, 26-35