A nurse should identify that clopidogrel is contraindicated

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What Is Clopidogrel and How Does It Work?
What Are Dosages of Clopidogrel?
Review Questions

What Is Clopidogrel and How Does It Work?

Clopidogrel is used to prevent heart attacks and strokes in persons with heart disease (recent heart attack), recent stroke, or blood circulation disease (peripheral vascular disease).

Clopidogrel is also used with aspirin to treat new/worsening chest pain (new heart attack, unstable angina) and to keep blood vessels open and prevent blood clots after certain procedures (such as cardiac stent).
Clopidogrel works by blocking platelets from sticking together and prevents them from forming harmful clots. It is an antiplatelet drug. It helps keep blood flowing smoothly in your body.
Clopidogrel is available under the following different brand names: Plavix.

What Are Dosages of Clopidogrel?

Dosages of Clopidogrel:

Dosage Forms and Strengths

Tablet

Dosage Considerations – Should be Given as Follows:

Acute Coronary Syndrome

Unstable angina, non-ST-segment elevation heart attack (myocardial infarction [MI]) (NSTEMI):

300 mg loading dose;
initiating therapy without a loading dose will delay the establishment of antiplatelet effect by several days;
following the loading dose, administer 75 mg/day orally for up to 12 months;
may administer beyond 12 months if used in combination with aspirin (75-100 mg/day);
long-term combination therapy with aspirin,
following stent placement is individualized depending on how a patient tolerates long-term dual antiplatelet therapy (DAPT),
whether they have stable coronary artery disease and do NOT have risk factors (e.g., transient ischemic attack [TIA] or stroke, age over 75 years, bleeding risk, low body weight, concurrent medications)

ST-segment elevation myocardial infarction (MI) (STEMI):

75 mg/day orally in combination with aspirin 162-325 mg/day and then 81-162 mg/day

Age under 75 years

300 mg loading dose followed by 75 mg for 14 days up to 12 months (if no bleeding)
Concomitant therapy with aspirin: Administer in combination with aspirin 75-325 mg once/day with or without thrombolytics

Age over 75 years

No loading dose
75 mg for 14 days up to 12 months (if no bleeding)

Recent heart attack (Myocardial Infarction [MI]), Stroke, or Established Peripheral Arterial Disease

75 mg orally once/day without a loading dose; recommended as an alternative to aspirin or concomitantly with aspirin if patient not at increased risk for bleeding but high risk for cardiovascular disease

Coronary Artery Disease

Cardioembolic Stroke

Prophylaxis if patient not a candidate for oral anticoagulation
75 mg/day orally

Dosing Modifications

Renal impairment: Dose adjustment not necessary
Hepatic impairment: Use caution; experience limited

Dosing Considerations

CYP2C19 poor metabolizers associated with diminished antiplatelet response to clopidogrel; although higher-dose regimen (600 mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response, no appropriate dosing regimen for poor metabolizers have been established in clinical outcome trials
Not recommended for pediatric use

Clopidogrel is FDA approved for the medical management of unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI), ST-segment elevation myocardial infarction (STEMI) in patients receiving fibrinolytic therapy, and for secondary prevention in recent myocardial infarction (MI), recent stroke, and peripheral arterial disease. There also a number of other FDA-approved uses. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of clopidogrel, pertinent for members of the interprofessional team where this agent is indicated.

Objectives:

Explain the mechanism of action of clopidogrel.
Review the indications for initiating therapy with clopidogrel.
Describe the significant drug-drug interactions that might occur when prescribing clopidogrel.
Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients on clopidogrel therapy.

Access free multiple choice questions on this topic.

FDA-approved indications for clopidogrel include:

Use during a percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) and stable ischemic heart disease.[4][5][6]
Primary prevention of thromboembolism atrial fibrillation
Symptomatic carotid artery stenosis
Secondary prevention post-coronary artery bypass grafting
Peripheral artery percutaneous angioplasty in peripheral artery bypass grafting

Clopidogrel is an irreversible inhibitor of the platelet P2Y12 adenosine diphosphate receptor. Inhibition of this receptor prevents the downstream activation of the glycoprotein IIb/IIIa receptor complex, which leads to reduced platelet aggregation. Clopidogrel is an inactive prodrug that requires enzymatic activation via a variety of CYP enzymes, including the CYP2C19 and CYP3A4 enzymes, through a two-step process of bioactivation. Genetic polymorphisms to these enzymes can influence response to therapy. The most commonly discussed genetic polymorphism related to clopidogrel is that of one or both alleles of the CYP2C19 enzyme. Patients with any loss of function allele will not effectively metabolize clopidogrel, leading to the inability to inhibit platelet activity. For example, patients who are homozygous for these non-functioning alleles often demonstrate the poorest metabolism and subsequent activation of clopidogrel, as indicated by high on-treatment platelet reactivity via platelet function testing.[7]

Typically, in a normal metabolizer, the drug has a bioavailability of 50%, with only 15% of an oral dose becoming active via esterase hydrolysis with the CYP enzymes. Active clopidogrel inhibits the platelet for the life of the platelet (7 to 10 days). However, platelet function can begin to return as new platelets turn over, and a return of full function is often seen within 5 days. Given this factor, clopidogrel should be held at least 5 days before any surgical procedure. It should be noted this decision should not occur in isolation, especially in high-risk patients (e.g., patients with recent stenting for ACS). Thus, in these situations, it is imperative to consult with the primary prescriber for the clopidogrel.[8]

Clopidogrel is only supplied in a tablet formulation, and thus all doses are given via an oral route. Doses of clopidogrel can be administered without respect to meals. Due to the dependence of CYP2C19 for metabolism for activation, the recommendation is that the administration of agents that inhibit CYP2C19 metabolism should be avoided (e.g., omeprazole, lansoprazole). Furthermore, recommendations are to avoid agents that slow down gastrointestinal motility can delay absorption (e.g., opioid agents) in the acute setting.

Regarding pregnancy risk factors, clopidogrel has a risk factor B classification, meaning no evidence of risk. However, most of the data supporting this have been from animal models that found no adverse events in reproduction studies. It is not known if clopidogrel is secreted into breast milk. At the moment, the expert recommendation is to stop nursing or stop the drug in these situations.

Below are the typical dosing regimens for clopidogrel:[9]

Medical treatment of UA/NSTEMI: Administer a 300 mg to 600 mg loading dose followed by 75 mg daily, in conjunction with aspirin, ideally for up to 12 months.
STEMI patients receiving fibrinolytic therapy: If the patient’s age is 75 years or younger, then give a 300 mg loading dose followed by 75 mg daily for at least 14 days and up to 1 year. If the patient is older than 75 years, then the loading dose is omitted.
PCI during ACS/non-ACS setting: Administer a 600 mg loading dose as early as possible before PCI, followed by 75 mg daily. Ideally, clopidogrel should be administered with aspirin for at least 12 months post-ACS. The duration can vary depending on the stent type, the location of the stent, and the risk of bleeding. Any decision to alter this duration should occur in conjunction with the primary prescriber.
Peripheral artery percutaneous angioplasty or peripheral artery bypass grafting: Administer 75 mg daily.
Primary prevention of thromboembolism in atrial fibrillation: Administer 75 mg daily.
Symptomatic carotid stenosis: Administer 75 mg daily.
Secondary prevention of coronary artery bypass graft surgery: Administer 75 mg daily.

Of note, there is no adjustment required for renal or hepatic impairment.

Bleeding is the most common side effect reported and can occur at varying degrees of severity and any site. Risk factors for bleeding include age older than 75 years, a recent bleeding event, low body weight, or use of medications (e.g., non-steroid anti-inflammatory agents or warfarin) that can increase the risk of bleeding. If bleeding should occur, the risk/benefit of continuing therapy should occur with the primary prescriber of the clopidogrel. There is currently no reversal agent for clopidogrel therapy. Theoretically, exogenous platelet administration could restore hemostasis; however, data exploring this strategy are mixed. The use of platelets should be reserved for severe, life-threatening bleeding.[10]

The other most common adverse effect is rash/pruritus. In cases of mild-to-moderate hypersensitivity (e.g., rash), the patient can receive a course of a steroid burst while maintaining their therapy. Other options to manage these patients or scenarios include desensitization and switching to an alternative agent with a different structure (e.g., ticagrelor). Rarely, clopidogrel has correlations with thrombotic thrombocytopenia (TTP). A patient who develops TTP while on clopidogrel should receive urgent plasmapheresis.

Clopidogrel is contraindicated in patients who have had anaphylaxis to clopidogrel or its components or have active bleeding.[11]

Patients on clopidogrel should have monitoring for signs of bleeding, both visibly and via laboratory testing (hemoglobin and hematocrit).

As noted, several patients can have genetic polymorphisms to the CYP enzymes. The CYP2C19 enzyme has been the most studied regarding medication metabolism and response. Genetic testing may be considered in patients prior to initiating therapy in patients at high risk for adverse outcomes (e.g., PCI patients with increased risk of stent thrombosis). However, based on available data, the most optimal dose has been determined. Furthermore, after drug administration, the use of platelet function testing can be used to determine patient response. There are various consensus opinions to the defined threshold for non-responsiveness and optimal strategy for management.[11]

Overdose following clopidogrel administration may result in bleeding complications. Based on animal studies, a single dose of 1500 to 2000 mg/kg was lethal to mice and rats, and 3000 mg/kg was lethal to baboons.

Clopidogrel is a widely used drug by cardiologists, emergency department physicians, family practice clinicians, and internists. While the drug is useful for the treatment of ischemic heart disease, its use must be monitored, which is best accomplished with an interprofessional healthcare team. Because the drug has the potential to cause bleeding, the patient's hemoglobin and hematocrit must have regular monitoring.[12] The interprofessional team, including all clinicians, specialists, nurses, and pharmacists, should work together to make sure patients on clopidogrel are followed up regularly, leading to improved patient outcomes with fewer adverse events. [Level 5]

Review Questions

Wang XH, Tao L, Zhou ZH, Li XQ, Chen HS. Antiplatelet vs. R-tPA for acute mild ischemic stroke: A prospective, random, and open label multi-center study. Int J Stroke. 2019 Aug;14(6):658-663. [PubMed: 30907301]

Lu H, Guan W, Zhou Y, Tang Z, Bao H. Cangrelor or Clopidogrel in Patients with Type 2 Diabetes Mellitus Undergoing Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Controlled Trials. Diabetes Ther. 2019 Jun;10(3):937-950. [PMC free article: PMC6531549] [PubMed: 30905057]

Jackevicius CA, An J, Ko DT, Ross JS, Angraal S, Wallach JD, Koh M, Song J, Krumholz HM. Submissions from the SPRINT Data Analysis Challenge on clinical risk prediction: a cross-sectional evaluation. BMJ Open. 2019 Mar 23;9(3):e025936. [PMC free article: PMC6475140] [PubMed: 30904868]

Berwanger O, Lopes RD, Moia DDF, Fonseca FA, Jiang L, Goodman SG, Nicholls SJ, Parkhomenko A, Averkov O, Tajer C, Malaga G, Saraiva JFK, Guimaraes HP, de Barros E Silva PGM, Damiani LP, Santos RHN, Paisani DM, Miranda TA, Valeis N, Piegas LS, Granger CB, White HD, Nicolau JC. Ticagrelor Versus Clopidogrel in Patients With STEMI Treated With Fibrinolysis: TREAT Trial. J Am Coll Cardiol. 2019 Jun 11;73(22):2819-2828. [PubMed: 30898608]

Liu Z, Xiang Q, Mu G, Xie Q, Zhou S, Wang Z, Chen S, Hu K, Gong Y, Jiang J, Cui Y. Effectiveness and Safety of Platelet ADP -P2Y12 Receptor Inhibitors Influenced by Smoking Status: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2019 Apr 02;8(7):e010889. [PMC free article: PMC6509729] [PubMed: 30898054]

Ma Q, Chen GZ, Zhang YH, Zhang L, Huang LA. Clinical outcomes and predictive model of platelet reactivity to clopidogrel after acute ischemic vascular events. Chin Med J (Engl). 2019 May 05;132(9):1053-1062. [PMC free article: PMC6595887] [PubMed: 30896564]

Duarte JD, Cavallari LH. Pharmacogenetics to guide cardiovascular drug therapy. Nat Rev Cardiol. 2021 Sep;18(9):649-665. [PMC free article: PMC8364496] [PubMed: 33953382]

Pop C, Matei C, Petris A. Anticoagulation in Acute Coronary Syndrome: Review of Major Therapeutic Advances. Am J Ther. 2019 Mar/Apr;26(2):e184-e197. [PubMed: 30839367]

Bossard M, Gao P, Boden W, Steg G, Tanguay JF, Joyner C, Granger CB, Kastrati A, Faxon D, Budaj A, Pais P, Di Pasquale G, Valentin V, Flather M, Moccetti T, Yusuf S, Mehta SR. Antiplatelet therapy in patients with myocardial infarction without obstructive coronary artery disease. Heart. 2021 Nov;107(21):1739-1747. [PubMed: 33504513]

10.

Holm M, Biancari F, Khodabandeh S, Gherli R, Airaksinen J, Mariscalco G, Gatti G, Reichart D, Onorati F, De Feo M, Santarpino G, Rubino AS, Maselli D, Santini F, Nicolini F, Zanobini M, Kinnunen EM, Ruggieri VG, Perrotti A, Rosato S, Dalén M. Bleeding in Patients Treated With Ticagrelor or Clopidogrel Before Coronary Artery Bypass Grafting. Ann Thorac Surg. 2019 Jun;107(6):1690-1698. [PubMed: 30898561]

11.

Iqbal AM, Lopez RA, Hai O. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): May 8, 2022. Antiplatelet Medications. [PubMed: 30725747]

12.

Hicks GL. Invited Commentary. Ann Thorac Surg. 2019 Jun;107(6):1698. [PubMed: 30890417]