Clopidogrel


Article Author:
Craig Beavers


Article Editor:
Imama Naqvi


Editors In Chief:
Myron Bodman
Donald Kushner


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
10/1/2019 1:28:47 PM

Indications

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.[1][2][3]

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.

Mechanism of Action

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 effective metabolize clopidogrel which leads 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. 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 by 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 patients who are high-risk (e.g., patients with recent stenting for ACS). Thus, in these situations, it is imperative to consult with the primary prescriber for the clopidogrel.[7]

Administration

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, it is recommended that administration of agents that inhibit CYP2C19 metabolism should be avoided (e.g., omeprazole, lansoprazole). Furthermore, agents that slow down gastrointestinal motility can delay absorption (e.g., opioid agents) and are recommended to be avoided in the acute setting.

Regarding pregnancy risk factor, clopidogrel has a risk factor B classification, meaning no evidence of risk. However, most of the data supporting this have been from animal models which found no adverse events in reproduction studies. It is not known if clopidogrel is secreted into the 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:

  • 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 fibrinolytics: 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 prior to 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 stent type, the location of the stent, and the risk of bleeding. Any decision to alter this duration should be done 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 coronary artery bypass graft surgery: Administer 75 mg daily.

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

Adverse Effects

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, 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, hemostasis could be restored via exogenous platelet administration; however, data exploring this strategy are mixed. The use of platelets should be reserved for severe, life-threatening bleeding.[8]

The other most common adverse effect is rash/pruritus. In cases of mild-to-moderate hypersensitivity (e.g., rash), the patient can be given a course of a steroid burst while being on maintained on 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 been associated with thrombotic thrombocytopenia (TTP). A patient who develops TTP while on clopidogrel should be treated with urgent plasmapheresis.

Contraindications

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

Monitoring

Patients on clopidogrel should be monitored 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 response. There are various consensus opinions to the defined threshold for non-responsiveness and optimal strategy for management.

Toxicity

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 in baboons.

Enhancing Healthcare Team Outcomes

Clopidogrel is a widely used drug by the cardiologists, emergency department physicians, nurse practitioners, and internists. While the drug is useful for the treatment of ischemic heart disease, its use must be monitored. Because the drug has the potential to cause bleeding, the patient's hemoglobin and hematocrit must be regularly monitored.[9] The interprofessional team should work together to make sure patients on clopidogrel are followed up on a regular basis. [Level V]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Clopidogrel - Questions

Take a quiz of the questions on this article.

Take Quiz
A 69-year-old male with diabetes mellitus and a long history of hypertension is admitted with chest pain. The ECG reveals that he is suffering from an acute myocardial infarction. Urgent cardiac catheterization is performed and the patient's circumflex coronary artery is successfully ballooned and stented. What is the best drug to use to prevent thrombosis of his stent?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which drug is used to prevent cardioembolic strokes by inhibiting platelet aggregation?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What medication inhibits ADP dependent platelet aggregation?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following medications inhibits ADP dependent platelet aggregation?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Clopidogrel works by what mechanism?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which adverse effect of clopidogrel is of greatest concern?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is more effective than aspirin at preventing myocardial infarction?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is not true of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 62-year-old male status post stent placement after angioplasty presents to your office to discuss his current medication regimen. He recalls aspirin as one of his medications but cannot remember the second drug. What is the mechanism of action of the most likely drug?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 56-year-old female admitted for myocardial infarction 3 days prior has a prescription for clopidogrel 75 mg daily. What patient education should be included in the plan of care? Select all that apply.



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Clopidogrel - References

References

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. International journal of stroke : official journal of the International Stroke Society. 2019 Mar 25;     [PubMed]
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 therapy : research, treatment and education of diabetes and related disorders. 2019 Mar 23;     [PubMed]
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;     [PubMed]
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 Fibrinolytic Therapy: TREAT Trial. Journal of the American College of Cardiology. 2019 Mar 12;     [PubMed]
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. Journal of the American Heart Association. 2019 Apr 2;     [PubMed]
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. Chinese medical journal. 2019 Mar 19;     [PubMed]
Pop C,Matei C,Petris A, Anticoagulation in Acute Coronary Syndrome: Review of Major Therapeutic Advances. American journal of therapeutics. 2019 Mar/Apr;     [PubMed]
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. The Annals of thoracic surgery. 2019 Mar 19;     [PubMed]
Hicks GL Jr, Bleeding in Patients Treated with Ticagrelor or Clopidogrel Before Coronary Artery Bypass Grafting (Commentary). The Annals of thoracic surgery. 2019 Mar 16;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Surgery-Podiatry APMLE Part 2. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Surgery-Podiatry APMLE Part 2, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Surgery-Podiatry APMLE Part 2, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Surgery-Podiatry APMLE Part 2. When it is time for the Surgery-Podiatry APMLE Part 2 board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Surgery-Podiatry APMLE Part 2.