Continuing Education Activity

Over time, numerous antiplatelet agents have been developed with a multitude of indications. Antiplatelet medications divide into oral and parenteral agents, and oral agents subdivide further based on the mechanism of action. Aspirin was the first antiplatelet medication and is a cyclooxygenase inhibitor. Other oral antiplatelet include clopidogrel, ticagrelor, and prasugrel, cilostazol, and dipyridamole. Glycoprotein IIb/IIIa inhibitors such as tirofiban and eptifibatide are only available as parenteral agents and are used in acute phases of acute coronary syndrome. This activity reviews the indications, contraindications, action, adverse events, and other key elements of antiplatelet drugs essential to clinical practice.

Objectives:

• Summarize the mechanisms of action of the different antiplatelet agents.
• Identify the appropriate indications for the various antiplatelet drugs.
• Describe the potential adverse event profiles of the different antiplatelet agents.
• Review interprofessional team strategies for improving care coordination and communication to enhance patient outcomes and minimize adverse events with antiplatelet medications.

Indications

Antiplatelet medications divide into oral and parenteral agents. Oral agents subdivide further based on the mechanism of action. Aspirin was the first antiplatelet medication and is a cyclooxygenase inhibitor. Other oral antiplatelet agents include clopidogrel, ticagrelor, prasugrel, pentoxifylline, cilostazol, and dipyridamole. Glycoprotein IIb/IIIa inhibitors such as tirofiban and eptifibatide are only available as parenteral agents and are used in acute coronary syndrome (ACS).[1]

The following is a list of indications of antiplatelet medications: 

• Acute coronary syndrome
• Post percutaneous coronary intervention (PCI) with stenting
• Mechanical heart valves in combination with warfarin
• Acute ischemic stroke
• Post percutaneous intervention of peripheral arterial disease
• Device closure of an atrial septal defect (ASD) for at least six months
• Stable angina
• Post-coronary artery bypass grafting surgery
• Essential thrombocytosis
• Primary prevention of coronary artery disease
• Prevention of colon cancer
• Kawasaki disease
• Acute rheumatic disease
• Post patent ductus arteriosus (PDA) device closure for the first six months
• Acute pericarditis
• Atrial fibrillation with a high risk of stroke
• Primary prevention of venous thromboembolism

Mechanism of Action

Antiplatelets can be classified based on the mechanism of action as follows[2][3]:

• Platelet aggregation inhibitors such as;
  • Aspirin and related cyclooxygenase inhibitors
  • Oral thienopyridines such as clopidogrel, ticagrelor, ticlopidine, and prasugrel
• Glycoprotein platelet inhibitors (e.g., abciximab, eptifibatide, tirofiban)
• Protease-activated receptor-1 antagonists (e.g., vorapaxar)
• Miscellaneous (e.g., dipyridamole - a nucleoside transport inhibitor and phosphodiesterase type 3 (PDE3) inhibitor, cilostazol - also a PDE3 inhibitor)

Aspirin is the most commonly used oral antiplatelet drug. It works by irreversibly inhibiting the cyclooxygenase enzyme (COX) activity in the prostaglandin synthesis pathway (PGH2). This prostaglandin is a precursor of thromboxane A2 (TXA2) and PGI2. Thromboxane A2 works by inducing platelet aggregation and vasoconstriction, and COX-1 mediates its production, while PGI2 works by inhibiting platelet aggregation and induces vasodilation, and is mediated by COX-2. Low-dose aspirin (75 mg to 150 mg) can induce complete or near-complete inhibition of COX-1, thus inhibiting the production of TXA2, while larger doses are required to inhibit COX-2.[4]

Oral thienopyridines selectively inhibit adenosine diphosphate-induced (ADP-induced) platelet aggregation. These drugs are converted into the active drug with the help of the hepatic CYP450 system that can irreversibly inhibit the platelet P2Y12 receptor. Prasugrel is the most potent of all three drugs, has a rapid onset of action, and is superior to clopidogrel in patients undergoing coronary stenting. Ticlopidine has fallen out of favor because of bone marrow toxicity. Cangrelor is a new intravenous, reversible P2Y12 receptor antagonist and has a rapid onset of action. It achieves a significant degree of platelet inhibition compared with clopidogrel.[5]

Glycoprotein platelet inhibitors work by inhibiting glycoprotein IIb/IIIa (GpIIb-IIIa) receptors on platelets, thus decreasing platelet aggregation, and most commonly used in ACS.[3] These drugs are only available in an intravenous form and are therefore used as short-term therapy.  

Dipyridamole has antiplatelet and vasodilating properties and inhibits platelet cyclic nucleotide phosphodiesterase. This enzyme is responsible for the degradation of adenosine monophosphate (AMP) to 5'AMP, which increases intra-platelet cyclic AMP accumulation and inhibits platelet aggregation. It also blocks the uptake of adenosine by the platelets, which also increases cyclic AMP.[6]

Cilostazol is also reported to have vasodilatory, antiplatelet properties, and antiproliferative effects. It also reduces smooth muscle cell hyperproliferation and intimal hyperplasia after an injury to the endothelium.[7]

Administration

Antiplatelet agent administration can be via oral, rectal, or intravenous routes. Oral medications include aspirin, clopidogrel, ticagrelor, cilostazol, and dipyridamole. Intravenous drugs include GpII-IIIA inhibitors and can be used for a short period, most commonly during acute coronary syndromes before or during PCI. Aspirin is available as a rectal suppository if the patient cannot take the drug orally.

Individual agent dosing is covered under the articles for each of these drugs on the Statpearls platform. The reader is advised to seek those articles out for specific dosing information.

Adverse Effects

Following are the most common adverse effects associated with antiplatelet medications:[8]

• Aspirin-induced asthma
• Nasal polyps
• Upper gastrointestinal bleeding because of chronic gastritis
• Ecchymosis
• Hematuria
• Epistaxis
• Ticagrelor-related dyspnea
• Hemorrhage
• Thrombocytopenia

Headache, nausea, diarrhea, pain, infection, upper respiratory symptoms, palpitations, arrhythmias, and peripheral edema are the most common side effects associated with cilostazol.

Contraindications

The most common contraindications for using antiplatelet agents are as follows[9]:

• Large esophageal varices
• Recent stroke within two years
• History of intracranial hemorrhage 
• Significant thrombocytopenia 
• Major surgery with 72 hours
• Hypersensitivity to the medication
• Acute clinically significant bleed
• End-stage renal disease on hemodialysis 
• Decompensated liver cirrhosis 
• Severe hypertension with a BP over 200/110 mmHg
• Congestive heart failure is a contraindication for the use of cilostazol

Monitoring

Before starting antiplatelet agents, the patient should undergo an assessment for bleeding risk. Advanced age, female gender, and impaired renal function are important factors to consider. The patient should be aware of the risks, benefits, and alternatives of antiplatelet agents. Monitoring is generally not required for antiplatelet medications; however, if bleeding is present, bleeding time will be helpful to determine if a platelet transfusion is needed or if the medication requires discontinuation. In life-threatening bleeding such as massive upper gastrointestinal bleed, the clinician should stop the drug as soon as possible. If the antiplatelet is an essential therapy, such as in post-coronary stenting patients, the medications should be resumed as quickly as safely possible.

The use of concomitant anticoagulants should be minimized as much as possible as it will increase the risk of bleeding by many times. Discontinuance of clopidogrel and ticagrelor should be at least five days and prasugrel at least seven days before major cardiac or non-cardiac surgery.

Toxicity

Aspirin is the most commonly used of all antiplatelet drugs, so accidental intake is common. The effect can be life-threatening if taken over 150 mg/kg of body weight. Supportive measure to decrease the absorption of the drug is achievable by using activated charcoal but only if administered within 4 hours of ingestion. The patient will need monitoring for signs and symptoms of bleeding and the development of metabolic derangements, such as acidosis. If acidosis develops, immediate dialysis is indicated.[10]

There is no antidote available for most of these drugs; however, a monoclonal antibody against ticagrelor is in development, but it is not commercially available as yet.

Enhancing Healthcare Team Outcomes

Antiplatelet drug therapy requires an interprofessional team approach, including clinicians (MDs, DOs, NPs, PAs), specialty-trained nurses, and pharmacists. These professionals must all collaborate and engage in open communication as an interprofessional team to achieve optimal patient results.

The choice of an antiplatelet agent depends on the clinical situation. Because of the availability of a large number of antiplatelet agents, the ordering/prescribing clinician should consult with a cardiology or pharmacotherapy specialized pharmacist. When prescribing these agents, the pharmacist should review the patient's medication list as well as past diagnoses to determine if specific agents are recommended or contraindicated. Communication between the clinical provider and the pharmacists is essential to minimize adverse outcomes for patients when using these drugs. A cardiac pharmacist can offer direction regarding agent selection, drug-drug interactions, dose verification, and overall medication reconciliation for high-risk patients.

The role of the cardiac nurse administering these medications in the acute setting involves monitoring for any acute adverse symptoms and patient education in regards to the same. Prompt communication by the astute nursing staff of an adverse reaction or a complication can significantly reduce patient morbidity and mortality.

Nurses are often the first healthcare provider to verify the therapeutic effectiveness of these agents and to monitor for adverse effects. This role becomes crucial in patients receiving dual antiplatelet therapy, as is often the case for the prevention of stent thrombosis or after an ACS event. The specialty-trained nurse not only educates the patient on possible complications but also regarding the indications for the prescribed therapy as well as the need for adherence to the medication treatment regimen. The nurse should communicate with the clinical provider and the pharmacist if noting any adverse reaction or if there is a concern for patient adherence with drug therapy so that alternative therapies can be considered. An interprofessional approach, with a multifaceted and targetted approach to treatment, is necessary to improve patient outcomes with antiplatelet medications. [Level 5]