Cangrelor

Mechanism of Action

Cangrelor, a novel nonthienopyridine adenosine triphosphate (ATP) analog, exerts its antiplatelet effects through a specific mechanism of action. This medication functions by inhibiting blood platelet activation and aggregation, ultimately reducing the risk of thrombotic events.

The primary mechanisms of action of cangrelor are listed below.

• P2Y₁₂ receptor antagonism: Cangrelor is a reversible antagonist of the P2Y₁₂ receptor, an essential receptor involved in platelet activation and aggregation. By binding to the P2Y₁₂ receptor on platelets, cangrelor effectively blocks the binding of adenosine diphosphate (ADP), a potent platelet activator (see Image. Cangrelor Mechanism of Action). This action leads to inhibiting the ADP-mediated signaling pathway and subsequent platelet activation. [10]
• Rapid onset and offset of action: Cangrelor exhibits a rapid onset of action, reaching maximum platelet inhibition within minutes of administration. This quick onset renders the drug particularly useful in the acute setting of PCI, where immediate platelet inhibition is essential. Moreover, cangrelor's effects are quickly reversible upon discontinuation, leading to a shorter duration of action than other antiplatelet agents.[11]
• Platelet inhibition without requiring metabolism: Unlike oral antiplatelet agents, such as clopidogrel or ticagrelor, cangrelor does not rely on metabolic activation within the body. Cangrelor is administered as an IV infusion directly into the bloodstream, eliminating the need for hepatic metabolism. This unique characteristic of cangrelor ensures consistent platelet inhibition without interpatient variability.
• Preservation of vascular function: Cangrelor exhibits selective inhibition of the P2Y₁₂ receptor on platelets while leaving other ADP receptors unaffected. This selectivity helps preserve endothelial function and maintain the balance between antithrombotic effects and the physiological hemostatic response. In addition, it enables platelet inhibition without compromising the overall integrity of the vascular system.

In summary, cangrelor is a potent and reversible intravenous P2Y12 inhibitor, which acts directly and has a short duration of action. Cangrelor quickly inhibits platelet function upon administration and restores normal platelet function within 1 hour of discontinuation.

According to ACC/AHA/SCAI guidelines, cangrelor leads to predictable, rapid, and profound inhibition of platelets. This action makes cangrelor effective in preventing stent thrombosis, especially in patients not pretreated with a P2Y₁₂ inhibitor. In addition, cangrelor proves beneficial in situations where the absorption of oral medications is inadequate.[8]

A meta-analysis of CHAMPION-PCI, CHAMPION-PLATFORM, and CHAMPION-PHOENIX trials provided substantial support for these observations, indicating a decreased incidence of the combined outcome of death, MI, revascularization driven by ischemia, or stent thrombosis within 48 hours with the use of cangrelor compared to clopidogrel. Furthermore, cangrelor exhibited a remarkable 41% reduction in the occurrence of stent thrombosis. Although significant bleeding events were comparable between the two cohorts, there was a higher frequency of minor bleeding in the cangrelor group.[12]

Pharmacokinetics

Understanding the pharmacokinetic profile of cangrelor is essential for appropriate dosing, monitoring, and optimizing therapeutic outcomes.

The key aspects of the cangrelor's pharmacokinetics are as follows:

Route of administration: Cangrelor is administered intravenously as a continuous infusion. The IV route enables rapid and predictable drug delivery, ensuring immediate platelet inhibition during and after PCI.[13]

Absorption: As cangrelor is administered intravenously, it is fully and immediately available in the systemic circulation, bypassing the need for absorption from the gastrointestinal tract, leading to peak plasma concentration within 2 minutes of its administration.

Distribution: Cangrelor exhibits rapid distribution throughout the bloodstream, facilitated by its high-water solubility and a volume of distribution of 3.9 L. Approximately 97% to 98% of the drug binds to protein. Notably, cangrelor binds extensively to platelets, primarily through the P2Y₁₂ receptor, enabling it to reach its site of action and exert potent antiplatelet effects.

Metabolism: Cangrelor undergoes primary metabolism through non-enzymatic hydrolysis in the blood plasma via dephosphorylation. This rapid and spontaneous degradation leads to the formation of an inactive metabolite. This metabolism occurs independently of hepatic enzymes and does not involve the cytochrome P450 system.

Elimination: Cangrelor and its metabolite are primarily eliminated through renal excretion, with a plasma clearance of about 43 L/h. The elimination half-life of cangrelor is relatively short, averaging about 3 to 6 minutes.[14] This short half-life allows rapid drug elimination, rendering it suitable for situations for prompt platelet inhibition.

Clinical implications: The favorable pharmacokinetic profile of cangrelor, characterized by its short half-life and rapid reversibility, holds significant clinical implications. Healthcare professionals can benefit from its predictable and controllable pharmacokinetics, enabling them to adjust and titrate the infusion rate as needed during PCI procedures.

Administration

Cangrelor is available in a parenteral dosage form, specifically as a lyophilized powder for IV infusion. The lyophilized powder is reconstituted with a suitable diluent to prepare a solution for IV administration. Cangrelor is typically supplied in vials or single-use infusion bags.

Available Dosage Forms

Cangrelor is available in an IV infusion form.

Strength

The available strength of cangrelor is 50 mg per vial.

Adult Dosage

Loading dose: A loading dose of cangrelor is usually administered before starting the infusion to ensure a rapid onset of platelet inhibition. The recommended loading dose of cangrelor is 30 mcg/kg, given as a bolus injection over a short duration, such as 1 minute.[15]

Continuous infusion: Following the loading dose, a continuous infusion of cangrelor is initiated. The infusion rate is adjusted according to the patient's weight to maintain therapeutic platelet inhibition. The recommended infusion rate of 4 mcg/kg/min allows for a continuous administration of cangrelor throughout the PCI procedure and up to 2 hours after the procedure.

Adjustment of dosing: The infusion rate of cangrelor can be adjusted based on individual patient factors, such as response to therapy, bleeding risk, and the complexity of the PCI procedure. Dosing may need to be titrated up or down to achieve the desired level of platelet inhibition while carefully managing the risk of bleeding complications.

Duration of therapy: Cangrelor therapy is typically limited to the duration of the PCI procedure and the immediate post-procedural period. Upon completion of the PCI procedure, patients are often transitioned to oral antiplatelet agents, such as clopidogrel (600 mg), ticagrelor (180 mg), or prasugrel (60 mg), for long-term maintenance therapy.[16][17]

Specific Patient Population

Hepatic impairment: Cangrelor has not been specifically studied in patients with hepatic impairment. As the metabolism of cangrelor is not dependent on hepatic function, dosage adjustment is not necessary for patients with hepatic impairment.[18]

Renal impairment: Typically, no dosage adjustment is necessary for patients with mild, moderate, or severe renal impairment when using cangrelor. However, close monitoring for potential adverse effects and platelet inhibition response is strongly recommended.

Pregnancy considerations: Limited clinical data exists regarding the use of cangrelor during pregnancy. In pregnant patients requiring intervention, IV heparin is the preferred anticoagulant.[19] As the safety of cangrelor for both the mother and the developing fetus has not been established, its use during pregnancy should be avoided unless the potential benefits outweigh the risks.

Breastfeeding considerations: Limited data exist on the excretion of cangrelor in human milk and its potential effects on breastfed infants. Therefore, caution should be exercised when considering the use of cangrelor during lactation.[18]

Pediatric patients: The safety and effectiveness of cangrelor have not been established in the pediatric population. 

Geriatric patients: Typically, no dosage adjustment is required for geriatric patients. Patients 75 and older have a higher risk of experiencing moderate-to-severe bleeding, which is approximately 3 times greater than younger patients. However, compared to clopidogrel, cangrelor provides comparable effectiveness in patients both older and younger than 75 without raising the chances of significant bleeding.[20]

Adverse Effects

Like other medications, cangrelor can potentially cause adverse drug reactions (ADRs) in some patients.[21]

The following is a list of some common ADRs associated with the use of cangrelor.

• Bleeding: The most common adverse effect of cangrelor is bleeding, ranging from minor events, such as nosebleeds or bruising, to more severe bleeding events. These bleeding events may occur at the site of vascular access, surgical sites, or other locations in the body.
• Thrombocytopenia: Cangrelor can lead to thrombocytopenia, which may increase the risk of bleeding.[22]
• Hypersensitivity reactions: Cangrelor may lead to hypersensitivity or allergic reactions in some patients, which may present as skin rash, itching, hives, or swelling.
• Nausea and vomiting: Cangrelor may cause gastrointestinal symptoms in some patients, such as nausea and vomiting.
• Hypotension: Cangrelor can potentially lower the blood pressure in patients, which may lead to hypotension. Therefore, healthcare professionals should closely monitor patients' blood pressure during cangrelor administration.
• Local site reactions: In certain instances, patients may experience local site reactions at the injection or infusion site, including pain, redness, or swelling.

Drug Interactions

Glycoprotein IIb/IIIa Inhibitors

Cangrelor should not be coadministered with glycoprotein IIb/IIIa inhibitors, such as abciximab, eptifibatide, or tirofiban, as this combination may increase bleeding risk.[23]

P2Y₁₂ Inhibitors

Cangrelor should be used cautiously with other P2Y₁₂ inhibitors, such as clopidogrel, ticagrelor, and prasugrel. Cangrelor is known for its high P2Y₁₂ receptor affinity, which prevents other P2Y₁₂ agents from binding to the receptor. Consequently, there is a concern that if additional P2₁₂ inhibitors are administered during cangrelor infusion, the other drugs (or their metabolites) will be unable to bind to the P2Y₁₂ receptor, resulting in a lack of antiplatelet effects and ischemic protection.[9] 

Specific recommendations for switching from IV cangrelor to oral P2Y₁₂ inhibitors are listed below.

• Clopidogrel: During cangrelor infusion, the high receptor occupancy prevents the binding of clopidogrel's active metabolite to the P2Y₁₂ receptor, leading to a lack of platelet inhibitory effect. Clopidogrel is administered at the end of the cangrelor infusion to avoid this interaction, allowing sufficient time for cangrelor to wash out from the system and subsequent binding of clopidogrel's active metabolite to the P2Y₁₂ receptor. Therefore, it is recommended to administer clopidogrel after the discontinuation of cangrelor infusion to avoid drug interactions.[24]
• Ticagrelor: Due to its extended systemic half-life and that of its major metabolite, ticagrelor can be safely administered at any time, whether it be before, during, or after cangrelor infusion, without significant drug interactions. A recent clinical trial, known as The Switching Antiplatelet (SWAP)-5 Study, specifically investigated the use of cangrelor in patients pretreated with ticagrelor. Results indicated that administering cangrelor to patients pretreated with ticagrelor enhanced platelet inhibition without any noticeable differences in pharmacokinetic or pharmacodynamic profiles upon discontinuing the drug infusion. Moreover, this study observed no significant drug interactions between cangrelor and ticagrelor.[25] 
• Prasugrel: The transition from cangrelor to prasugrel should occur after the infusion discontinues to avoid potential drug interactions. For an effective transition, initiating the shift approximately 30 minutes before the cangrelor infusion is completed is advisable.[26] International expert consensus recommends early administration of ticagrelor during PCI to minimize the potential gap in platelet inhibition during the transition from cangrelor infusion.[27]

In vitro studies have demonstrated that cangrelor does not inhibit the activity of cytochrome P450 enzymes at therapeutic concentrations. Consequently, the administration of cangrelor is not anticipated to interfere with the hepatic metabolism of other concurrently administered therapeutic agents.[28]

Thrombolytic Agents

Cangrelor requires close monitoring and caution when used concomitantly with thrombolytic agents, such as alteplase or reteplase, due to an increased risk of bleeding.[29]

Abrocitinib

Cangrelor can potentiate the antiplatelet effect of abrocitinib. Therefore, the combination of these medications should be avoided.[30]

Anticoagulants

The administration of P2Y₁₂ inhibitors with anticoagulants such as heparin, warfarin, or direct oral anticoagulants may increase the risk of bleeding. Therefore, it is essential to exercise caution when using this combination of medications.[31]

Contraindications

Cangrelor is contraindicated in individuals with known hypersensitivity or allergic reactions to cangrelor or its components. Cangrelor is contraindicated in cases of active pathological bleeding, including gastrointestinal bleeding or intracranial hemorrhage.[18]

Box Warning

The FDA has issued no specific boxed warnings for cangrelor. However, it is essential to recognize that drug safety information can evolve over time.

Precautions 

Bleeding risk: Cangrelor increases the risk of bleeding, which can be severe or even life-threatening.[32] therefore, clinicians should exercise caution when administering cangrelor to patients at an increased risk of bleeding, including those with a recent history of surgery, bleeding disorders, or significant trauma. Close monitoring for signs of bleeding and appropriate management strategies should be implemented to mitigate potential risks and ensure patient safety.

Thrombocytopenia: Cangrelor can cause a decrease in platelet count, a condition known as thrombocytopenia. Therefore, regular monitoring of platelet counts is recommended, especially during prolonged use or in patients with risk factors for thrombocytopenia.

Surgical procedures: Cangrelor's antiplatelet effects can prolong bleeding time; therefore, physicians should exercise caution when scheduling surgical procedures. The decision to discontinue cangrelor before surgery should be carefully considered, considering the patient's bleeding risk and the desired duration of the antiplatelet effects. 

According to the American Society of Regional Anesthesia (ASRA) and Pain Medicine guidelines, the risk of severe bleeding associated with a neuraxial block while the residual effect of cangrelor is present remains unknown. ASRA recommends removing neuraxial catheters before reinstituting cangrelor therapy postoperatively. The first postoperative dose of cangrelor should be administered 8 hours after the neuraxial catheter has been removed.[33]

Monitoring

Patients receiving cangrelor should be closely monitored for signs of bleeding, both visibly and through laboratory testing (complete blood count). An advanced monitoring technique known as the P2Y₁₂ monitoring assay can also be employed. The P2Y₁₂ assay estimates the degree of platelet inhibition by P2Y₁₂ inhibitors, such as cangrelor. The normal reference range for P2Y₁₂ reaction units (PRUs) is 194 to 418. However, PRU results may be unreliable in patients with altered hematocrit, platelet counts, or fibrinogen levels. Therefore, it is crucial to monitor hematocrit, platelet count, and fibrinogen levels during cangrelor infusion.[34]

Toxicity

Severe toxicity related specifically to cangrelor is rare.[35] Nevertheless, some potential toxicity concerns are associated with cangrelor use, including bleeding, allergic reactions, thrombocytopenia, and local site reactions. Data on cangrelor overdose were assessed in a pooled analysis of the CHAMPION trials. The study identified 36 patients who experienced an overdose of cangrelor. In most cases, the cangrelor dose did not exceed 2.5 times the recommended dosage. Notably, only 1 patient who experienced an overdose had a severe bleeding event.[36]

Signs and Symptoms of Overdose

Common signs and symptoms of cangrelor overdose include bleeding and thrombocytopenia.

Managing Overdose

Managing cangrelor overdose involves providing supportive care and closely monitoring the patient's condition as no specific antidote is available for the drug.

• Stop the cangrelor infusion immediately and seek assistance from a rapid response team.[37]
• Monitor the patient's vital signs, including blood pressure, heart rate, and oxygen saturation.
• Perform continuous cardiac monitoring to assess for any arrhythmias or changes in the electrocardiogram.
• Consider platelet transfusion under the guidance of a hematologist in cases of severe bleeding or refractory thrombocytopenia to restore platelet function and aid in clot formation.
• Consult a toxicologist in severe cases for assistance.

Enhancing Healthcare Team Outcomes

Interdisciplinary collaboration and effective communication among these healthcare professionals are essential to optimize patient outcomes and ensure the safe use of cangrelor. By working together, they can provide comprehensive care, monitor for potential adverse events, and adjust the treatment plan to achieve the best possible results for the patient. When cangrelor is administered to a patient, several disciplines may be involved in treating the patient and managing their condition.

The cardiologist plays a central role in the administration of cangrelor, as they are responsible for determining the appropriate indication, dosage, and duration of therapy. In addition, the cardiology team monitors the patient's cardiovascular status, assesses the need for antiplatelet therapy, and evaluates the response to treatment.

Clinical pharmacists play a crucial role in ensuring the safe and effective use of cangrelor. They provide medication reconciliation, assess potential drug interactions, recommend appropriate dosing adjustments in patients with renal or hepatic impairment, and educate patients on the medication. Cardiothoracic surgery is required for off-label uses. A hematologist consultation may be necessary for severe bleeding. Pathologist provides valuable input regarding the appropriate laboratory monitoring. Nursing should monitor the patient and inform the team regarding any adverse event.  

According to the CAMEO registry (Cangrelor in Acute Myocardial Infarction: Effectiveness and Outcomes), considerable variation in the utilization of cangrelor is evident across different hospitals, with only 27% of patients receiving cangrelor and transitioning to an oral P2Y₁₂ inhibitor in adherence to the clinical trial and FDA label.

Additionally, over one-third of patients are administered a cangrelor infusion for a duration shorter than what is recommended by the FDA (<2 h). These results have important clinical implications, emphasizing the need for improvement in P2Y₁₂ inhibitor transition for individuals undergoing PCI after experiencing an MI. The strategy suggested is improving the knowledge and understanding of clinicians and pharmacists to facilitate the appropriate utilization and smooth transition of cangrelor to an oral P2Y₁₂ inhibitor.[38]

Consequently, an interprofessional team approach utilizing open communication and shared decision-making among clinicians, including specialists, pharmacists, and toxicologists, is essential to improve patient outcomes related to cangrelor therapy.