Optimizing the Use of Cangrelor in the Real World

Arman Qamar; Deepak L. Bhatt


Am J Cardiovasc Drugs. 2017;17(1):5-16. 

In This Article


Platelet activation and aggregation plays a crucial role in atherothrombosis and subsequent ischemic events.[1] Indeed, platelets are a pivotal therapeutic target in the management of patients across the full spectrum of acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI). The last decade has witnessed significant progress in the development of new antiplatelet agents.[2] These advances have revolutionized the treatment of patients in the settings of ACS and PCI. Currently, dual antiplatelet therapy with aspirin in addition to P2Y12 receptor inhibitors is the standard of care for patients with ACS as well as those treated with PCI.[3–6] In patients undergoing PCI, thrombotic events such as myocardial infarction (MI) or stent thrombosis are the major cause of death and adverse events. Although periprocedural antithrombotic therapy with platelet inhibitors has reduced ischemic events in patients undergoing PCI, a substantial risk still remains.

Clopidogrel, the most widely used P2Y12 receptor inhibitor, has been shown to reduce ischemic events in stable coronary artery disease (CAD) and ACS patients undergoing PCI.[7–9] However, despite its efficacy, clopidogrel has several limitations, including slower onset and offset of action, interindividual variability and only modest platelet inhibition.[10–13] More potent oral P2Y12 receptor inhibitors such as prasugrel and ticagrelor have faster onset of effect and less variable response than clopidogrel. In ACS patients, treatment with prasugrel or ticagrelor as compared with clopidogrel has proved to be more effective in preventing ischemic events, including stent thrombosis.[14–17] However, consistent with increased platelet inhibition, this benefit is associated with a significant increase in the rates of bleeding. Similar to clopidogrel, prasugrel and ticagrelor can only be administered orally. Many patients with ACS have conditions such as nausea, vomiting, impaired gut perfusion, therapeutic hypothermia, or use of narcotics that reduce the absorption of oral antiplatelet agents.[18–21] As a result, these patients are at an increased risk of stent thrombosis and adverse ischemic events in the vulnerable peri-PCI period.

Furthermore, as management of ACS has evolved, the time from hospital admission to PCI has continued to shorten in all settings.[22] Accordingly, there is a need for a faster-onset antiplatelet therapy. Although quicker than clopidogrel, both prasugrel and ticagrelor may take several hours to achieve optimal platelet inhibition even following a loading dose in patients with ACS, particularly in those with ST-segment elevation myocardial infarction (STEMI).[23–25] Use of a high loading dose regimen or crushing tablets has been tried to enhance the bioavailability of oral P2Y12 receptor inhibitors in STEMI patients undergoing PCI.[26,27] However, to date, none of these strategies have resulted in the desired immediate platelet inhibition, warranting the need for intravenous therapies such as cangrelor. Thus far, randomized trials have shown uncertain benefit and possible harm with oral P2Y12 receptor inhibitor preloading before coronary angiography with intent to perform PCI.[28–31] This equipoise has led to marked practice variation in the timing of oral P2Y12 receptor inhibitor loading in patients undergoing PCI.[32,33] Notably, less than one-third of patients undergoing coronary angiography with the goal of revascularization are pretreated with an oral P2Y12 receptor inhibitor.[34] Many physicians are concerned that coronary angiography could show an indication for coronary artery bypass graft (CABG) surgery, and refrain from administering P2Y12 receptor inhibitors until coronary anatomy is delineated. Approximately 10–15 % of ACS patients require CABG. It takes 5–7 days for platelet function to recover in patients treated with clopidogrel, prasugrel, or ticagrelor; consequently, CABG is often delayed, causing inconvenience to patients, families and prolongation of hospitalizations. Current guidelines recommend stopping oral P2Y12 receptor inhibitors at least 5 days before CABG. Discontinuing antiplatelet therapy in patients with ACS increases thrombotic risk, and continuing through surgery increases surgical bleeding risk.[35] While intravenous antiplatelet therapy with glycoprotein IIb/IIIa receptor inhibitors such as abciximab, eptifibatide, and tirofiban reduces thrombotic events in ACS patients receiving PCI, it also increases bleeding, and platelet function may take hours to days to normalize after discontinuation.[36] A parenteral antiplatelet agent with a rapid onset of action to achieve an early desirable level of platelet inhibition that is quickly reversible if an urgent CABG is needed would address these concerns.