Guideline-recommended treatment in patients with acute coronary syndrome is dual anti-platelet therapy (DAPT) with aspirin and a P2Y12 inhibitor, with clopidogrel or ticagrelor the preferred options for initial therapy. Ticagrelor has been demonstrated to have improved efficacy, and is preferred over clopidogrel in the absence of contraindications or the need for oral anticoagulation. However, it is not uncommon that patients are switched to clopidogrel after starting on ticagrelor. Reasons for this may be related to recognition of the increased risk of bleeding, the higher costs of ticagrelor, or adverse effects such as adenosine-mediated dyspnea. It is therefore important to understand the optimal dosing strategy in patients undergoing a switch from ticagrelor to clopidogrel. A loading dose of clopidogrel is standard when initiating therapy for acute coronary syndrome or before coronary stenting. However, whether this is required in patients who have already achieved adequate platelet inhibition with ticagrelor is unknown. Owing to the short half-life of the unbound active metabolite of clopidogrel at standard doses, there are concerns of high on-treatment platelet activity for a period of time following switching. However, this must be balanced against concerns of an increased risk of bleeding if a loading dose is used. To investigate this, the Optimizing Crossover From Ticagrelor To Clopidogrel In Patients With Acute Coronary Syndrome (CAPITAL OPTICROSS) clinical trial was conducted to compare a clopidogrel bolus dose with no bolus among patients currently treated with ticagrelor and whose treating physician had decided to switch therapy to clopidogrel. This review summarizes the CAPITAL OPTICROSS trial and its findings, and discusses the implications for clinical practice.
Dual anti-platelet therapy (DAPT) with aspirin and a P2Y12 inhibitor reduces recurrent ischemic events in patients with acute coronary syndrome and is recommended by guidelines for patients treated with either an early invasive or ischemia-guided strategy.1,2 For initial therapy, either clopidogrel or ticagrelor are the preferred options, with prasugrel also an option at the time of percutaneous coronary intervention in some patients. Based on improved efficacy demonstrated in the randomized Platelet Inhibition And Patient Outcomes (PLATO) trial, ticagrelor is preferred over clopidogrel in the absence of contraindications or a requirement for oral anticoagulants.2,3 In PLATO, the primary endpoint of cardiovascular death, MI or stroke (10.0 versus 12.3 %; p=0.0013) as well as all-cause mortality (4.3 versus 5.8 %; p=0.0020) and cardiovascular mortality (3.7 versus 4.9 %; p=0.0070) were significantly lower for ticagrelor compared with clopidogrel. There was a slight increase for ticagrelor in major bleeding not related to coronary artery bypass surgery (4.8 versus 3.8 %; p=0.0139), but no difference in lifethreatening or fatal bleeds.
The favorable efficacy and safety profile for ticagrelor is related in part to differences in pharmacokinetics. Unlike clopidogrel or prasugrel, ticagrelor is a reversible non-competitive inhibitor of the P2Y12 receptor.
It is active as the parent compound and is (also) rapidly converted to an active metabolite that has similar pharmacokinetics; thus has more rapid onset as well as more potent platelet inhibition than clopidogrel.4 Despite these advantages and the intent to use ticagrelor as part of a DAPT strategy, it is not uncommon that a switch to clopidogrel is necessitated after initiation of ticagrelor. Common reasons for this switch include recognition of increased bleeding risk, requirement for initiation of oral anticoagulation, issues with added cost and insurance coverage for ticagrelor, and development of adenosine-mediated dyspnea as an adverse effect of ticagrelor.
It is unknown whether a loading dose of clopidogrel, as is standard with initiation of therapy for acute coronary syndrome or before coronary stenting, is required when switching from ticagrelor in patients who have achieved therapeutic platelet inhibition. Continued inactivation of the P2Y12 receptor at the time of clopidogrel dosing and the extremely short half-life of the unbound clopidogrel active metabolite following a standard daily dose raise concerns of high on-treatment platelet activity for a period of time after switching. Whether a loading dose of clopidogrel mitigates this concern or may increase bleeding risk is uncertain. These strategies were compared in the Optimizing Crossover From Ticagrelor To Clopidogrel In Patients With Acute Coronary Syndrome (CAPITAL OPTICROSS) clinical trial.5
Clinical Trial Summary
The CAPITAL OPTICROSS trial was a single-center, randomized, openlabel study designed to compare a clopidogrel bolus dose (600 mg) with no bolus among patients who were currently being treated with ticagrelor (180 mg bolus and at least 24 hours of maintenance 90 mg twice daily) and whose physician had decided to switch therapy to clopidogrel. The primary endpoint was P2Y12 reactivity units (PRU) at 72 hours and secondary endpoints included PRU at 12 hour intervals after initial clopidogrel dosing, the incidence of high on-treatment platelet reactivity, (defined as PRU ≥208) major adverse cardiac events (MACE) at 30 days, and thrombolysis in myocardial infarction (TIMI) minor or major bleeding at 30 days. Patients randomized to bolus dose received clopidogrel 600 mg 12 hours after last ticagrelor dose and then clopidogrel 75 mg daily. Patients randomized to no bolus received clopidogrel 75 mg daily beginning 12 hours after last ticagrelor dose.
Sixty patients were randomized, with 30 patients in each group. At 72 hours, there was no difference in PRU for bolus versus no bolus (165.8 ± 71.0 versus 184.1 ± 67.7; p=0.19). During earlier time intervals there was a gradual separation in PRU such that there was a significant difference at 48 hours (114.1 ± 73.1 versus 165.1 ± 70.5; p=0.0076), followed by convergence of the groups thereafter. The frequency of high on-treatment platelet reactivity was also significantly lower in the bolus group (26.7 % versus 56.7 %; p=0.02). There were no differences in MACE (one event in each group), TIMI major bleeding (no events) or TIMI minor bleeding (one versus two events).
Discussion of Results
The results of the CAPITAL OPTICROSS trial suggest that a 600 mg bolus of clopidogrel 12 hours after ticagrelor is associated with early reduction in platelet reactivity compared with no bolus, but that by 72 hours this difference is attenuated. Furthermore, the risk of high on-treatment platelet reactivity was significantly lower after a bolus dose. Although there was not an increase in risk of ischemic or bleeding events with either strategy, the numbers were too small to draw conclusions.
Based on the pharmacokinetics of ticagrelor and clopidogrel, the results are not unexpected. As a non-competitive reversible inhibitor of the P2Y12 receptor, ticagrelor continues to inactivate platelets for a limited period of time after the last dose. In pharmacodynamic studies, the offset is rapid with inhibition of platelet aggregation <50 % by 24–36 hours after discontinuation of ticagrelor.4 The ticagrelor binding site on the P2Y12 receptor is distinct from the adenosine diphosphate (ADP) site bound by thienopyridines.6 However, binding by ticagrelor at the remote site renders the receptor locked in an inactive state and prevents ADP signaling. As ticagrelor dissociates from the receptor, it returns to active state. ADP is able to bind and initiate signaling for platelet aggregation. If the active metabolite of clopidogrel is unable to bind to its site on the P2Y12 receptor, it is rapidly cleared and thus ineffective. Given the rapid offset of ticagrelor there would be an expected loss of platelet inhibition during this transition until a steady state is achieved by repeat clopidogrel dosing. Previous studies have shown that effective inhibition of platelet activity requires several days with daily dosing of 75 mg,7 but is achieved within several hours after a 600 mg loading dose. The data from CAPITAL OPTICROSS indicate that an initial loading dose provides more effective platelet inhibition during the first 48 hours compared with initiating therapy with clopidogrel 75 mg daily. The increase in PRU after 24–48 hours in the bolus group raises the question whether an additional clopidogrel bolus dose after 24 hours may have provided a longer duration of effective platelet inhibition as the concentration and inhibitory effect of ticagrelor continue to decrease and more P2Y12 receptor binding sites become available. This hypothesis, of course, was not tested in this study.
The absence of an increase in bleeding is of limited value given the small number of patients included in the study. Nevertheless, given the known differences in efficacy between ticagrelor and clopidogrel for platelet inhibition it is unlikely that a bolus dose of clopidogrel 12 hours after the last ticagrelor dose would increase bleeding.
There are several limitations in generalizing these data to clinical practice. First, the study was a single-center pharmacodynamic study conducted in the acute setting. Although this is the most common time to initiate a change from ticagrelor, the findings may not apply to later time periods. For example, PRU at baseline and on-treatment may be higher in patients in the acute setting and the impact of a loading dose may be greater. The platelet function results are limited to 72 hours. This is reasonable for testing the effect of an initial bolus dose, but does include a window where there is possible residual effect of ticagrelor and does not allow estimates for a steady state of clopidogrel platelet inhibition. For example, depending on the observations between 3–7 days, it may be reasonable to question the value of a subsequent clopidogrel bolus dose. The primary endpoint at 72 hours was not met and the significance in a secondary endpoint at 48 hours is subject to type 1 error. However, the trends in the assessments before 48 hours are consistent, and support the finding at 48 hours. Finally, the study is underpowered to make inference on clinical outcomes of MACE or bleeding. This does not, however, lessen the importance of the pharmacodynamic results.
Clinical Practice Implications
A planned switch from a more potent P2Y12 inhibitor to clopidogrel is common, with a frequency of 5–14 % in registry reports.8 In the acute phase after acute coronary syndrome presentation, a bolus dose of clopidogrel 600 mg given 12 hours after the last dose of ticagrelor is associated with improved platelet inhibition at 48 hours and reduces the risk for high on-treatment platelet reactivity during the 72 hours after switching. In this setting, when a switch from ticagrelor to clopidogrel is required for clinical or economic reasons, it seems reasonable to initiate the switch with an initial 600 mg bolus followed by a daily dose thereafter. Whether subsequent bolus dosing for switching early after acute coronary syndrome may be even more effective or if similar bolus dosing is required for later time of switching is not known.
- Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: A report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2014;130:e344–426.
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- Roffi M, Patrono C, Collet JP, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37: 267–315.
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- Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57.
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- Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the onset and offset of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The onset/offset study. Circulation 2009;120: 2577–85.
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- Pourdjabbar A, Hibbert B, Chong AY, et al. A randomised study for optimising crossover from ticagrelor to clopidogrel in patients with acute coronary syndrome. The CAPITAL OPTI-CROSS study. Thromb Haemost 2017;117:303–10.
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- Husted S, van Giezen JJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther 2009;27:259–74.
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- Savcic M, Hauert J, Bachmann F, et al. Clopidogrel loading dose regimens: Kinetic profile of pharmacodynamic response in healthy subjects. Semin Thromb Hemost 1999;25 Suppl 2:15–9.PubMed
- Rollini F, Franchi F, Angiolillo DJ. Switching p2y12-receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol 2016;13:11-27.
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