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Consider the benefits and risks when switching antiplatelet agents
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Clopidogrel has been the primary antiplatelet agent prescribed since its approval by the FDA in November 1997. Recently, new antiplatelet drugs were approved, which makes switching between agents possible.
Prasugrel (Effient, Daiichi Sankyo) and ticagrelor (Brilinta, AstraZeneca) are two of the recently approved antiplatelet agents with indications for use in patients with ACS and/or in those undergoing PCI. While the availability of generic clopidogrel makes it considerably less expensive than either prasugrel or ticagrelor, there are other important differences in the pharmacokinetics, pharmacogenomics, safety and efficacy when comparing these agents.
Switching between agents may be considered for several reasons, including differences in platelet reactivity, onset or offset of platelet inhibition, and cost. Unfortunately, evidence about the safety and efficacy of switching antiplatelet drugs in patients with CAD is limited. The purpose of this article is to describe the evidence regarding switching antiplatelet agents.
Potency of antiplatelet effect
One reason to switch from clopidogrel to another agent is because the newer agents may have more potent antiplatelet effects.
The Switching Anti Platelet (SWAP) study was a phase 2, multicenter, randomized, double blind, double-dummy, active-control trial that evaluated the pharmacodynamic response after switching patients from a maintenance dose of clopidogrel therapy to prasugrel after an ACS. A total of 139 patients were included in the study. After 1 week of treatment with prasugrel at maintenance dose, the maximum ADP-induced platelet aggregation was lower than that observed with the clopidogrel maintenance dose (41.1% vs. 55%, P<.0001). In those patients administered a loading dose of prasugrel, the reduction in platelet function was observed within 2 hours. SWAP concluded that patients who were switched from clopidogrel to prasugrel had a rapid reduction in platelet activity, a surrogate outcome for improved efficacy in preventing ischemic events and that switching from clopidogrel to prasugrel could be considered in patients who require additional platelet function inhibition.
Pharmacogenetic considerations
Alyssa Bortz
Jennifer Stahl
Judith Kristeller
Another reason to switch from clopidogrel to an alternate antiplatelet agent is the presence of genetic polymorphisms known to affect clopidogrel metabolism. Because clopidogrel is a pro-drug that requires a two-step metabolism before it is activated, primarily by CYP2C19, consideration of genetic makeup is important. This is particularly relevant for patients who appear to be nonresponsive to clopidogrel. Patients with CYP2C19 variants that result in intermediate or poor metabolism of clopidogrel, and are at increased risk for ischemic events, should be considered for switching agents.
In a follow-up analysis of the SWAP study, the incidence of high platelet reactivity (HPR), which is associated with an increase in ischemic events, was evaluated after the switch from clopidogrel to prasugrel. Because the effect of prasugrel is not associated with genetic variation of the CYP2C19 allele, it could be expected that a reduced incidence of HPR might be observed if at least a portion of the HPR observed in clopidogrel-treated patients is due to genetic variation of CYP2C19. While SWAP did not determine CYP2C19 genotype, switching from clopidogrel to prasugrel was associated with a reduced prevalence of HPR, suggesting that treatment with prasugrel may overcome HPR associated with impaired clopidogrel metabolism and activation.
In the RESPOND study, clopidogrel nonresponders (n=41) and responders (n=57) were randomly assigned to either clopidogrel 600 mg load followed by 75 mg daily or ticagrelor 180 mg load followed by 90 mg twice daily for 14 days. Nearly all clopidogrel nonresponders had decreased platelet aggregation when switched to ticagrelor, indicating that like prasugrel, ticagrelor may also overcome HPR associated with impaired clopidogrel metabolism and activation.
Cost considerations
When maximal platelet inhibition is desired, prasugrel or ticagrelor may be prescribed instead of the less expensive clopidogrel. However, if a patient is unable to pay for the more expensive agent, nonadherence may be a major problem and can lead to worse outcomes overall. Switching from the newer agents to clopidogrel is often a consideration due to cost, although no pharmacoeconomic studies have yet assessed this.
In a study of 300 patients with ACS treated with prasugrel 10 mg daily, patients with low on-treatment platelet reactivity and/or high risk for bleeding were switched to clopidogrel 75 mg and tested again 15 days later. Using the VerifyNow P2Y12 platform (Accumetrics), low and high platelet reactivity were defined as <30 and >208, respectively. In the cohort of patients who were switched (n=31), platelet reactivity increased and the percentage of patients with low platelet reactivity dropped from 45% to 10% after the switch from prasugrel to clopidogrel. The rate of patients with HPR after the switch in this small cohort of patients increased from 0% with prasugrel to 29% with clopidogrel, exposing a group of clopidogrel nonresponders. Thus, switching from prasugrel to clopidogrel due to cost, or other issues, may be associated with an increase in platelet activity that may lead to ischemic events. It is also possible that switching from ticagrelor to clopidogrel may unmask clopidogrel nonresponders as well.
Patients may also be switched from the more expensive agent ticagrelor to clopidogrel to improve adherence related to affordability. However, before changing therapy, prescribers should consider the different pharmacodynamic properties of these agents. For instance, the onset and offset of the antiplatelet effects of ticagrelor is more rapid than the onset and offset of clopidogrel. The slower offset of clopidogrel may present an increase in risk in patients who then must undergo emergent surgery.
To shorten the onset of action, a loading dose of prasugrel before PCI is sometimes used. This is especially desirable in patients with STEMI because of a more rapid inhibition of platelet function. Following the prasugrel load with a maintenance dose of clopidogrel has been employed as a strategy to reduce bleeding risk as well as drug cost. However, there are no data to support this strategy, and some have argued that the improved platelet inhibition with prasugrel may outweigh the increased bleeding risk and lower cost of clopidogrel.
Benefit, risk, preference
Prasugrel and ticagrelor are more potent platelet inhibitors than clopidogrel. The newer agents may be an option for patients with a genetic polymorphism or those taking concomitant interacting drugs that may render clopidogrel less effective. However, the cost of the newer drugs may deter a patient’s willingness to take the medication as prescribed or even fill the prescription at all. Switching from the newer drugs to clopidogrel may be an appropriate option for patients at increased risk for adverse bleeding events, but clinicians must note the possibility of uncovering a poor metabolizer of clopidogrel and subsequent reduction in efficacy. While additional data are needed to fully understand the implications of genetic testing, genetic testing may be helpful in patients who need maximal antiplatelet therapy but cannot afford the newer agents or in patients who appear nonresponsive to clopidogrel. Before considering genetic testing, however, it may be prudent to determine if the newer agents are affordable for the individual patient. Practitioners should also note that there are currently no data regarding risk for bleeding or ischemic events after switching between available antiplatelet agents.
The benefits and risks of different antiplatelet agents should be considered in the context of an individual patient’s treatment goals and preferences in order to achieve the best overall outcome.
Disclosures: The authors report no relevant financial disclosures.