Prasugrel: A New Antiplatelet for the Management of Acute Coronary Syndrome

Role of Thienopyridines in Patients with Acute Coronary Syndrome

The advent of dual antiplatelet therapy with clopidogrel and aspirin has led to significant advances in the management of patients with acute coronary syndrome (ACS), particularly those undergoing interventional procedures such as percutaneous coronary intervention (PCI) with coronary stenting.^3,4 Current practice guidelines recommend at least 1 year of dual antiplatelet therapy with clopidogrel and aspirin for all non–ST-segment elevation ACS patients and for those without stents.^5–7 ACS patients undergoing PCI with stenting should also receive dual antiplatelet therapy, in most cases for at least 1 year and perhaps indefinitely.^5–7 Despite its proven efficacy, therapy with clopidogrel has raised numerous clinical issues and challenges, including moderate potency and delayed onset of action with standard dosing. Also concerning is the individual variability in clopidogrel's antiplatelet response and its potential for drug interactions that may also decrease clopidogrel's antiplatelet activity.^8,9 With the development and marketing of prasugrel, it was hoped that this third-generation thienopyridine might overcome some of these concerns.

Comparative Efficacy and Safety of Prasugrel and Clopidogrel

The Food and Drug Administration's (FDA's) decision to approve prasugrel was based largely on the findings of The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). ¹⁰ The study randomized 13,608 moderate- to high-risk ACS patients undergoing PCI to either prasugrel (60 mg loading dose, 10 mg maintenance dose) or clopidogrel (300 mg loading dose, 75 mg maintenance dose) plus aspirin for 6 to 15 months. The primary study end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke. Major bleeding was the key safety end point. The primary end point was reduced with prasugrel compared with clopidogrel (9.9% vs 12.1%, respectively; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.73 to 0.90; P < 0.001). The superiority of prasugrel over clopidogrel was evident by day 3 and persisted through the end of the study. However, major bleeding occurred more frequently in those receiving prasugrel (2.4% vs 1.8%; HR, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Similarly, fatal bleeding was more common with prasugrel (0.4% vs 0.1%; P = 0.002). Overall, this trial indicated that for every 1,000 patients treated with prasugrel rather than clopidogrel, 23 MIs were prevented at a cost of 6 major hemorrhages. The estimated number needed to treat (NNT) with prasugrel rather than standard-dose clopidogrel to prevent 1 primary clinical efficacy end point was 46. There was no significant difference in overall mortality. Post-randomization comparison of those patients undergoing PCI with or without stenting demonstrated similar clinical benefit favoring prasugrel over clopidogrel, and similar increases in bleeding risk. ¹¹

Post hoc subgroup analyses identified several subgroups for which prasugrel resulted in less clinical efficacy and increased bleeding risk, leading to no net benefit. Patients who underwent coronary artery bypass graft (CABG) surgery were at greater risk for major or minor bleeding with prasugrel compared with clopidogrel (14.1% vs 4.5%, respectively). Among elderly patients 75 years of age or older, fatal hemorrhages were more common with prasugrel (1% vs 0.1%). Two notable exceptions among this elderly subgroup were those with diabetes or prior MI, who actually derived greater benefit from prasugrel. Another subgroup that experienced no net benefit with prasugrel compared with clopidogrel were those with body weight of less than 60 kg. For patients with a prior history of stroke or transient ischemic attack (TIA), prasugrel therapy was associated with net harm based on no decrease in the primary efficacy end point and increased bleeding risk (HR, 1.54; 95% CI, 1.02 to 2.32; P = 0.04). These findings are reflected in the drug's labeling, which includes a boxed warning indicating that the drug should not be used in patients with a prior history of stroke or TIA, or in those undergoing CABG surgery. The warning also advises against using prasugrel in patients 75 years of age and older, except for those with a history of diabetes or prior MI. ¹²

Factors Impacting Individual Response to Prasugrel or Clopidogrel

Both clopidogrel and prasugrel are prodrugs that undergo metabolism by the cytochrome P450 (CYP-450) enzymes to their respective active metabolites. ² Prasugrel is rapidly metabolized in the blood and intestines to an inactive metabolite, which is then converted to the active form in a 1-step process. Although the major CYP-450 enzyme involved in this conversion is CYP3A4, other enzymes, including cytochromes 2B6, 2C9, and 2C19, are involved to varying degrees. Thus, it has been argued that potential prasugrel drug interactions involving CYP3A4 may be offset to some extent by the ability of other cytochrome enzymes to activate the drug. Conversely, clopidogrel requires a less efficient 2-step process for activation to its active form. ¹³ A pooled analysis of 24 studies compared the antiplatelet effects of prasugrel and clopidogrel in 846 subjects. A 60 mg prasugrel loading dose resulted in faster onset, greater magnitude, and more consistent levels of platelet inhibition compared with clopidogrel in loading doses of 300 or 600 mg. Similarly, the degree of platelet inhibition was greater and more consistent with prasugrel maintenance doses of 10 mg compared with clopidogrel 75 mg. ¹⁴ The PRINCIPLE-TIMI 44 trial compared the platelet-inhibiting effects of prasugrel and clopidogrel in 201 patients undergoing planned PCI. ¹⁵ Patients were randomized to prasugrel with a 60 mg loading dose followed by 10 mg daily or a clopidogrel 600 mg loading dose followed by 150 mg daily for 14 days. Even when compared with this high-dose clopidogrel regimen, the inhibition of platelet aggregation (IPA) at 6 hours was greater with prasugrel (74.8 ± 13% vs 31.8 ± 21.1%, respectively; P < 0.001). Moreover, this difference was apparent within 30 minutes of dosing. Similarly, at day 14, the IPA continued to be greater with prasugrel compared with clopidogrel (61.3 ± 17.8% versus 46.1 ± 21.3%; P < 0.001). It has been suggested that the more efficient activation of prasugrel to its active form and greater degree of IPA may explain not only the greater clinical efficacy, but also the higher bleeding risks seen in TRITON-TIMI 38.

Pharmacogenetic variation may also contribute to differences in the relative potency of prasugrel and clopidogrel for individual patients. CYP2C19, which plays a key role in the activation of clopidogrel, has been associated with polymorphisms, which have been shown in vitro to decrease the antiplatelet response to clopidogrel.^13,16 For example, individuals with the CYP2C19*2 allele have been shown to have resistance to clopidogrel after coronary stent placement and following ST-segment elevation MI.^17,18 Similarly, a cohort study demonstrated increased cardiovascular events and death during the 12 months following MI in individuals with CYP2C19 loss-of-function alleles compared with noncarriers (21.5% vs 13.3%, adjusted HR, 1.98; 95% CI, 1.10 to 3.58) and an almost 4-fold increase in cardiovascular events for individuals with these genetic variants who underwent PCI. ¹⁹

Drug interactions, particularly those involving inhibition of CYP2C19, have also been implicated as a possible cause of decreased antiplatelet activity with clopidogrel. For example, much attention has focused on the potential interaction between clopidogrel and proton pump inhibitors (PPIs). Although the data remain inconclusive, several observational studies have shown increased cardiovascular events in patients receiving combined therapy with clopidogrel and PPIs.^20,21 In contrast, a recently reported but not yet published randomized clinical trial failed to support this adverse drug interaction. ²² In addition, an analysis of both PRINCIPLE 44 and TRITON-TIMI 38 found no evidence to support the need to avoid concomitant PPI therapy with either clopidogrel or prasugrel. Until the discrepancies between the observational and randomized clinical trials can be fully understood, no definitive conclusions can be reached. Nonetheless, the current evidence suggests that pharmacogenetic variation and drug interactions may be less of a concern with prasugrel.

Prasugrel's Place in Therapy

Some experts have hailed prasugrel as a potential replacement for clopidogrel in the treatment of ACS; however, the limited data that are currently available are far from definitive, and many questions remain unanswered. Despite the greater efficacy of prasugrel compared with clopidogrel reported from TRITON-TIMI 38, critics have cited important limitations of the trial.^12,23 It has been suggested that the use of a lower clopidogrel loading dose (300 mg) could potentially have reduced the efficacy of clopidogrel. Studies have shown that a 600 mg loading dose is more effective in reducing cardiovascular end points without increasing the risk of bleeding. ²⁴ Additionally, it has been suggested that the timing of the loading doses may have favored prasugrel because of its faster onset of action. ²⁵ Studies have shown that the antiplatelet activity of prasugrel at 30 minutes is approximately equal to that of clopidogrel at 6 hours. ²⁶ In TRITON-TIMI 38, 25% of patients received the loading dose prior to PCI, whereas 75% received the drug after the procedure was underway. Second, the definition for MI, which was a key component of the primary end point, was modified to include “transient increases in cardiac biomarkers.” In fact, the net clinical benefit of prasugrel would have been eliminated if only clinically reported MIs had been included. In several subsets of patients, the potential for increased efficacy is clearly outweighed by the increased risk for bleeding. These include high-risk patients with prior history of stroke or TIA, the majority of patients older than 75 years of age, patients weighing less than 60 kg, and patients undergoing CABG surgery. While it is possible that the use of a lower maintenance dose of prasugrel might reduce the bleeding risk for these patient groups, the impact on efficacy is not known. An ongoing phase 3 study may shed some light on this issue. Therefore, clopidogrel should remain the preferred thienopyridine in these high-risk patients. Conversely, among elderly patients (older than 75 years of age) at high risk because of diabetes or prior MI, prasugrel may provide greater clinical benefit. In fact, a post hoc analysis of the TRITON-TIMI 38 study population found that the greatest net clinical benefit of prasugrel over clopidogrel occurred in patients with diabetes treated with or without insulin (NNT 13 and 26 for insulin-treated and non–insulin-treated patients, respectively). ²⁷

Additionally, some have suggested that prasugrel may be the preferred agent for patients who have demonstrated variable responsiveness to clopidogrel. For patients in whom decreased antiplatelet activity is caused by genetic variants of CYP2C19, prasugrel would offer an attractive alternative. Conversely, for patients taking concomitant drugs that inhibit CYP2C19, the clinical implications are less clear. Although in vitro studies and observational studies do support an inhibitory effect of these drugs on clopidogrel's antiplatelet effects, randomized trials have not provided clinical evidence for this interaction.

It must also be kept in mind that the current FDA-approved indications for prasugrel are limited to patients experiencing ACS who will be managed by PCI with or without stenting. An ongoing phase 3 trial, Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) is comparing combined therapy with aspirin and prasugrel or clopidogrel in ACS patients managed medically, with completion estimated for 2011 or 2012. ²⁸ This study will also evaluate the efficacy and safety of lower prasugrel doses in certain patients based on age and weight. Finally, the higher costs of prasugrel must be taken into account particularly in view of the anticipated availability of generic clopidogrel by 2011. In the final analysis, prasugrel may offer an attractive alternative for antiplatelet therapy in a select group of ACS patients undergoing PCI. However, in view of the current evidence, prasugrel's limited indications and potential for increased bleeding, clopidogrel should remain the first-line thienopyridine for ACS. Until additional studies are available, hospitals will likely need to develop specific guidelines for prasugrel patient selection and parameters for ongoing monitoring.