Prasugrel: A novel thienopyridine prodrug for the treatment of acute coronary syndrome

Key Points

Abstract

Prasugrel is a thienopyridine prodrug under FDA review for the treatment of acute coronary syndrome (ACS) managed with percutaneous coronary intervention (PCI). This agent inhibits platelet aggregation with a rapid onset of effect and long duration of action, allowing for once-daily dosing. Clinical trials have demonstrated statistically significant inhibition of platelet aggregation with prasugrel relative to placebo and clopidogrel. Prasugrel has also demonstrated a statistically significant decrease compared with clopidogrel in the composite end point of death related to cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke. However, this improved efficacy outcome entails a significantly increased rate of bleeding. Prasugrel is otherwise well tolerated and has an adverse event profile similar to that of clopidogrel. If approved, prasugrel will be an effective antiplatelet agent for the treatment of ACS with PCI, but its benefit will have to outweigh its increased risk of bleeding, and dosing guidelines for specific patient populations will be warranted. An additional phase 3 study currently under way should help to determine if dose adjustments in patient subgroups reduce the risk of bleeding while still maintaining efficacy. (Formulary. 2008;43:402–408.)

Dr Schillig is a clinical pharmacist, Henry Ford Hospital, Detroit, Michigan. Dr Kalus is the senior manager, Patient Care Services, Henry Ford Hospital.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, clinical manager and director of Drug Information, Department of Pharmacy Services, Hartford Hospital, Hartford, Conn, and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

Platelet activation and subsequent platelet aggregation play a central role in the formation of thrombi after acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI). Because platelets play an important role in the development of ischemic complications, the reduction of platelet activation is important to help prevent complications during PCI and ACS. Adenosine diphosphate (ADP) and thromboxane A₂ are released with platelet activation. When ADP is released, platelet activation is promoted via the G-protein-linked P2Y₁ and P2Y₁₂ receptors, leading to further platelet activation and aggregation. There are currently 2 approved thienopyridine antiplatelet agents, ticlopidine and clopidogrel, which irreversibly bind to P2Y₁₂ receptors and block ADP binding, thereby inhibiting platelet activation and aggregation.^1,2

Prasugrel (Effient, Daiichi Sankyo/Lilly) is a novel, thienopyridine P2Y₁₂ receptor antagonist prodrug that inhibits ADP-induced platelet aggregation in vivo after oral administration.³ In December 2007, an NDA was submitted for prasugrel as a potential treatment for patients with ACS that is managed with PCI. In February 2008, the agent was granted priority review designation by FDA. In June 2008, FDA was expected to make a decision on prasugrel; the agency pushed the action date back to September 26, 2008. On that date, however, FDA announced that the agency had not completed its review.⁴

CHEMISTRY AND PHARMACOLOGY

Prasugrel (2-acetoxy-5-[alpha-cyclopropylcarbonyl-2-fluorobenzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine) is structurally similar to other thienopyridines. The active metabolite of prasugrel (R-138727), a sulfhydryl compound, binds covalently and irreversibly to the platelet P2Y₁₂ receptor via a disulfide bond.¹ Because of this irreversible binding of the active metabolite, there is permanent blockade of ADP-mediated P2Y₁₂ signaling and inhibition of both glycoprotein IIb/IIIa receptor activation and platelet aggregation.¹

Studies in rats have demonstrated that prasugrel acts as an inhibitor of platelet activation and aggregation. In these studies, prasugrel demonstrated a faster onset of action, increased potency, and less response variability compared with clopidogrel.^3,5 Prasugrel produced a dose-related inhibition of platelet aggregation (IPA); in single oral doses, this agent was approximately 10- and 100-fold more potent than clopidogrel and ticlopidine, respectively.³ More than 80% of the platelet inhibitory effect was apparent at 30 minutes and lasted for 3 days, indicating fast onset and long duration of action, which may reflect irreversible P2Y₁₂ blockade.^3,4 The combination of prasugrel and aspirin in rats resulted in greater IPA and inhibition of thrombus formation compared with the use of either agent as monotherapy.³

The observation that prasugrel was approximately 10 times more potent than clopidogrel in animal studies was confirmed in early studies in humans.^6,7 Prasugrel loading doses (LDs) and maintenance doses (MDs) were associated with more rapid, consistent, and greater IPA compared with clopidogrel.

PHARMACOKINETICS

CLINICAL TRIALS

Phase 1 trials. IPA with prasugrel has been compared with the IPA of both clopidogrel and placebo.^7,9,10 When prasugrel 10 mg was compared with placebo, steady-state IPA was achieved with prasugrel beginning on Day 3 and continuing through Day 10.⁹ When prasugrel was compared with clopidogrel, prasugrel 60 mg consistently achieved greater IPA at 30 minutes than clopidogrel 300 and 600 mg.^7,10 In one study, prasugrel achieved greater IPA at 1 and 2 hours than the IPA peak achieved at 6 hours for both clopidogrel LDs.¹⁰ In another study, prasugrel achieved ≥20% IPA 3 times faster than clopidogrel; the mean IPA levels began to plateau approximately 1 hour after prasugrel administration compared with approximately 4 hours after clopidogrel administration.⁷ The mean IPA was also significantly higher for MDs of prasugrel compared with clopidogrel.¹⁰

JUMBO-TIMI 26 was a dose-ranging safety study that included patients with native target coronary artery stenosis >60% who were candidates for elective or urgent PCI with intended coronary stenting.¹¹ The study was designed to evaluate non-CABG-related "significant hemorrhage" at 30 days, defined as the composite of TIMI major and minor hemorrhage. Additional safety end points included major adverse cardiac event components individually and in combination. Patients were randomized to receive prasugrel at low-dose (40-mg LD/7.5-mg MD), intermediate-dose (60-mg LD/10-mg MD), or high-dose (60-mg LD/15-mg MD) levels or clopidogrel (300-mg LD/75-mg MD). The rate of non-CABG-related significant hemorrhage for prasugrel was 1.7% compared with 1.2% for clopidogrel (P=.59). The difference between prasugrel- and clopidogrel-treated groups in the incidence of major adverse cardiac events was not statistically significant, occurring in 7.2% of patients treated with prasugrel and in 9.4% of patients treated with clopidogrel (P=.26).

The crossover study PRINCIPLE-TIMI 44 included patients who were scheduled to undergo cardiac catheterization with planned PCI for angina.¹² Patients were randomized to receive prasugrel or clopidogrel for 14±2 days (Period 1); patients were then switched directly to the other maintenance therapy for an additional 14±2 days (Period 2) without washout. The primary safety end point was non-CABG-related TIMI major or minor hemorrhage through both periods of the crossover study. The primary efficacy end point of the LD phase was IPA at 6 hours in patients who did not receive a glycoprotein IIb/IIIa inhibitor. The end point of the MD phase was the same as the LD phase, except IPA was determined after 14±2 days, including precrossover and postcrossover periods. A secondary end point was major adverse cardiac events occurring during the combined LD and precrossover MD phase. Patients received prasugrel 60-mg LD/10-mg MD or clopidogrel 600-mg LD/150-mg MD for 14±2 days, followed directly by crossover to the alternate maintenance therapy for an additional 14±2 days. There was a statistically significant increase in IPA with prasugrel (74.8% LD/61.3% MD) compared with clopidogrel (31.8% LD/46.1% MD; P<.0001 for both LD and MD). No TIMI major bleeds were observed in either treatment group. TIMI minor bleeding was reported in 2 patients (2%) in the prasugrel group and no patients in the clopidogrel group before the crossover. After the LD phase, no TIMI major or minor bleeding events were reported in either treatment group.

Phase 3 trials. The key landmark clinical trial for prasugrel was the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON)-TIMI 38.¹³ This was a double-blind, randomized trial that compared prasugrel 60-mg LD/10-mg MD with clopidogrel 300-mg LD/75-mg MD in 13,608 patients with moderate- to high-risk ACS and with scheduled PCI. Key exclusion criteria included cardiogenic shock, an increased risk of bleeding (eg, recent fibrinolytic therapy [24 h for fibrin specific and 48 h for nonfibrin specific], active internal bleeding or bleeding diathesis, history of hemorrhagic stroke or ischemic stroke within 3 mo, and international normalized ratio >1.5), anemia, thrombocytopenia, and use of any thienopyridine within 5 days before enrollment. Both therapies were used in combination with low-dose aspirin (75–162 mg) and were administered any time between randomization and 1 hour after the patient left the catheterization laboratory. The primary efficacy end point was a composite of the rate of death from cardiovascular (CV) causes, nonfatal myocardial infarction (MI), or nonfatal stroke during the follow-up period. Secondary end points at 30 and 90 days included the primary composite end point and a composite of death from CV causes, nonfatal MI, or urgent target-vessel revascularization. Key safety end points included non-CABG-related TIMI major bleeding, TIMI life-threatening bleeding (defined as bleeding that is fatal, that is a symptomatic intracranial hemorrhage, or that leads to hypotension requiring treatment with intravenous inotropic agents, requires surgical intervention for ongoing bleeding, or necessitates the transfusion of ≥4 units of blood over a 48-h period), and TIMI major or minor bleeding. The results of the trial are summarized in Table 2.^13,14

The median duration of therapy was 14.5 months.¹³ Baseline characteristics, use of anticoagulants to support PCI (ie, heparin, low molecular weight heparin, bivalirudin), and use of glycoprotein IIb/IIIa inhibitors were similar between treatment groups. Prasugrel and clopidogrel had similar administration times. The drug was administered before the first coronary guidewire was placed in 25% of patients, after the first guidewire was placed and during PCI or within 1 hour after PCI in 74% of patients, and >1 hour after PCI in 1% of patients.

The primary efficacy end point was significantly improved in patients treated with prasugrel (9.9%) compared with those treated with clopidogrel (12.1%; P<.001); most of this benefit was driven by a reduction in nonfatal MI in the follow-up period.¹³ There were minimal, nonsignificant differences between the therapies in the other 2 components of the composite end point. Significant reductions were also noted in the prasugrel group for the secondary efficacy end point at both 30 and 90 days (P<.001).

Among patients treated with prasugrel, there was a significant increase in all key safety end points of bleeding (all P≤.03).¹³ The rates of intracranial hemorrhage were similar in both treatment groups (P=.74), but there was a higher incidence of spontaneous major bleeding and major bleeding related to instrumentation in the prasugrel group. A significantly higher number of patients receiving prasugrel discontinued therapy because of hemorrhagic adverse events (P<.001). The most frequent locations of life-threatening bleeding were gastrointestinal, intracranial, puncture, and retroperitoneal sites.

A post-hoc analysis identified 3 subgroups of patients with less clinical efficacy and greater absolute levels of bleeding compared with the overall cohort.¹³ These subgroups included patients with a history of stroke or transient ischemic attack (TIA) before enrollment, elderly patients (aged ≥75 y), and patients with a body weight <60 kg. In the subgroup of patients with stroke or TIA, investigators observed worse clinical outcomes, based on the primary end point, and more frequent bleeding than in those patients without a history of stroke. The primary end point was reached in 19.1% of prasugrel-treated patients and in 14.4% of clopidogrel-treated patients with a history of stroke or TIA compared with patients without a history of stroke or TIA (prasugrel, 9.5%; clopidogrel, 12%; P=.02). Among patients with a history of stroke or TIA, 5% of those treated with prasugrel and 2.9% of those treated with clopidogrel developed non-CABG-related TIMI major bleeding compared with 2.3% of prasugrel-treated and 1.8% of clopidogrel-treated patients with no history of stroke or TIA (P=.22). Elderly patients and patients who weighed <60 kg were at an increased risk of bleeding; this was attributed to altered drug disposition or smaller body size.

Another post-hoc analysis assessed patients with diabetes and patients without diabetes enrolled in TRITON-TIMI 38.¹⁵ Diabetes was a prespecified subgroup in the TRITON-TIMI 38 trial; however, randomization was not stratified by diabetes status. A total of 3,146 (23%) patients enrolled in TRITON-TIMI 38 had diabetes, and 776 (6%) patients reported treatment with insulin. There was a significant improvement in the primary efficacy end point (composite of CV death, nonfatal MI, and nonfatal stroke) in patients with diabetes who were treated with prasugrel versus those treated with clopidogrel (12.2% vs 17%; P<.001); a significant improvement was also observed in patients without diabetes who were treated with prasugrel versus those treated with clopidogrel (9.2% vs 10.6%; P=.02). Although there was a larger quantitative difference between the 2 therapies in the diabetes group, there was no significant difference in the primary end point between patients with diabetes and those without diabetes (P=.09). Similar to the overall TRITON-TIMI 38 results, a decreased incidence of MI drove the reduction in the primary end point with prasugrel in patients with diabetes. The key safety end point of non-CABG-related TIMI major bleeding was similar between patients with and without diabetes treated with prasugrel or clopidogrel (P=.29).

Another large, phase 3 clinical trial, Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS), began recruiting patients in July 2008.¹⁶ This trial is designed to compare prasugrel 30-mg LD/10- or 5-mg MD with clopidogrel 300-mg LD/75-mg MD in aspirin-treated, medically managed patients enrolled within 7 days of the unstable angina/non-ST elevation MI (UA/NSTEMI) index event. This study will include elderly patients and those with a low body weight, but a dose reduction is planned for these patients (prasugrel 5-mg MD). The primary outcome measure will be the reduction in risk of the composite of first occurrence of CV death, nonfatal MI, or nonfatal stroke.

Adverse Events

Overall, prasugrel has been well tolerated, with the exception of bleeding rates, when compared with placebo and clopidogrel. Adverse events in phase 1 studies that occurred in >5% of patients included headache, increased alanine aminotransferase (ALT), and transient increases in ALT or aspartate aminotransferase (AST).⁶ Rash, gingival bleeding, and positive fecal occult blood occurred in both the prasugrel- and placebo-treated patients.^6,9

In a phase 3 trial, prasugrel was associated with a significantly higher rate of TIMI major hemorrhage not related to CABG, life-threatening bleeding, and fatal TIMI major bleeding.¹³ The rate of serious adverse events not related to bleeding was similar in patients treated with prasugrel and those treated with clopidogrel. Reported adverse events in prasugrel-treated patients included severe thrombocytopenia (0.3%) and colonic neoplasms (0.2%). Neutropenia occurred in <0.1% of patients receiving prasugrel, which was significantly lower than the incidence reported in patients receiving clopidogrel (0.2%; P=.02).

Drug Interactions

Prasugrel is hydrolyzed to a thiolactone metabolite, which is then metabolized to the active metabolite by the cytochrome P-450 system; therefore, there is a potential for drug interactions. In vitro studies have demonstrated that the CYP enzymes predominantly responsible for metabolism of prasugrel are CYP3A4 and CYP2B6, with lesser contributions from CYP2C9 and CYP2C19.¹⁷ In vitro studies have confirmed these findings by demonstrating that co-administration of a CYP inhibitor with prasugrel does not result in decreased active metabolite formation. These study results suggested that alternative CYP enzymes are capable of forming the active metabolite if a specific CYP pathway is inhibited.¹⁷ In vivo studies evaluating ketoconazole and bupropion co-administered with prasugrel have confirmed this theory.^18,19 The combination of prasugrel with ketoconazole or bupropion resulted in pharmacokinetic changes; however, the clinical effects were not significantly altered.

DOSING AND ADMINISTRATION

Because prasugrel is pending FDA approval, formal dosing recommendations are not available. The regimen typically used in clinical trials has been a 60-mg LD followed by a 10-mg/d MD.^12,13 Because of the bleeding events observed in TRITON-TIMI 38, TRILOGY ACS will test a decreased LD of 30 mg followed by a 10-mg/d MD. For the subgroups of patients identified in TRITON-TIMI 38 as having an increased risk of bleeding (history of stroke or TIA, aged ≥75 years, and weight <60 kg), the MD will likely be 5 mg/d.¹⁶ The results of TRILOGY ACS will help to determine if these dosing strategies result in the same efficacy with a decreased risk of bleeding.

REFERENCES

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14. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: A subanalysis of a randomised trial. Lancet. 2008;371:1353–1363.

15. Wiviott SD, Braunwald E, Angiolillo DJ, et al; TRITON-TIMI 38 Investigators. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38. Circulation. 2008;118:1626–1636.

16.A comparison of prasugrel and clopidogrel in acute coronary syndrome subjects (TRILOGY ACS). http://Clinicaltrials.gov/. http://clinicaltrials.gov/ct2/show/NCT00699998?term=TRILOGY+ACS&rank=1/. Accessed October 17, 2008.

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18. Farid NA, Payne CD, Small DS, et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007;81:735–741.

19. Farid NA, Payne CD, Ernest CS 2nd, et al. Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans. J Clin Pharmacol. 2008;48:53–59. F