Clinical profile of prasugrel, a novel thienopyridine

Phase I studies 

In a phase I crossover study, 68 healthy subjects not taking aspirin received either a 300-mg loading dose of clopidogrel or a 60-mg loading dose of prasugrel followed by the alternate therapy after a 2-week washout period. A greater inhibition of ADP-induced platelet aggregation was shown with prasugrel 60 mg than with clopidogrel 300 mg, and with repeated dosing with prasugrel 10 mg than with clopidogrel 75 mg.1 Thus, the peak inhibitory effect on platelet aggregation with 20 μmol/L ADP was higher for prasugrel than for clopidogrel (mean inhibition 78.8% vs 35%, P < .001). In addition, the onset of antiplatelet activity was more rapid with prasugrel than with clopidogrel, as evidenced by the significant inhibition of ADP-induced platelet aggregation seen within 15 minutes and the maximal inhibitory effect achievable within 60 minutes. By contrast, the maximal inhibitory effect was not achieved with clopidogrel for 4 to 6 hours.

The incidence of patient nonresponsiveness to the antiplatelet effects of these compounds was lower with a prasugrel 60-mg loading dose than with a clopidogrel 300-mg loading dose, both in the study of Brandt et al1 and in a separate study involving patients with CAD.2 Of note, 42% of subjects were resistant to clopidogrel, whereas 0% of subjects were resistant to prasugrel, when drug resistance was defined as ≤20% inhibition of platelet aggregation (IPA) to 20 μmol/L ADP at 24 hours.1 Although the subpopulations of poor responders to clopidogrel (42% of subjects) may be uniquely characteristic of the particular patient population tested, all subjects responded to prasugrel, implying less variability in response. Pharmacokinetic analysis indicated that there was less generation of the active metabolite among the clopidogrel-resistant population than among the clopidogrel-responding population. Because the active metabolites for both prasugrel and clopidogrel have similar platelet antiaggregatory potencies in vitro (prasugrel active metabolite half-maximal inhibitory concentration [IC50] 1.8 μmol/L, clopidogrel active metabolite IC50 2.4 μmol/L),3 the difference in antiplatelet responses between these 2 thienopyridine derivatives appears related to the more efficient generation of the prasugrel active metabolite than the clopidogrel active metabolite.1

In a double-blind, placebo-controlled, multiple oral dose phase I study, 30 healthy male volunteers were randomized to receive maintenance doses of prasugrel 5, 10, or 20 mg; the approved clopidogrel maintenance dose of 75 mg; or placebo for 10 days.4 At the end of treatment, the maximum level of platelet inhibition was greater for all the prasugrel doses than for clopidogrel 75 mg (P < .011). In another phase I study, 60-mg loading and 10-mg/d maintenance doses of prasugrel were compared with 300- and 600-mg loading doses of clopidogrel (both given with the approved clopidogrel 75-mg/d maintenance dose) in a 3-period crossover design in 41 aspirin-free healthy volunteers.5 The 60-mg loading dose of prasugrel showed a faster onset of action and greater IPA than did either the approved 300-mg loading dose of clopidogrel or the higher 600-mg loading dose. It is notable that the difference in IPA between prasugrel and clopidogrel 600 mg exceeded the difference between the 300- and 600-mg doses of clopidogrel. Thirty minutes after oral administration, the level of platelet inhibition with a prasugrel 60-mg dose was significantly higher than that observed with either loading dose of clopidogrel. Furthermore, at 1 hour after prasugrel administration, the magnitude of IPA observed with prasugrel surpassed that seen with the respective doses of clopidogrel at up to 6 hours after administration.

In a phase Ib study, 101 aspirin-treated patients with stable atherosclerotic vascular disease were assigned to 1 of 5 regimens encompassing loading and maintenance doses of prasugrel (40 mg and 5 mg/d, 40 mg and 7.5 mg/d, 60 mg and 10 mg/d, and 60 mg and 15 mg/d) or clopidogrel (300 mg and 75 mg/d). Loading doses were administered on day 1, and maintenance doses were administered on days 2 through 28.2 At 28 days, patients who received the 10- and 15-mg maintenance doses of prasugrel, compared with the patients who received 75 mg clopidogrel, demonstrated a lower incidence of nonresponse (0% and 0% vs 45%, P < .0001) and higher inhibition of ADP-induced platelet aggregation (60.6% and 68.4% vs 30.0%, P < .0001).2 However, there was a trend toward minor bruising and bleeding with the 15-mg maintenance dose of prasugrel compared with clopidogrel. Minor bleeding events were numerically, but not statistically, more frequent with the highest dose of prasugrel. The results demonstrated that both prasugrel loading doses yielded more rapid and higher levels of IPA in response to 20 μmol/L ADP.

In a separate phase Ib study, 110 aspirin-treated patients with CAD were randomized in a double-blind fashion to receive a 600-mg loading dose of clopidogrel followed by a 75-mg/d maintenance dose (n = 55) or a 60-mg loading dose of prasugrel followed by a 10-mg/d maintenance dose (n = 55) for 28 days.6 This study demonstrated that the peak level of the active metabolite and P2Y12 inhibition was observed earlier and was greater with prasugrel than with clopidogrel (P < .001). Consequently, the mean platelet aggregation observed at 2 hours after administration of the loading dose was significantly lower for prasugrel than for clopidogrel (31% vs 55%, P < .001). Similarly, during administration of the maintenance dose, mean maximal platelet aggregation was 42% and 54% with prasugrel and clopidogrel, respectively (P < .001). It was further demonstrated that the ex vivo addition of the active metabolite of clopidogrel further reduced the platelet reactivity index in all patients whose platelets were not already maximally inhibited. The results of this study in aspirin-treated patients with CAD indicate that the greater, more efficient generation of the active metabolite of prasugrel results in a faster onset and greater inhibition of P2Y12 receptor–mediated platelet aggregation than does clopidogrel at the doses studied.

Phase II studies 

Although aspirin plus clopidogrel is the current mainstay of antiplatelet treatment in patients with ACS who are undergoing PCI, platelet-mediated thrombotic events continue to occur. Because of its faster onset of action, less interpatient variability, and greater potency compared with clopidogrel, prasugrel may represent a more efficacious and safer alternative to clopidogrel therapy.7 A phase II dose-ranging trial, the JUMBO-TIMI 26, studied clopidogrel and prasugrel regimens in 900 patients undergoing elective or urgent PCI plus stenting.7 Patients were randomized to 1 of 3 combinations of prasugrel loading and maintenance doses: 40 mg and 7.5 mg/d, 60 mg and 10 mg/d, and 60 mg and 15 mg/d, or to standard-dose clopidogrel 300 mg and 75 mg/d. The loading dose was administered at the initiation of the PCI, and the maintenance doses were subsequently given for 30 days. There was a higher absolute rate for prasugrel versus clopidogrel for the primary end point of significant (Thrombolysis In Myocardial Infarction [TIMI] major or minor) non–coronary artery bypass graft-related bleeding, which did not achieve statistical significance (1.7% vs 1.2%, P = .59). The TIMI major bleeding was similar in patients receiving prasugrel and clopidogrel (0.5% vs 0.8%, P = .54). In this safety study, which was not powered to assess efficacy, prasugrel was well tolerated; and the patients receiving this drug showed a lower incidence of the composite end point of 30-day major adverse cardiac events and the end points of myocardial infarction (MI) and recurrent ischemia. Of importance, significantly lower rates of coronary target vessel thrombosis were seen in prasugrel-treated patients (P < .024).7 The acceptable safety profile of prasugrel provided further support for the progression to phase III testing.

An additional evaluation of prasugrel compared with clopidogrel was undertaken in the PRINCIPLE-TIMI 44 study.8 This study was a randomized, double-blind, 2-phase crossover of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterization for planned PCI. In the first phase, a prasugrel 60-mg loading dose was compared with a clopidogrel 600-mg loading dose, with a primary end point of ADP-stimulated IPA at 6 hours. In the second phase, subjects received prasugrel 10 mg or clopidogrel 150 mg (after the loading dose) for 14 days and then were crossed over to the alternate treatment for an additional 14 days. The primary end point was IPA at 6 hours with 20 μmol/L ADP. The IPA at 6 hours was significantly higher in the patients receiving prasugrel (mean 74.8% ± 13.0%) than in the patients receiving clopidogrel (mean 31.8% ± 21.1%), with a least-squares mean difference of 43.2% (95% CI 38.0-48.4, P < .0001). The greater antiplatelet effect of the prasugrel loading dose was seen after 30 minutes (30.8% ± 29.0% vs 4.9% ± 13.2%, P < .0001) and was maintained for 18 to 24 hours (Figure 1, A).8 Greater inhibition of ADP signaling, as measured by vasodilator-stimulated phosphoprotein, also was demonstrated at each time point (Figure 1, B).8 Overall, patients treated with prasugrel had more consistent levels of inhibition, with lower interpatient variability (F test probability value comparing SDs < .0001). Fewer patients in the prasugrel group than in the clopidogrel group demonstrated hyporesponsiveness. The IPA after 14 ± 2 days of maintenance therapy (ie, day 15 and day 29 data combined) was significantly greater in subjects receiving prasugrel 10 mg/d (mean 61.3% ± 17.8%) than in subjects receiving clopidogrel 150 mg/d (mean 46.1% ± 21.3%), with a least-squares mean difference of 14.9% (95% CI 10.6-19.3, P < .0001). Overall, prasugrel was well tolerated, with no TIMI major bleeding and no subject discontinuing therapy prematurely. Two subjects (2.0%) in the prasugrel group and no subjects in the clopidogrel group experienced a TIMI minor bleeding episode before the crossover, and there were no TIMI major or minor bleeding events after the loading dose phase in either group.

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Figure 1. The PRINCIPLE-TIMI 44 IPA with 20 μmol/L ADP. A, Loading dose phase with prasugrel 60 mg and clopidogrel 600 mg. The primary end point of the loading dose phase is the 6-hour comparison. Black circles and lines indicate prasugrel measurements and treatment periods; gray triangles and lines, clopidogrel measurements and treatment periods. B, Maintenance dose phase with prasugrel 10 mg and clopidogrel 150 mg. The primary end point of the maintenance dose phase is the combined 15- and 29-day comparison. Gray circles and lines indicate prasugrel measurements and treatment periods; black triangles and lines, clopidogrel measurements and treatment periods. Data in both figures are mean ± SD. LSM, Least-squares mean. Reprinted with permission from Circulation, Vol 116, Issue 25, Wiviott SD, Trenk D, Frelinger AL, et al, Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial, pp 2923-32, Copyright © 2007 Lippincott, Williams, & Wilkins, www.lww.com. All rights reserved.8

The PRINCIPLE-TIMI 44 is the first study to compare prasugrel with high–maintenance dose clopidogrel. The data from PRINCIPLE-TIMI 44 indicate that prasugrel is more potent and consistent in the setting of PCI and vascular access procedures than is clopidogrel and also support the ability of prasugrel to yield rapid, high, and consistent levels of inhibition of ADP-induced platelet aggregation. The PRINCIPLE-TIMI 44 extends previous observations of the pharmacologic superiority of a 10-mg/d maintenance dose of prasugrel compared with clopidogrel administered in higher-than-standard doses (ie, 150 mg/d) by demonstrating the achievement of greater levels of inhibition of platelet function and fewer poorly responsive patients.9, 10

The PRINCIPLE-TIMI 44 has provided important comparative pharmacodynamic information for prasugrel compared with the higher doses of clopidogrel that are used by some practitioners during and after PCI. In a recent study in aspirin-treated patients with CAD, preliminary results indicate a faster onset of action and greater level of IPA with a prasugrel 60-mg loading dose and 10-mg/d maintenance dose regimen than with a clopidogrel 600-mg loading dose and 75-mg/d maintenance dose regimen.11 Recent results from a randomized crossover study support the observation that the greater IPA observed with prasugrel 60 mg than with clopidogrel 600 mg can be explained by a higher exposure to the active metabolite.12

Phase III study 

The TRITON-TIMI 38 was a randomized, double-blind, parallel-group, multinational, phase III trial comparing prasugrel with clopidogrel in 13,608 patients with moderate- to high-risk ACS who were undergoing PCI including coronary stenting.13, 14 The trial included 10,074 patients with moderate- to high-risk unstable angina or non–ST-segment elevation MI (non-STEMI) and 3,534 patients with STEMI seen at 707 sites in 30 countries. This was the first large-scale clinical study to assess whether a thienopyridine regimen that yields a higher IPA than the standard clopidogrel regimen would result in improved clinical outcomes. Patients were randomized to treatment with either a prasugrel 60-mg loading dose followed by a 10-mg/d maintenance dose or a clopidogrel 300-mg loading dose followed by a 75-mg/d maintenance dose (Figure 2) for 6 to 15 months, with a median duration of therapy of 14.5 months.13 The 60-mg prasugrel loading dose was selected based on its faster onset of platelet inhibition, and the 10-mg maintenance dose was selected based on its superior safety profile without compromise of its antiplatelet efficacy.13

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Figure 2. Design schema for TRITON-TIMI 38. Shown here is the study design, study population, and drug dosing and scheduling for TRITON-TIMI 38, a randomized, double-blind, double-dummy, parallel-group clinical trial with an active comparator. (Reprinted from American Heart Journal, Vol 152, Issue 4, Wiviott SD, Antman EM, Gibson CM, et al, Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction [TRITON-TIMI 38], pp 627-35, 2006, with permission from Elsevier.13)

The primary efficacy end point (ie, death from cardiovascular causes, nonfatal MI, or nonfatal stroke) occurred in 781 patients (12.1%) receiving clopidogrel and 643 patients (9.9%) receiving prasugrel (hazard ratio [HR] for prasugrel vs clopidogrel 0.81, 95% CI 0.73-0.90, P < .001), thus supporting the primary hypothesis of superior efficacy (Table I).14 A significant reduction in the primary end point was seen in the prasugrel group by the first prespecified time point, 3 days (5.6% in the clopidogrel group vs 4.7% in the prasugrel group, HR 0.82, 95% CI 0.71-0.96, P = .01), which persisted throughout the follow-up period. Reduction in the rate of early MI despite no pretreatment may be related to the more rapid onset of antiplatelet activity exhibited by prasugrel.1 From 3 days to the end of the study, the primary end point had occurred in 6.9% of patients receiving clopidogrel and 5.6% of patients receiving prasugrel (HR 0.80, 95% CI 0.70-0.93, P = .003). Significant reduction in the rate of ischemic end points persisting after day 3 suggests a continued benefit of greater IPA during maintenance therapy when steady-state IPA was achieved. Reduction in MI was the principal factor in the difference in primary end points between the groups.

Table I. TRITON-TIMI 38: major efficacy end point in the overall cohort at 15 months

	End point	Prasugrel (n = 6813)	Clopidogrel (n = 6795)	HR for prasugrel (95% CI)	Absolute % reduction in prasugrel group	P⁎
	Death from cardiovascular causes, nonfatal MI, or nonfatal stroke (primary end point)	643 (9.9)	781 (12.1)	0.81 (0.73-0.90)	2.2	<.001
	Death from cardiovascular causes	133 (2.1)	150 (2.4)	0.89 (0.70-1.12)	0.3	.31
	Nonfatal MI	475 (7.4)	620 (9.7)	0.76 (0.67-0.85)	2.3	<.001
	Nonfatal stroke	61 (1.0)	60 (1.0)	1.02 (0.71-1.45)	0	.93
	Death from any cause	188 (3.0)	197 (3.2)	0.95 (0.78-1.16)	0.2	.64
	Death from cardiovascular causes, nonfatal MI, or urgent target-vessel revascularization	652 (10.0)	798 (12.3)	0.81 (0.73-0.89)	2.3	<.001
	Death from any cause, nonfatal MI, or nonfatal stroke	692 (10.7)	822 (12.7)	0.83 (0.75-0.92)	2.0	<.001
	Urgent target-vessel revascularization	156 (2.5)	233 (3.7)	0.66 (0.54-0.81)	1.2	<.001
	Death from cardiovascular causes, nonfatal MI, nonfatal stroke, or rehospitalization for ischemia	797 (12.3)	938 (14.6)	0.84 (0.76-0.92)	2.3	<.001
	Stent thrombosis†	68 (1.1)	142 (2.4)	0.48 (0.36-0.64)	1.3	<.001
	Non–CABG-related TIMI major bleeding (key safety end point)	146 (2.4)	111 (1.8)	1.32 (1.03-1.68)	–	.03
	TIMI major or minor bleeding	303 (5.0)	231 (3.8)	1.31 (1.11-1.56)	–	.002

The percentages are Kaplan-Meier estimates of the rate of the end point at 15 months. Patients could have had more than 1 type of end point. Death from cardiovascular causes and fatal bleeding are not mutually exclusive because intracranial hemorrhage and death after cardiovascular procedures that were complicated by fatal bleeding were included in both end points. CABG, Coronary artery bypass graft.

⁎ P values were calculated with the use of the log-rank test. The prespecified analysis for the primary end point used the Gehan-Wilcoxon test, for which the P value was < .001. † Stent thrombosis was defined as definite or probable thrombosis, according to the Academic Research Consortium; the numbers of patients at risk were all patients whose index procedure included at least 1 intracoronary stent: 6422 patients in each of the 2 treatment groups. Adapted and reprinted with permission from Wiviott SD et al. (N Engl J Med. 2007;357:2001-2015). Copyright © 2007 Massachusetts Medical Society. All rights reserved.14

The reduction in the rate of the primary efficacy end point favored prasugrel among the patients with unstable angina or non-STEMI (HR 0.82, 95% CI 0.73-0.93, P = .002), and a significant benefit of prasugrel was also observed in the STEMI cohort alone (HR 0.79, 95% CI 0.65-0.97, P = .02). The prasugrel group also showed a significant reduction in the secondary end point of death from cardiovascular causes, nonfatal MI, or urgent target-vessel revascularization at 30 days (HR 0.78, 95% CI 0.69-0.89, P < .001) and 90 days (HR 0.79, 95% CI 0.70-0.90, P < .001), as well as in the end point of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or rehospitalization for ischemia (HR 0.84, 95% CI 0.76-0.92, P < .001) (Table I). Significant reductions were seen in the prasugrel group compared with the clopidogrel group in the rates of MI (9.5% vs 7.3%, HR 0.76, 95% CI 0.67-0.85, P < .001), urgent target-vessel revascularization (3.7% vs 2.5%, HR 0.66, 95% CI 0.54-0.81, P < .001), and stent thrombosis (2.4% vs 1.1%, HR 0.48, 95% CI 0.36-0.64, P<0.001) (Table I). The findings on stent thrombosis were statistically significant irrespective of stent type.15

The TIMI major bleeding was observed in 2.4% of patients receiving prasugrel and 1.8% of patients receiving clopidogrel (HR 1.32, 95% CI 1.03-1.68, P = .03) (Table I). The rate of life-threatening bleeding was greater in the prasugrel group than in the clopidogrel group (1.4% vs 0.9%, P = .01), which included nonfatal bleeding (1.1% vs 0.9%, HR 1.25, P = .23) and fatal bleeding (0.4% vs 0.1%, P = .002). In general, both TIMI major and minor bleeding episodes were more frequent with prasugrel than with clopidogrel (Table I). Despite the increased bleeding risk, when subjected to a prespecified analysis of net clinical benefit, the findings still favored prasugrel (13.9% of patients in the clopidogrel group vs 12.2% in the prasugrel group, HR 0.87, 95% CI 0.79-0.95, P = .004).

Certain categories of patients may be more responsive than others to the increased antiplatelet activity of prasugrel. In the 3,146 TRITON-TIMI 38 patients, those with diabetes showed the best clinical benefit with a 30% relative risk reduction in the primary end point without any differences in major bleedings. On the other hand, in a post hoc subgroup analysis, 3 subgroups were identified that demonstrated less clinical efficacy and greater absolute levels of bleeding than in the overall cohort, resulting in less net clinical benefit or clinical harm with prasugrel: patients with a history of stroke or transient ischemic attack before enrollment, elderly patients (aged ≥75 years), and patients with a body weight of <60 kg. In particular, prasugrel was associated with increased intracranial hemorrhage in patients with a history of cerebrovascular disease in whom this drug should be avoided. It may be suggested that optimized (ie, lower) prasugrel maintenance doses are warranted in patients >75 years or those weighing <60 kg. Furthermore, patients who require surgery would have to wait several days for the drug to clear.

Because the prasugrel regimen used here produced higher and more consistent levels of active metabolite than clopidogrel, resulting in higher mean levels of inhibition of platelet function, as well as less interpatient variability and fewer patients with hyporesponsiveness,1 the implication from the TRITON-TIMI 38 results is that regimens that improve the IPA are associated with fewer ischemic events.

Other ongoing and planned trials 

The ongoing SWAP study is a multicenter, randomized, double-blind, double-dummy, parallel-group, active controlled trial with 3 arms designed to assess the impact of prasugrel after a switch from clopidogrel against clopidogrel on multiple parameters of platelet function. Upon study enrollment, subjects (n ≈ 150) with a prior history of ACS (≥30 days after the index event and ≤11 months after) and an indication for 12 months of dual antiplatelet therapy, according to guidelines, will receive open-label clopidogrel 75 mg to be taken daily with aspirin for 10 to 14 days. Afterward, subjects will be randomly assigned to receive a placebo loading dose followed by a 10-mg/d prasugrel maintenance dose, a placebo loading dose followed by a 75-mg/d clopidogrel maintenance dose, or a 60-mg prasugrel loading dose followed by a 10-mg/d prasugrel maintenance dose. The maintenance dose phase will continue for 13 to 15 days. Platelet function profiles will be compared across the assigned treatment groups.

The ACAPULCO study is a phase II trial that has recently finished its enrollment. The study will compare pharmacodynamic differences between high loading and maintenance doses of clopidogrel and standard doses of prasugrel in patients who have ACS and are undergoing PCI. The primary outcome measure is to establish the pharmacodynamic advantage of prasugrel compared with high-dose clopidogrel as assessed by mean maximal platelet aggregation.

The TRILOGY ACS study is a phase III multicenter, double-blind, randomized, controlled trial that will include approximately 10,000 patients at 800 hospitals in 35 countries. It will evaluate the safety and efficacy of prasugrel compared with clopidogrel in reducing the risk of cardiovascular death, MI, or stroke in patients with ACS who are medically managed and in whom no revascularization is planned.

The OPTIMUS-3 study is a phase II pharmacodynamic study that will compare standard doses of prasugrel with high loading and maintenance doses of clopidogrel (600 mg and 150 mg/d, respectively) in patients with type 2 diabetes mellitus and CAD. The primary outcome measure is to establish the pharmacodynamic advantage of prasugrel compared with high-dose clopidogrel as assessed by the Accumetrics VerifyNow P2Y12 assay (Accumetrics Inc, San Diego, CA).

Conclusions 

The clinical characteristics of prasugrel summarized here indicate that this novel thienopyridine may effectively overcome a number of the limitations associated with clopidogrel. Prasugrel has more potent antiplatelet activity, faster onset of action, and less interpatient variability in response compared with clopidogrel even when administered at high doses. These pharmacodynamic properties lead prasugrel to be more efficacious in preventing ischemic events in patients with ACS undergoing PCI. However, the greater platelet inhibitory effects exerted by prasugrel are also associated with an increased risk of bleeding. Nevertheless, the net clinical benefit continues to favor prasugrel over clopidogrel.