Challenges in Oral Antiplatelet Therapy
are the recently approved prasugrel and ticagrelor, which is in late stage clinical development.
Prasugrel
Prasugrel, a thienopyridine administered once daily, was approved in Europe and the US in 2009 for the reduction of risk of thrombotic CV events in patients with ACS undergoing PCI. PRINCIPLE-TIMI 44, a randomised, double-blind, cross-over trial, compared prasugrel (60mg loading dose followed by 10mg/day maintenance dose) with clopidogrel (600mg loading dose followed by 150mg/day maintenance dose); it should be noted that all patients also received aspirin. The results of this study showed the loading dose (60mg) of prasugrel to result in a significantly faster, greater and more consistent inhibition of platelet aggregation than the loading dose (600mg) of clopidogrel in patients undergoing cardiac catheterisation for planned PCI (see Figure 2; p<0.0001).46
The greater potency and speed
of action may be partly attributed to the more efficient absorption of prasugrel and its rapid conversion to the active metabolite, since the prodrug requires only one CYP450-dependent metabolisation
step.7,47–49
The greater consistency of platelet inhibition may be largely
attributed to the more efficient formation of the active metabolite as prasugrel has a much lower genetically determined resistance than clopidogrel.50,51
Despite these benefits, prasugrel has one
pharmacological limitation when used pre-operatively: it cannot overcome the delayed offset of action problem because, similar to clopidogrel, prasugrel also binds irreversibly to the P2Y12 receptor.
The randomised, double-blind TRITON-TIMI 38 phase II trial compared the clinical safety and efficacy of prasugrel (60mg loading dose followed by 10mg daily maintenance dose) with that of clopidogrel (600mg loading dose followed by 75mg daily maintenance dose) in moderate- to high-risk ACS patients undergoing scheduled PCI.52
At
15-month follow-up, the primary end-point (composite of CV death, non-fatal MI or non-fatal stroke) was achieved in a significantly lower proportion of patients in the prasugrel group versus the clopidogrel group (9.9 versus 12.1%; p<0.001).52,53
The superior efficacy of
prasugrel over clopidogrel was noticeable during the first three days of treatment and was still apparent at the end of the study.54
These
results indicate that the efficacy of both the loading and the maintenance doses of prasugrel was superior to that of the relevant doses of clopidogrel. They also emphasise the importance of
maintaining high levels of inhibition of platelet aggregation via P2Y12 receptor inhibition, not only for the prevention of peri-procedural ischaemic events but also during long-term follow-up. Finally, in the TRITON-TIMI 38 study, the rates of definite/probable stent thrombosis were significantly lower with prasugrel versus clopidogrel (1.13 versus 2.35%; p<0.0001).53
Prasugrel therefore may be effective in long-term
treatment after stent implantation. Further studies are needed to evaluate the optimal duration of prasugrel-based dual therapy.
Prasugrel may be more suitable than clopidogrel for patient subsets. For instance, a TRITON-TIMI 44 sub-analysis of patients with STEMI who underwent either primary or secondary PCI showed the primary end- point to be reached significantly more frequently in prasugrel-treated patients than in clopidogrel-treated patients (p=0.022). There was a similar rate of non-CABG-related TIMI major or minor bleeding in the two groups.55
Prasugrel may be especially useful in patients with
diabetes who are predisposed to a prothrombotic risk. It has been shown that prasugrel induced a larger net clinical benefit in patients with diabetes (p=0.001) than in those without diabetes (p=0.16)
EUROPEAN CARDIOLOGY
compared with clopidogrel-treated patients.56 Furthermore, there were
similar rates of TIMI major haemorrhage and TIMI major or minor bleeding in prasugrel- and clopidogrel-treated diabetic patient groups.
Results from the safety cohort of the TRITON-TIMI 38 study showed that the incidence of TIMI major bleeding was significantly greater in patients receiving prasugrel than in those receiving clopidogrel (2.4 versus 1.8%; p=0.03).52
Similarly, the incidence of life-threatening
bleeding (1.4 versus 0.9%; p=0.01), including non-fatal bleeding (1.1 versus 0.9%; p=0.23) and fatal bleeding (0.4 versus 0.1%; p=0.002), was also higher in prasugrel-treated patients.52
Furthermore, according
to post hoc exploratory analyses, in patients with a prior stroke or transient ischaemic attack, those 75 years of age or older and patients weighing less than 60kg, there was a higher bleeding risk and little net clinical benefit of prasugrel over clopidogrel (see Table 1).52
It has been
suggested that in these patients either prasugrel should not be given or a lower maintenance dose should be utilised in order to reduce the bleeding risk. This lower dose is currently being investigated in the randomised, double-blind TRILOGY-ACS phase III trial, with an estimated accrual of 10,300 medically managed patients with UA/NSTEMI ACS. The primary outcome measure of the study is the reduction in risk of the composite end-point of first occurrence of CV death, MI or stroke. Future studies need to investigate the optimal dose of prasugrel in these patients. Since the above-mentioned post hoc analysis linked prasugrel with increased intracranial haemorrhage, prasugrel is contraindicated in patients with a history of cerebrovascular disease.
Finally, study evidence indicates that
prasugrel therapy should not be started in patients with ACS who are expected to undergo CABG surgery since the drug has been associated with an increased risk of major bleeding (p<0.001).52
The
results of the TRITON-TIMI 38 study emphasise the importance of balancing a reduction in thrombotic risk with minimisation of bleeding risk, and also indicate the need to consider the bleeding risk/efficacy ratio with prasugrel in patients with ACS.
Ticagrelor
Ticagrelor is the first reversible, direct-acting, twice-daily-administered
oral P2Y12 antagonist and is currently in late-stage clinical development. It belongs to a new chemical class of antiplatelet agents: the cyclopentyl-triazolo-pyrimidines.57
Ticagrelor differs from the
55
Figure 2: Rate of Onset of Action of Prasugrel versus Clopidogrel
p<0.0001 for each IPA <20% = hyporesponsive
100
40 60 80
64.5 74.8
(n=74) 69.3
(n=78) 30.8 20 4.9 20.3 31.8 Mean ± SD
0048 12 Hours
Prasugrel 60mg 16 20 Clopidogrel 600mg
Data (mean ± standard deviation [SD]) are based on results of the PRINCIPLE-TIMI 44 trial. ADP = adenosine diphosphate; IPA = inhibition of platelet aggregation. Source: Wiviott et al., 2007.46
24 32.6
IPA (%; 20µmol/l ADP)
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