2014 Volume 78 Issue 12 Pages 2840-2842
The “one size fits all” approach to P2Y12 inhibition is more and more being challenged. Early treatment strategies with clopidogrel did not take into account the large degree of interindividual pharmacodynamic (PD) responses,1,2 leaving patients with lesser degrees of platelet inhibition and/or higher residual platelet reactivity (HPR) exposed to an increased risk of cardiovascular events.3 The newer agents, prasugrel and ticagrelor, despite a faster onset of action and a higher degree of P2Y12 inhibition, also display a certain degree of interindividual PD responses, depending on the treated population and the clinical setting. HPR can be overcome with these newer drugs,4 with <5% of poor responders, but high on-treatment platelet inhibition has become a drawback,5 accounting for an increased bleeding risk,6 especially during the period of maintenance therapy up to 1 year, in combination with aspirin. This excess bleeding risk has also been shown over short periods of treatment when treatment is started early before angiographic confirmation of the diagnosis of non ST-elevation acute coronary syndrome (ACS).7
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Elective PCI is the last bastion where clopidogrel remains the preferred option in combination with aspirin to prevent recurrent ischemic events. The phenomenon of “resistance” or “non-response” to clopidogrel has been extensively studied and linked to recurrent cardiovascular events in this setting.8 However, despite the need for better antiplatelet therapy in elective PCI for high-risk cases or high-risk patients as now recommended in the guidelines,9 there is currently no demonstration of superiority of the new drugs over clopidogrel to prevent periprocedural events and short-term complications such as stent thrombosis. Double dose of clopidogrel loading dose (LD) at 600 mg followed by a double dose (150 mg) of clopidogrel maintenance dose (MD) did not provide much benefit for ischemic events in elective patients,10 and was even associated with higher major bleeding rates in ACS.11 Platelet function testing to tailor clopidogrel treatment failed to improve patients’ prognosis in elective PCI,12 although it did improve pharmacological response. Cangrelor13 provided an additional degree of reduction of ischemic events, especially acute stent thrombosis, and could be a new costly option. Prasugrel and ticagrelor can overcome high platelet reactivity, but clinical data in elective PCI are missing. Moreover, the risk of bleeding associated which the current standard dosage is a concern in these low-risk patients.
East Asian populations have several specific characteristics regarding the PD of P2Y12 inhibition with clopidogrel, including a more frequent HPR than Western populations accounted for by more frequent poor metabolizers carrying CYP2C19*2 and *3 loss-of-function genetic variants.14,15 Age and body weight may also differ on average from Caucasian populations, knowing that in the FEATHER trial16 5 mg prasugrel in low body weight patients provided a similar level of platelet inhibition to 10 mg prasugrel in higher body weight patients. The Asian population also displays a higher PD response to prasugrel and ticagrelor with higher exposure to the active metabolite than do Caucasians,17 suggesting that these drugs are not suitable at the standard dose regimens.
In the Japanese population, a new low dose of prasugrel has been evaluated in the PRASFIT-ACS trial and tested now in the population undergoing elective PCI. This dosage is supposed to provide an intermediate level of P2Y12 inhibition between 10 mg prasugrel MD and clopidogrel 75 mg MD, with the final aim of having a better risk-benefit ratio. The combination of prasugrel 20 mg LD followed by 3.75 mg MD demonstrated a reduction of MACE from 6.7% to 4.1% (RRR of 39%) vs. the classic clopidogrel dose (300 mg/75 mg) without harm. Bleeding events were even fewer in the prasugrel arm (0% vs. 2.2%) in this double-blind study. These findings are supportive of the PRASFIT-ACS trial18 in which low-dose prasugrel did reduce ischemic events (MACE) from 11.8% to 9.4% (RRR 23%) without any increase in major bleeding events (1.9% vs. 2.2%). Both studies were underpowered and did not provide adequate statistics to definitely conclude a reduction of ischemic events, and these are major limitations of both PRASFIT-Elective19 and PRASFIT-ACS.18 However, the results are consistent across the 2 studies and to a lesser degree, with TRITON and PLATO and the meta-analysis of newer P2Y12 inhibitors when compared with clopidogrel.20 It must be noted that most of the benefit was found in the first 30 days, which seems logical considering the endpoints and the use of last-generation drug-eluting stents.
In both PRASFIT trials, low-dose prasugrel led to a much better PD response in patients identified as genetic poor metabolizers. Overall, the PD response was always better than with clopidogrel, but lower than with 10 mg or prasugrel, a finding that is in line with the clinical data. The level of platelet inhibition obtained in these studies with this new low-dose regimen of prasugrel does not seem, on average, more potent than 150 mg of clopidogrel when compared with other studies and is even closer to the effect of 75 mg of clopidogrel in the Western population (Figure).21
Levels of platelet reactivity unit measured by VerifyNow with the different regimens of prasugrel and clopidogrel reported in the literature, with regard to age category and weight data if available.21 MD, maintenance dose; PCI, percutaneous coronary intervention.
Thanks to studies such as PRASFIT-ACS18 and PRASFIT-Elective,19 data are accumulating on the concept of low dosing with new P2Y12 inhibitors. Indeed, TRILOGY studied different doses of prasugrel (10 mg or 5 mg) according to (<75> years) and weight (>60 kg) of the patients and showed an excellent safety profile for the low-dose regimen, although ischemic events were not significantly reduced with prasugrel in comparison with clopidogrel.22 However, the TRILOGY population was a medically treated population and the only trial of PCI patients is the ongoing ANTARCTIC trial (NCT01538446) which is evaluating the 5-mg dose of prasugrel compared with a tailored therapy arm using prasugrel or clopidogrel at different doses in a fragile elderly population over 75 years of age.
Whether longer treatment with low-dose prasugrel or ticagrelor would benefit PCI patients with similar safety warrants further investigation. In the secondary prevention PEGASUS trial (NCT01225562) trial, a low-dosing strategy is also tested with ticagrelor (60 mg twice daily) in comparison with clopidogrel, both in association with aspirin, while the standard dose of ticagrelor (90 mg twice a day) is also tested in a third arm with aspirin alone. Ticagrelor is also being evaluated as single therapy during the maintenance phase following PCI (GLOBAL leader (NCT01813435)). Lowering the dose and/or removing aspirin are new ways under exploration to reduce bleeding while keeping optimal protection against ischemic events.
In conclusion, low-dose prasugrel appears to work and results suggest that the currently recommended dose regimen may be too strong in certain populations or conditions. We may be entering a new era with prasugrel and ticagrelor, starting an opposite strategy to the one we knew with clopidogrel, when we increased clopidogrel doses to improve efficacy. We are now trying to reduce the doses of the new P2Y12 inhibitors to improve safety.
Professor Montalescot reports receiving consulting fees from Bayer, Boehringer-Ingelheim, Cardiovascular Research Foundation, Europa Organisation, the Gerson Lehrman Group, Iroko Cardio International, Lead-Up, LLC, Luminex, Mc Kinsey & Company, Inc, Remedica, Servier, TIMI Group, WebMD, and Wolters Kluwer Health; consulting fees and grant support from Bristol-Myers Squibb, AstraZeneca, Biotronik, Eli Lilly, The Medicines Company, Medtronic, Menarini Group, Sanofi-Aventis, Pfizer, and Accumetrics; and grant support from Abbott Vascular, Daiichi-Sankyo, Nanospheres Inc, and Stentys.
Professor Collet reports receiving research grants from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, Fédération Française de Cardiologie, and Société Française de Cardiologie; consulting fees from Sanofi-Aventis, Eli Lilly, and Bristol-Myers Squibb; and lecture fees from Bristol-Myers Squibb, Sanofi-Aventis, and Eli Lilly.
Dr Kerneis has received research grants from Fédération Française de Cardiologie.
Dr Silvain reports receiving research grants to the institution from Boehringer-Ingelheim, Daiichi-Sankyo, Eli Lilly, BRAHMS, and Sanofi-Aventis, Fédération Française de Cardiologie and Société Française de Cardiologie, INSERM; consultant fees from Daiichi-Sankyo, Eli Lilly, AstraZeneca and the Medicines company; and lecture fees from AstraZeneca, Cordis, Daiichi-Sankyo, Eli Lilly, Iroko Cardio and STENTYS.
