A combination of aspirin and P2Y12 inhibitors (thienopyridine or ticagrelor) is recommended with a high level of evidence for the treatment of acute coronary syndrome (ACS) [1,2]. The TRITON TIMI38 study [3,4] has shown that, compared with clopidogrel, prasugrel, a third generation thienopyridine P2Y12 blocker, decreases the recurrence of ischemic events in ACS. In stable patients receiving a maintenance dose of clopidogrel, switching from clopidogrel to prasugrel is associated with increased platelet inhibition and this effect is obtained within 2 h when a loading dose of 60 mg of prasugrel is given [5]. However, in ACS, the switch to prasugrel after a clopidogrel loading dose has not been assessed because pretreatment with clopidogrel was an exclusion criterion in the TRITON TIMI38 study [3,4]. Therefore, there is no consensus on the way to manage this switch in the early phase of ACS in patients who are not on a maintenance dose of clopidogrel but who have just received a clopidogrel loading dose before their admission to the cardiology unit. In particular, the optimal dose of prasugrel re-load (RL) in such patients is unknown. This prompted us to perform a prospective non-randomized observational study to assess platelet residual activity in response to various doses of prasugrel RL after recent clopidogrel administration.

Eighty consecutive patients referred to our centre and scheduled for percutaneous coronary intervention (PCI) for ACS were included, provided that they were not being treated with clopidogrel or vitamin K antagonists before the ACS and that they had received a pre-hospital loading dose of 300 mg of clopidogrel within 4 h before their admission. Patients with contra-indications to prasugrel (age > 75 years, body weight < 60 kg, a history of a stroke or transient ischemic attack), additional risk factors for bleeding (hematocrit < 30%, platelet count < 90 G. L−1) or treated with a glycoprotein IIb/IIIa antagonist were not included. All patients were treated according to current standards and received a loading dose of 250 mg of aspirin with clopidogrel. This study was approved by the institutional review board of our hospital and all patients gave their informed consent.

The main criterion of the study was the residual platelet reactivity after prasugrel RL, assessed on citrated blood using the VerifyNow® P2Y12 assay (VN-P2Y12; Accumetrics, San Diego, CA, USA) and expressed as platelet reactivity unit (PRU), and vasodilator-stimulated phosphoprotein phosphorylation (VASP; Biocytex, Marseille, France) expressed as the geometric mean platelet reactivity index (PRI), according to the manufacturers’ instructions [6]. The cut-off values of the VerifyNow and VASP assays, which define high on-treatment platelet reactivity predictive of cardiovascular events, were a PRU ≥ 235 and a PRI ≥ 60%, respectively [7–9].

Statistical analyzes were performed using stata se version 10 (StataCorp LP, College Station, TX, USA), in the same way for the two phases of the study (first 10 vs. 30 mg of prasugrel and second 30 vs. 60 mg of prasugrel). Potential differences between the two groups (clinical characteristics, markers of platelet activity levels before and after RL) were tested using chi-squared tests for categorical data and Mann–Whitney non-parametric tests for quantitative data.

The study was performed according a stepwise design of escalating doses of prasugrel RL from 10 to 60 mg. The laboratory tests were performed on admission of the patient to the cardiology unit, usually between 2 and 3 h after clopidogrel LD, and at various times after prasugrel RL. Prasugrel RL was given in the hour after admission. Therefore, the delay between clopidogrel and prasugrel was at least 3 h (estimated mean: 3.5 h), in all groups. PCI was performed within 72 h after admission.

In a first phase (40 patients), we compared the effects of 10 and 30 mg of prasugrel 12–18 h after RL before starting the maintenance treatment. The first 20 patients received 10 mg of prasugrel and the next 20 received 30 mg of prasugrel. The baseline clinical characteristics of the two groups and the levels of platelet inhibition by clopidogrel at admission were not significantly different (Table 1). In contrast, residual platelet reactivity was significantly lower in the 30-mg compared with the 10-mg group, irrespectively of the test used (Fig. 1A,B and Table 1). Although all patients but one in the 10-mg dose group, displayed platelet reactivity below the cut-off values of either test, the 10-mg dose appeared to be suboptimal.

Table 1.   Clinical characteristics and markers of platelet reactivity
Prasugrel RL doseFirst study phaseSecond study phase
10 mg (n = 20)30 mg (= 20) P 30 mg (= 20)60 mg (= 20) P
  1. Continuous data are presented as median value (interquartile range). RL, reload; MI, myocardial infarction; PRU (VerifyNow®), platelet reactivity unit; PRI (VASP), platelet reactivity index.

Age (years)57 (49–68)58 (46–61)0.5963 (56–70)62 (49–66)0.59
Male gender (%)85851.0060800.17
ACS type (%)  0.56  0.47
 STEMI4035 2540 
 NSTEMI with biomark4030 4040 
 NSTEMI without biomark2035 3520 
Before RL: PRU166 (57–225)150 (112–267)0.30147 (35–198)144 (56–236)0.55
Before RL: PRI44 (20–66)56 (24–76)0.2935 (18–45)52 (23–70)0.14
4 h after RL: PRU   21 (8–68)26 (4–68)0.86
4 h after RL: PRI   7 (5–15)2 (0–10)0.043
12–18 h after RL: PRU66 (32–141)31 (10–57)0.03541 (34–50)6 (3–37)0.011
12–18 h after RL: PRI32 (23–42)12 (6–26)0.000311 (7–14)7 (1–12)0.06

Figure 1.  Platelet response to prasugrel re-load at various times after the initial clopidogrel loading dose. (A,B) first study phase 10 vs. 30 mg; (C,D) second study phase: 30 vs. 60 mg. The data are presented as box plots, where the boxes represent the 25th to 75th percentiles, the lines within the boxes the median, and the whiskers the adjacent values. Plots indicate outliers. The dotted lines represent the cut-off values for high on-treatment platelet reactivity.

Download figure to PowerPoint

As PCI is usually performed within hours of admission, in a second phase of the study, we compared the kinetics of platelet inhibition with 30 or 60 mg of prasugrel RL. Blood samples were obtained in 40 new patients before, and 4 h and 12–18 h after prasugrel RL. The first 20 patients received 30 mg of prasugrel RL and the next 20 received 60 mg. The baseline clinical characteristics of the two groups and their levels of platelet inhibition by clopidogrel at admission were not significantly different (Table 1); they were also not different from those of the patients included in the first phase of the study (not shown). Table 1 and Fig. 1C,D show that the antiplatelet effect of prasugrel RL was obtained early within 4 h, and was sustained for 12–18 h. The residual platelet activity was significantly lower in the 60-mg dose at 4 h (VASP assay) and at 12–18 h (both tests). No patient had a value of PRU or PRI above the cut-off in the 30-mg group at 12–18 h or in the 60-mg group at any time. One patient in the 30-mg group displayed platelet inhibition values close to the cut-offs (PRU: 230; PRI: 64%) at 4 h.

Many patients admitted for ACS and referred for PCI treatment receive a clopidogrel loading dose before their admission to the cardiology unit and would benefit from more intensive antiplatelet therapy. In our study, considering the whole group of 80 patients, after 300 mg of clopidogrel and before prasugrel, the PRU was above the cut-off of 235 in 17 (21%) patients and the PRI was above 60% in 23 (29%) patients, indicating high on-treatment reactivity and the need for reloading with a P2Y12 antagonist in about one-quarter of patients. Our study is the first to assess the pharmacodynamic effect of prasugrel RL soon after clopidogrel during ACS. We show that 30-mg prasugrel RL decreases platelet function more efficiently than 10 mg and that although 60-mg prasugrel RL did result in further platelet inhibition, the desirable level of platelet inhibition was obtained within 4 h with 30-mg prasugrel RL, allowing the performance of PCI without delay, and persisted until the start of maintenance treatment.

This study was based on laboratory endpoints and was not sized to assess the efficacy and safety of the strategy. At this time there are no studies that define a laboratory cut-off associated with bleeding risk during the days immediately after PCI for an ACS. So, it is difficult to define the therapeutic window with a maximum reduction in thrombotic events and a minimum rate of serious bleeding, as it has recently been reported for elective PCI in patients with stable angina [10]. After the switch, all patients received standard maintenance doses of prasugrel (10 mg) and aspirin (75 mg). Although no serious adverse events, particularly no TIMI major bleeding events, occurred either in the 10-, 30- or 60-mg groups during the hospital stay, larger trials with clinical endpoints are required. In addition, we did not test the situation where 600-mg clopidogrel loading dose would be used, a practice current in other centers.

We conclude that 30-mg prasugrel RL seems to be the optimal dose for switching patients pretreated with 300 mg of clopidogrel.


  1. Top of page
  2. Acknowledgements
  3. Disclosure of Conflict of Interests
  4. References

We thank V. Bataille (ADIMEP) for his help in data analysis. This work was supported by a grant research from Lilly and Daïchii Sankyo.

Disclosure of Conflict of Interests

  1. Top of page
  2. Acknowledgements
  3. Disclosure of Conflict of Interests
  4. References

The authors state that they have no conflict of interest.


  1. Top of page
  2. Acknowledgements
  3. Disclosure of Conflict of Interests
  4. References
  • 1
    Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D, Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF, Wijns W, Zahger D, ESC Committee for Practice Guidelines. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European society of cardiology (ESC). Eur Heart J 2011; 23: 29993054.
  • 2
    Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC), the European Association for Cardio-Thoracic Surgery (EACTS), European Association for Percutaneous Cardiovascular Interventions (EAPCI), Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, Garg S, Huber K, James S, Knuuti J, Lopez-Sendon J, Marco J, Menicanti L, Ostojic M, Piepoli MF, Pirlet C, Pomar JL, et al. Guidelines on myocardial revascularization. Eur Heart J 2010; 20: 250155.
  • 3
    Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 200115.
  • 4
    Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH, Antman EM, TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 72331.
  • 5
    Angiolillo DJ, Saucedo JF, Deraad R, Frelinger AL, Gurbel PA, Costigan TM, Jakubowski JA, Ojeh CK, Effron MB, SWAP Investigators. Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes: results of the SWAP (switching anti platelet) study. J Am Coll Cardiol 2010; 56: 101723.
  • 6
    Carrié D, Garcia C, Gratacap MP, Voisin S, Payrastre B, Sié P. Assessment of platelet response to clopidogrel through measurement of ADP-induced Akt phosphorylation. J Thromb Haemost 2009; 8: 14113.
  • 7
    Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, Bhatt DL, Cattaneo M, Collet JP, Cuisset T, Gachet C, Montalescot G, Jennings LK, Kereiakes D, Sibbing D, Trenk D, van Werkum JW, Paganelli F, Price MJ, Waksman R et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 91933.
  • 8
    Freynhofer MK, Bruno V, Willheim M, Hübl W, Wojta J, Huber K. Vasodilator-stimulated phosphoprotein-phosphorylation assay in patients on clopidogrel: does standardisation matter? Thromb Haemost 2012; 107: 53844.
  • 9
    Jeong YH, Bliden KP, Tantry US, Gurbel PA. High on-treatment platelet reactivity assessed by various platelet function tests: is the consensus-defined cut-off of VASP-P platelet reactivity index too low? J Thromb Haemost 2012; 10: 4879.
  • 10
    Mangiacapra F, Patti G, Barbato E, Peace AJ, Ricottini E, Vizzi V, Gatto L, D’Ambrosio A, De Bruyne B, Wijns W, Di Sciascio G. A therapeutic window for platelet reactivity for patients undergoing elective percutaneous coronary intervention: results of the ARMYDA-PROVE (Antiplatelet therapy for reduction of myocardial damage during angioplasty-platelet reactivity for outcome validation effort) study. J Am Coll Cardiol Cardiovasc Interv 2012; 5: 2819.