LD, loading dose; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; GP, glycoprotein; BMS, bare metal stent; DES, drug eluting stent; PLT, platelet; PRU, P2Y12 reactivity unit; TIA, transient ischemic attack; TVR, target vessel revascularization.
LETTERS TO THE EDITOR
Effects of pre-hospital clopidogrel administration on early and late residual platelet reactivity in ST-segment elevation myocardial infarction patients undergoing primary intervention
Article first published online: 27 JAN 2013
© 2012 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 11, Issue 1, pages 192–194, January 2013
How to Cite
BISCAGLIA, S., TEBALDI, M., VRANCKX, P., CAMPO, G. and VALGIMIGLI, M. (2013), Effects of pre-hospital clopidogrel administration on early and late residual platelet reactivity in ST-segment elevation myocardial infarction patients undergoing primary intervention. Journal of Thrombosis and Haemostasis, 11: 192–194. doi: 10.1111/jth.12049
- Issue published online: 27 JAN 2013
- Article first published online: 27 JAN 2013
- Accepted manuscript online: 31 OCT 2012 10:50PM EST
- Received 18 September 2012, accepted 23 October 2012
Calling on prior experience with patients affected by non-ST-segment elevation acute coronary syndromes, as well as with patients undergoing coronary stenting, clopidogrel, given as soon as possible at a loading dose of 300 or preferably 600 mg is recommended for patients with ST-segment elevation myocardial infarction undergoing mechanical treatment [1,2].
One single small study has so far evaluated the pharmacokinetic effect of a 600 mg loading dose of clopidogrel in 11 STEMI patients. The effect of clopidogrel was negligible at 4 h and it persisted to be suboptimal when compared with that achieved in healthy controls at 6 h after administration .
Therefore, it remains unclear whether clopidogrel, given at various loading doses immediately after presentation in STEMI patients, achieves a measurable and clinically meaningful effect on ADP-induced residual platelet reactivity at the time of percutaneous intervention.
From October 2008 to May 2010, 122 patients with STEMI referred to two tertiary centers in Italy (Ferrara) and Belgium (Hasselt) received pre-hospital clopidogrel loading dose administration prior to hospital admission and were included in the study. One hundred and nine patients subsequently underwent PCI and culprit lesion stenting, while eight patients showed no culprit lesion and five patients underwent urgent CABG. For each patient, a blood sample was collected via the arterial sheath immediately prior to guiding catheter insertion and before the implementation of anticoagulation, which was achieved with unfractionated heparin (n = 105) or bivalirudin (n = 4). For 62 patients, an additional blood sample was collected via standard vein puncture technique at 30 ± 5 days. On-treatment platelet reactivity was measured with the VerifyNow System . The VerifyNow instrument is a turbimetric optical detection system, which measures platelet induced aggregation as an increase in light transmittance . A specific assay to test clopidogrel is available (VerifyNow P2Y12™).
In the P2Y12 cartridge, VerifyNow uses ADP to stimulate platelets in the presence of prostaglandin (PG) E1, which inhibits activation downstream of a second ADP receptor P2Y1, thus making the assay more sensitive to the activity of P2Y12.
In a separate channel iso-TRAP is used as an agonist in order to obtain a baseline value (BASE) for platelet function. Iso-TRAP-induced platelet aggregation can occur independently of P2Y12 receptors; its effect is only partly mediated by secreted ADP.
Results from the device are reported as P2Y12 reaction units (PRU), BASE and % inhibition of platelet aggregation (IPA). The per cent inhibition is calculated as [(1−PRU/BASE) × 100].
There is no previously validated cut-off value for the identification of patients at high residual platelet reactivity (HRPR) in STEMI setting. Therefore, we used the common cut-off value of 235 PRU to identify HRPR patients . The clinical end-points of interest were death, stroke, transient ischemic attack, myocardial infarction (MI) and stent thrombosis. Continuous data are presented as means ± SD and categorical variables as numbers (percentages). Comparisons were performed by t-test or anova and two-sided Fisher’s test. Probability was significant at < 0.05.
The local ethics committees of both participating institutions approved the study and all patients gave written informed consent.
Table 1 resumes the baseline and procedural characteristics of the study population. The mean total ischemic time was 244 ± 214 min (median, 180; interquartile range, 150–270; range, 20–1080), with a mean pretreatment duration of 50 ± 36 min (median, 44.5; interquartile range, 35–60; range, 5–270). The first consecutive 47 patients recruited into the study received a 300 mg clopidogrel loading dose whereas the subsequent 75 were treated with a 600 mg clopidogrel loading dose. All patients were then treated with clopidogrel 75 mg for at least 6 months. As shown in Table 1, patients were well matched with respect to all baseline clinical and angiographic characteristics, including pretreatment duration, except for a difference in the use of DES between the two groups.
|All (n = 122)||LD 300 mg (n = 47)||LD 600 mg (n = 75)||P|
|Age (years)||65 ± 13||65 ± 14||64 ± 13||0.81|
|Men, no. (%)||95 (78)||34 (72)||61 (81)||0.24|
|Diabetes mellitus, no. (%)||23 (19)||7 (15)||16 (21)||0.38|
|Hypertension, no. (%)||67 (55)||23 (49)||44 (59)||0.29|
|Current smoker, no. (%)||73 (60)||28 (60)||45 (60)||0.96|
|Hypercholesterolemia, no. (%)||56 (46)||19 (40)||37 (49)||0.34|
|CABG, no. (%)||7 (6)||3 (6)||4 (6)||0.81|
|PCI, no. (%)||11 (9)||5 (11)||6 (8)||0.62|
|Myocardial infarction, no. (%)||12 (10)||3 (6)||9 (12)||0.81|
|Left anterior descending, no. (%)||46 (43)||20 (45)||26 (41)||0.62|
|Right coronary artery, no. (%)||41 (38)||17 (39)||24 (37)||0.90|
|Circumflex, no. (%)||21 (19)||7 (16)||14 (22)||0.44|
|Use of GP IIb/IIIa, no. (%)||69 (64)||30 (68)||39 (61)||0.44|
|Number of implanted stents||1.24 ± 0.8||1.19 ± 0.65||1.27 ± 0.88||0.60|
|Total stent length (mm)||31.4 ± 16.5||29.8 ± 14.8||32.5 ± 17.7||0.42|
|BMS, no. (%)||34 (32)||5 (12)||29 (46)||0.0002|
|DES, no. (%)||72 (68)||38 (88)||34 (54)||0.0002|
|Total ischemic time (min)||244 ± 214||282 ± 246||215 ± 183||0.13|
|Pretreatment duration (min)||50 ± 36||52 ± 40||48 ± 34||0.56|
|Platelet assay results|
|BASE||266.7 ± 53.7||259.3 ± 56.3||271.2 ± 51.9||0.24|
|PRU||310.3 ± 61.8||297.2 ± 62.7||318.4 ± 60.2||0.07|
|IPA||0.9 ± 3||1 ± 3.2||0.8 ± 2.9||0.08|
|1 month follow-up|
|BASE||296.3 ± 57.5||299.7 ± 65.5||292.3 ± 47.4||0.66|
|PRU||120.5 ± 77.7||137.1 ± 79||102.9 ± 73.4||0.08|
|IPA||61.6 ± 26.5||59.6 ± 28.3||63.8 ± 24.8||0.57|
|Follow-up (months)||11.7 ± 2.6||12.2 ± 2.3||11.4 ± 2.8||0.11|
|Death, no. (%)||2 (2)||1 (2)||1 (2)||0.79|
|Stroke/TIA, no. (%)||0 (0)||0 (0)||0 (0)|
|Reinfarction, no. (%)||4 (4)||2 (5)||2 (3)||0.70|
|Bleeding, no. (%)||9 (8)||5 (11)||4 (6)||0.35|
|TVR, no. (%)||6 (6)||3 (7)||3 (5)||0.63|
At the time of intervention, the mean BASE was 266.7 ± 53.7, while the mean PRU was 310.3 ± 61.8, leading to an average IPA of 0.9 ± 3%. Overall, 86% of patients would qualify for being at high residual platelet reactivity based on the 235 PRU threshold.
As shown in Table 1, a 600 mg clopidogrel loading dose failed to provide a higher level of platelet inhibition or a lower residual platelet reactivity as compared with the standard 300 mg regimen.
Only six (13%) and 10 (13%) patients in the 300 or 600 mg loading dose regimen showed a level of IPA > 0, and in this patient subset, mean %IPA was 7.7% in the 300 vs. 6.2% in the 600 mg clopidogrel regimen (P = 0.62).
When patients were divided based on tertiles of pretreatment duration, those receiving clopidogrel < 30 min before testing showed similar PRU levels (306 ± 52) to patients in the middle (PRU 312 ± 65) or higher tertile 312 ± 66 groups (P at anova = 0.92), with no interaction noted between clopidogrel loading dose and pretreatment duration (P for interaction = 0.72). Similar results were noted for %IPA. No significant difference regarding PRU or BASE was found between patients receiving GpIIb-IIIa plus heparin and patients receiving heparin only, either at the time of intervention or at 1 month follow-up.
At 1 month follow-up, mean PRU was 120.5 ± 77.7, leading to IPA percentage of 61.6 ± 26.5%, with overall 14 (11%) showing PRU levels above 235.
The mean clinical follow-up was 11.7 ± 2.6 months. The cumulative 1-year incidence of death or non-fatal MI was 6% with no detectable association between PRU at baseline or at 1 month and subsequent cardiovascular events.
The results of our observational study can be summarized as follows:
- 1The pre-hospital administration of clopidogrel in STEMI patients resulted in a negligible level of platelet inhibition and as a consequence in high residual on-treatment platelet reactivity at the time of intervention in the great majority of patients at the time of intervention.
- 2Patients receiving a 600 mg clopidogrel loading dose did not show an improved platelet profile in terms of %IPA or residual PRU levels as compared with those receiving a 300 mg regimen at the time of intervention.
- 3The proportion of patients with residual high on-treatment platelet reactivity fell from 86% at the time of intervention to 11% at 1 month.
When taken together our study findings suggest that pre-hospital clopidogrel administration, irrespective of the loading dose regimen, fails to lead to a detectable and reliable degree of platelet inhibition in STEMI at the time of intervention. This is largely explained by delayed drug absorption or activation as the vast majority of included patients failed to maintain a high degree of residual platelet inhibition when reassessed at steady state for the drug. This finding is consistent with previous evidence  and may explain the increased risk of acute stent thrombosis observed in clopidogrel-treated patients with STEMI undergoing stent implantation without the assistance of intravenous glycoprotein IIb/IIIa inhibitors, although glycoprotein IIb/IIIa utilization did not affect the stent thrombosis rate at 30 days . The use of more potent and quick P2Y12 inhibitors, such as prasugrel  or ticagrelor, has been shown to provide a detectable level of platelet inhibition as early as 15 min after administration, and represents therefore a more attractive option .
Disclosure of Conflict of Interests
The authors state that they have no conflict of interests
- 1ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J. 2012;33: 2569–619., , , , , , , , , , , , , , , , , , , , et al.
- 22009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54:2205–41., , , , , , , , , , , , , , , , , , , , et al.
- 4Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation 2009; 119: 237–42., , , , , , , , , .
- 6FABOLUS PRO Investigators. Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial. JACC Cardiovasc Interv 2012; 5: 268–77., , , , , , , ;
- 7TRITON-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: 723–31., , , , , , ;