Prehospital Clopidogrel Administration in Patients With ST-Segment Elevation Myocardial Infarction Treated With Primary PCI: Real-Life Experience From the Multicenter NRDES Registry

To the Editor:

Rapid platelet inhibition is one of the key elements of pharmacological treatment of patients with ST-segment elevation myocardial infarction (STEMI) referred to primary percutaneous coronary intervention (PCI). Current European Society of Cardiology guidelines recommend administration of antiplatelet drugs in STEMI “as early as possible.” However, the value of prehospital administration of antiplatelet drugs is still a matter of debate.¹ Despite the introduction of new oral antiplatelet agents (prasugrel/ticagrelor), clopidogrel is widely used in the prehospital phase of STEMI treatment in many countries. On the other hand, the value of early clopidogrel administration in STEMI is not clear since there are limited data from clinical trials to support this strategy.

We sought to compare outcomes of STEMI patients from the National Registry of Drug-Eluting Stents (NRDES) stratified by time of clopidogrel loading dose administration (early = before transfer to catheterization laboratory; late = periprocedural). The NRDES was a registry based on the Polish national PCI database. Patients with acute coronary syndromes were enrolled from October 2010 until October 2011 in 13 catheterization laboratories with 24/7 primary PCI service. The NRDES complied with the declaration of Helsinki and has obtained local bioethics committee approval. The registry methods and results have been previously published.² Clinical follow-up was conducted up to 1 year. The primary endpoint was overall mortality at 1 year. Data were analyzed according to the established statistical standards. Categorical variables were presented as percentages and continuous variables as median with interquartile range (IQR). Differences between groups were tested using chi-square test and Mann-Whitney U-test for continuous variables. Moreover, a propensity score for the likelihood of receiving clopidogrel early was calculated based on baseline clinical characteristic variables.

A total of 1667 patients with STEMI who received loading dose of clopidogrel were included. Clopidogrel loading dose was administered early in 1215 patients (73%) and during the procedure in 452 patients. Baseline characteristics were similar in both groups. On admission, patients not receiving early clopidogrel were more likely to present with heart failure symptoms as assessed with Killip class. Infarct-related artery distribution was similar between groups. Interestingly, a higher rate of infarct-related artery patency (TIMI grade 2-3 flow) as well as smaller thrombus burden on baseline angiography were observed after early clopidogrel administration. However, this did not translate into a lower rate of periprocedural complications such as slow-flow/no-reflow. The rate of aspiration thrombectomy and glycoprotein IIb/IIIa inhibitor usage was not different between groups. Finally, the rate of TIMI grade 3 flow after PCI was comparably high in both groups (Tables 1 and 2). At 1 year, a trend toward a lower mortality in the early clopidogrel group was found. However, the trend was no longer observed after adjustment for propensity score. In addition, no significant differences between groups (early vs late clopidogrel) in terms of both unadjusted and adjusted rates of stent thrombosis, target-vessel revascularization, reinfarction, and need for urgent revascularization at 1 year were found (Table 3).

Effective antiplatelet treatment represents the most important element of pharmacotherapy in patients with STEMI referred to primary PCI. Loading dose of clopidogrel was a cornerstone of such therapy for many years. However, in STEMI patients, impaired response for clopidogrel was observed mainly due to delayed intestinal absorption.³ Two hours after the administration of a 600 mg loading dose of clopidogrel in STEMI patients, high on-treatment platelet reactivity may be found in as many as two-thirds of patients.⁴ Thus, in many cases, primary PCI is performed with insufficient platelet inhibition. The new oral antiplatelet agents prasugrel and ticagrelor show faster and more potent antiplatelet effect as compared with clopidogrel.^5,6 However, their rapid onset of action was confirmed mainly in healthy volunteers and patients with stable angina. A delayed onset of antiplatelet effect in STEMI was shown for both prasugrel and ticagrelor. In the FABOLUS PRO study, the suboptimal inhibition of platelet aggregation was observed for at least 2 hours after administration of 60 mg of prasugrel.⁷ Similarly, Alexopoulos et al showed high on-treatment platelet reactivity 2 hours after loading dose of prasugrel or ticagrelor in a significant proportion of patients with STEMI. In some of them, inadequate antiplatelet effect was seen even after 6 hours post loading dose.⁸ Despite this, both new oral antiplatelet drugs showed better clinical outcomes compared with clopidogrel in acute coronary syndromes.^9-11 One of the potential strategies to overcome the lack of full antiplatelet effect during PCI is the early administration of antiplatelet drugs. This concept was implemented in many European primary-PCI networks based on expert opinions or results of observational rather than randomized studies. Moreover, the results of these studies are inconsistent in terms of benefits but importantly, no study showed a significant increase of bleeding in patients with early administration of antiplatelet drugs. In an analysis of the SCAAR database, early clopidogrel administration was associated with reduction of clinical events at 1 year.¹² However, the CIPAMI randomized study failed to show a benefit (early infarct-related artery patency) of early clopidogrel administration.¹³ On the contrary, we observed a higher rate of early infarct-related artery patency with early clopidogrel, but this did not translate into procedural and postprocedural benefit. The discussed strategy was also studied with ticagrelor in the ATLANTIC study, which failed to show a benefit of early administration. One potential reason is that the median time difference between early and late ticagrelor administration was only about 30 minutes.¹⁴ This shows logistic improvement in STEMI networks and poses a question about the point of oral administration for such a short delay. Intravenous administration with rapid antiplatelet effect may be more adequate in such a scenario. Early intravenous antiplatelet drug administration was studied with glycoprotein IIb/IIIa inhibitors and a clinical benefit was observed in some studies, but this strategy is currently not often used in clinical practice.^15,16 Cangrelor, an intravenous P2Y12 inhibitor, may be an attractive option due to a rapid and predictable antiplatelet effect, but its use in the prehospital setting of STEMI treatment has not yet been studied. 

This study has a number of limitations. The main limitation is its non-randomized design. Analysis was performed based on registry data and the decision regarding the early administration of clopidogrel was left to operator discretion. However, study groups was relatively similar in terms of baseline characteristics and propensity score analysis was used to limit the influence of confounding factors. Time difference between early and periprocedural clopidogrel administration was not measured. Angiographic data were not validated by an independent core lab and were based on operator assessment. Thus, our study results should be considered rather exploratory and hypothesis generating.  

In conclusion, early clopidogrel administration before primary PCI for STEMI is associated with a higher rate of infarct-related artery patency in baseline angiography, but without any benefits in terms of PCI result and 1-year clinical outcome as compared with periprocedural administration.

References

1.     Steg PG, James SK, Atar D, et al; Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569-2619.

2.    Siudak Z, Dziewierz A, Rakowski T, et al. Borderline trend towards long-term mortality benefit from drug eluting stents implantation in ST-elevation myocardial infarction patients in Poland – data from NRDES registry. Catheter Cardiovasc Interv. 2014;83:436-442.

3.    Heestermans AA, van Werkum JW, Taubert D, et al. Impaired bioavailability of clopidogrel in patients with a ST-segment elevation myocardial infarction. Thromb Res. 2008;122:776-781.

4.    Alexopoulos D, Theodoropoulos KC, Stavrou EF, et al. Prasugrel versus high dose clopidogrel to overcome early high on clopidogrel platelet reactivity in patients with ST elevation myocardial infarction. Cardiovasc Drugs Ther. 2012;26:393-400.

5.    Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor–mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29:21-30.

6.    Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120:2577-2585.

7.    Valgimigli M, Tebaldi M, Campo G, et al. 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 trial. JACC Cardiovasc Interv. 2012;5:268-277.

8.    Alexopoulos D, Xanthopoulou I, Gkizas V, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv. 2012;5:797-804.

9.    Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.

10.    Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045-1057. 

11.    Winter MP, Koziński M, Kubica J, et al. Personalized antiplatelet therapy with P2Y12 receptor inhibitors: benefits and pitfalls. Postepy Kardiol Interwencyjnej. 2015;11:259-280.

12.    Koul S, Smith JG, Schersten F, et al. Effect of upstream clopidogrel treatment in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Eur Heart J. 2011;32:2989-2997.

13.    Zeymer U, Arntz HR, Mark B, et al. Efficacy and safety of a high loading dose of clopidogrel administered prehospitally to improve primary percutaneous coronary intervention in acute myocardial infarction: the randomized CIPAMI trial. Clin Res Cardiol. 2012;101:305-312.

14.    Montalescot G, van‘t Hof AW, Lapostolle F, et al; ATLANTIC Investigators. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med. 2014;371:1016-1027.

15.    De Luca G, Bellandi F, Huber K, et al. Early glycoprotein IIb-IIIa inhibitors in primary angioplasty-abciximab long-term results (EGYPT-ALT) cooperation: individual patient’s data meta-analysis. J Thromb Haemost. 2011;9:2361-2370.

16.    Rakowski T, Siudak Z, Dziewierz A, et al. Early abciximab administration before transfer for primary percutaneous coronary interventions for ST-elevation myocardial infarction reduces 1-year mortality in patients with high-risk profile. Results from EUROTRANSFER registry. Am Heart J. 2009;158:569-575.

From the ¹2nd Department of Cardiology and ²Department of Interventional Cardiology, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted April 13, 2016 and accepted April 14, 2016.

Address for correspondence: Tomasz Rakowski, MD, PhD, 2nd  Department of Cardiology, Institute of Cardiology, Jagiellonian University Medical College,

Kopernika 17 Street, 31-501 Krakow, Poland. Email: mcrakows@cyfronet.pl