Comparison of pre-hospital 600 mg or 900 mg vs. peri-interventional 300 mg clopidogrel in patients with ST-elevation myocardial infarction undergoing primary coronary angioplasty. The Load&Go randomized trial ☆ Kenneth Ducci a , Simone Grotti a , Giovanni Falsini a , Paolo Angioli a , Francesco Liistro a , Massimo Mandò b , Italo Porto a , Leonardo Bolognese a, ⁎ a Cardiovascular and Neurologic Department, San Donato Hospital, Arezzo, Italy b Emergency Department, San Donato Hospital, Arezzo, Italy article info Article history: Received 31 May 2013 Accepted 1 July 2013 Available online 3 August 2013 Keywords: Acute myocardial infarction Clopidogrel pretreatment Clopidogrel loading dose Platelet reactivity Data regarding the benefit of clopidogrel pretreatment in primary percutaneous coronary interventions (PCI) are sparse, and the optimal timing of the loading dose is uncertain. The objective of our single-center, prospective, open-label randomized trial was thus to assess whether high doses (600 or 900 mg) of clopidogrel given at first medical contact, as compared with a 300 mg loading dose given in the catheterization laboratory, resulted in a higher degree of optimal myocardial perfusion after primary PCI. We studied 168 patients with STEMI referred from the territorial emergency medical services for primary coronary angioplasty. Patients were randomized to the following arms at first medical contact: clopidogrel 900 mg; 600 mg or no pretreatment. The latter group of patients received a standard loading dose of 300 mg of clopidogrel just prior to primary PCI. All patients also received acetylsalicylic acid 500 mg i.v. and 5000 I.U. of unfractioned heparin. We used the P2Y12 cartridge of the Verify-Now (Accumetrics Inc., San Diego, California) to evaluate on-clopidogrel platelet reactivity. Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. The primary end point of the study was the comparison of the rate of Thrombolysis in Myocardial Infarction Perfusion Grade 3 (TMPG 3, open microvasculature) between patients randomized to pre-hospital loading dose (600 or 900 mg clopidogrel) and those randomized to no pretreatment (300 mg) [1]. The key secondary end point was platelet inhibition assessed as Verify-Now Platelet Reaction Units immediately prior to PCI [2]. Other secondary end points included TIMI 2–3 grade flow of the infarct-related artery prior to PCI; pre and post procedure TIMI flow; corrected TIMI Frame Count (cTFC); no reflow phenomenon; bleeding complications; and 30-day major adverse cardiovascular events, a composite of cardiovascular death, myocardial infarction, stroke, and angiographically-confirmed stent thrombosis. Patient disposition as per CONSORT Statement flowchart (http:// www.consort-statement.org/) is shown in Fig. 1 . Clinical and angio- graphic characteristics are shown in Table 1 . No significant difference regarding the primary end point (rate of TMPG 3) was observed between patients pretreated (600 mg or 900 mg) and those not (64.9% vs. 66.1%; p = 0.88). There was also no significant difference between the 600-mg vs. 900-mg pre-hospital treatment groups with regard to the primary end point (57.1% vs. 72.7%; p = 0.12). No statistically significant differences in PRU values prior to PCI in the pretreatment groups as compared to the no pretreatment group (342 ± 59 vs. 333 ± 72; p = 0.20), nor between the 900 mg, 600 mg or no pretreatment group (337 ± 48 vs. 356 ± 52 vs. 333 ± 72; p = 0.08) could be found. No statistically significant differences were observed when comparing patients pretreated (600 mg or 900 mg) and those not regarding the rate of pre-PCI TIMI 2 or 3 or in the cTFC post-PCI. We had only 2 cases of major bleeding in the pretreatment arms as compared to the no pretreatment arm (1.8% vs. 0%; p = 0.55) and very few major adverse clinical events at 30 days, with only 2 deaths (1.2%, both cardiac) and one STEMI (0.6%) in the whole population (p = ns for all comparisons). Thus, the major findings in our study are as follows: 1) there are no differences in terms of reperfusion angiographic indexes and patency rate of the culprit vessel between different pre-treatment regiments of clopidogrel in patients with STEMI undergoing primary PCI; 2) pre- treatment with both loading doses of 600 mg and 900 mg of clopidogrel was not associated with increased rates of major or minor bleeding; and 3) in the setting of an acute myocardial infarction network with short first medical contact-to balloon times, residual platelet reactivity prior to PCI is considerably high even in the group of patients assigned to pretreatment with the highest loading dose of clopidogrel. To date, only observational investigations [3–8] have evaluated the comparison of pre-hospital versus peri-interventional clopidogrel administration, suggesting that clopidogrel pretreatment was asso- ciated with a higher TIMI myocardial perfusion rate [6], and to clinical benefit [3,4,7,8]. Our negative results are mainly explained by the unexpectedly short clopidogrel loading to balloon time in our sample, further highlighting the time dependency of the clopidogrel benefit. In fact, following a 600-mg loading dose of clopidogrel, 2 to 8 h are needed to achieve maximal inhibition. Ambulance-based clopidogrel loading was assessed in the CIPAMI trial, [9] where clopidogrel preloading was not associated to increased pre-PCI infarct vessel patency rate in patients with clopidogrel-to-balloon times of less than 1 h. Finally, in the CRUSADE registry, patients who received clopidogrel pre-PCI had a paradoxically higher rate of post-admission myocardial infarction compared with those who received the medica- tion peri-PCI [10]. In observational studies a higher loading dose was associated with better short and long-term outcome [11]. While no data on the 900-mg loading dose in STEMI are available, 600-mg clopidogrel produces a faster antiplatelet effect than 300-mg dose [12]. However, primary PCI is often completed well under 2 h from clopidogrel administration. The only randomized trial comparing 600-mg and 300-mg clopidogrel in STEMI patients showed a significant reduction in infarct size in the 600- mg group, [13] although a significantly lower incidence of post- procedural TIMI flow grade b 3 in the high dose clopidogrel arm (5.8% vs. 16.3%; p = 0.031) was found and these findings were obtained with an exceptionally low clopidogrel load to balloon time of around 30 min. In the present study, although the average clopidogrel load to balloon time was twofold that of the ARMYDA-6 MI, we could not find any ☆ Clinical trial registration: ClinicalTrials.gov Identifier: NCT00882739; Eudract code 2009-010295-23. ⁎ Corresponding author at: Cardiovascular and Neurologic Department, San Donato Hospital, Via Pietro Nenni 20 52100, Arezzo, Italy. Tel.: +39 0575 255529; fax: +39 0575 255617. E-mail address: leonardobolognese@hotmail.com (L. Bolognese). 4814 Letters to the Editor