Safety of Prasugrel Loading Doses in Patients Pre-Loaded With Clopidogrel in the Setting of Primary Percutaneous Coronary Intervention: Results of a Nonrandomized Observational Study.

The aim of this study was to assess the safety of the concurrent administration of a clopidogrel and prasugrel loading dose in patients undergoing primary percutaneous coronary intervention. Prasugrel is one of the preferred P2Y12 platelet receptor antagonists for ST-segment elevation myocardial infarction patients. The use of prasugrel was evaluated clinically in clopidogrel-naive patients. Between September 2009 and October 2012, a total of 2,023 STEMI patients were enrolled in the COMFORTABLE (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI]) and the SPUM-ACS (Inflammation and Acute Coronary Syndromes) studies. Patients receiving a prasugrel loading dose were divided into 2 groups: 1) clopidogrel and a subsequent prasugrel loading dose; and 2) a prasugrel loading dose. The primary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding in hospital at 30 days. Of 2,023 patients undergoing primary percutaneous coronary intervention, 427 (21.1%) received clopidogrel and a subsequent prasugrel loading dose, 447 (22.1%) received a prasugrel loading dose alone, and the remaining received clopidogrel only. At 30 days, the primary safety endpoint was observed in 1.9% of those receiving clopidogrel and a subsequent prasugrel loading dose and 3.4% of those receiving a prasugrel loading dose alone (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.25 to 1.30, p = 0.18). The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) bleeding score tended to be higher in prasugrel-treated patients (p = 0.076). The primary safety endpoint results, however, remained unchanged after adjustment for these differences (clopidogrel and a subsequent prasugrel loading dose vs. prasugrel only; HR: 0.54 [95% CI: 0.23 to 1.27], p = 0.16). No differences in the composite of cardiac death, myocardial infarction, or stroke were observed at 30 days (adjusted HR: 0.66, 95% CI: 0.27 to 1.62, p = 0.36). This observational, nonrandomized study of ST-segment elevation myocardial infarction patients suggests that the administration of a loading dose of prasugrel in patients pre-treated with a loading dose of clopidogrel is not associated with an excess of major bleeding events. (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI] [COMFORTABLE]; NCT00962416; and Inflammation and Acute Coronary Syndromes [SPUM-ACS]; NCT01000701).

Räber L ，Klingenberg R ，Heg D ，Kelbæk H ，Roffi M ，Tüller D ，Baumbach A ，Zanchin T ，Carballo D ，Ostojic M ，Stefanini GG ，Rodondi N ，von Birgelen C ，Moschovitis A ，Engstrøm T ，Gencer B ，Auer R ，Meier B ，Mach F ，Lüscher TF ，Jüni P ，Matter CM ，Windecker S ，COMFORTABLE and SPUM-ACS Trial Investigators ... -  《-》

Double-blind, randomized, prospective comparison of loading doses of 600 mg clopidogrel versus 60 mg prasugrel in patients with acute ST-segment elevation myocardial infarction scheduled for primary percutaneous intervention: the ETAMI trial (early thieno

This study compared the timing of onset of antiplatelet action after treatment with clopidogrel and prasugrel at first medical contact in patients with ST-segment elevation myocardial infarction (STEMI) scheduled for primary percutaneous coronary intervention (PPCI). Little is known about the timing of onset of antiplatelet action after a pre-percutaneous coronary intervention (PCI) loading dose of clopidogrel or prasugrel in patients with STEMI. This double-blind, prospective study randomized 62 patients with STEMI scheduled for PPCI in the ambulance or the emergency department to 60 mg prasugrel (n = 31) or 600 mg clopidogrel (n = 31). The primary endpoint was the platelet reactivity index (PRI) measured with the vasodilator-stimulated phosphoprotein assay 2 h after intake of the study medication. Secondary endpoints were PRI after 4 h, TIMI (Thrombolysis In Myocardial Infarction) patency of the infarct-related artery before and after PCI, and clinical events until day 30. The PRI after 2 h (50.4 ± 32.7% vs. 66.3 ± 22.2%; p = 0.035) and after 4 h (39.1 ± 27.5% vs. 54.5 ± 49.3%; p = 0.038) were significantly lower with prasugrel compared with clopidogrel. In addition, the rate of patients with a PRI <50% tended to be higher with prasugrel compared with clopidogrel after 2 h (46.7% vs. 28.6%; p = 0.15) and after 4 h (63.0% vs. 38.9%; p = 0.06). There were no significant differences in TIMI 2/3 patency before PCI (39.2% vs. 31.0%; p = 0.43) and TIMI 3 patency after PCI (88.5% vs. 89.3%; p = 0.92). The pre-PCI administration of prasugrel in patients with STEMI undergoing PPCI was associated with a significant faster platelet inhibition compared with clopidogrel. Therefore, prasugrel should be preferred to clopidogrel in this setting. (ETAMI-Study: Early Thienopyridine Treatment to Improve Primary PCI in Patients With Acute Myocardial Infarction; NCT01327534).

Zeymer U ，Mochmann HC ，Mark B ，Arntz HR ，Thiele H ，Diller F ，Montalescot G ，Zahn R ... -  《-》

Comparison of prasugrel and clopidogrel-treated patients with acute coronary syndrome undergoing percutaneous coronary intervention: A propensity score-matched analysis of the Acute Myocardial Infarction in Switzerland (AMIS)-Plus Registry.

The purpose of this study was to investigate outcomes of patients treated with prasugrel or clopidogrel after percutaneous coronary intervention (PCI) in a nationwide acute coronary syndrome (ACS) registry. Prasugrel was found to be superior to clopidogrel in a randomized trial of ACS patients undergoing PCI. However, little is known about its efficacy in everyday practice. All ACS patients enrolled in the Acute Myocardial Infarction in Switzerland (AMIS)-Plus registry undergoing PCI and being treated with a thienopyridine P2Y12 inhibitor between January 2010-December 2013 were included in this analysis. Patients were stratified according to treatment with prasugrel or clopidogrel and outcomes were compared using propensity score matching. The primary endpoint was a composite of death, recurrent infarction and stroke at hospital discharge. Out of 7621 patients, 2891 received prasugrel (38%) and 4730 received clopidogrel (62%). Independent predictors of in-hospital mortality were age, Killip class >2, STEMI, Charlson comorbidity index >1, and resuscitation prior to admission. After propensity score matching (2301 patients per group), the primary endpoint was significantly lower in prasugrel-treated patients (3.0% vs 4.3%; p=0.022) while bleeding events were more frequent (4.1% vs 3.0%; p=0.048). In-hospital mortality was significantly reduced (1.8% vs 3.1%; p=0.004), but no significant differences were observed in rates of recurrent infarction (0.8% vs 0.7%; p=1.00) or stroke (0.5% vs 0.6%; p=0.85). In a predefined subset of matched patients with one-year follow-up (n=1226), mortality between discharge and one year was not significantly reduced in prasugrel-treated patients (1.3% vs 1.9%, p=0.38). In everyday practice in Switzerland, prasugrel is predominantly used in younger patients with STEMI undergoing primary PCI. A propensity score-matched analysis suggests a mortality benefit from prasugrel compared with clopidogrel in these patients.

Kurz DJ ，Radovanovic D ，Seifert B ，Bernheim AM ，Roffi M ，Pedrazzini G ，Windecker S ，Erne P ，Eberli FR ... -  《-》

Optimal P2Y12 Inhibitor in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: A Network Meta-Analysis.

The study sought to compare the clinical efficacy and safety of P2Y12 inhibitors in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous intervention (PPCI). Limited data exist regarding the comparative efficacy and safety of P2Y12 inhibitors in STEMI patients undergoing PPCI. Clinical trials enrolling STEMI patients were identified and relevant data was extracted. Major adverse cardiovascular events (MACE) were defined as the composite of all cause mortality, MI, and target vessel revascularization. Network meta-analysis was performed using Bayesian methods. A total of 37 studies with 88,402 STEMI patients and 5,077 MACE were analyzed. Outcomes at 1 month (22 studies and 60,783 patients) suggest that prasugrel was associated with: lower MACE than clopidogrel (standard dose odds ratio [OR]: 0.59, 95% confidence interval [CI]: 0.50 to 0.69; high-dose OR: 0.60, 95% CI: 0.51 to 0.71; upstream OR: 0.79, 95% CI: 0.66 to 0.94), and ticagrelor (standard dose OR: 0.69, 95% CI: 0.56 to 0.84; upstream OR: 0.72, 95% CI: 0.50 to 1.05); lower mortality and MI than clopidogrel and standard ticagrelor; lower stroke risk than standard clopidogrel and standard or upstream ticagrelor; and lower stent thrombosis than standard or upstream clopidogrel. At 1-year (10 studies, n = 40,333) prasugrel was associated with lower mortality and MACE than other P2Y12 inhibitors. MACE was particularly lower with prasugrel in studies where patients received bivalirudin, drug-eluting stents, and but not glycoprotein IIb/IIIa inhibitor. In STEMI patients undergoing PPCI, prasugrel and ticagrelor are more efficacious than clopidogrel; in addition, prasugrel was superior to ticagrelor particularly in conjunction with bivalirudin and drug-eluting stents.

Rafique AM ，Nayyar P ，Wang TY ，Mehran R ，Baber U ，Berger PB ，Tobis J ，Currier J ，Dave RH ，Henry TD ... -  《-》

MULTInational non-interventional study of patients with ST-segment elevation myocardial infarction treated with PRimary Angioplasty and Concomitant use of upstream antiplatelet therapy with prasugrel or clopidogrel--the European MULTIPRAC Registry.

Early initiation of dual antiplatelet therapy (DAPT) is guideline-recommended. MULTIPRAC was conducted to gain insights into the use patterns and outcomes of pre-hospital DAPT initiation with prasugrel or clopidogrel. MULTIPRAC is a multinational, multicentre, prospective registry enrolling 2053 ST-segment elevation myocardial infarction (STEMI) patients. Patients were grouped according to adherence to the initially prescribed thienopyridine. Pre-hospital use of prasugrel increased from 12.5% to 67.1% at study end. Prasugrel compared to clopidogrel-initiated patients more often adhered to the medication through discharge (87% vs. 38%) whereas 49% of the clopidogrel-initiated patients were switched to prasugrel. Patients who continued on clopidogrel were substantially older. In-hospital mortality was 0.5%, early stent thrombosis 0.1%. The major adverse cardiac events (MACE) rate was 1.6% in prasugrel-treated vs. 2.3% in clopidogrel-treated patients (adjusted OR 0.749, 95% CI [0.285-1.968]). Non-coronary artery bypass graft (non-CABG) bleeding occurred in 4.1% of prasugrel-treated vs. 6.1% of clopidogrel-treated patients (adjusted OR 0.686 [0.349-1.349]). Pre-percutaneous coronary intervention (PCI) TIMI flow 2-3 was seen in 38.7% treated with prasugrel vs. 35.6% with clopidogrel (adjusted OR 1.170 [0.863-1.585]). Post PCI ST-segment resolution ⩾50%, was 71.6% with prasugrel vs. 65.0% with clopidogrel (adjusted OR 1.543 [1.138-2.093], p=0.0052). MULTIPRAC demonstrated a steady increase in prasugrel use over time without an increase in bleeding rates compared to clopidogrel. ST resolution was more pronounced with prasugrel. Switching between antiplatelet drugs occurs frequently. The low rates of MACE, in-hospital mortality and bleeding, suggests that pre-hospital loading with thienopyridines is confined to low-risk patients. These results emphasize the need for more randomized pre-hospital studies and should be seen in the context of upcoming randomized trials involving pre-hospital antiplatelet therapies.

Clemmensen P ，Grieco N ，Ince H ，Danchin N ，Goedicke J ，Ramos Y ，Schmitt J ，Goldstein P ，MULTIPRAC study investigators ... -  《-》