Prasugrel versus clopidogrel in acute coronary syndromes treated with PCI: Effects on clinical outcome according to culprit artery location.

BACKGROUND: Acute coronary syndrome (ACS) mortality increases when the culprit lesion is in the left anterior descending (LAD) artery. We investigated the effects of prasugrel versus clopidogrel according to site of culprit lesion causing ACS treated with percutaneous coronary intervention (PCI) in the TRITON-TIMI 38 study. METHODS: Patients were divided into three groups based on the native coronary artery culprit lesion location. The LAD artery group included also patients with the culprit lesion in the left main (LM) artery. RESULTS: In the whole ACS population, prasugrel recipients had lower rates of the primary endpoint that included cardiovascular (CV) death, non-fatal myocardial infarction (MI) or non-fatal stroke without significant differences across vessel groups. CV death was significantly decreased with prasugrel in the whole ACS population (p=0.03) and in ST-elevation MI (STEMI) patients undergoing primary PCI (p=0.04), with pronounced differences in favour of prasugrel versus clopidogrel when the LAD-LM was the culprit vessel (relative risk reduction 50% in the whole ACS population, 57% in STEMI treated with primary PCI, p for interaction 0.07 and 0.08 respectively). CONCLUSIONS: Prasugrel effects were particularly favourable when LAD-LM was the culprit vessel, resulting in CV mortality reduction in the whole ACS population and in STEMI patients when treated with primary PCI.

Mortality in primary angioplasty patients starting antiplatelet therapy with prehospital prasugrel or clopidogrel: a 1-year follow-up from the European MULTIPRAC Registry.

AIM: MULTIPRAC was designed to provide insights into the use and outcomes associated with prehospital initiation of antiplatelet therapy with either prasugrel or clopidogrel in the context of primary percutaneous coronary intervention. After a previous report on efficacy and safety outcomes during hospitalization, we report here the 1-year follow-up data, including cardiovascular (CV) mortality. METHODS AND RESULTS: MULTIPRAC is a multinational, prospective registry of patients with ST-elevation myocardial infarction (STEMI) from 25 hospitals in nine countries, all of which had an established practice of prehospital start of dual antiplatelet therapy in place. The key outcome was CV death at 1 year. Among 2,036 patients followed-up through 1 year, 49 died (2.4%), 10 during the initial hospitalization and 39 within 1 year after hospital discharge. The primary analysis was based on the P2Y12-inhibitor, used from prehospital loading dose through hospital discharge. Prasugrel (n=824) was more commonly used than clopidogrel (n=425). The observed 1-year rates for CV death were 0.5% with prasugrel and 2.6% with clopidogrel. After adjustment for differences in baseline characteristics, treatment with prasugrel was associated with a significantly lower risk of CV death than treatment with clopidogrel (odds ratio 0.248; 95% confidence interval 0.06-0.89). CONCLUSION: In STEMI patients from routine practice undergoing primary angioplasty, who were able to start oral antiplatelet therapy prehospital, treatment with prasugrel as compared to clopidogrel was associated with a lower risk of CV death at 1-year follow-up.

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.

AIMS: 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. METHODS AND RESULTS: 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). CONCLUSIONS: 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.

Clinical outcomes for prasugrel versus clopidogrel in patients with unstable angina or non-ST-elevation myocardial infarction: an analysis from the TRITON-TIMI 38 trial.

AIMS: In the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38), prasugrel reduced the primary ischaemic endpoint as compared with clopidogrel in acute coronary syndrome (ACS) patients planned to undergo percutaneous coronary interventions, but increased the risk of bleeding. The present analysis shows the efficacy and safety data for the 10,074 non-ST segment elevation (NSTE)-ACS patients included in that trial. METHODS AND RESULTS: The primary endpoint was significantly reduced by prasugrel in the overall NSTE-ACS population (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.73-0.93, p=0.002) as well as in unstable angina (UA) and in non-ST elevation myocardial infarction (NSTEMI) patient subgroups (interaction p value=0.39). Although non-coronary artery bypass graft (CABG) TIMI major bleeding was increased with prasugrel as compared with clopidogrel (HR 1.40, 95% CI 1.05-1.88, p=0.02), there was a net clinical benefit in patients assigned to prasugrel (HR 0.89, 95% CI 0.80-1.00, p=0.043), which was consistent for UA and NSTEMI subgroups (interaction p value=0.84 and 0.72). In patients who met the criteria for prasugrel use recommended by the European Medicines Agency, thus excluding from the analysis patients with prior transient ischemic attack (TIA)/stroke, with weight <60 kg or age ≥75 years, and censoring follow-up at 365 days, (European Union (EU)-label cohort) prasugrel showed superiority over clopidogrel with regard to the primary endpoint (HR 0.73, 95% CI 0.63-0.85, p<0.0001) for the entire NSTE-ACS population, as well as for UA patients and NSTEMI patients without significant differences in non-CABG TIMI major bleeding. CONCLUSION: Prasugrel, as compared with clopidogrel, significantly reduced the primary endpoint of the TRITON-TIMI 38 trial in NSTE-ACS patients, as well as in the UA and NSTEMI groups. A significant reduction in the primary endpoint without increased bleeding was observed in the EU-label cohort.

Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes.

BACKGROUND: Although P2Y12 antagonists are effective in patients with non-ST-segment elevation (NSTE) acute coronary syndromes, the effect of the timing of administration--before or after coronary angiography--is not known. We evaluated the effect of administering the P2Y12 antagonist prasugrel at the time of diagnosis versus administering it after the coronary angiography if percutaneous coronary intervention (PCI) was indicated. METHODS: We enrolled 4033 patients with NSTE acute coronary syndromes and a positive troponin level who were scheduled to undergo coronary angiography within 2 to 48 hours after randomization. Patients were randomly assigned to receive prasugrel (a 30-mg loading dose) before the angiography (pretreatment group) or placebo (control group). When PCI was indicated, an additional 30 mg of prasugrel was given in the pretreatment group at the time of PCI and 60 mg of prasugrel was given in the control group. RESULTS: The rate of the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy (glycoprotein IIb/IIIa bailout) through day 7, did not differ significantly between the two groups (hazard ratio with pretreatment, 1.02; 95% confidence interval [CI], 0.84 to 1.25; P=0.81). The rate of the key safety end point of all Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, whether related or not related to coronary-artery bypass grafting (CABG), through day 7 was increased with pretreatment (hazard ratio, 1.90; 95% CI, 1.19 to 3.02; P=0.006). The rates of TIMI major bleeding and life-threatening bleeding not related to CABG were increased by a factor of 3 and 6, respectively. Pretreatment did not reduce the rate of the primary outcome among patients undergoing PCI (69% of the patients) but increased the rate of TIMI major bleeding at 7 days. All the results were confirmed at 30 days and in prespecified subgroups. CONCLUSIONS: Among patients with NSTE acute coronary syndromes who were scheduled to undergo catheterization, pretreatment with prasugrel did not reduce the rate of major ischemic events up to 30 days but increased the rate of major bleeding complications. (Funded by Daiichi Sankyo and Eli Lilly; ACCOAST ClinicalTrials.gov number, NCT01015287.).

A comparison of prasugrel at the time of percutaneous coronary intervention or as pretreatment at the time of diagnosis in patients with non-ST-segment elevation myocardial infarction: design and rationale for the ACCOAST study.

BACKGROUND: The precise risk/benefit of thienopyridine pretreatment and the optimal dosage and timing of a thienopyridine loading dose (LD) for patients presenting with non-ST-segment elevation (NSTE) acute coronary syndromes are still being debated. Prasugrel, a novel thienopyridine, is an appropriate drug to address this issue as it provides predictably high and rapid inhibition of platelet aggregation. STUDY DESIGN: ACCOAST is a phase 3, multicenter, parallel-group, double-blind, and event-driven study designed to compare 2 prasugrel LD schedules in patients with NSTE myocardial infarction who are scheduled for coronary angiography/percutaneous coronary intervention (PCI). Approximately 4,100 patients will be randomly assigned to an initial LD of 30 mg of prasugrel after the diagnosis followed by coronary angiography with an additional dose of 30 mg of prasugrel given at the time of PCI (pretreatment) or an LD of 60 mg of prasugrel given to patients undergoing PCI at the time of the procedure (non-pretreatment). All patients undergoing PCI will receive 5 or 10 mg of prasugrel daily. The primary objective is to test the hypothesis that prasugrel pretreatment is superior to prasugrel non-pretreatment as measured by a reduction in the composite end point of cardiovascular death, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor bailout through 7 days from randomization. Key safety end points include TIMI (Thrombolysis In Myocardial Infarction) major and minor bleeding risks. CONCLUSIONS: The ACCOAST study will provide important evidence with regard to the benefits and risks of prasugrel pretreatment compared with administration of prasugrel at the time of PCI in patients with NSTE myocardial infarction.

European registry on patients with ST-elevation myocardial infarction transferred for mechanical reperfusion with a special focus on early administration of abciximab -- EUROTRANSFER Registry.

BACKGROUND: Abciximab is established as adjunct to primary percutaneous coronary intervention (PCI). Based on some smaller studies, ST-segment elevation myocardial infarction (STEMI) networks in various European countries have adopted the start of abciximab before transfer to the catheterization laboratory (cathlab) hospital as part of their routine treatment options. Although a recently published study did not reveal improved clinical outcome when starting abciximab before the cathlab, a potential benefit from such early administration, in particular in the setting of transfer networks, remains unclear and has been the subject of debate. METHODS: Data of consecutive patients with STEMI transferred for primary PCI in hospital/ambulance-feeded STEMI networks treated between November 2005 and January 2007 at 15 PCI centers from 7 European countries were collected in the web-based EUROTRANSFER Registry. RESULTS: Data from a total of 1,650 patients were collected. Abciximab was administered to 1086 patients (66%), of whom 727 received early abciximab (EA group: abciximab started before admission to cathlab, at least 30 minutes before balloon). Another 359 patients received late abciximab (LA group: periprocedural administration of abciximab in the cathlab). Preprocedural TIMI 3 flow was observed in 17.7% of patients with EA and in 8.9% in the LA group (P < .0001). Thirty-day mortality was 3.9% in the EA group versus 7.5% with LA (OR 0.49, 95% CI 0.29-0.85, P = .011), and composite 30-day outcome including death, repeated myocardial infarction, and urgent revascularization was present in 5.5% and 10.3%, respectively (OR 0.51, 95% CI 0.32-0.81, P = .004). These differences remain statistically significant in favor of early abciximab after accounting and adjustment for differences between the groups by means of a multivariate regression model and propensity score. CONCLUSIONS: Patients in STEMI networks transferred for primary PCI who have received abciximab before transfer rather than in the cathlab had more patent arteries before PCI and showed lower rates for death and the composite clinical outcome at 30-day follow-up.