The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting.

OBJECTIVES: To investigate the impact of genotypes on the basis of the loss-of-function variant CYP2C19*2 and the gain-of-function variant CYP2C19*17 on on-treatment platelet reactivity and on the occurrence of Thrombolysis in Myocardial Infarction (TIMI) major bleedings in 820 clopidogrel-treated patients who underwent elective coronary stenting. METHODS: On-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. Postdischarge TIMI major bleedings within 1 year after enrollment were recorded. RESULTS: In total, 25 major bleedings (3.0% of the study population) were observed. Patients with the CYP2C19*1/*17 and *17/*17 diplotypes exhibited a lower magnitude of platelet reactivity as compared with patients with the CYP2C19*1/*1 diplotype (for the light transmittance aggregometry-adjusted mean difference: -5.8%, 95% confidence interval: -9.6 to -2.1, P=0.002). Patients with the *1/*17 and *17/*17 genotype had a 2.7-fold increased risk in the occurrence of major bleedings [adjusted hazard ratio: 2.7, 95% confidence interval: 1.1-7.0, P=0.039]. The diplotypes *2/*17, *1/*2, and *2/*2 exhibited higher on-treatment platelet reactivity as compared with the wild type (P<0.0001). However, this was not translated into an altered risk on major bleedings as compared with the wild type [hazard ratio: 1.3 (0.45-4.0), P=0.60]. Results have not been adjusted for multiple testing. CONCLUSION: Patients with the CYP2C19*1/*17 and *17/*17 diplotype have a lower magnitude of on-treatment platelet reactivity and are at a 2.7-fold increased risk of postdischarge TIMI major bleeding events after coronary stenting than patients with the *1/*1 genotype. The diplotypes *2/*17, *1/*2, and *2/*2 are associated with increased on-treatment platelet reactivity; however, this is not translated into a lower risk of bleeding events.

Predictors and outcome of grade 3 ischemia in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

PURPOSE: Grade 3 ischemia (G3I: distortion of the terminal portion of the QRS complex) is a predictor of serious complications after acute myocardial infarction. However, less is known about which patients are more prone to present with G3I. METHODS: Patients who were enrolled in the Ongoing Tirofiban In Myocardial infarction Evaluation trial 2 were included. These patients were divided in 2 groups based on the enrolment electrocardiogram: grade 2 ischemia (G2I) or G3I. RESULTS: Between June 2004 and November 2007, 1308 patients with interpretable electrocardiograms were enrolled. Grade 3 ischemia was found in 426 (32.6%) patients. Patients with G3I were older, more often male, more often had diabetes, had a Thrombolysis In Myocardial Infarction (TIMI) risk score of greater than 3, had 3 vessel disease, had an anterior infarction, more often presented in Killip class greater than 1, less often had a preprocedural TIMI 3 flow, and less often had a myocardial blush grade 3 post-PCI. One hour post-PCI, residual ST deviation was higher in patients with G3I compared with patients with G2I. Furthermore, G3I was associated with more major cardiac events (including death, myocardial infarction, urgent target vessel revascularization). After multivariate adjustment, G3I was an independent predictor of failure of ST-segment resolution 1 hour post-PCI (odds ratio, 1.4; 95% confidence interval, 1.1-1.9) and 30-day mortality (odds ratio, 3.2; 95% confidence interval, 1.2-8.7). CONCLUSION: Grade 3 ischemia was associated with high-risk patient criteria (older age, diabetes, TIMI risk score >3, Killip class >1, and anterior myocardial infarction) and represents a subgroup of high-risk patients who seems to be associated with poor myocardial reperfusion and worse outcome.

Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis.

OBJECTIVE: To evaluate the accumulated information from genetic association studies investigating the impact of variants of the cytochrome P450 (CYP) 2C19 genotype on the clinical efficacy of clopidogrel. DESIGN: Systematic review and meta-analysis with a structured search algorithm and prespecified eligibility criteria for retrieval of relevant studies; dominant genetic model assumptions and quantitative methods for calculating summary effect estimates from study level odds ratios; systematic assessment of bias within and between studies; and grading of the cumulative evidence by consensus criteria. DATA SOURCES: Medline, Embase, the Cochrane Library, online databases, contents pages and bibliographies of general medical, cardiovascular, pharmacological, and genetic journals. Eligibility criteria for selecting studies Original full length reports assessing the cumulative incidence of major adverse cardiovascular events or stent thrombosis over a follow-up period of at least a month in association with carrier status for the loss of function or gain of function CYP2C19 allele in adult patients with coronary artery disease and a clinical presentation of acute coronary syndrome or stable angina pectoris who were taking clopidogrel. RESULTS: 15 studies met the inclusion criteria. The random effects summary odds ratio for stent thrombosis in carriers of at least one CYP2C19 loss of function allele versus non-carriers combining nine studies was 1.77 (95% confidence interval 1.31 to 2.40; P < 0.001). This nominally significant odds ratio was subject to considerable bias across the studies (small study effect bias and replication diversity). The adjustment for these quality modifiers tended to abolish the association. The corresponding random effects summary odds ratio of major adverse cardiovascular events for 12 studies combined was 1.11 (0.89 to 1.39; P = 0.36). The random effects summary odds ratio of stent thrombosis in carriers versus non-carriers of at least one CYP2C19*17 gain of function allele for three studies combined was 0.99 (0.60 to 1.62; P = 0.96), and the corresponding odds ratio of major adverse cardiovascular events in five studies was 0.93 (0.75 to 1.14; P = 0.48). The overall quality of epidemiological evidence was graded as low, which excludes reliable clinical assessments. CONCLUSIONS: Accumulated information from genetic association studies does not indicate a substantial or consistent influence of CYP2C19 gene polymorphisms on the clinical efficacy of clopidogrel. The current evidence does not support the use of individualised antiplatelet regimens guided by CYP2C19 genotype.

Higher efficacy of pre-hospital tirofiban with longer pre-treatment time to primary PCI: protection for the negative impact of time delay.

AIMS: To evaluate the impact of longer duration of pre-hospital initiated antiplatelet and antithrombotic therapy on outcome in patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: In this sub-analysis of the Ongoing Tirofiban in Myocardial Evaluation (On-TIME) 2 trial, we studied, in 1,370 patients, the effect of pre-treatment time (time from administering study medication to time of angiography) on complete ST-segment resolution (STR), initial patency and 30-day mortality. Study medication consisted of high dose tirofiban (HDT) or control (placebo or no HDT) on top of high dose clopidogrel, aspirin and unfractionated heparin. Median pre-treatment time was 55 min (44-70). Longer pre-treatment was associated with longer transportation times, longer in-hospital delay, longer total ischaemic time (all p<0.001) and higher 30-day mortality (3.6% vs. 1.8%, p=0.046). Longer HDT pre-treatment time was independently associated with increased complete STR both before (odds ratio [OR] 1.51, 95%; confidence interval [CI] 0.98-2.32; p=0.06) and after PCI (OR 1.43, 95%; CI 1.02-2.02; p=0.039) and with a significantly improved initial TIMI 2 or 3 flow (51.4% vs. 43.4%, p=0.042) and reduced 30-day mortality (2.1% vs. 5.0%, p=0.047) as compared to longer control pre-treatment. CONCLUSIONS: Longer time delay before primary PCI is associated with increased mortality. Pre-treatment with high dose tirofiban, however, may compensate for this negative effect by improving ST-segment resolution and initial patency and by reducing mortality. Further studies should be performed to confirm that this is an attractive therapy for patients with longer delays to reperfusion.

The relationship between platelet reactivity and infarct-related artery patency in patients presenting with a ST-elevation myocardial infarction.

Both heightened platelet reactivity and an occluded infarct related artery (IRA) on initial angiography and at the time of primary percutaneous coronary intervention (PCI) are associated with a worsened clinical outcome in patients with ST-elevation myocardial infarction (STEMI). However, the relationship between platelet reactivity and IRA patency has not yet been established. Consecutive STEMI-patients were enrolled in this study. Patients who had TIMI-flow (thrombolysis in myocardial infarction) 0 or 1 on initial angiography constituted the occluded IRA group and patients having TIMI-flow 2 or 3 comprised the IRA patent group. Platelet function measurements were performed using the PFA-100 COL/ADP cartridge and light transmittance aggregometry without agonist (spontaneous) and after stimulation with adenosine diphosphate (ADP) and arachidonic acid (AA). Ninety-nine patients were enrolled, of whom 49 presented with an occluded IRA. Multivariate analysis identified the following independent factors to be associated with an occluded IRA; short COL/ADP closure time (ORper quartile increase=0.60; 95% CI, 0.39-.93; p=0.02), the 20 µM ADP-induced light transmittance aggregometry (ORper quartile increase =1.77; 95% CI, 1.15-2.73; p=0.01) and leukocyte counts (odds ratio [OR]=1.21; 95% CI, 1.05-1.39; p = 0.008). In conclusion, heightened platelet reactivity and elevated leukocyte counts are associated with an occluded IRA upon presentation in STEMI-patients. These results emphasise the importance of potent antithrombotic therapy early after the onset of symptoms, to obtain early recanalisation of the IRA.

Variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest in clopidogrel pretreated patients undergoing coronary stenting.

BACKGROUND: An inadequate response to clopidogrel is mainly attributable to the variable formation of its active metabolite. The CYP2C19*2 loss-of-function polymorphism leads to reduced generation of the active metabolite and is, similarly to high on-treatment platelet reactivity (HPR), associated with recurrent atherothrombotic events following coronary stent implantation. AIM: To determine the relative contribution of CYP2C19*2 genotype to HPR. METHODS AND RESULTS: CYP2C19*2 genotyping and platelet function testing using 5 and 20 µmol/l ADP-induced light transmittance aggregometry (LTA), the PlateletWorks assay and the VerifyNow P2Y12 assay, were performed in 1069 clopidogrel pretreated patients undergoing elective coronary stenting (POPular study, http://clinicalTrials.gov/ NCT00352014). The relative contributions of CYP2C19*2 genotype and clinical variables to the interindividual variability of on-treatment platelet reactivity and the occurrence of HPR were established using multivariate regression models. CYP2C19*2 carrier status was associated with a more frequent occurrence of HPR. CYP2C19*2 genotype alone could explain 5.0%, 6.2%, 4.4% and 3.7% of the variability in 5 and 20 µmol/l ADP-induced LTA, the PlateletWorks assay and the VerifyNow P2Y12 assay, respectively, which increased to 13.0%, 15.2%, 5.6% and 20.6% when clinical variables were considered as well. Besides the CYP2C19*2 genotype, multiple clinical variables could be identified as independent predictors of HPR, including age, gender, body mass index, diabetes mellitus, clopidogrel loading dose regimen, use of amlodipine and platelet count. CONCLUSION: The CYP2C19*2 loss-of-function polymorphism is associated with a more frequent occurrence of HPR. However, the part of the interindividual variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest.

High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention.

AIM: High on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are associated with atherothrombotic events following coronary stenting. There are, however, few data concerning high on-treatment platelet reactivity to both aspirin and clopidogrel simultaneously. The aim of the present study was to determine the incidence of dual high on-treatment platelet reactivity (DAPR) and its impact on clinical outcome. METHODS: On-treatment platelet reactivity was measured in parallel by ADP- and arachidonic acid-induced light transmittance aggregometry (LTA) (n=921) and the point-of-care VerifyNow system (P2Y12 and aspirin) (n=422) in patients on dual antiplatelet therapy undergoing elective stent implantation. HCPR and HAPR were established by receiver-operator characteristic curve analysis. The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischaemic stroke at 1-year follow-up. RESULTS: The incidence of DAPR varied between 14.7% and 26.9% depending on the platelet function test used. DAPR, assessed by LTA and the VerifyNow system, was highly associated with an adverse clinical outcome. At 1-year follow-up the primary endpoint occurred more frequently in patients with isolated HCPR (11.7%), isolated HAPR (9.6%) or DAPR (10.7%) compared with patients without high on-treatment platelet reactivity (4.2%, all p<0.01) when platelet function was evaluated with LTA. Using the VerifyNow system, patients exhibiting DAPR had the highest risk for the primary endpoint (17.7% vs 4.1% in patients without high on-treatment platelet reactivity, p=0.001). CONCLUSIONS: In patients undergoing elective percutaneous coronary intervention, DAPR to aspirin and clopidogrel is present in one in five patients and is associated with a high risk for atherothrombotic events. DAPR measured by the point-of-care VerifyNow system has a higher predictability for atherothrombotic events than LTA. CLINICAL TRIAL REGISTRATION INFORMATION: www.clinicaltrials.gov: NCT00352014.

Triggering mechanisms of stent thrombosis.

AIMS: The aim of this study was to determine the role of potential triggers of stent thrombosis. METHODS AND RESULTS: Patients (n = 437) with "definite" ST were recruited consecutively in the setting of a large multicentre observational cohort study. Patients were interviewed with validated questionnaires to identify one of the following triggers: i) timing of onset of ST, ii) performance of vigorous ( ≥ 6 MET) physical activity in the two hours preceding ST, iii) presence of emotional stress (experiencing a serious life event in the 14 days preceding the ST or feelings of anger in the 12 hours of ST) and iv) presence of a documented active infection at the time of ST. A total of 363 patients (83.1%) were able to supply adequate information. A significant trigger was identified in 83 patients (22.9%). Analysis of the different categories according to timing of ST revealed a higher prevalence of triggers with an increasing time-interval between index PCI and ST. Analysis of circadian variation showed a steep peak incidence from 7 am-12 pm. CONCLUSIONS: Triggering mechanisms such as time of the day, physical exertion, emotional stress and infection may play an important role in a considerable number of patients presenting with ST, in particular in patients with (very) late ST.

Prasugrel as alternative treatment strategy in a case with a hypersensitivity reaction to clopidogrel.

We report a case with a hypersensitivity reaction to clopidogrel that resolved after clopidogrel discontinuation and recurred on rechallenge. The reaction included fever, tachycardia, rash and mild angioedema. As an alternative to clopidogrel, the more potent thienopyridine prasugrel was administered without any signs of an allergic reaction in the hours, days and weeks following administration.

Facilitated reperfusion with prehospital glycoprotein IIb/IIIa inhibition: predictors of complete ST-segment resolution before primary percutaneous coronary intervention in the On-TIME 2 trial: correlates of reperfusion before primary PCI.

OBJECTIVE: The objective of this study is to evaluate the incidence, predictors, and outcome of complete ST-segment resolution (STR) during transportation after pretreatment with dual or triple antiplatelet therapy in the Ongoing Tirofiban in Myocardial Infarction Evaluation (On-TIME) 2 trial. METHODS: Patients with ST-segment elevation myocardial infarction were randomized in the ambulance to pretreatment with high-dose tirofiban (HDT) or to a control pretreatment (placebo or no HDT) on top of 600-mg clopidogrel, 500-mg aspirin, and 5000-IU unfractionated heparin. Complete STR was defined as ≥70% STR on the electrocardiogram obtained before percutaneous coronary intervention (PCI) as compared with the inclusion electrocardiogram. RESULTS: Complete STR before PCI occurred in 16.8% (n = 188/1121) and more frequently in the HDT group (19.0% vs 14.6%, P = .05). Independent predictors for complete STR before PCI were younger age (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.70-0.96, P = .01 per 10 year increase), fast diagnosis (OR, 0.97; 95% CI, 0.97-1.0, P = .004 per 15-minute increase time from symptom onset to diagnosis), longer pretreatment time (OR, 1.09; 95% CI, 1.03-1.16, P = .003 per 15-minute increase time start study medication to angiography), and randomization to HDT (OR, 1.39; 95% CI, 1.0-1.9, P = .05). Complete STR before PCI was associated with very low 30-day (0.5% vs 2.8%, P = .07) and 1-year (1.1% vs 5.0%, P = .019) mortality. CONCLUSIONS: Dual or triple antiplatelet pretreatment in the ambulance results in complete STR before PCI in 17% of patients. Fast ST-segment elevation myocardial infarction diagnosis, prehospital initiation of pretreatment early after symptom onset, and HDT independently predicted STR before PCI. Complete STR is associated with improved clinical outcome.

Sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients.

Clopidogrel is a prodrug that needs to be converted in?vivo by several cytochrome (CYP) P450 iso-enzymes to become active. Both clopidogrel and the oral hypoglycemic drug class sulfonylureas are metabolized by the iso-enzyme CYP2C9. The objective of the study was to evaluate the relationship of sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients undergoing elective coronary stent implantation. In this prospective, observational study, on-clopidogrel platelet reactivity was quantified using adenosine diphosphate (ADP)-induced light transmittance aggregometry in 139 type 2 diabetes mellitus patients undergoing elective coronary stent implantation treated with clopidogrel and aspirin. High on-clopidogrel platelet reactivity was defined as >70.7% platelet reactivity to 20 µmol/L ADP. A total of 53 patients (38.1%) were on concomitant treatment with sulfonylureas. The remaining 86 patients were on other hypoglycemic drugs. On-clopidogrel platelet reactivity was significantly higher in patients with concomitant sulfonylurea treatment as compared to patients without concomitant sulfonylurea treatment (for 5 µmol/L ADP: 46.0% ± 11.8 vs. 40.6% ± 16.0; p=0.035, adjusted p=0.032 and for 20 µmol/L ADP: 64.6% ± 10.8 vs. 58.7% ± 15.5; p=0.019, adjusted p=0.017). The concomitant use of sulfonylureas was associated with a 2.2-fold increased risk of high on-clopidogrel platelet reactivity (OR 2.2, 95% CI 1.1-4.7, p=0.039 and after adjustment for confounders: OR(adj) 2.0, 95% CI 1.0-5.7, p=0.048). Concomitant treatment with sulfonylureas might be associated with decreased platelet inhibition by clopidogrel in type 2 diabetes mellitus patients on dual antiplatelet therapy undergoing elective coronary stent implantation.

Paraoxonase-1 is a major determinant of clopidogrel efficacy.

Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.

The golden hour of prehospital reperfusion with triple antiplatelet therapy: a sub-analysis from the Ongoing Tirofiban in Myocardial Evaluation 2 (On-TIME 2) trial early initiation of triple antiplatelet therapy.

BACKGROUND: It is known that the efficacy of thrombolytic therapy in ST-segment elevation myocardial infarction (STEMI) is highly time dependent with the best efficacy when given within the so-called golden hour. This analysis from the On-TIME 2 trial evaluated the efficacy of triple antiplatelet therapy on initial patency and ST-segment resolution (STR) in relation to time from symptom onset to first medical contact. METHODS: The On-TIME 2 trial included 1,398 consecutive STEMI patients referred for primary percutaneous coronary intervention (PCI). Patients were randomized to dual (500 mg aspirin and 600 mg clopidogrel) or triple antiplatelet (500 mg aspirin, 600 mg clopidogrel, and tirofiban 25 µg/kg bolus and 0.15 µg/kg per minute maintenance infusion for 18 hours) pretreatment in the ambulance. Primary outcome of this sub-analysis was initial patency of the infarct-related vessel and STR before PCI according to time from symptom onset to first medical contact in quartiles. In addition, the incidence of aborted myocardial infarction, defined as the absence of a rise in creatinine kinase, was assessed. RESULTS: Initial patency, STR before PCI, and the incidence of aborted myocardial infarction gradually increased with shorter time from symptom onset to first medical contact. Initial Thrombolysis in Myocardial Infarction flow was present in 21.2% in the total population and 26.2%, 21.5%, 18.1%, and 18.8% in the time quartiles, respectively (P for trend=.01). The incidence of complete STR pre-angiography was 16.6% in the total population and 23.4%, 18.2%, 14.7%, and 9.9% in the 4 quartiles, respectively (P for trend<.001). This was largely driven by the effect of triple antiplatelet therapy, which further improved initial patency and STR and led to a significantly higher incidence of aborted myocardial infarction (13.2% vs 8.7%, P=.011), especially in the patients with short duration of symptoms. CONCLUSION: Antiplatelet pretreatment before primary PCI, including a glycoprotein IIb/IIIa blocker, seems to be most effective when given shortly after symptom onset. Further studies should be performed to test this hypothesis.

Prehospital triple antiplatelet therapy in patients with acute ST elevation myocardial infarction leads to better platelet aggregation inhibition and clinical outcome than dual antiplatelet therapy.

OBJECTIVE: To assess whether prehospital initiation of high-dose tirofiban in addition to high-dose clopidogrel results in more adequate inhibition of platelet aggregation (IPA) and better clinical outcome after primary percutaneous coronary intervention (PCI). METHODS: Prespecified two-centre substudy of the prospective, international, multicentre, placebo controlled Ongoing Tirofiban in Myocardial Infarction Evaluation trial 2 (On-TIME-2 trial). 648 of 964 (67%) patients in the On-TIME-2 trial with ST elevation myocardial infarction undergoing primary PCI were studied. Pre-PCI IPA after early prehospital initiation of high-bolus dose (25 µg/kg) tirofiban was compared to placebo in addition to acetylsalicylic acid, unfractionated heparin and 600 mg clopidogrel. RESULTS: IPA was measured at a median of 60 min after study medication administration. In all four tests: Fe induced platelet aggregation, ADP induced platelet aggregation, platelet function analyser (PFA)-100 (collagen-epinephrine and collagen-ADP cartridge) IPA was higher in patients pretreated with high-dose tirofiban (p<0.001 for all tests), even after >74 min of pretreatment. Patients in the highest quartile of IPA had less residual ST segment deviation 1 h post-PCI (p value for trend: p=0.001, 0.004, 0.001, 0.002 respectively). There was a significant relationship between PFA-100 (both cartridges) and major adverse cardiovascular events (MACE, p=0.028, p=0.035) and early thrombosis (p=0.009, p=0.007). CONCLUSIONS: 60 min of prehospital initiated antiplatelet treatment including high-dose tirofiban resulted in higher levels of IPA compared to pretreatment with acetylsalicylic acid and high-dose clopidogrel alone, even after longer pretreatment times. Levels of IPA were significantly related to ST resolution and MACE, including stent thrombosis. This substudy confirms the main findings of the On-TIME2 trial that clopidogrel alone is suboptimal, even at high dose and administered well in advance of primary PCI.

Pre-hospital administration of tirofiban in diabetic patients with ST-elevation myocardial infarction undergoing primary angioplasty: a sub-analysis of the On-Time 2 trial.

AIMS: Glycoprotein IIb/IIIa blocking agents seem to improve percutaneous coronary intervention (PCI) results in patients with ST-elevation myocardial infarction (STEMI). We aimed to compare the effect of pre-hospital administration of tirofiban in STEMI patients with and without diabetes mellitus (DM) treated with primary PCI. METHODS AND RESULTS: We performed a pre-specified sub-analysis of the randomised On-Time II trial (n=984) and it's open label run-in phase (n=414), which investigated pre-hospital administration of high dose tirofiban in STEMI patients treated with primary PCI. Two-hundred and twenty (16%) diabetic patients (known DM or Hba1C ≥6.2%) were included, 101 in the placebo group and 119 in the tirofiban group. In patients with DM, randomisation to tirofiban resulted in a lower residual ST deviation (5.1±8.5 mm vs. 6.2±5.6 mm, p=0.003), a reduced infarct size (CK 1694±1925 U/L vs. CK 2040±1829 U/L, p=0.02) and a trend towards lower one-year mortality (4.6% vs. 11.6%, p=0.07). The beneficial effects of tirofiban were more pronounced in diabetic patients compared to patients without diabetes. CONCLUSIONS: Pre-hospital administration of tirofiban in diabetic STEMI patients treated with primary PCI improves ST resolution and reduces myocardial infarct size. Tirofiban seems particularly beneficial in patients with diabetes.