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1.  A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial 
European Heart Journal  2012;34(31):2481-2489.
Aims
We sought to determine the degree of anticoagulation reversal required to mitigate bleeding, and assess the feasibility of using pegnivacogin to prevent ischaemic events in acute coronary syndrome (ACS) patients managed with an early invasive approach. REG1 consists of pegnivacogin, an RNA aptamer selective factor IXa inhibitor, and its complementary controlling agent, anivamersen. REG1 has not been studied in invasively managed patients with ACS nor has an optimal level of reversal allowing safe sheath removal been defined.
Methods and results
Non-ST-elevation ACS patients (n = 640) with planned early cardiac catheterization via femoral access were randomized 2:1:1:2:2 to pegnivacogin with 25, 50, 75, or 100% anivamersen reversal or heparin. The primary endpoint was total ACUITY bleeding through 30 days. Secondary endpoints included major bleeding and the composite of death, myocardial infarction, urgent target vessel revascularization, or recurrent ischaemia. Enrolment in the 25% reversal arm was suspended after 41 patients. Enrolment was stopped after three patients experienced allergic-like reactions. Bleeding occurred in 65, 34, 35, 30, and 31% of REG1 patients with 25, 50, 75, and 100% reversal and heparin. Major bleeding occurred in 20, 11, 8, 7, and 10% of patients. Ischaemic events occurred in 3.0 and 5.7% of REG1 and heparin patients, respectively.
Conclusion
At least 50% reversal is required to allow safe sheath removal after cardiac catheterization. REG1 appears a safe strategy to anticoagulate ACS patients managed invasively and warrants further investigation in adequately powered clinical trials of patients who require short-term high-intensity anticoagulation. Clinical Trials Registration: ClinicalTrials.gov NCT00932100.
doi:10.1093/eurheartj/ehs232
PMCID: PMC3895957  PMID: 22859796
Acute coronary syndromes; Anticoagulation reversal; REG1
2.  Bridging Anti-Platelet Therapy With the Intravenous Agent Cangrelor In Patients Undergoing Cardiac Surgery 
Context
Thienopyridines are among the most widely prescribed medications, but their use can be complicated by the unanticipated need for surgery. Despite increased risk of thrombosis, guidelines recommend discontinuing thienopyridines 5–7 days prior to surgery to minimize bleeding.
Objective
To evaluate the use of cangrelor, an intravenous, reversible P2Y12 platelet inhibitor for bridging thienopyridine-treated patients to coronary artery bypass grafting (CABG).
Design, Setting, and Patients
Prospective, randomized double-blind, placebo-controlled, multicenter trial, in patients (n=210) with an acute coronary syndrome (ACS) or treated with a coronary stent on a thienopyridine awaiting CABG to receive either cangrelor or placebo after an initial open-label, dose-finding phase (n=11) conducted between January 2009 and April 2011.
Interventions
Thienopyridines were stopped and patients administered cangrelor or placebo for at least 48 hours, which was discontinued 1–6 hours prior to CABG.
Main outcome measures
The primary efficacy endpoint was platelet reactivity (measured in P2Y12 Reaction Units [PRU]), assessed daily with the VerifyNow™ P2Y12 assay. The main safety endpoint was excessive CABG-related bleeding.
Results
The dose of cangrelor determined in the open-label stage was 0.75 µg/kg/min. In the randomized phase, a greater proportion of patients treated with cangrelor had low levels of platelet reactivity throughout the entire treatment period compared with placebo (primary endpoint, PRU<240: 98.8% (83/84) vs. 19.0% (16/84); relative risk [RR]: 5.2, 95% confidence interval [CI]:3.3–8.1, p<0.001). Excessive CABG-related bleeding occurred in 11.8% (12/102) vs. 10.4% (10/96) in the cangrelor and placebo groups, respectively (RR=1.1, 95% CI: 0.5–2.5, p=0.763). There were no significant differences in major bleeding prior to CABG, although minor bleeding was numerically higher with cangrelor.
Conclusions
Among patients who must wait for cardiac surgery after thienopyridine discontinuation, the use of cangrelor compared with placebo resulted in a higher rate of maintenance of platelet inhibition.
doi:10.1001/jama.2011.2002
PMCID: PMC3774162  PMID: 22253393
3.  Management and outcomes of patients presenting with STEMI by use of chronic oral anticoagulation: results from the GRACE registry 
Aims:
To describe the characteristics, treatment, and mortality in patients with ST-elevation myocardial infarction (STEMI) by use of chronic oral anticoagulant (OAC) therapy.
Methods:
Using data from the Global Registry of Acute Coronary Syndromes (GRACE), patient characteristics, treatment, and reperfusion strategies of STEMI patients on chronic OAC are described, and relevant variables compared with patients not on chronic OAC. Six-month post-discharge mortality rates were evaluated by Cox proportional hazard models.
Results:
Of 19,094 patients with STEMI, 574 (3.0%) were on chronic OAC at admission. Compared with OAC non-users, OAC users were older (mean age 73 vs. 65 years), more likely to be female (37 vs. 29%), were more likely to have a history of atrial fibrillation, prosthetic heart valve, venous thromboembolism, or stroke/transient ischaemic attack, had a higher mean GRACE risk score (166 vs. 145), were less likely to be Killip class I (68 vs. 82%), and were less likely to undergo catheterization/percutaneous coronary intervention (52 vs. 66%, respectively). Of the patients who underwent catheterization, fewer OAC users had the procedure done within 24 h of admission (56.5 vs. 64.5% of OAC non-users). In propensity-matched analyses (n=606), rates of in-hospital major bleeding and in-hospital and 6-month post-discharge mortality were similar for OAC users and OAC non-users (2.7 and 3.7%, p=0.64; 15 and 13%, p=0.56; 15 and 12%, p=0.47, respectively), rates of in-hospital recurrent myocardial infarction (8.6 and 2.0%, p<0.001) and atrial fibrillation (32 and 22%, p=0.004) were higher in OAC patients, and rates of 6-month stroke were lower (0.6 and 4.3%, p=0.038). Patients in both groups who underwent catheterization had lower mortality than those who did not undergo catheterization.
Conclusions:
This is the largest study to describe the characteristics and treatment of STEMI patients on chronic OAC. The findings suggest that patients on chronic OAC are less likely to receive guideline-indicated management, but have similar adjusted rates of in-hospital and 6-month mortality.
doi:10.1177/2048872613483019
PMCID: PMC3821815  PMID: 24222840
Acute coronary syndrome; anticoagulant; guidelines; myocardial infarction
5.  Composition of Coronary Thrombus in Acute Myocardial Infarction 
Objective
To analyse composition of coronary thrombus in vivo, in ST-elevation Myocardial Infarction (STEMI) patients.
Background
The dynamic process of intracoronary thrombus formation in STEMI patients is poorly understood.
Methods
Intracoronary thrombi (n=45) were obtained by thromboaspiration in 288 consecutive STEMI patients presenting for primary percutaneous intervention and analyzed using high definition pictures taken with a scanning electron microscope. Plasma biomarkers (TnI, CRPus, IL-6, PAI-1, sCD40 ligand and TNF-α) and plasma fibrin clots viscoelastic properties were measured simultaneously on peripheral blood.
Results
Thrombi were mainly composed of fibrin (55.9±18%) with platelets (16.8±18%), erythrocytes (11.5±9%), cholesterol crystal (5.2±8.4%) and leukocytes (1.3±2.0%). The median ischemic time was 175 min [IQR 140-297]. Ischemic time impacted thrombi composition, resulting in a positive correlation with intracoronary thrombus fibrin content, r=0.38, p=0.01 and a negative correlation with platelet content r=-0.34, p=0.02. Thus, fibrin content increased with ischemic time, ranging from 48.4±21% (<3 hours) up to 66.9±9% (>6 hours) (p=0.02), while platelet content decreased from 24.9±23% (<3 hours) to 9.1±6% (>6 hours) (p=0.07). Soluble CD40 ligand was positively correlated to platelet content in the thrombus (r=0.40, p=0.02) and negatively correlated with fibrin content (r=-0.36; p=0.04). Multivariate analysis indicated that ischemic time was the only predictor of thrombus composition with a 2-fold increase of fibrin-content per ischemic hour (adjusted OR2 [1.03-3.7] p=0.01).
Conclusions
In acute STEMI, platelet and fibrin contents of the occlusive thrombus are highly dependent of ischemic time, which may have a direct impact on the efficacy of drugs or devices used for coronary reperfusion.
doi:10.1016/j.jacc.2010.09.077
PMCID: PMC3071619  PMID: 21414532
Thrombus; STEMI
6.  Integrating Genome-Wide Genetic Variations and Monocyte Expression Data Reveals Trans-Regulated Gene Modules in Humans 
PLoS Genetics  2011;7(12):e1002367.
One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns—independent component analysis—to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify major trans-acting regulators. We detected three genomic regions significantly associated with co-regulated gene modules. Association of these loci with multiple expression traits was replicated in Cardiogenics, an independent study in which expression profiles of monocytes were available in 758 subjects. The locus 12q13 (lead SNP rs11171739), previously identified as a type 1 diabetes locus, was associated with a pattern including two cis eQTLs, RPS26 and SUOX, and 5 trans eQTLs, one of which (MADCAM1) is a potential candidate for mediating T1D susceptibility. The locus 12q24 (lead SNP rs653178), which has demonstrated extensive disease pleiotropy, including type 1 diabetes, hypertension, and celiac disease, was associated to a pattern strongly correlating to blood pressure level. The strongest trans eQTL in this pattern was CRIP1, a known marker of cellular proliferation in cancer. The locus 12q15 (lead SNP rs11177644) was associated with a pattern driven by two cis eQTLs, LYZ and YEATS4, and including 34 trans eQTLs, several of them tumor-related genes. This study shows that a method exploiting the structure of co-expressions among genes can help identify genomic regions involved in trans regulation of sets of genes and can provide clues for understanding the mechanisms linking genome-wide association loci to disease.
Author Summary
One major expectation from the transcriptome in humans is to help characterize the biological basis of associations identified by genome-wide association studies. Here, we take advantage of recent technical and methodological advances to examine the influence of natural genetic variability on >12,000 genes expressed in the monocyte, a blood cell playing a key role in immunity-related disorders and atherosclerosis. By examining 1,490 European population-based subjects, we identify three regions of the genome reproducibly associated with specific patterns of gene expression. Two of these regions overlap genetic variants previously known to be involved in the susceptibility to type 1 diabetes, celiac disease, and hypertension. Genes whose expression is modulated by these genetic variants may act as mediators in the causal relationship linking the variability of the genome to complex disease. These findings illustrate how integration of genetic and transcriptomic data at an epidemiological scale can help decipher the genetic basis of complex diseases.
doi:10.1371/journal.pgen.1002367
PMCID: PMC3228821  PMID: 22144904
7.  Reduced-Function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes Among Patients Treated With Clopidogrel Predominantly for PCI: A Meta-Analysis 
Content
Clopidogrel, one of the most commonly prescribed medications, is a pro-drug requiring CYP450 biotransformation. Data suggest its pharmacologic effect varies based on CYP2C19 genotype, but there is uncertainty regarding the clinical risk imparted by specific genotypes.
Objective
In patients treated with clopidogrel, to define the risk of major adverse cardiovascular outcomes among carriers of one (∼26% prevalence in whites) and carriers of two (∼2% prevalence in whites) reduced-function CYP2C19 variants.
Data Sources and Study Selection
A literature search was conducted (January 2000-August 2010) of the MEDLINE, Cochrane, and EMBASE databases. Genetic studies were included where clopidogrel was initiated in predominantly invasively managed patients in a manner consistent with the current guideline recommendations and where clinical outcomes were ascertained.
Data Extraction
Investigators from nine studies evaluating CYP2C19 genotype and clinical outcomes in patients treated with clopidogrel contributed the relevant hazard ratios (HRs) and their 95% confidence intervals (CI) for specific cardiovascular outcomes by genotype.
Results
Among 9685 patients [91.3% of whom underwent percutaneous coronary intervention (PCI) and 54.5% of whom had an acute coronary syndrome (ACS)], 863 experienced the composite endpoint of cardiovascular death, myocardial infarction, or stroke; 84 patients had stent thrombosis among the 5894 evaluated for such. Overall, 71.5% were non-carriers, 26.3% had one, and 2.2% had two CYP2C19 reduced-function alleles. A significantly increased risk of the composite endpoint was evident in both carriers of one (HR 1.55, 95% CI 1.11-2.27, P=0.01) and two (HR 1.76, 95% CI 1.24-2.50, P=0.002) CYP2C19 reduced-function alleles. Similarly, there was a significantly increased risk of stent thrombosis in both carriers of one (HR 2.67, 95% CI 1.69-4.22, P<0.0001) and two (HR 3.97, 95% CI 1.75-9.02, P=0.001) CYP2C19 reduced-function alleles.
Conclusion
Among patients treated with clopidogrel for PCI, carriage of even one reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.
doi:10.1001/jama.2010.1543
PMCID: PMC3048820  PMID: 20978260
8.  The P2Y12 receptor as a target of antithrombotic drugs 
Purinergic Signalling  2011;7(3):325-332.
doi:10.1007/s11302-011-9241-z
PMCID: PMC3166993  PMID: 21710143
ACS; Platelets; P2Y12 inhibitors; ADP; Clopidogrel; Prasugrel; Thrombosis; Platelets
9.  Delay to reperfusion in patients with acute myocardial infarction presenting to acute care hospitals: an international perspective 
European Heart Journal  2010;31(11):1328-1336.
Aims
To examine the extent of delay from initial hospital presentation to fibrinolytic therapy or primary percutaneous coronary intervention (PCI), characteristics associated with prolonged delay, and changes in delay patterns over time in patients with ST-segment elevation myocardial infarction (STEMI).
Methods and results
We analysed data from 5170 patients with STEMI enrolled in the Global Registry of Acute Coronary Events from 2003 to 2007. The median elapsed time from first hospital presentation to initiation of fibrinolysis was 30 min (interquartile range 18–60) and to primary PCI was 86 min (interquartile range 53–135). Over the years under study, there were no significant changes in delay times to treatment with either strategy. Geographic region was the strongest predictor of delay to initiation of fibrinolysis >30 min. Patient's transfer status and geographic location were strongly associated with delay to primary PCI. Patients treated in Europe were least likely to experience delay to fibrinolysis or primary PCI.
Conclusion
These data suggest no improvements in delay times from hospital presentation to initiation of fibrinolysis or primary PCI during our study period. Geographic location and patient transfer were the strongest predictors of prolonged delay time, suggesting that improvements in modifiable healthcare system factors can shorten delay to reperfusion therapy even further.
doi:10.1093/eurheartj/ehq057
PMCID: PMC2878967  PMID: 20231154
Percutaneous coronary intervention; ST-segment elevation myocardial infarction; Reperfusion; Fibrinolysis
10.  Smoking, Clopidogrel, and Mortality in Patients with Established Cardiovascular Disease 
Circulation  2009;120(23):2337.
Background
Smoking increases platelet aggregability, and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown.
Methods and Results
We evaluated the relationship between smoking status (current smoker (CS), former smoker (FS), and never smoker (NS)) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12,152 participants from the CHARISMA trial with established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, [1.85–3.60]), cardiovascular (HR 2.26, [1.48–3.45]), and cancer mortality (HR 4.16, [2.46–7.03]) compared to NS. The impact of clopidogrel and mortality differed by smoking status (P for interaction = 0.018 for current smokers). Among CS, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, [0.49–0.94]); clopidogrel did not reduce all cause mortality among FS (HR 0.95, [0.75–1.19]) or NS (HR 1.14, [0.83–1.58]). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding seemed to differ according to smoking status; randomized clopidogrel was associated with a significantly increased hazard of severe or moderate bleeding (HR 1.62, P=0.04) among CS, but a smaller and nonsignificant increase among NS (HR 1.31, P=0.15).
Conclusion
Clopidogrel therapy may be more effective, but with a greater bleeding risk in CS than in patients who are not smokers. Further studies are needed to investigate this possibility.
doi:10.1161/CIRCULATIONAHA.109.866533
PMCID: PMC2814172  PMID: 19933933
Smoking; Clopidogrel; Mortality; Cardiovascular disease
11.  Unprotected left main revascularization in patients with acute coronary syndromes 
European Heart Journal  2009;30(19):2308-2317.
Aims
In acute coronary syndromes (ACS), the optimal revascularization strategy for unprotected left main coronary disease (ULMCD) has been little studied. The objectives of the present study were to describe the practice of ULMCD revascularization in ACS patients and its evolution over an 8-year period, analyse the prognosis of this population and determine the effect of revascularization on outcome.
Methods and results
Of 43 018 patients enrolled in the Global Registry of Acute Coronary Events (GRACE) between 2000 and 2007, 1799 had significant ULMCD and underwent percutaneous coronary intervention (PCI) alone (n = 514), coronary artery bypass graft (CABG) alone (n = 612), or no revascularization (n = 673). Mortality was 7.7% in hospital and 14% at 6 months. Over the 8-year study, the GRACE risk score remained constant, but there was a steady shift to more PCI than CABG over time. Patients undergoing PCI presented more frequently with ST-segment elevation myocardial infarction (STEMI), after cardiac arrest, or in cardiogenic shock; 48% of PCI patients underwent revascularization on the day of admission vs. 5.1% in the CABG group. After adjustment, revascularization was associated with an early hazard of hospital death vs. no revascularization, significant for PCI (hazard ratio (HR) 2.60, 95% confidence interval (CI) 1.62–4.18) but not for CABG (1.26, 0.72–2.22). From discharge to 6 months, both PCI (HR 0.45, 95% CI 0.23–0.85) and CABG (0.11, 0.04–0.28) were significantly associated with improved survival in comparison with an initial strategy of no revascularization. Coronary artery bypass graft revascularization was associated with a five-fold increase in stroke compared with the other two groups.
Conclusion
Unprotected left main coronary disease in ACS is associated with high mortality, especially in patients with STEMI and/or haemodynamic or arrhythmic instability. Percutaneous coronary intervention is now the most common revascularization strategy and preferred in higher risk patients. Coronary artery bypass graft is often delayed and performed in lower risk patients, leading to good 6-month survival. The two approaches therefore appear complementary.
doi:10.1093/eurheartj/ehp353
PMCID: PMC2755115  PMID: 19720640
Left main disease; Acute coronary syndrome
12.  Has the frequency of bleeding changed over time for patients presenting with an acute coronary syndrome? The Global Registry of Acute Coronary Events 
European Heart Journal  2009;31(6):667-675.
Aims
To determine whether changes in practice, over time, are associated with altered rates of major bleeding in acute coronary syndromes (ACS).
Methods and results
Patients from the Global Registry of Acute Coronary Events were enrolled between 2000 and 2007. The main outcome measures were frequency of major bleeding, including haemorrhagic stroke, over time, after adjustment for patient characteristics, and impact of major bleeding on death and myocardial infarction. Of the 50 947 patients, 2.3% sustained a major bleed; almost half of these presented with ST-elevation ACS (44%, 513). Despite changes in antithrombotic therapy (increasing use of low molecular weight heparin, P < 0.0001), thienopyridines (P < 0.0001), and percutaneous coronary interventions (P < 0.0001), frequency of major bleeding for all ACS patients decreased (2.6 to 1.8%; P < 0.0001). Most decline was seen in ST-elevation ACS (2.9 to 2.1%, P = 0.02). The overall decline remained after adjustment for patient characteristics and treatments (P = 0.002, hazard ratio 0.94 per year, 95% confidence interval 0.91–0.98). Hospital characteristics were an independent predictor of bleeding (P < 0.0001). Patients who experienced major bleeding were at increased risk of death within 30 days from admission, even after adjustment for baseline variables.
Conclusion
Despite increasing use of more intensive therapies, there was a decline in the rate of major bleeding associated with changes in clinical practice. However, individual hospital characteristics remain an important determinant of the frequency of major bleeding.
doi:10.1093/eurheartj/ehp499
PMCID: PMC2838680  PMID: 20007159
Acute coronary syndrome; Bleeding; Unstable angina; Myocardial infarction
13.  Performance comparison of two microarray platforms to assess differential gene expression in human monocyte and macrophage cells 
BMC Genomics  2008;9:302.
Background
In this study we assessed the respective ability of Affymetrix and Illumina microarray methodologies to answer a relevant biological question, namely the change in gene expression between resting monocytes and macrophages derived from these monocytes. Five RNA samples for each type of cell were hybridized to the two platforms in parallel. In addition, a reference list of differentially expressed genes (DEG) was generated from a larger number of hybridizations (mRNA from 86 individuals) using the RNG/MRC two-color platform.
Results
Our results show an important overlap of the Illumina and Affymetrix DEG lists. In addition, more than 70% of the genes in these lists were also present in the reference list. Overall the two platforms had very similar performance in terms of biological significance, evaluated by the presence in the DEG lists of an excess of genes belonging to Gene Ontology (GO) categories relevant for the biology of monocytes and macrophages. Our results support the conclusion of the MicroArray Quality Control (MAQC) project that the criteria used to constitute the DEG lists strongly influence the degree of concordance among platforms. However the importance of prioritizing genes by magnitude of effect (fold change) rather than statistical significance (p-value) to enhance cross-platform reproducibility recommended by the MAQC authors was not supported by our data.
Conclusion
Functional analysis based on GO enrichment demonstrates that the 2 compared technologies delivered very similar results and identified most of the relevant GO categories enriched in the reference list.
doi:10.1186/1471-2164-9-302
PMCID: PMC2464609  PMID: 18578872
14.  Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis 
Objective To determine the efficacy and safety of enoxaparin compared with unfractionated heparin during percutaneous coronary intervention.
Design Systematic review and meta-analysis.
Data sources Medline and Cochrane database of systematic reviews, January 1996 to May 2011.
Study selection Randomised and non-randomised studies comparing enoxaparin with unfractionated heparin during percutaneous coronary intervention and reporting on both mortality (efficacy end point) and major bleeding (safety end point) outcomes.
Data extraction Sample size, characteristics, and outcomes, extracted independently and analysed.
Data synthesis 23 trials representing 30 966 patients were identified, including 10 243 patients (33.1%) undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction, 8750 (28.2%) undergoing secondary percutaneous coronary intervention after fibrinolysis, and 11 973 (38.7%) with non-ST elevation acute coronary syndrome or stable patients scheduled for percutaneous coronary intervention. A total of 13 943 patients (45.0%) received enoxaparin and 17 023 (55.0%) unfractionated heparin. Enoxaparin was associated with significant reductions in death (relative risk 0.66, 95% confidence interval 0.57 to 0.76; P<0.001), the composite of death or myocardial infarction (0.68, 0.57 to 0.81; P<0.001), and complications of myocardial infarction (0.75, 0.6 to 0.85; P<0.001), and a reduction in incidence of major bleeding (0.80, 0.68 to 0.95; P=0.009). In patients who underwent primary percutaneous coronary intervention, the reduction in death (0.52, 0.42 to 0.64; P<0.001) was particularly significant and associated with a reduction in major bleeding (0.72, 0.56 to 0.93; P=0.01).
Conclusion Enoxaparin seems to be superior to unfractionated heparin in reducing mortality and bleeding outcomes during percutaneous coronary intervention and particularly in patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction.
doi:10.1136/bmj.e553
PMCID: PMC3271999  PMID: 22306479
15.  Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: a systematic review and meta-analysis 
Objective To investigate the effect of pretreatment with P2Y12 receptor inhibitors compared with no pretreatment on efficacy and safety of treatment of non-ST elevation acute coronary syndrome (ACS).
Data sources Two reviewers independently searched Medline, Embase, Cochrane Controlled Trials, and BioMed Central databases for randomized placebo controlled trials and observational studies from August 2001 to March 2014.
Study eligibility Studies must have reported both all-cause mortality (primary efficacy endpoint) and major bleeding (safety endpoint) outcomes.
Data extraction Data on sample size, characteristics, drug dose and delay of administration, and outcomes were independently extracted and analyzed.
Data synthesis A random-effect model was applied. The analysis was performed (i) in all patients independently of the management strategy and (ii) only in patients undergoing percutaneous coronary intervention.
Results Of the 393 titles identified, seven (four randomized controlled trials, one observational analysis from a randomized controlled trial, and three observational studies) met the inclusion criteria. No study was identified for ticagrelor or cangrelor, and analyses were thus limited to thienopyridines. A total of 32 383 non-ST elevation ACS patients were included, 18 711 coming from randomized controlled trials. Of these, 55% underwent percutaneous coronary intervention (PCI). Pretreatment was not associated with a significant lower risk of mortality in all patients (odds ratio 0.90 (95% confidence interval 0.75 to 1.07), P=0.24), in particular when considering only the randomized controlled trials (odds ratio 0.90 (0.71 to 1.14), P=0.39). Similar results were observed in the cohort of patients undergoing PCI. A significant 30-45% excess of major bleeding was consistently observed in all patients (odds ratio 1.32 (1.16 to 1.49), P<0.0001) and in those undergoing PCI, as well as in the subset analyses of randomized controlled trials of these two cohorts of patients. There was a reduction in major adverse cardiovascular events in the analysis of all patients (odds ratio 0.84 (0.72 to 0.98), P=0.02), driven by the old clopidogrel studies (CURE and CREDO), but the difference was not significant for the cohort of patients undergoing PCI. Stent thrombosis, stroke, and urgent revascularization did not differ between groups (pretreatment v no pretreatment). The results were consistent for both thienopyridines and confirmed in sensitivity analyses.
Limitations Analysis was not performed on individual patient’s data.
Conclusion In patients presenting with non-ST elevation ACS, pretreatment with thienopyridines is associated with no significant reduction of mortality but with a significant excess of major bleeding no matter the strategy adopted, invasive or not. Our results do not support a strategy of routine pretreatment in patients with non-ST elevation ACS.
doi:10.1136/bmj.g6269
PMCID: PMC4208629

Results 1-15 (15)