Stephen A. O’Connor

Association of Clopidogrel Pretreatment With Mortality, Cardiovascular Events, and Major Bleeding Among Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-analysis

CONTEXT Clopidogrel pretreatment is recommended for patients with acute coronary syndromes (ACS) and stable coronary artery disease who are scheduled for percutaneous coronary intervention (PCI), but whether using clopidogrel as a pretreatment for PCI is associated with positive clinical outcomes has not been established. OBJECTIVE To evaluate the association of clopidogrel pretreatment vs no treatment with mortality and major bleeding after PCI. DATA SOURCES MEDLINE, EMBASE, Cochrane Controlled Trials Register databases, and reference lists of qualifying articles. STUDY SELECTION Studies reporting clinical data on mortality and major bleeding were included. Of the 392 titles identified, 15 articles published between August 2001 and September 2012 met the inclusion criteria: 6 randomized controlled trials (RCTs), 2 observational analyses of RCTs, and 7 observational studies. DATA EXTRACTION Quality of studies was assessed with the Ottawa Scale and the Jadad Score as appropriate. Results were independently extracted by 2 reviewers. A random-effect model was applied. Pretreatment was defined as the administration of clopidogrel before PCI or catheterization. The main analysis was performed on RCTs and confirmed by observational analyses and observational studies. Prespecified subgroups--clinical presentation and clopidogrel loading dose--were analyzed. The primary efficacy and safety end points were all-cause mortality and major bleeding. Secondary end points included major cardiac events. RESULTS Of the 37 814 patients included in the meta-analysis, 8608 patients had participated in RCTs; 10,945, in observational analyses of RCTs; and 18,261, in observational studies. Analysis of RCTs showed that clopidogrel pretreatment was not associated with a reduction of death (absolute risk, 1.54% vs 1.97%; OR, 0.80; 95% CI, 0.57-1.11; P = .17) but was associated with a lower risk of major cardiac events (9.83% vs 12.35%; OR, 0 .77; 95% CI, 0.66-0.89; P < .001). There was no significant association between pretreatment and major bleeding overall (3 .57% vs 3.08%; OR, 1.18; 95% CI, 0.93-1.50; P = .18). Analyses from observational analyses of RCTs and observational studies were consistent for all results. CONCLUSIONS Among patients scheduled for PCI, clopidogrel pretreatment was not associated with a lower risk of mortality but was associated with a lower risk of major coronary events.

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.

Efficacy of Ex Vivo Autologous and In Vivo Platelet Transfusion in the Reversal of P2Y12 Inhibition by Clopidogrel, Prasugrel, and Ticagrelor The APTITUDE Study

Background—Allogenic platelet transfusions (PT) are administered to treat excessive bleeding in patients on P2Y12 receptor inhibitors (RI). We assessed the effect of ex vivo and in vivo PT on platelet activation and aggregation in patients on dual antiplatelet therapy. Methods and Results—In the Antagonize P2Y12 Treatment Inhibitors by Transfusion of Platelets in an Urgent or Delayed Timing After Acute Coronary Syndrome or Percutaneous Coronary Intervention Presentation-Acute Coronary Syndrome (APTITUDE-ACS) study, patients presenting with acute coronary syndrome or for elective percutaneous coronary intervention, receiving loading doses of clopidogrel (600 mg, n=13 or 900 mg, n=12), prasugrel 60 mg (n=10), or ticagrelor 180 mg (n=10) were included. PT was performed ex vivo by mixing platelet-rich plasma from blood sampling performed at baseline in increasing proportions with platelet-rich plasma sampled 4 hours after loading dose. The percentage restoration of residual platelet aggregation achieved with 80% proportion PT (residual platelet aggregation 80% PT mix/residual platelet aggregation baseline×100) significantly decreased with increasing potency of P2Y12 RI (83.9±11%, 73±14%, 66.3±15%, 40.9±19% for clopidogrel 600 mg, clopidogrel 900 mg, prasugrel, and ticagrelor, respectively; P for trend <0.0001). In the APTITUDE-Coronary Artery Bypass Graft (APTITUDE-CABG) study, vasodilator-stimulated phosphoprotein-platelet reactivity index, a specific marker of the P2Y12 RI drug–effect, was assessed before and after in vivo PT administered for excessive bleeding in patients undergoing cardiac surgery while on a maintenance dose of aspirin and clopidogrel (n=45), prasugrel (n=6), or ticagrelor (n=3). When compared with baseline, there was a significant relative increase of 23.1% in platelet activation after PT transfusion (42.2±23.6% versus 56.6±18.2%; P=0.0008). Conclusions—PT restores platelet reactivity in patients with acute coronary syndrome/percutaneous coronary intervention and in patients undergoing cardiac surgery on P2Y12 RI while bleeding with a less effect with increasing potency of P2Y12 inhibition. Clinical Trial Registration—URL: http://www.recherche-biomedicale.sante.gouv.fr/pro/comites/coordonnees.htm and http://www.cnil.fr/. Unique identifiers: No. 301111 and No. 1547216v0.

High-On Treatment Platelet Reactivity as a Risk Factor for Secondary Prevention after Coronary Stent Revascularization: A Landmark Analysis of the ARCTIC Study

Background— Individualizing antiplatelet therapy after platelet function testing did not improve outcome after coronary stenting in the Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation One Year After Stenting (ARCTIC) study. Whether results are different during the phase of secondary prevention starting after hospital discharge, when periprocedural events have been excluded, is unknown. Methods and Results— In ARCTIC, 2440 patients were randomized before coronary stenting to a strategy of platelet function monitoring (VerifyNow P2Y12/aspirin point-of-care assay) with drug adjustment in suboptimal responders to antiplatelet therapy or to a conventional strategy without monitoring and without drug or dose changes. We performed a landmark analysis starting at the time of hospital discharge evaluating the primary end point of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization through 1 year. After discharge, the primary end point occurred in 8.6% of patients in the monitoring arm and 7.9% in the conventional arm (hazard ratio, 1.105; 95% confidence interval, 0.835–1.461; P=0.48). Stent thrombosis or urgent revascularization occurred in 4.4% and 4.5% in the monitoring and conventional arms, respectively (P=0.99). There was no difference for any of the other ischemic end points. Major bleeding event rates were 1.8% in the monitoring arm and 2.8% in the conventional arm (P=0.11), whereas major or minor bleeding event rates were 2.3% and 3.4%, respectively (P=0.10). Conclusions— Detection of platelet hyper-reactivity by platelet function testing in patients undergoing coronary stenting with further therapeutic adjustment does not reduce ischemic recurrences after intervention. On-treatment platelet hyperreactivity cannot be considered as a risk factor requiring intervention for secondary prevention after percutaneous coronary revascularization. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00827411.

Provisional vs. two-stent technique for unprotected left main coronary artery disease after ten years follow up: A propensity matched analysis

AIMS There is uncertainty on which stenting approach confers the best long-term outlook for unprotected left main (ULM) bifurcation disease. METHODS AND RESULTS This is a non-randomized, retrospective study including all consecutive patients with 50% stenosis of the left main involving at least 1 of the arteries stemming from the left main treated with drug-eluting stents (DES) in 9 European centers between 2002 and 2004. Patients were divided into two groups: those treated with provisional stentings vs. those treated with two stent strategy. The outcomes of interest were 10-year rates of target lesion revascularization (TLR), major adverse cardiac events (MACE), and their components (cardiovascular death, myocardial infarction [MI], or repeat revascularization), along with stent thrombosis (ST). A total of 285 patients were included, 178 (62.5%) in the provisional stenting group and 87 (37.5%) in the two stent group. After 10 years, no differences in TLR were found at unadjusted analysis (19% vs 25%, p>0.05) nor after propensity score matching (25% vs 28%, p>0.05). Similar rates of MACE (60% vs 66%, p>0.05), death (34% vs 43%, p>0.05), MI (9% vs 14%, p>0.05) and ST were also disclosed at propensity-based analysis. CONCLUSION Even after 10 year follow-up, patients treated with provisional stenting on left main showed comparable rates of target lesion revascularization compared to two stent strategy.

Left Ventricular Assist Device in a Patient With a Concomitant Subcutaneous Implantable Cardioverter Defibrillator

A 51-year-old male, with prior coronary artery bypass grafts and a more recent history of recurrent hospital admissions for refractory heart failure, presented with advanced heart failure caused by ischemic cardiomyopathy. The patient was placed on the heart transplantation list. A subcutaneous-implantable cardioverter/defibrillator (S-ICD; Cameron Health, San Clemente, CA) was electively implanted 1 month later for primary prevention. At implant, sustained ventricular fibrillation was induced and successfully converted to normal sinus rhythm with a submaximal 65 J standard polarity shock with time to therapy of 13 s and impedance of 55 Ω. After an uneventful postoperative period, the patient was discharged home but readmitted a few weeks later with …

Subcutaneous implantable cardioverter-defibrillators and sternal wires: a cautionary tale.

We commenced implanting the subcutaneous implantable cardioverter-defibrillators (S-ICD) in July 2010, and a surgeon (J.W.) has implanted 86 systems to date without surgical complications until this case study. This patient was a man, aged 71 years, 1.68 m, 79 kg with left ventricular ejection fraction of 30% with previous myocardial infarctions, atrial fibrillation, mechanical aortic valve, and single coronary artery bypass graft via median sternotomy in 1999, renal insufficiency since 2003 with hemodialysis via a catheter in the right internal jugular vein, and bare metal stents in 2013. The patient fulfilled Multi center Automatic Defibrillator Implantation Trial (MADIT) II criteria for primary ICD implantation. Surgery under general anesthesia was uneventful. The S-ICD has 3 sensing vectors, described in Figure 1. The chosen sensing vector at implant was secondary with 1.8-mV amplitude after automatic assessment of QRS:T wave ratio. Ventricular fibrillation conversion …

Usefulness of a Simple Clinical Risk Prediction Method, Modified ACEF Score, for Transcatheter Aortic Valve Implantation.

BACKGROUND We assessed the predictive accuracy of a simple risk score, modified age, creatinine clearance, ejection fraction (ACEFmodif) score, for outcome of transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS We prospectively included 703 consecutive patients undergoing TAVI. Patients were divided into low, middle and high ACEFmodif tertiles. Increased ACEFmodif score was associated with a significantly higher 1-year mortality rate (22%, 28% and 36%, P<0.01) and higher risk of acute kidney injury (AKI; 10%, 10% and 22%, P<0.01). On multivariate logistic regression analysis, ACEFmodif score was the only independent predictor of AKI. On multivariate Cox regression, ACEFmodif score was an independent predictor of 1-year cumulative mortality. Although the area under curve (AUC) showed that all risk scores poorly predicted the incidence of AKI and 1-year cumulative mortality, ACEFmodif score was more efficient in predicting the incidence of AKI compared with STS, LES and ES II (AUC, 0.61, 0.55, 0.54, 0.57, respectively). Furthermore, ACEFmodif score had similar accuracy in predicting 1-year mortality compared with other risk scores (AUC, 0.61, 0.61, 0.61, 0.61, respectively). CONCLUSIONS ACEFmodif score may provide useful information for predicting AKI, 30-day and 1-year mortality in patients undergoing TAVI, but these results need further confirmation.

Clinical effects and outcomes with new P2Y12 inhibitors in ACS

Thienopyridines have become the cornerstone of treatment for percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses. Newly developed P2Y12 inhibitors are more potent, more predictable, and have a faster onset of action than clopidogrel, characteristics that make them particularly attractive for high‐risk percutaneous coronary intervention (PCI). Four new P2Y12 inhibitors have been tested each of them having particular individual properties. Prasugrel is an oral pro‐drug leading to irreversible blockade of the P2Y12 receptor and is approved worldwide for ACS PCI. Ticagrelor is a direct‐acting and reversible inhibitor of the P2Y12 receptor with potentially more pleiotropic effects. Cangrelor is an intravenous direct and reversible inhibitor of the P2Y12 receptor providing the highest level of inhibition, and elinogrel is an intravenous and oral P2Y12 antagonist with a direct and reversible action. Both prasugrel and ticagrelor, opposed to clopidogrel, have shown that stronger P2Y12 inhibition led respectively to significant 19 and 16% relative risk reduction of a similar primary end point combining cardiovascular death, non‐fatal myocardial infarction, or non‐fatal stroke. Both drugs showed a significant 0.6% absolute excess of TIMI major bleeding not related to CABG surgery. Because in clinical trials, patients perceived to be at higher risk of bleeding usually are excluded, the risk of major and even fatal bleeding might even be higher in a ‘real‐world’ setting, i.e. in the elderly patient with comorbidities. On the other hand, these newly developed P2Y12 inhibitors decrease mortality after PCI compared with clopidogrel. The risk/benefit ratio is particularly favorable in PCI for patients with STEMI.

Short-term effects of the smoke-free legislation on haemostasis and systemic inflammation due to second hand smoke exposure: The AERER* study

It was the objective of this study to assess the effect of the implementation of the smoke-free legislation on haemostasis and systemic inflammation in second-hand smoking (SHS)-exposed healthy volunteers. Fibrin-rich clot properties, platelet reactivity and inflammatory biomarkers were measured before and four months following the implementation of the smoke-free legislation in gender and age-matched healthy volunteers exposed (n=23, exposed) and unexposed (n=23, controls) to occupational SHS. The primary objective was to compare fibrin-rich clot stiffness before and after implementation of the smoke-free legislation. There was 40% reduction in fibrin-rich clot stiffness following the implementation of the smoke-free legislation in SHS-exposed volunteers (17 ± 7 vs. 10.6 ± 7 dynes/cm², before and after, respectively, p=0.001). These dramatic changes were associated with a 20% reduction in fibrin fiber density (p<0.01) and a 20% reduction in clot lysis time (p=0.05). No change in fibrin properties was observed in the control group of SHS-unexposed volunteers related to the implementation of the smoke-free legislation. Of interest, neither platelet reactivity nor systemic inflammatory biomarkers were changed in either group. The smoke-free legislation is associated with significant changes in fibrin-rich clot properties toward a less thrombogenic conformation with a better fibrinolysis response while neither platelet reactivity nor systemic inflammatory biomarkers are modified. These improvements may explain the observed reduction in acute coronary syndrome following the implementation of the smoke-free legislation.