András Vorobcsuk

Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis.

BACKGROUND A growing number of observational studies suggest that high on-clopidogrel platelet reactivity (HPR) is associated with recurrent thrombotic events after percutaneous coronary intervention. We aimed to perform an updated systematic review and meta-analysis on the clinical relevance of HPR to summarize the available evidence and to define more precise effect estimates. METHODS Relevant observational studies published between January 2003 and February 2010 were searched that presented intent-to-treat analyses on the clinical relevance of HPR measured with an adenosine diphosphate (ADP)-specific platelet function assay. The main outcome measures were cardiovascular (CV) death, definite/probable stent thrombosis (ST), nonfatal myocardial infarction (MI), and a composite end point of reported ischemic events. The outcome parameters were pooled with the random-effect model via generic inverse variance weighting. RESULTS Twenty studies comprising a total number of 9,187 patients qualified. High on-clopidogrel platelet reactivity appeared to be a strong predictor of MI, ST, and the composite end point of reported ischemic events (odds ratios [95% CI]: 3.00 [2.26-3.99], 4.14 [2.74-6.25], and 4.95 [3.34-7.34], respectively; P < .00001 for all cases). According to the meta-analysis, patients with HPR had a 3.4-fold higher risk for CV death compared with patients with normal ADP reactivity (odds ratio 3.35, 95% CI 2.39-4.70, P < .00001). Although there were large differences in the methodology as well as in the definition of HPR between studies, the predicted risk for CV death, MI, or ST was not heterogeneous (I(2): 0%, 0%, and 12%, respectively; P = not significant for all cases). CONCLUSIONS High on-clopidogrel platelet reactivity, measured by an ADP-specific platelet function assay, is a strong predictor of CV death, MI, and ST in patients after percutaneous coronary intervention.

Transradial versus transfemoral percutaneous coronary intervention in acute myocardial infarction: Systematic overview and meta-analysis

BACKGROUND Although transradial percutaneous coronary intervention (TRPCI) is widely applied for percutaneous procedures, its safety in the setting of ST-segment elevation (STEMI) is controversial. Our aim was to assess the safety and efficacy of TRPCI versus transfemoral PCI in the context of treating patients suffering acute myocardial infarction with STEMI. METHODS Randomized, case-control, and cohort studies comparing access-related complications were analyzed. Our objective was to determine if radial access reduces major bleeding and thereby reduces death and ischemic events compared to femoral access in this setting. A fixed-effects model was used with random effects for sensitivity analysis. RESULTS Twelve studies involving 3324 patients were identified. Transradial PCI reduced major bleeding compared to transfemoral PCI (P = .0001), and significant reductions were found in the composite of death, myocardial infarction, or stroke (P = .001). Mortality reduction showed a significant toward benefit in the case of TRPCI (2.04% vs 3.06%, OR 0.54 [95% CI 0.33-0.86], P = .01). The fluoroscopic time was longer, and access site crossover was more frequent for TRPCI (P = .001, P < .00001, respectively). CONCLUSIONS Transradial PCI reduces the risk of periprocedural major bleeding and major adverse events in the STEMI setting.

Use of New-Generation Oral Anticoagulant Agents in Patients Receiving Antiplatelet Therapy After an Acute Coronary Syndrome: Systematic Review and Meta-analysis of Randomized Controlled Trials

BACKGROUND Despite receipt of dual antiplatelet therapy, patients after an acute coronary syndrome (ACS) remain at significant risk for thrombotic events. The role of orally activated Xa antagonist (anti-Xa) and direct thrombin inhibitors is debated in this setting. Our study objective was to evaluate the efficacy and safety of new-generation oral anticoagulant agents compared with placebo in patients receiving antiplatelet therapy after an ACS. METHODS Electronic databases were searched to identify prospective randomized placebo-controlled clinical trials that evaluated the effects of anti-Xa or direct thrombin inhibitors in patients receiving antiplatelet therapy after an ACS. Efficacy measures included stent thrombosis, overall mortality, and a composite end point of major ischemic events, while thrombolysis in myocardial infarction-defined major bleeding events were used as a safety end point. The net clinical benefit was calculated as the sum of composite ischemic events and major bleeding events. RESULTS For the period January 1, 2000, through December 31, 2011, we identified 7 prospective randomized placebo-controlled clinical trials that met the study criteria, involving 31 286 patients. Based on the pooled results, the use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an ACS was associated with a dramatic increase in major bleeding events (odds ratio, 3.03; 95% CI, 2.20-4.16; P < .001). Significant but moderate reductions in the risk for stent thrombosis or composite ischemic events were observed, without a significant effect on overall mortality. For the net clinical benefit, treatment with new-generation oral anticoagulant agents provided no advantage over placebo (odds ratio, 0.98; 95% CI, 0.90-1.06; P = .57). CONCLUSION The use of anti-Xa or direct thrombin inhibitors is associated with a dramatic increase in major bleeding events, which might offset all ischemic benefits in patients receiving antiplatelet therapy after an ACS.

The impact of cardiopulmonary manifestations on the mortality of SSc: a systematic review and meta-analysis of observational studies

OBJECTIVES Internal organ involvement reduces the life expectancy of SSc patients. Cardiopulmonary manifestations are currently the primary cause of death. We aimed to perform a systematic review and meta-analysis to define more precise effect estimates of different cardiopulmonary manifestations and to verify trends in the mortality of SSc. METHODS A systematic literature search was performed to identify relevant cohort studies. Reports analyzing the role of the organ manifestations in mortality or analysing survival compared with the control population were included. The outcome parameters were pooled with the random-effect model via generic inverse-variance weighting in conventional and cumulative meta-analysis. RESULTS Eighteen studies comprising a total of 12, 829 patients qualified. The reported causes of death were as follows: 19.7% cardiac, 16.8% interstitial pulmonary disease, 13.1% pulmonary hypertension and 13.8% renal disease. The risk of death was significantly increased in patients with cardiac involvement [hazard ratio (HR) 3.15], with pulmonary interstitial disease (HR 2.58), with pulmonary hypertension (HR 3.50) and with renal manifestations (HR 2.76). A trend for survival improvement (R2)= 0.4295, P = 0.04) was found, and the difference in survival between the diffuse and limited scleroderma subgroups was diminishing (R2)= 0.4119. P = 0.02). CONCLUSION Meta-analysis of observational studies indicates a trend for improvement over the last decades in which the life expectancy of SSc patients approaches that of the general population. A decreasing tendency in the survival differences between the limited and diffuse SSc subgroups was also verified. Internal organ involvements have similarly unfavourable predictive impact on survival.

Justification of 150 mg clopidogrel in patients with high on-clopidogrel platelet reactivity.

Eur J Clin Invest 2012; 42 (4): 384–392

Meta-Analysis Comparing Carvedilol Versus Metoprolol for the Prevention of Postoperative Atrial Fibrillation Following Coronary Artery Bypass Grafting

A systematic review and meta-analysis was performed to evaluate the effects of carvedilol versus metoprolol on the incidence of postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting in randomized controlled trials. Ovid MEDLINE, PubMed, CENTRAL, and Excepta Medica (EMBASE) were searched up to March 2013 for suitable randomized controlled trials. Data were pooled using random-effects model for pairwise analyses. A total of 4 trials with 601 patients were included in this analysis. Pairwise analyses showed that compared with metoprolol, carvedilol significantly reduced the incidence of postoperative atrial fibrillation (odds ratio 0.50, 95% confidence interval 0.32 to 0.80). In conclusion, compared with metoprolol, carvedilol significantly reduces the incidence of postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting.

Comparison of conventional aggregomerty with VASP for monitoring P2Y12-specifc platelet inhibition

No consensus exists regarding the optimal estimate of light transmission aggregometry (LTA) to reflect P2Y12 ADP receptor inhibition in patients receiving thienopyridine therapy. Currently, the only completely P2Y12-receptor specific method is the measurement of vasodilator stimulated phosphoprotein (VASP) phosphorylation (PRI) with flow cytometry. In the current analysis, we aimed to test the superiority of the late platelet aggregation value over other estimates of light transmission aggregometry in determining P2Y12-receptor inhibition by comparing them to VASP-PRI. On-clopidogrel platelet reactivity was measured in 121 clopidogrel-naïve patients who underwent elective coronary stent implantation. Samples for LTA and VASP assessments were drawn at 12–18 hours after a 600-mg loading dose of clopidogrel and 25 days after the intervention. ADP 5 µM-induced maximal aggregation (AGGmax), 6-minute late aggregation (AGGlate), 6-minute disaggregation (disAGG) and area under the aggregation curve (AUC) were compared to VASP-PRI. Categorical agreement with VASP-defined normal and high platelet reactivity (HPR: PRI≥50%) was calculated according to the optimal cutoff values obtained with receiver-operating characteristic (ROC) curves. The evaluation of 242 measurements showed significant, moderate-strength correlations between VASP-PRI and LTA estimates without the superiority of AGGlate over other estimates (AGGmax: ρ = 0.47; AGGlate: ρ = 0.45; disAGG: ρ = −0.44; AUC: ρ = 0.50). Notably, there were considerable intra-individual differences between VASP and LTA testing. LTA estimates were similar in classifying patients to VASP-defined normal or HPR categories (AGGmax: κ = 0.41; AGGlate: κ = 0.45; disAGG: κ = 0.44; AUC: κ = 0.44). When all estimates of LTA were compared in multivariable models, AUC proved to be the independent linear determinant of VASP-PRI and the best predictor of HPR. Estimates of LTA seem equal in determining the degree of P2Y12-receptor inhibition or in predicting VASP-defined HPR without the superiority of AGGlate over others. These results reject a commonly used hypothesis and might contribute to the standardization of the LTA assay.

Low platelet disaggregation predicts poor response to 150 mg clopidogrel in patients with elevated platelet reactivity

Raising the maintenance dose of clopidogrel to 150 mg enhances platelet inhibition (PI) in patients with elevated platelet reactivity (EPR); however, large differences were observed between individuals in the extent of this benefit. We aimed to find clinical and platelet function variables that might predict the response to 150 mg clopidogrel in patients with EPR. ADP 5 µM-stimulated peak aggregation (Aggmax), 6-minute late aggregation (Agglate) and 6-minute disaggregation (disAgg) were measured with light transmission aggregometry (LTA) in a consecutive cohort of 202 patients admitted for emergent or elective percutaneous coronary intervention (PCI) after receiving a 600-mg loading dose of clopidogrel. PI was assessed 12 to 18 hours after loading dose and 30 days after the intervention. EPR was defined as a Aggmax value greater than 34%. From the first day of PCI, 85 patients with EPR received 150 mg clopidogrel for 30 days, while others with normal platelet reactivity (NPR) took 75 mg clopidogrel. Baseline clinical and LTA variables were analyzed in multivariable regression models. Administration of 150 mg clopidogrel enhanced PI and decreased the prevalence of EPR at 30 days compared to the peri-interventional period (Aggmax: 46.9 ± 8.3 vs. 37.3 ± 11.5; EPR: 100% vs. 62.4%; p < 0.001 in both cases); however, the achieved level of platelet reactivity was higher than patients with NPR (Aggmax: 20.6 ± 8.1 vs. 25.3 ± 10.8, p < 0.001). Multivariable logistic regression revealed low platelet disaggregation (odds ratio (OR): 12.49; 95% CI: 2.52–62.00; P = 0.002) and acute coronary syndrome (OR: 4.83; 95% CI: 1.54–15.09; P = 0.008) as independent predictors of EPR. The area under the receiver-operating-characteristic curve was 0.72 ± 0.06 for disaggregation to predict NPR after 150 mg clopidogrel. The optimal disaggregation cut-off was 16.5% with a sensitivity of 94% and a specificity of 43%. Administering 150 mg maintenance dose of clopidogrel enhanced antiplatelet potency; however, more than half of the patients persisted with EPR. Acute coronary syndrome and low (<16.5%) platelet disaggregation are independent predictors of poor benefit from dose shift.

Meta-analysis of randomized trials on access site selection for percutaneous coronary intervention in ST-segment elevation myocardial infarction.

Introduction Superior outcomes with transradial (TRPCI) versus transfemoral coronary intervention (TFPCI) in the setting of acute ST-segment elevation myocardial infarction (STEMI) have been suggested by earlier studies. However, this effect was not evident in randomized controlled trials (RCTs), suggesting a possible allocation bias in observational studies. Since important studies with heterogeneous results regarding mortality have been published recently, we aimed to perform an updated review and meta-analysis on the safety and efficacy of TRPCI compared to TFPCI in the setting of STEMI. Material and methods Electronic databases were searched for relevant studies from January 1993 to November 2012. Outcome parameters of RCTs were pooled with the DerSimonian-Laird random-effects model. Results Twelve RCTs involving 5,124 patients were identified. According to the pooled analysis, TRPCI was associated with a significant reduction in major bleeding (odds ratio (OR): 0.52 (95% confidence interval (CI) 0.38–0.71, p < 0.0001)). The risk of mortality and major adverse events was significantly lower after TRPCI (OR = 0.58 (95% CI: 0.43–0.79), p = 0.0005 and OR = 0.67 (95% CI: 0.52–0.86), p = 0.002 respectively). Conclusions Robust data from randomized clinical studies indicate that TRPCI reduces both ischemic and bleeding complications in STEMI. These findings support the preferential use of radial access for primary PCI.

Outcomes of patients receiving clopidogrel prior to cardiac surgery

BACKGROUND Clinical impact of the concomitant clopidogrel therapy on clinical outcomes in patients undergoing cardiac surgery is unclear. We aimed to pool and systematically analyze outcomes in clopidogrel-treated patients undergoing cardiac operations to achieve greater statistical power and to define precise effect-estimates. METHODS PubMed and Central databases were searched for relevant studies published between January 2001 and May 2010. The main outcome measures were the rates of red blood cell (RBC) transfusion, reoperation, myocardial infarction and postoperative mortality. The outcome parameters were pooled with the random-effect model via generic-inverse variance-weighting. RESULTS Twenty studies comprising a total number of 23,668 patients were analyzed. Pooled analysis revealed that the administration of clopidogrel had a higher risk for postoperative mortality (OR: 1.24; 95% CI: 1.03-1.49, p=0.03) that was consistent among studies. The rates of myocardial infarction were similar between groups. Clopidogrel-exposed patients were associated with a significantly higher rate of RBC transfusion (OR: 1.82; 95% CI: 1.40-2.37; p<0.00001) and reoperation (OR: 2.15; 95% CI: 1.38-3.34; p<0.00001), although there was a marked heterogeneity among studies. According to subgroup analysis the mortality and the rates of transfusions were higher in studies in which clopidogrel was not discontinued 5 days prior to surgery, while the higher risk for reoperation was only apparent in studies published before 2006. CONCLUSION Meta-analysis of observational studies demonstrated that concomitant treatment with clopidogrel before cardiac surgery is associated with a significant risk of bleeding-related complications and with a higher mortality.