András Komócsi

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.

Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention

Optimizing outcomes after percutaneous coronary intervention (PCI) requires balancing between the risks of thrombotic and bleeding events in individual patients.1–3 However, finding the optimal balance is not always straightforward since the risks of thrombotic and bleeding complications may differ extremely between individuals. In addition, the individual effects of anticoagulant and antiplatelet drugs are not uniform in patients.4 Recent European guidelines1,3 recommend the use of prasugrel or ticagrelor instead of clopidogrel in all PCI-treated acute coronary syndrome (ACS) patients without contraindication, acknowledging that laboratory assessment of P2Y12-receptor inhibition may be considered only in selected cases when clopidogrel is used.1 However, there is no guidance with respect to the appropriate methodology and the suggested interpretation of results. The Working Group on Thrombosis of the European Society of Cardiology aimed to review the available evidence and the clinical relevance of platelet function testing in order to reach a consensus regarding the methodology, evaluation, and clinical interpretation of platelet function in patients undergoing PCI. Regarding the choice between available P2Y12-inhibitors, the 2011 ESC guidelines on non-ST segment elevation acute coronary syndromes (NSTE-ACS)1 and the 2012 guidelines on ST-segment elevation myocardial infarction3 recommend prasugrel and ticagrelor for all ACS patients without contraindication, and clopidogrel is only recommended if these agents are not available. Despite the restrictive recommendations for clopidogrel, it still holds a class I indication in ACS due to the large differences in the availability of the new-generation P2Y12-inhibitors among European countries. According to the 2011 ACCF/AHA/SCAI guidelines for PCI,5 a P2Y12-inhibitor should be given for ACS patients without preferring novel P2Y12-inhibitors over clopidogrel. Similarly, the 2012 ACCF/AHA unstable angina/non-ST-segment elevation myocardial infarction guidelines6 and the 2013 ACCF/AHA ST-elevation myocardial infarction guidelines …

Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after percutaneous coronary intervention: Systematic review and meta-analysis

BACKGROUND ADP-specific platelet function assays were shown to predict thrombotic events, and might be helpful to select candidates for more potent antiplatelet therapy. We aimed to determine the efficacy and safety of giving intensified antiplatelet therapy on the basis of platelet reactivity testing for patients undergoing percutaneous coronary intervention (PCI). METHODS Electronic databases were searched to find prospective, randomized trials that reported the clinical impact of using an intensified antiplatelet protocol (repeated loading or elevated maintenance doses of clopidogrel, prasugrel or glycoprotein IIb/IIIa inhibitor) on the basis of ADP-specific platelet reactivity testing (VerifyNow, Multiplate, VASP or light transmission aggregometry) compared to standard-dose clopidogrel. Evaluated efficacy measures included cardiovascular death, non-fatal myocardial infarction and definite/probable stent thrombosis (ST), while major bleeding events were recorded as safety endpoint. RESULTS Between 2008 and 2011, 10 clinical trials comprising 4213 randomized patients were identified. Compared to standard antiplatelet therapy, the intensified protocol was associated with a significant reduction in cardiovascular mortality, ST and myocardial infarction (p<0.01 for all). There was no difference in the rate of major bleeding events between intensified and standard groups (p=0.44). Although the observed effects regarding mortality, ST and bleeding were not heterogeneous, meta-regression analysis revealed that the net clinical benefit of the intensified treatment significantly depended on the risk of ST with standard-dose clopidogrel (p=0.023). CONCLUSION Intensifying antiplatelet therapy on the basis of platelet reactivity testing reduces cardiovascular mortality and ST after PCI; however, the net benefit of this approach depends on the risk of ST with standard-dose clopidogrel.

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.

Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): A randomised, open-label, multicentre trial

BACKGROUND Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti-ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT). METHODS In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22. FINDINGS Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (pnon-inferiority=0·0004; hazard ratio [HR] 0·81 [95% CI 0·62-1·06], psuperiority=0·12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; pnon-inferiority=0·0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0·82 [95% CI 0·59-1·13]; p=0·23). INTERPRETATION Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. FUNDING Klinikum der Universität München, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.

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.

Impact of genetic variants on post-clopidogrel platelet reactivity in patients after elective percutaneous coronary intervention.

AIM To determine the effect of various SNPs on post-clopidogrel platelet reactivity and clinical outcome. MATERIALS & METHODS Cytochrome 2C19 (CYP2C19) loss-of-function (LOF; *2, *3) and gain-of-function (GOF; *17) allelic variants, together with ABCB1 (3435 C→T and 2677 G→T/A) and paraoxonase-1 (PON-1; 192 Q→R) SNPs were analyzed in 189 patients after elective stent implantation who participated in a randomized, placebo-controlled trial (NCT00638326). Platelet reactivity was determined with light transmission aggregometry and vasodilator stimulated phosphoprotein phosphorylation (VASP-PRI) 12-24 h after 600 mg clopidogrel. High on-treatment platelet reactivity (HTPR) was defined according to the consensus definition (ADP 5 µM >46%; VASP-PRI>50%). RESULTS In the case of CYP2C19 genotypes, a gene-dose effect was observed in ADP reactivity with the lowest values in GOF homozygotes and the highest degree in patients carrying two LOF alleles. The odds for HTPR also increased with the number of LOF alleles. There were no significant differences in platelet reactivity according to PON-1 or ABCB1 genotypes. In multivariate analysis, the presence of a CYP2C19 LOF allele turned out to be the independent determinant of HTPR. Although the study was not powered to clinical outcome (not LOF heterozygotes), only patients with two LOF alleles had a significantly higher risk for cardiovascular death, myocardial infarction or unplanned target vessel revascularization at 1 year compared with non-LOF carriers. CONCLUSION Genetic variants in CYP2C19 have a gene-dose effect on post-clopidogrel platelet reactivity, with homozygote LOF carriers having the highest risk for HTPR and for adverse ischemic events. Neither ABCB1 nor PON-1 genotypes significantly influenced platelet reactivity or outcome.

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

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

Overlap of coronary disease and pulmonary arterial hypertension in systemic sclerosis

Objectives: Pulmonary arterial hypertension (PAH) is a common complication of systemic sclerosis (SSc). Symptoms of coronary artery disease (CAD) and PAH are closely related and cardiac catheterisation is needed to confirm their diagnosis. The aim of the present work was to investigate of the extent of overlap between CAD and PAH in patients with SSc. Methods: Based on non-invasive investigations, 20 patients out of 120 were suspected to have PAH (“suspected PAH” group). Another 10 patients showed signs of coronary disease (“suspected CAD” Group). In these 30 patients, right heart catheterisation and coronary angiography were performed, and the coronary flow reserve (CFR) was assessed by thermodilution technique. Results: In the “suspected PAH” and the “suspected CAD” groups, PAH was found in 12/20 and 2/10 cases, and coronary artery stenosis in 9/20 and 6/10 cases, respectively. Severely reduced CFR was revealed in 7/20 and 3/10 cases, respectively. Conclusions: PAH, CAD and reduced CFR all show a considerable overlap in symptomatic patients with SSc. The current non-invasive investigations are neither sensitive nor specific enough to make an appropriate distinction between these different disease manifestations. A more invasive approach, such as coronary angiography at the initial catheterisation, is required to properly characterise and treat the different forms of cardiac involvement in SSc.