Argirios E. Tsantes

Procalcitonin-guided algorithms of antibiotic therapy in the intensive care unit: a systematic review and meta-analysis of randomized controlled trials.

Objective:There is increasing interest for strategies that could curtail antibiotic resistance in the critical care setting. We sought to determine the effectiveness and safety of procalcitonin-guided algorithms in the management of septic patients in the intensive care unit. Data Sources:MEDLINE, Scopus, Cochrane Central Register of Controlled Trials (through April 2010), reference lists of retrieved publications, and queries of corresponding authors. No language restrictions were applied. Study Selection:We included only randomized controlled studies reporting on antibiotic use and clinical outcomes of intensive care unit patients managed with a procalcitonin-guided algorithm or according to routine practice. Data Extraction:Data on study characteristics, interventions, and outcomes were retrieved by two independent reviewers. Pooled odds ratios, weighted mean differences, and 95% confidence intervals were calculated by implementing both the Mantel-Haenszel fixed effect model and the DerSimonian-Laird random effects model. Data Synthesis:Seven randomized controlled studies involving 1131 intensive care unit patients (adults = 1010; neonates = 121) were included. In comparison with routine practice, the implementation of procalcitonin-guided algorithms decreased the duration of antibiotic therapy for the first episode of infection by approximately 2 days (weighted mean difference = −2.36 days; 95% confidence interval, −3.11 to −1.61) and the total duration of antibiotic treatment by 4 days (fixed effect model: weighted mean difference: −4.19 days; 95% confidence interval, −4.98 to −3.39). The comparison between the procalcitonin and the routine practice group was not associated with any apparent adverse clinical outcome: 28-day mortality (fixed effect model: odds ratio = 0.93; 95% confidence interval, 0.69 to 1.26), intensive care unit length of stay (fixed effect model: pooled weighted mean difference = −0.49 days, 95% confidence interval, −1.55 to 0.57), and relapsed/persistent infection rate (fixed effect model: odds ratio = 0.97; 95% confidence interval, 0.56 to 1.69). Conclusions:The implementation of a procalcitonin-based algorithm may reduce antibiotic exposure in critically ill, septic patients without compromising clinical outcomes, but further research is necessary before the wide adoption of this strategy.

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis - A meta-analysis

The effect of the 675 insertion/deletion (4G/5G) polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene on the risk of venous thromboembolism (VTE) remains controversial. In this study, we performed a meta-analysis of published data regarding this issue. A comprehensive electronic search was carried out up until September 2006. A total of 22 articles were included in the analysis that was performed using random effects models. Eighteen papers, concerning patients without another known risk factor, comprised 2,644 cases and 3,739 controls. The alleles contrast (4G vs. 5G allele) yielded a statistically significant odds ratio (OR) of 1.153 (95% confidence interval [CI]: 1.068-1.246). In a sub-analysis of five studies that included 256 cases with another genetic risk factor and 147 controls, the combined per-allele OR was still significant (OR: 1.833,95% CI: 1.325-2.536). On the contrary, the analysis of five studies regarding cases with a non-genetic risk factor for VTE (antiphospholipid antibody syndrome, Behcet disease) provided insignificant results in all aspects. There was no evidence for heterogeneity and publication bias in all analyses. Based on our findings, the 4G allele appears to increase the risk of venous thrombosis, particularly in subjects with other genetic thrombophilic defects. Recommendation for detection of this polymorphism in evaluating thrombophilia in such patients might be considered.

Diagnostic and prognostic value of procalcitonin among febrile critically ill patients with prolonged ICU stay

BackgroundProcalcitonin (PCT) has been proposed as a diagnostic and prognostic sepsis marker, but has never been validated in febrile patients with prolonged ICU stay.MethodsPatients were included in the study provided they were hospitalised in the ICU for > 10 days, were free of infection and presented a new episode of SIRS, with fever >38°C being obligatory. Fifty patients fulfilled the above criteria. PCT was measured daily during the ICU stay. The primary outcome was proven infection.ResultsTwenty-seven out of 50 patients were diagnosed with infection. Median PCT on the day of fever was 1.18 and 0.17 ng/ml for patients with and without proven infections (p < 0.001). The area under the curve for PCT was 0.85 (95% CI; 0.71-0.93), for CRP 0.65 (0.46-0.78) and for WBC 0.68 (0.49-0.81). A PCT level of 1 ng/mL yielded a negative predictive value of 72% for the presence of infection, while a PCT of 1.16 had a specificity of 100%. A two-fold increase of PCT between fever onset and the previous day was associated with proven infection (p 0.001) (OR = 8.55; 2.4-31.1), whereas a four-fold increase of PCT of any of the 6 preceding days was associated with a positive predictive value exceeding 69.65%. A PCT value less than 0.5 ng/ml on the third day after the advent of fever was associated with favorable survival (p 0.01).ConclusionThe reported data support that serial serum PCT may be a valuable diagnostic and prognostic marker in febrile chronic critically ill patients.

Plasminogen activator inhibitor-1 4G/5G polymorphism and risk of ischemic stroke : a meta-analysis

This study investigated the hypothesis that the insertion/deletion (4G/5G) polymorphism of the plasminogen activator inhibitor type-1 gene affects the risk for ischemic stroke, since results concerning this association have been controversial. We therefore performed a meta-analysis of published data regarding this issue. A comprehensive electronic search was carried out until January 2006. The analysis was performed using random-effects models and meta-regression. Eighteen eligible studies were retrieved (15 case–control studies and three cohort studies). The case–control studies included 3104 cases and 4870 control individuals concerning the contrast of 4G/4G versus remaining genotypes. The 4G pooled allele frequencies in cases and controls were 54.21 and 54.75%, respectively. Overall, the per-allele odds ratio of the 4G allele was 0.98 (95% confidence interval, 0.858–1.121). Regarding genotypes, we derived nonsignificant odds ratios in all contrasts. The subanalysis including the three studies with a prospective design in the 4G/4G versus 5G/5G contrast derived a significant result (relative risk, 0.523; 95% confidence interval, 0.353–0.775), but the estimated effect size was insignificant when cohort and case–control studies were analyzed together (relative risk, 0.848; 95% confidence interval, 0.662–1.087). We failed to demonstrate a significant association between the 4G/5G polymorphism and ischemic stroke under basal conditions. Determination of plasminogen activator inhibitor type-1 function seems of much higher clinical value than determination of the 4G/5G polymorphism. The effect of this genotype on risk of ischemic stroke in acute stressful diseases and the role of cohort studies in genetic epidemiology, however, warrant further investigation.

Evaluation of the role of the new INNOVANCE PFA P2Y test cartridge in detection of clopidogrel resistance

Light transmittance aggregometry (LTA) has been extensively used in monitoring clopidogrel therapy. However, the availability of simple and rapid point-of-care platelet function assays is of great clinical importance. Thus, the manufacturer of the Platelet Function Analyzer (PFA)-100 System has recently produced the INNOVANCE PFA P2Y test cartridge. We assessed the ability of this new test to reliably detect clopidogrel resistance. We enrolled 90 consecutive patients with coronary artery disease receiving chronic clopidogrel maintenance therapy in combination with aspirin. Twenty healthy volunteers served as controls. Clopidogrel resistance was simultaneously analysed by the INNOVANCE PFA P2Y test cartridge, ADP-induced LTA, the flow-cytometric vasodilator-stimulated phosphoprotein (VASP)-phosphorylation assay and the multiple electrode aggregometry (Multiplate). Agreement among the four platelet function methods by two was assessed using Cohens kappa coefficient. According to the cut-off points for clopidogrel resistance proposed by the literature, agreement was fair between INNOVANCE PFA-100 P2Y and LTA (74.4%) and Multiplate (75.6%), while poor agreement was noticed in VASP assay (63.3%). Based on cut-off points indicating a higher thrombotic risk, agreement between the PFA-100 System and the other three methods did not significantly differ compared to the previous cut-offs (72.2%, 71.1% and 55.1%, respectively). The INNOVANCE PFA-100 P2Y test seems to be comparable to other established platelet function assays in detecting clopidogrel resistance. However, the modest agreement among platelet function methods makes the performance of platelet function testing crucial with more than one technique in order to reliably identify poor responders to clopidogrel treatment.

Intravenous versus oral iron for the treatment of anemia in inflammatory bowel disease: A systematic review and meta-analysis of randomized controlled trials

AbstractAnemia is the most prevalent extraintestinal complication of inflammatory bowel disease (IBD). Our aim was to evaluate the comparative efficacy and harm of intravenous (IV) versus oral iron supplementation for correcting anemia in adult IBD patients.We conducted a systematic review and meta-analysis to integrate evidence from randomized controlled trials having enrolled adults with IBD, and comparing IV versus oral iron (head-to-head) for correcting iron-deficiency anemia. Medline, Embase, Scopus, and the Web of Science database were searched through July 2015. The Cochrane Central Register of Controlled Trials, the WHO International Clinical Trials Registry Platform, the ClinicalTrials.gov, and international conference proceedings were also investigated. Two reviewers independently abstracted study data and outcomes, and rated each trials risk-of-bias. Pooled odds ratio (OR) estimates with their 95% CIs were calculated using fixed- and random-effects models.Five eligible studies, including 694 IBD patients, were identified. In meta-analysis, IV iron demonstrated a higher efficacy in achieving a hemoglobin rise of ≥2.0 g/dL as compared to oral iron (OR: 1.57, 95% CI: 1.13, 2.18). Treatment discontinuation rates, due to adverse events or intolerance, were lower in the IV iron groups (OR: 0.27, 95% CI: 0.13, 0.59). Similarly, the occurrence of gastrointestinal adverse events was consistently lower in the IV iron groups. On the contrary, serious adverse events (SAEs) were more frequently reported among patients receiving IV iron preparations (OR: 4.57, 95% CI: 1.11, 18.8); however, the majority of the reported SAEs were judged as unrelated or unlikely to be related to the study medication. We found no evidence of publication bias, or between-study heterogeneity, across all analyses. Risk of bias was high across primary studies, because patients and personnel were not blinded to the intervention.IV iron appears to be more effective and better tolerated than oral iron for the treatment of IBD-associated anemia.

The association between plasminogen activator inhibitor type 1 (PAI-1) levels, PAI-1 4G/5G polymorphism, and myocardial infarction: a Mendelian randomization meta-analysis

Abstract Background: The circulating levels of plasminogen activator inhibitor type 1 (PAI-1) are increased in individuals carrying the 4G allele at position –675 of the PAI-1 gene. In turn, overexpression of PAI-1 has been found to affect both atheroma and thrombosis. However, the association between PAI-1 levels and the incidence of myocardial infarction (MI) is complicated by the potentially confounding effects of well-known cardiovascular risk factors. The current study tried to investigate in parallel the association of PAI-1 activity with the PAI-1 4G/5G polymorphism, with MI, and some components of metabolic syndrome (MetS). Methods: Using meta-analytical Mendelian randomization approaches, genotype-disease and genotype-phenotype associations were modeled simultaneously. Results: According to an additive model of inheritance and the Mendelian randomization approach, the MI-related odd ratio for individuals carrying the 4G allele was 1.088 with 95% confidence interval (CI) 1.007, 1.175. Moreover, the 4G carriers had, on average, higher PAI-1 activity than 5G carriers by 1.136 units (95% CI 0.738, 1.533). The meta-regression analyses showed that the levels of triglycerides (p=0.005), cholesterol (p=0.037) and PAI-1 (p=0.021) in controls were associated with the MI risk conferred by the 4G carriers. Conclusions: The Mendelian randomization meta-analysis confirmed previous knowledge that the PAI-1 4G allele slightly increases the risk for MI. In addition, it supports the notion that PAI-1 activity and established cardiovascular determinants, such as cholesterol and triglyceride levels, could lie in the etiological pathway from PAI-1 4G allele to the occurrence of MI. Further research is warranted to elucidate these interactions.

Impact of the proton pump inhibitors and CYP2C19*2 polymorphism on platelet response to clopidogrel as assessed by four platelet function assays

BACKGROUND Previous studies suggested a possible negative interference of proton pump inhibitors (PPIs) on clopidogrels antiplatelet effect because of the competitive inhibition of the CYP 2C19 isoenzyme. Moreover, carriers of the loss-of-function allele of CYP2C19 polymorphism (CYP2C19*2) display significantly lower responses to clopidogrel. In this study, we investigated the association between CYP2C19*2 genotype, PPI intake and clopidogrel resistance in patients with coronary artery disease (CAD) and their effect on clinical outcome. METHODS We recruited 95 patients with CAD receiving chronic clopidogrel therapy in combination with aspirin. Platelet reactivity was simultaneously assessed by INNOVANCE PFA-100 P2Y, ADP-induced light transmission aggregometry (LTA), flow-cytometric vasodilator-stimulated phosphoprotein (VASP)-phosphorylation assay and multiple electrode aggregometry (Multiplate). Cardiovascular outcomes were recorded during 1-year follow-up period. RESULTS Only platelet reactivity assessed by measuring platelet phosphorylated-VASP demonstrated a significant higher platelet reactivity in carriers of CYP2C19*2 (p=0.023). The other methods displayed higher - but not statistically significant - platelet reactivity in patients carrying the CYP2C19*2 variant as compared with non-carriers. Patients on PPIs demonstrated almost similar suppression of platelet reactivity in comparison with those not treated with PPIs by all platelet function assays. In logistic regression analysis none of the platelet function assays measurements were related with clinical outcomes. Similarly neither CYP2C19*2 genetic variant nor PPI treatment were associated with adverse clinical events. CONCLUSIONS PPI co-administration did not influence clopidogrels antiplatelet effect on laboratory testing by all platelet function assays used. On the contrary, patients carrying CYP2C19*2 genotype had significantly higher residual platelet reactivity as estimated by VASP-phosphorylation assay.

Monitoring aspirin treatment in patients with thrombocytosis: Comparison of the platelet function analyzer (PFA)-100 with optical aggregometry

Aspirin provides satisfactory protection against thrombotic episodes in essential thrombocythemia (ET), but at higher platelet counts has been less effective. Our aim was to compare the platelet function analyzer (PFA)-100 with optical aggregometry in order to determine a reliable method in monitoring aspirins influence on platelet function in patients with thrombocytosis. We studied 36 patients with thrombocytosis. Sixteen of them, receiving aspirin, composed group A, while group B consisted of 20 patients not taking aspirin. In all patients, we compared the platelet function measured by classic optical aggregation tests with closure times (CT) obtained by the PFA-100. The definition of platelet responses as normal or pathological showed that PFA-100 collagen and/or epinephrine (CEPI) CTs and epinephrine-induced aggregometry is the pair of methods with the higher agreement in monitoring of platelet dysfunction due to ASA treatment (a=94%). Satisfactory results were also obtained for group B (a=81%). The comparison between PFA-100 CEPI CTs and arachidonic acid-induced aggregometry exhibited moderate agreement both in the total number of patients and in group A (a=79% and 94%, respectively). PFA-100 collagen and/or ADP (CADP) CTs and ADP-induced aggregometry were not concordant. The PFA-100 system appears to be a reliable and rapid method in the assessment of aspirins antiplatelet effect in patients with thrombocytosis. Regarding aggregometry, the selection of the inducer, its concentration and cut-off points is crucial in defining the response to antiaggregating agents. It still remains to determine whether there is any relevance between the measurements obtained by these methods and clinical outcome in thrombocythemic patients.

The role of the Platelet Function Analyzer (PFA)-100 and platelet aggregometry in the differentiation of essential thrombocythemia from reactive thrombocytosis.

INTRODUCTION The most crucial component of all diagnostic criteria for essential thrombocythemia (ET) has been the exclusion of reactive thrombocytosis (RT). Our aim was to evaluate the diagnostic performance of the PFA-100 collagen-epinephrine (CEPI) cartridge test and epinephrine-induced aggregometry individually, but mainly combined, in the differentiation of ET from RT. MATERIALS AND METHODS 26 patients with ET and 25 with RT were studied. Platelet function was analyzed by the PFA-100 and by light transmission aggregometry with epinephrine and ADP. The JAK2 mutational status was identified and hematological parameters, plasma von Willebrand factor antigen and activity levels were also assessed. RESULTS The sensitivity (Se), specificity (Sp), positive predictive value (PPV), and the negative predictive value (NPV) of PFA-100 CEPI vs epinephrine-induced aggregometry in the differentiation of ET from RT were estimated as follows: Se (%): 78.9 vs 84.6, Sp (%): 92.0 vs 96.0, PPV (%): 88.2 vs 95.7, NPV (%): 85.2 vs 85.7, respectively. When both of these methods were combined, a lower sensitivity of 68.4%, but a specificity of 100% was attained. The PPV observed with this double abnormal combination was 100% and the NPV 80.6%. Lastly, when we assessed the abnormality for either CEPI CT or epinephrine-induced aggregometry, the sensitivity was 100%, the specificity 88.0%, PPV 86.4% and NPV 100%. Thus, an abnormal combination was strongly suggestive of ET, while normal results with both methods excluded ET. CONCLUSIONS If our results are replicated by further studies, these two methods could be used very effectively as adjunct markers in the differentiation between ET and RT.