Publications by authors named "Gian Franco Gensini"

570 Publications

Personalized-medicine on carotid endarterectomy and stenting.

Ann Transl Med 2020 Oct;8(19):1274

Permanent Technical Committee for Guidelines, Tuscany Regional Health Service, Florence, Italy.

Evidence based medicine (EBM) is the core of current clinical guidelines and is considered as the gold standard of clinical practice. Despite this, a number of limitations and criticisms are moved to EBM. The major one is that this method privileges randomized controlled trials (RCTs), in which the selection of patients is often based on rigid inclusion criteria. The lack of "pragmatism" of some RCTs sometimes makes it difficult to apply guidelines that derive from them to patients observed in clinical practice, who are often affected by comorbidities and disabilities. The new paradigm to overcome this limitation is personalized medicine (PM), which aims to take into account the particular characteristics displayed by the individual. In order to tailor the best treatment for the patient, PM uses EBM but emphasizes the person's specific information from the assessment of the clinic, lifestyle and risk/benefit scores. This narrative review tries to find the best evidence by analysing subgroups and risk scores of patients from meta-analysis and RCTs in order to try to apply PM and to provide good practice points (GPP) on grey aspects and open questions not fully covered by current guidelines on carotid endarterectomy (CEA) and stenting for stroke prevention.
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http://dx.doi.org/10.21037/atm-20-1126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607117PMC
October 2020

Influence of chest conformation on myocardial strain parameters in healthy subjects with mitral valve prolapse.

Int J Cardiovasc Imaging 2021 Mar 30;37(3):1009-1022. Epub 2020 Oct 30.

Cardiology and Cardiovascular Pathophysiology, Azienda Ospedaliero-Universitaria "S. Maria della Misericordia", Perugia, Italy.

Chest shape might affect myocardial strain parameters. However, the relationship between myocardial strain parameters and chest conformation has not been previously investigated in subjects with mitral valve prolapse (MVP). Between April 2019 and May 2020, 60 healthy subjects (50.1 ± 8.6 year/old, 46.6% females) with MVP and mild-to-moderate mitral regurgitation, and 60 controls matched by age, sex, and cardiovascular risk factors were consecutively studied. Participants underwent modified Haller index (MHI) assessment (ratio of chest transverse diameter over the distance between sternum and spine), and transthoracic echocardiography implemented with 2D-speckle tracking analysis. MHI was significantly greater in MVP group than controls (2.6 ± 0.35 vs 2.1 ± 0.23, p < 0.0001). Left ventricular (LV) ejection fraction was similar in MVP and controls (63.5 ± 3.7% vs 64.3 ± 3.9%, p = 0.25). LV regional and global longitudinal (GLS), circumferential (GCS) and radial strain (GRS) parameters and LV peak twist were all significantly lower in MVP compared to controls (all p < 0.0001). MVP subjects with a tight chest (MHI > 2.5, n = 30), and those with MHI ≤ 2.5 (n = 30) were then separately analyzed. A significant impairment in myocardial strain parameters and LV peak twist was documented in MVP subjects with MHI > 2.5, but not in those with MHI ≤ 2.5. MHI showed a strong inverse correlation with LV-GLS (r = - 0.85), GCS (r = - 0.84), GRS (r = - 0.84) and LV peak twist (r = - 0.94). In MVP subjects, impairment of myocardial strain parameters is not due to intrinsic reduction of cardiac contractility function, but it appears to be related to the degree of chest deformity.
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http://dx.doi.org/10.1007/s10554-020-02085-zDOI Listing
March 2021

Association between neutrophil to lymphocyte ratio and carotid artery wall thickness in healthy pregnant women.

Eur J Obstet Gynecol Reprod Biol 2020 Dec 17;255:98-104. Epub 2020 Oct 17.

Cardiology and Cardiovascular Pathophysiology, Azienda Ospedaliero-Universitaria "S. Maria della Misericordia", Perugia, Italy.

Objective: Pregnancy may elicit a state of mild inflammation that might affect, either directly or indirectly, haematological parameters associated with systemic inflammation. In particular, both Neutrophil-to-lymphocyte ratio (NLR) and Red blood cells Distribution Width (RDW) have been found to be elevated in complicated pregnancy. However, data regarding the association of these haematological parameters with common carotid artery (CCA) intima-media thickness (IMT) in healthy pregnancy are scanty. Aim of this study was to evaluate possible changes in CCA-IMT during normal pregnancy and in the postpartum period, and to correlate these changes with NLR and RDW.

Study Design: Between October 2019 and February 2020, a prospective study was carried out on 73 consecutive healthy pregnant women (32.8 ± 4.9 yrs/old). Women underwent obstetric assessment, complete blood cell counts with calculation of NLR and RDW, two-dimensional transthoracic echocardiography and carotid Doppler ultrasonography.

Results: During normal pregnancy, both NLR and RDW progressively increased (p < 0.0001); likewise, parameters of carotid dimensions also significantly increased (p < 0.0001). Hematological and morphological changes all decreased in postpartum period. By univariable logistic regression, the variables which showed the greatest independent association with CCA-IMT (defined as CCA-IMT ≥0.55 mm) were: age (HR 1.33, 95% CI 1.15-1.53, p < 0.0001), pre-pregnant BMI (HR 2.75, 95% CI 1.72-4.41, p < 0.0001), third trimester E/e' ratio (HR 1.64, 95% CI 1.34-2.02, p < 0.0001), and third trimester NLR (HR 3.00, 95% CI 1.64-5.50, p < 0.0001). Multivariable logistic regression analysis demonstrated that third trimester NLR was the only variable that retained statistical significance (HR 2.49, 95% CI 1.35-4.59, p = 0.003). An NLR ≥ 2 reached 83% of sensitivity and 99% of specificity in identifying a CCA-IMT ≥0.55 mm (AUC = 0.95). A strong linear correlation of both third trimester NLR and RDW with CCA-IMT was observed (r = 0.89 and 0.83, respectively).

Conclusions: Pregnancy is a state of chronic mild inflammation and the progressive increase in NLR and RDW during normal pregnancy is significantly associated with CCA intimal-medial thickening.
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http://dx.doi.org/10.1016/j.ejogrb.2020.10.034DOI Listing
December 2020

[HCF-ANMCO/AICPR/GIEC/ITAHFA/SICOA/SICP/SIMG/SIT Cardiological Societies Council Consensus document: Anticoagulant therapy in venous thromboembolism and atrial fibrillation of the patient with cancer. Current knowledge and new evidence].

G Ital Cardiol (Rome) 2020 Sep;21(9):687-738

A.S.U.R. Marche, Area Vasta 4 Fermo, Ospedale Civile Augusto Murri, Fermo.

Venous thromboembolism (VTE), including pulmonary embolism and deep venous thrombosis, either symptomatic or incidental, is a common complication in the history of cancer disease. The risk of VTE is 4-7-fold higher in oncology patients, and it represents the second leading cause of death, after cancer itself. In cancer patients, compared with the general population, VTE therapy is associated with higher rates of recurrent thrombosis and/or major bleeding. The need for treatment of VTE in patients with cancer is a challenge for the clinician because of the multiplicity of types of cancer, the disease stage and the imbricated cancer treatment. Historically, in cancer patients, low molecular weight heparins have been preferred for treatment of VTE. More recently, in large randomized clinical trials, direct oral anticoagulants (DOACs) demonstrated to reduce the risk of VTE. However, in the "real life", uncertainties remain on the use of DOACs, especially for the bleeding risk in patients with gastrointestinal cancers and the potential drug-to-drug interactions with specific anticancer therapies.In cancer patients, atrial fibrillation can arise as a perioperative complication or for the side effect of some chemotherapy agents, as well as a consequence of some associated risk factors, including cancer itself. The current clinical scores for predicting thrombotic events (CHA2DS2-VASc) or for predicting bleeding (HAS-BLED), used to guide antithrombotic therapy in the general population, have not yet been validated in cancer patients. Encouraging data for DOAC prescription in patients with atrial fibrillation and cancer are emerging: recent post-hoc analysis showed safety and efficacy of DOACs for the prevention of embolic events compared to warfarin in cancer patients. Currently, anticoagulant therapy of cancer patients should be individualized with multidisciplinary follow-up and frequent reassessment. This consensus document represents an advanced state of the art on the subject and provides useful notes on clinical practice.
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http://dx.doi.org/10.1714/3413.33967DOI Listing
September 2020

Cautions and Opportunities for Botanicals in COVID-19 Patients: A Comment on the Position of the French Agency for Food, Environmental and Occupational Health & Safety.

J Altern Complement Med 2020 Oct 21;26(10):851-853. Epub 2020 Sep 21.

CERFIT, Research and Innovation Center in Phytotherapy and Integrated Medicine, Careggi University Hospital, Florence, Italy.

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http://dx.doi.org/10.1089/acm.2020.0266DOI Listing
October 2020

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.

Clin Pharmacol Ther 2020 Nov 9;108(5):1067-1077. Epub 2020 Jul 9.

Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.
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http://dx.doi.org/10.1002/cpt.1911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689744PMC
November 2020

[New insights into the seriousness of acute myocardial injury during COVID-19].

G Ital Cardiol (Rome) 2020 May;21(5):328-331

CESMAV (Centro Studi di Medicina Avanzata), Firenze - IRCCS Multimedica, Sesto San Giovanni (MI).

Retrospective data from Chinese cohorts published in the last few days have placed a strong emphasis on the possibility that acute myocardial injury represents a critical component in the development of serious complications in patients hospitalized with COVID-19. These analyses showed that 19-27% of hospitalized patients with moderate/severe COVID-19 developed acute myocardial injury, defined as an increase in troponin levels. Fifty-sixty percent of these patients died. The highest mortality rate was detected among patients with both progressively incremental troponin levels and a history of cardiovascular disease. Some pathophysiological reasons have been hypothesized regarding the frequently observed increase in troponin levels in patients hospitalized with COVID-19, but, at the moment, these data could already suggest some clinical management implications, also with the aim of prospectively collecting research data: a troponin dosage should be considered, as a prognostic indicator, in all patients with moderate/severe COVID-19 at hospital admission, periodically during hospitalization, and in the case of clinical deterioration. In those patients with increased troponin levels, serial determinations should be carried out to define the enzymatic trajectory and therefore also the degree of clinical attention that must necessarily be closer in those who turn out to have persistently high or increasing troponin levels. In order to reduce the overdiagnosis risk of acute myocardial injury in critically ill patients, detection of increased troponin levels should always be contextualized into a multi-parametric evaluation.
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http://dx.doi.org/10.1714/3343.33128DOI Listing
May 2020

Reading and interpreting reviews for health professionals: a practical review.

Intern Emerg Med 2020 09 12;15(6):945-955. Epub 2020 Apr 12.

Terme di Monticelli, via Basse 5, Monticelli Terme, 43022, Parma, Italy.

Literature reviews can be directly used by clinicians and other health professionals to support many decision-making processes. This review aims to offer health professionals an essential practical guide to critically evaluate and properly understand results of review articles published in the scientific literature. An evidence-based methodological review with step-by-step theoretical concepts and practical suggestions was developed. Key steps of this guide are: to consider the topic and the research question (a), to check the review type (b), to evaluate the methodology (with a keen focus on review guidelines, search strategy and study-selection process, evaluation of the quality and certainty of included evidence, and statistical analysis) (c), and to define the real impact of review results (d). This guide offers a description of essential and easy-to-apply key steps which can help health professionals to evaluate the reliability and implications of a literature review, and to select the latest high-quality scientific evidence to keep updated with.
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http://dx.doi.org/10.1007/s11739-020-02334-yDOI Listing
September 2020

Genetic and nutritional factors determining circulating levels of lipoprotein(a): results of the "Montignoso Study".

Intern Emerg Med 2020 10 28;15(7):1239-1245. Epub 2020 Jan 28.

Department of Experimental and Clinical Medicine, University of Florence, Atherothrombotic Diseases Center, Careggi Hospital, Largo Brambilla 3, 50134, Florence, Italy.

Increasing evidence shows an association between high lipoprotein(a) [Lp(a)] levels and atherothrombotic diseases. Lp(a) trait is largely controlled by kringle-IV type 2 (KIV-2) size polymorphism in LPA gene, encoding for apo(a). Environmental factors are considered to determinate minor phenotypic variability in Lp(a) levels. In the present study, we investigated the possible gene-environment interaction between KIV-2 polymorphism and Mediterranean diet adherence or fish weekly intake in determining Lp(a) levels. We evaluated Lp(a), KIV-2 polymorphism, fish intake and Mediterranean diet adherence in 452 subjects [median age (range) 66 (46-80)years] from Montignoso Heart and Lung Project (MEHLP) population. In subjects with high KIV-2 repeats number, influence of Mediterranean diet adherence in reducing Lp(a) levels was observed (p = 0.049). No significant difference in subjects with low KIV-2 repeats according to diet was found. Moreover, in high-KIV-2-repeat subjects, we observed a trend towards influence of fish intake on reducing Lp(a) levels (p = 0.186). At multivariate linear regression analysis, high adherence to Mediterranean diet remains a significant and independent determinant of lower Lp(a) levels (β = - 64.97, standard error = 26.55, p = 0.015). In conclusion, this study showed that only subjects with high KIV-2 repeats can take advantage to lower Lp(a) levels from correct nutritional habits and, in particular, from Mediterranean diet.
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http://dx.doi.org/10.1007/s11739-020-02276-5DOI Listing
October 2020

Association between anthraquinone laxatives and colorectal cancer: protocol for a systematic review and meta-analysis.

Syst Rev 2020 01 24;9(1):19. Epub 2020 Jan 24.

Research and Innovation Center in Phytotherapy and Integrated Medicine CERFIT, Referring Center for Phytotherapy, Tuscany Region, Careggi University Hospital, Florence, Italy.

Introduction: Products containing anthraquinones (AQ) are mainly used as laxatives and have several biological effects. Long-term use of AQ laxatives is associated with an increased risk of serious adverse events (AEs), such as colorectal cancer (CRC). We will systematically synthesize the evidence on the potential association between the use of AQ laxatives and the risk of CRC.

Methods And Analysis: We will search MEDLINE, Embase, Scopus, the Cochrane Library, Google Scholar, and Clinicaltrials.gov. To avoid missing any relevant studies, we will search the bibliographies of retrieved papers and recent reviews in the field. Interventions will include products containing oral AQ laxatives, in particular, those derived from rhubarb, senna, cascara, buckhorn, and aloe. Two review authors will independently screen title, abstract, and full texts and will independently extract data from included studies. The primary outcome is the number of participants diagnosed with CRC, while the secondary outcome will be cases of melanosis coli. We will also consider all other AEs reported in the included studies, in particular, intestinal bleeding, alterations of gastrointestinal motility, and potential for dependence. When possible and appropriate, for each outcome, a meta-analysis will be performed.

Discussion: This protocol is prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. The protocol gives an insight into the scope and parameters for the systematic review to be carried out.

Systematic Review Registration: PROSPERO CRD42019125414.
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http://dx.doi.org/10.1186/s13643-020-1280-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979293PMC
January 2020

Differential Network Analysis Reveals Metabolic Determinants Associated with Mortality in Acute Myocardial Infarction Patients and Suggests Potential Mechanisms Underlying Different Clinical Scores Used To Predict Death.

J Proteome Res 2020 02 17;19(2):949-961. Epub 2020 Jan 17.

Laboratory of Systems and Synthetic Biology , Wageningen University & Research , Wageningen 6708 WE , the Netherlands.

We present here the differential analysis of metabolite-metabolite association networks constructed from an array of 24 serum metabolites identified and quantified via nuclear magnetic resonance spectroscopy in a cohort of 825 patients of which 123 died within 2 years from acute myocardial infarction (AMI). We investigated differences in metabolite connectivity of patients who survived, at 2 years, the AMI event, and we characterized metabolite-metabolite association networks specific to high and low risks of death according to four different risk parameters, namely, acute coronary syndrome classification, Killip, Global Registry of Acute Coronary Events risk score, and metabolomics NOESY RF risk score. We show significant differences in the connectivity patterns of several low-molecular-weight molecules, implying variations in the regulation of several metabolic pathways regarding branched-chain amino acids, alanine, creatinine, mannose, ketone bodies, and energetic metabolism. Our results demonstrate that the characterization of metabolite-metabolite association networks is a promising and powerful tool to investigate AMI patients according to their outcomes at a molecular level.
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http://dx.doi.org/10.1021/acs.jproteome.9b00779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011173PMC
February 2020

Effects of lavender on anxiety: A systematic review and meta-analysis.

Phytomedicine 2019 Dec 26;65:153099. Epub 2019 Sep 26.

Research and Innovation Center in Phytotherapy and Integrated Medicine, CERFIT, Referring Center for Phytotherapy of Tuscany Region, Careggi University Hospital, 50139 Florence, Italy.

Background: Anxiety is one of the uprising psychiatric disorders of the last decades and lavender administration has been traditionally suggested as a possible treatment. The objective of this review is to assess the efficacy of lavender, in any form and way of administration, on anxiety and anxiety-related conditions.

Methods: The PRISMA guidelines were followed. Retrieved data were qualitatively and quantitatively synthesized. Randomized Controlled Trials (RCTs) and Non-Randomized Studies (NRSs) which investigated the efficacy of lavender, in any form and way of administration, on patients with anxiety, involved in anxiety-inducing settings or undergoing anxiety-inducing activities, compared to any type of control, without language restrictions, were identified through electronic database searches. Medline via PubMed, Scopus, Web of Science, Cochrane Library, EMBASE, and Google Scholar were systematically searched. All databases were screened up to November 2018. Risk of bias was assessed with the Cochrane risk-of-bias tool and the following domains were considered: randomization, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases.

Results: 65 RCTs (7993 participants) and 25 NRSs (1200 participants) were included in the qualitative synthesis and 37 RCTs (3964 participants) were included in the quantitative synthesis. Overall, the qualitative synthesis indicated that 54 RCTs and 17 NRSs reported at least a significant result in favor of lavender use for anxiety. The quantitative synthesis showed that lavender inhalation can significantly reduce anxiety levels measured with any validated scale (Hedges' g = -0.73 [95% CI -1.00 to -0.46], p < 0.00001, 1682 participants), as well as state anxiety (Spielberger's state-trait anxiety inventory (STAI)-State mean difference = -5.99 [95% CI -9.39 to -2.59], p < 0.001, 901 participants) and trait anxiety (STAI-Trait mean difference = -8.14 [95% CI -14.44 to -1.84], p < 0.05, 196 participants). Lavender inhalation did not show a significant effect in reducing systolic blood pressure as a physiological parameter of anxiety. A significant effect in diminishing anxiety levels was also found in favor of the use of oral Silexan® 80 mg/die for at least 6 weeks (Hamilton Anxiety Scale mean difference = -2.90 [95% CI -4.86 to -0.95], p = 0.004, 1173 participants; Zung Self-rating Anxiety Scale mean difference = -2.62 [95% CI -4.84 to -0.39], p < 0.05, 451 participants) or of the administration of massage with lavender oil (Hedges' g = -0.66 [95% CI -0.97 to -0.35], p < 0.0001, 448 participants).

Discussion: The most important limitation of this review is the low average quality of available studies on the topic. The majority of included RCTs were characterized by a high overall risk of bias. Another limitation regards the heterogeneity of study designs, especially with regard to non-oral ways of administration. Overall, oral administration of lavender essential oil proves to be effective in the treatment of anxiety, whereas for inhalation there is only an indication of an effect of reasonable size, due to the heterogeneity of available studies. Lavender essential oil administered through massage appears effective, but available studies are not sufficient to determine whether the benefit is due to a specific effect of lavender. Further high-quality RCTs with more homogeneous study designs are needed to confirm these findings. Available information outlines a safe profile for lavender-based interventions, although more attention should be paid to the collection and reporting of safety data in future studies. Considering these findings, since treatments with lavender essential oil generally seem safe, and, in the case of inhalation, also simple and inexpensive, they are a therapeutic option which may be considered in some clinical contexts.

Other: The present systematic review was not funded and was registered in PROSPERO under the following number: CRD42019130126.
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http://dx.doi.org/10.1016/j.phymed.2019.153099DOI Listing
December 2019

Preclinical and Clinical Evidence Supporting Use of Cannabidiol in Psychiatry.

Evid Based Complement Alternat Med 2019 29;2019:2509129. Epub 2019 Aug 29.

Research and Innovation Center in Phytotherapy and Integrated Medicine (CERFIT), Referring Center for Phytotherapy of Tuscany Region, Careggi University Hospital, Florence, Italy.

Background: Cannabidiol (CBD) is a major chemical compound present in . CBD is a nonpsychotomimetic substance, and it is considered one of the most promising candidates for the treatment of psychiatric disorders.

Objective: The aim of this review is to illustrate the state of art about scientific research and the evidence of effectiveness of CBD in psychiatric patients.

Methods: This review collects the main scientific findings on the potential role of CBD in the psychiatric field, and results of clinical trials carried out on psychiatric patients are commented. A research was conducted in the PUBMED, SCOPUS, and ScienceDirect databases using combinations of the words cannabidiol, psychiatry, and neuropsychiatric.

Results: Preclinical and clinical studies on potential role of CBD in psychiatry were collected and further discussed. We found four clinical studies describing the effects of CBD in psychiatric patients: two studies about schizophrenic patients and the other two studies carried out on CBD effects in patients affected by generalized social anxiety disorder (SAD).

Conclusion: Results from these studies are promising and suggest that CBD may have a role in the development of new therapeutic strategies in mental diseases, and they justify an in-depth commitment in this field. However, clinical evidence we show for CBD in psychiatric patients is instead still poor and limited to schizophrenia and anxiety, and it needs to be implemented with further studies carried out on psychiatric patients.
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http://dx.doi.org/10.1155/2019/2509129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735178PMC
August 2019

Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients.

Eur Heart J Cardiovasc Pharmacother 2020 07;6(4):203-210

Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, 670 W. Baltimore St., Baltimore, MD 21201, USA.

Aims: Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial.

Methods And Results: We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles.

Conclusion: Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.
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http://dx.doi.org/10.1093/ehjcvp/pvz045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363022PMC
July 2020

Chelidonium majus: Relevant safety aspects of a hepatotoxic plant, trawling the web.

Phytother Res 2019 09 22;33(9):2465-2469. Epub 2019 Jul 22.

Research and Innovation Center in Phytotherapy and Integrated Medicine - CERFIT, Referring Center for Phytotherapy, Tuscany Region,, Careggi University Hospital, Florence, Italy.

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http://dx.doi.org/10.1002/ptr.6437DOI Listing
September 2019

NMR-based metabolomics identifies patients at high risk of death within two years after acute myocardial infarction in the AMI-Florence II cohort.

BMC Med 2019 01 7;17(1). Epub 2019 Jan 7.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

Background: Risk stratification and management of acute myocardial infarction patients continue to be challenging despite considerable efforts made in the last decades by many clinicians and researchers. The aim of this study was to investigate the metabolomic fingerprint of acute myocardial infarction using nuclear magnetic resonance spectroscopy on patient serum samples and to evaluate the possible role of metabolomics in the prognostic stratification of acute myocardial infarction patients.

Methods: In total, 978 acute myocardial infarction patients were enrolled in this study; of these, 146 died and 832 survived during 2 years of follow-up after the acute myocardial infarction. Serum samples were analyzed via high-resolution H-nuclear magnetic resonance spectroscopy and the spectra were used to characterize the metabolic fingerprint of patients. Multivariate statistics were used to create a prognostic model for the prediction of death within 2 years after the cardiovascular event.

Results: In the training set, metabolomics showed significant differential clustering of the two outcomes cohorts. A prognostic risk model predicted death with 76.9% sensitivity, 79.5% specificity, and 78.2% accuracy, and an area under the receiver operating characteristics curve of 0.859. These results were reproduced in the validation set, obtaining 72.6% sensitivity, 72.6% specificity, and 72.6% accuracy. Cox models were used to compare the known prognostic factors (for example, Global Registry of Acute Coronary Events score, age, sex, Killip class) with the metabolomic random forest risk score. In the univariate analysis, many prognostic factors were statistically associated with the outcomes; among them, the random forest score calculated from the nuclear magnetic resonance data showed a statistically relevant hazard ratio of 6.45 (p = 2.16×10). Moreover, in the multivariate regression only age, dyslipidemia, previous cerebrovascular disease, Killip class, and random forest score remained statistically significant, demonstrating their independence from the other variables.

Conclusions: For the first time, metabolomic profiling technologies were used to discriminate between patients with different outcomes after an acute myocardial infarction. These technologies seem to be a valid and accurate addition to standard stratification based on clinical and biohumoral parameters.
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http://dx.doi.org/10.1186/s12916-018-1240-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323789PMC
January 2019

Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC).

Am Heart J 2018 04 17;198:152-159. Epub 2017 Dec 17.

Department of Medicine, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

Rationale: The P2Y receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response.

Study Design: Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies.

Results: In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate-stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (P value=5.1 × 10).

Conclusion: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.
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http://dx.doi.org/10.1016/j.ahj.2017.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903579PMC
April 2018

Value of Telemonitoring and Telemedicine in Heart Failure Management.

Card Fail Rev 2017 Nov;3(2):116-121

Cardiology Unit, New Versilia Hospital,Lido di Camaiore (LU), Italy.

The use of telemonitoring and telemedicine is a relatively new but quickly developing area in medicine. As new digital tools and applications are being created and used to manage medical conditions such as heart failure, many implications require close consideration and further study, including the effectiveness and safety of these telemonitoring tools in diagnosing, treating and managing heart failure compared to traditional face-to-face doctor-patient interaction. When compared to multidisciplinary intervention programs which are frequently hindered by economic, geographic and bureaucratic barriers, non-invasive remote monitoring could be a solution to support and promote the care of patients over time. Therefore it is crucial to identify the most relevant biological parameters to monitor, which heart failure sub-populations may gain real benefits from telehealth interventions and in which specific healthcare subsets these interventions should be implemented in order to maximise value.
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http://dx.doi.org/10.15420/cfr.2017:6:2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739893PMC
November 2017

Benefits and Risks of Machine Learning Decision Support Systems-Reply.

JAMA 2017 12;318(23):2356-2357

Centro Studi Medicina Avanzata, Florence, Italy.

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http://dx.doi.org/10.1001/jama.2017.16635DOI Listing
December 2017

["Handle with care": about the potential unintended consequences of oracular artificial intelligence systems in medicine.]

Recenti Prog Med 2017 Oct;108(10):397-401

CESMAV - Centro Studi Medicina Avanzata, Firenze - Florence EBM/Renaissance Group.

Decisional support systems based on machine learning (ML) in medicine are gaining a growing interest as some recent articles have highlighted the high diagnostic accuracy exhibited by these systems in specific medical contexts. However, it is implausible that any potential advantage can be obtained without some potential drawbacks. In light of the current gaps in medical research about the side effects of the application of these new AI systems in medical practice, in this article we summarize the main unexpected consequences that may result from the widespread application of "oracular" systems, that is highly accurate systems that cannot give reasonable explanations of their advice as those endowed with predictive models developed with ML techniques usually are. These consequences range from the intrinsic uncertainty in the data that are used to train and feed these systems, to the inadequate explainability of their output; through the risk of overreliance, deskilling and context desensitization of their end-users. Although some of these issues may be currently hard to evaluate due to the still scarce adoption of these decisional systems in medical practice, we advocate the study of these potential consequences also for a more informed policy of approval beyond hype and disenchantment.
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http://dx.doi.org/10.1701/2802.28353DOI Listing
October 2017

[Fractional flow reserve: a practical guide for interventional cardiologists and the cardiologist's point of view].

G Ital Cardiol (Rome) 2017 Sep;18(9 Suppl 1):2S-8S

Unità di Cardiologia Interventistica Strutturale, AOU Careggi, Firenze.

Fractional flow reserve (FFR) is considered the gold standard for functional assessment of coronary stenosis in stable coronary artery disease. The use of FFR enables an ischemia-guided revascularization with improvement of clinical outcomes in a cost-effective fashion. Both clinical and interventional cardiologists should be aware of the advantages and potential pitfalls of this technique. We focus on FFR with the aim to provide the clinical cardiologist with information on indications and technical aspects to confirm a correct execution of FFR in different coronary anatomical settings.
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http://dx.doi.org/10.1714/2743.27964DOI Listing
September 2017

ANMCO/SIT Consensus Document: telemedicine for cardiovascular emergency networks.

Eur Heart J Suppl 2017 May 2;19(Suppl D):D229-D243. Epub 2017 May 2.

Italian Society for Telemedicine and eHealth (Digital SIT), Florence, Italy.

Telemedicine has deeply innovated the field of emergency cardiology, particularly the treatment of acute myocardial infarction. The ability to record an ECG in the early prehospital phase, thus avoiding any delay in diagnosing myocardial infarction with direct transfer to the cath-lab for primary angioplasty, has proven to significantly reduce treatment times and mortality. This consensus document aims to analyse the available evidence and organizational models based on a support by telemedicine, focusing on technical requirements, education, and legal aspects.
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http://dx.doi.org/10.1093/eurheartj/sux028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520753PMC
May 2017

ANMCO/AIIC/SIT Consensus Information Document: definition, precision, and suitability of electrocardiographic signals of electrocardiographs, ergometry, Holter electrocardiogram, telemetry, and bedside monitoring systems.

Eur Heart J Suppl 2017 May 2;19(Suppl D):D190-D211. Epub 2017 May 2.

Italian Society for Telemedicine and eHealth (Digital SIT), Florence, Italy.

The electrocardiogram (ECG) signal can be derived from different sources. These include systems for surface ECG, Holter monitoring, ergometric stress tests, and telemetry systems and bedside monitoring of vital parameters, which are useful for rhythm and ST-segment analysis and ECG screening of electrical sudden cardiac death predictors. A precise ECG diagnosis is based upon correct recording, elaboration, and presentation of the signal. Several sources of artefacts and potential external causes may influence the quality of the original ECG waveforms. Other factors that may affect the quality of the information presented depend upon the technical solutions employed to improve the signal. The choice of the instrumentations and solutions used to offer a high-quality ECG signal are, therefore, of paramount importance. Some requirements are reported in detail in scientific statements and recommendations. The aim of this consensus document is to give scientific reference for the choice of systems able to offer high quality ECG signal acquisition, processing, and presentation suitable for clinical use.
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http://dx.doi.org/10.1093/eurheartj/sux031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520765PMC
May 2017

The future of telemedicine for the management of heart failure patients: a Consensus Document of the Italian Association of Hospital Cardiologists (A.N.M.C.O), the Italian Society of Cardiology (S.I.C.) and the Italian Society for Telemedicine and eHealth (Digital S.I.T.).

Eur Heart J Suppl 2017 May 2;19(Suppl D):D113-D129. Epub 2017 May 2.

Cardiology Unit and Interventional Cardiology Department, Policlinico "Tor Vergata", Rome, Italy.

Telemedicine applied to heart failure patients is a tool for recording and providing remote transmission, storage and interpretation of cardiovascular parameters and/or useful diagnostic images to allow for intensive home monitoring of patients with advanced heart failure, or during the vulnerable post-acute phase, to improve patient's prognosis and quality of life. Recently, several meta-analyses have shown that telemedicine-supported care pathways are not only effective but also economically advantageous. Benefits seem to be substantial, with a 30-35% reduction in mortality and 15-20% decrease in hospitalizations. Patients implanted with cardiac devices can also benefit from an integrated remote clinical management since all modern devices can transmit technical and diagnostic data. However, telemedicine may provide benefits to heart failure patients only as part of a shared and integrated multi-disciplinary and multi-professional 'chronic care model'. Moreover, the future development of remote telemonitoring programs in Italy will require the primary use of products certified as medical devices, validated organizational solutions as well as legislative and administrative adoption of new care methods and the widespread growth of clinical care competence to remotely manage the complexity of chronicity. Through this consensus document, Italian Cardiology reaffirms its willingness to contribute promoting a new phase of qualitative assessment, standardization of processes and testing of telemedicine-based care models in heart failure. By recognizing the relevance of telemedicine for the care of non-hospitalized patients with heart failure, its strategic importance for the design of innovative models of care, and the many challenges and opportunities it raises, ANMCO and SIC through this document report a consensus on the main directions for its widespread and sustainable clinical implementation.
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http://dx.doi.org/10.1093/eurheartj/sux024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520762PMC
May 2017

Unintended Consequences of Machine Learning in Medicine.

JAMA 2017 Aug;318(6):517-518

Centro Studi Medicina Avanzata, Florence, Italy.

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http://dx.doi.org/10.1001/jama.2017.7797DOI Listing
August 2017

An update of the Italian Stroke Organization-Stroke Prevention Awareness Diffusion Group guidelines on carotid endarterectomy and stenting: A personalized medicine approach.

Int J Stroke 2017 07 1;12(5):560-567. Epub 2017 Jan 1.

12 Department of Critical Care, University of Florence, Florence, Italy.

Although proof-based medicine has generated much valid evidence for the drawing up of guidelines and recommendations for best clinical practice in symptomatic and asymptomatic carotid stenosis, whether and when it is better to employ endarterectomy or stenting as the intervention of choice still remain matters of debate. Moreover, guidelines have been targeted up to now to the 'representative' patient, as resulting from the statistical analyses of the studies conducted on the safety and efficacy of both interventions as well as on medical therapy alone. The Italian Stroke Organization (ISO) and Stroke Prevention and Awareness Diffusion (SPREAD) group has thus decided to update its statements for an 8th edition. To this end, a multidisciplinary team of authors representing Italian scientific societies in the neurology, neuroradiology, vascular and endovascular surgery, interventional cardiology, and general medicine fields re-examined the literature available on stroke. Analyses and considerations on patient subgroups have allowed to model the risks/benefits of endarterectomy and stenting in the individual. Accordingly, the guideline's original methodology has been revised to follow the new SIGN (Scottish Intercollegiate Guideline Network) Grade-like approach, integrating it with new considerations on Precision, or Personalized Medicine. Therefore, this guideline offers recommendations on precision medicine for the single patient, and can be followed in addition to the more standard guidelines.
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http://dx.doi.org/10.1177/1747493017694395DOI Listing
July 2017

Bleeding events and maintenance dose of prasugrel: BLESS pilot study.

Open Heart 2016;3(2):e000460. Epub 2016 Oct 31.

Department of Cardiology , Careggi Hospital , Florence , Italy.

Objective: To evaluate changes in residual platelet reactivity (RPR) over time, and bleeding and ischaemic events rate using 5 vs 10 mg maintenance dose (MD) regimens of prasugrel 1 month after acute coronary syndrome (ACS).

Background: The optimal level of RPR with prasugrel may change over time after an ACS.

Methods: After 60 mg loading dose of prasugrel (T0) followed by 10 mg/day for 1 month, patients were randomised to receive prasugrel 10 mg/day (n=95, group A) or 5 mg/day MD (n=98, group B) up to 1 year. RPR was assessed at T0, 37 (T1) and 180 days (T2). The primary end point was Bleeding Academic Research Consortium (BARC) bleeding events ≥2 between 1 and 12 months, and the secondary composite end point was cardiac death, myocardial infarction, stroke and definite/probable stent thrombosis.

Results: From T0 to T1, RPR significantly increased in both groups A and B and the increase was higher for group B (δ ADP 10 µmol: 13.8%±14.7% vs 23.5%±19.2%, p=0.001). At T2 a lower rate of high RPR patients were found in group A (2.6% vs13.3%; p=0.014). The BARC type ≥2 bleeding occurred in 12.6% of group A versus 4.1% of group B (OR 0.29, 95% CI 0.09 to 0.94) and secondary end point in 2.1% vs 1.0% (p=0.542), respectively, without stent thrombosis.

Conclusions: RPR increases shifting from 60 mg loading dose to 10 mg/day prasugrel MD with a further increase of RPR reducing prasugrel MD to 5 mg 1 month after ACS. Clinical value of these pharmacodynamic findings should be proved in larger clinical trials.

Trial Registration Number: NCT01790854.
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http://dx.doi.org/10.1136/openhrt-2016-000460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093371PMC
October 2016

Erratum to: Uric acid in the early risk stratification of ST-elevation myocardial infarction.

Intern Emerg Med 2017 03;12(2):275-277

Intensive Cardiac Care Unit, Heart and Vessel Department, Azienda Ospedaliero-Universitaria Careggi, Viale Morgagni 85, 50134, Florence, Italy.

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http://dx.doi.org/10.1007/s11739-016-1556-xDOI Listing
March 2017

Residual thrombin potential predicts cardiovascular death in acute coronary syndrome patients undergoing percutaneous coronary intervention.

Thromb Res 2016 Nov 19;147:52-57. Epub 2016 Sep 19.

Don Gnocchi Foundation, Florence, Italy; University of Florence, Italy; CESMAV, Florence, Italy.

Introduction: Thrombin generation (TG) is a central step of the coagulation system involved in hemostatic and thrombotic roles. Scarce data evaluating in the acute phase the association between TG and the risk of cardiovascular death of acute coronary syndrome (ACS) patients are available, in the era of percutaneous coronary intervention (PCI) and stenting with the use of dual antiplatelet treatment.

Materials And Methods: We investigated TG in 292 ACS patients undergoing PCI with stent implantation on dual antiplatelet treatment. Venous samples were obtained 12-24h after PCI. TG was assessed using the Calibrated Automated Thrombogram (CAT).

Results: At two years of follow-up, 57 out of 292 patients (19.5%) died from cardiovascular causes. Higher values of endogenous thrombin potential (ETP) [1115.9 (705-1441.3) vs 940.2 (666.0-1253.1), p=0.049], peak [176.1 (80.5-259.4) vs 107.3 (59.9-181.1), p=0.002] and velocity index [61.75 (21.03-97.88) vs 25.64 (11.95-50.90), p<0.001] were observed in relation to survival patients. At the multivariate model adjusted for the Global Registry of Acute Coronary Events risk score, the association between TG and cardiovascular death remained significant for ETP [OR (95% CI): 2.58 (1.10-6.03), p=0.029], peak [OR (95%CI): 3.27 (1.35-7.92), p=0.009] and velocity index [OR (95% CI): 3.06 (1.27-7.39), p=0.013]. This result was confirmed after adjustment for high on-treatment platelet reactivity [ETP: OR (95% CI) 2.35 (1.11-5.00), p=0.027; peak: OR (95% CI) 2.42 (1.13-5.15), p=0.022; velocity index: OR (95% CI) 2.43 (1.14-5.20), p=0.022].

Conclusions: ACS patients with a residual TG after PCI and stent implantation have a significantly higher risk of long-term cardiovascular death. These results might be useful in improving risk stratification for ACS patients and support the need of a tailored antithrombotic therapy.
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http://dx.doi.org/10.1016/j.thromres.2016.09.020DOI Listing
November 2016

Absorb vs. DESolve: an optical coherence tomography comparison of acute mechanical performances.

EuroIntervention 2016 Aug 5;12(5):e566-73. Epub 2016 Aug 5.

Interventional Cardiology Unit, Cardiology Department, Moriggia-Pelascini Hospital, Gravedona (CO), Italy.

Aims: The aim of the study was to compare retrospectively the acute mechanical performance of the Absorb vs. DESolve scaffolds in terms of appropriate deployment with OCT.

Methods And Results: Final post-deployment OCT pullbacks of consecutive patients treated with either Absorb or DESolve were reviewed. The following parameters were calculated and compared: mean and minimal lumen area (MLA), residual in-scaffold area stenosis (RAS), incomplete strut apposition (ISA), tissue prolapse area, eccentricity index, asymmetry index, strut fracture and edge dissection. A total of 72 patients were included. The Absorb group consisted of 35 patients treated with 63 Absorb scaffolds and was compared to a well-matched group of 37 patients treated with 50 DESolve scaffolds. Baseline characteristics did not differ significantly between the two groups. Procedural characteristics were different with respect to maximal balloon inflation pressure (Absorb vs. DESolve: 21.5±0.4 atm vs. 16.8±3.8 atm, p<0.01) and mean NC balloon diameter used for post-dilatation (Absorb vs. DESolve 3.3±0.4 mm vs. 3.5±0.4 mm, p<0.01). OCT analysis showed similar MLA (Absorb vs. DESolve: 5.8±1.9 mm2 vs. 6.1±2.6 mm2, p=0.43) and mean luminal area (Absorb vs. DESolve: 7.1±2.2 mm2 vs. 7.2±1.9 mm2, p=0.77). The mean eccentricity index was 0.85±0.05 with Absorb and 0.80±0.05 with DESolve, p<0.01. There was no difference in the incidence of overall ISA. A smaller prolapse area was found with Absorb (Absorb vs. DESolve 1.0±1.1 mm2 vs. 3.6±6.2 mm², p<0.01).

Conclusions: The two scaffolds showed similar MLA while there was a trend towards a lower RAS and a larger maximum and minimum scaffold diameter with DESolve. The DESolve scaffold was more eccentric as compared to the Absorb. These results might be related to the DESolve's unique expansion properties or they may reflect baseline and procedural differences which cannot be excluded in a retrospective study. Randomised studies are needed to address this aspect.
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http://dx.doi.org/10.4244/EIJV12I5A96DOI Listing
August 2016