Publications by authors named "Danilo Menichelli"

32 Publications

Comparison of Anticoagulation Quality between Acenocoumarol and Warfarin in Patients with Mechanical Prosthetic Heart Valves: Insights from the Nationwide PLECTRUM Study.

Molecules 2021 Mar 6;26(5). Epub 2021 Mar 6.

I Clinica Medica, Atherothrombosis Centre, Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy.

Vitamin K antagonists are indicated for the thromboprophylaxis in patients with mechanical prosthetic heart valves (MPHV). However, it is unclear whether some differences between acenocoumarol and warfarin in terms of anticoagulation quality do exist. We included 2111 MPHV patients included in the nationwide PLECTRUM registry. We evaluated anticoagulation quality by the time in therapeutic range (TiTR). Factors associated with acenocoumarol use and with low TiTR were investigated by multivariable logistic regression analysis. Mean age was 56.8 ± 12.3 years; 44.6% of patients were women and 395 patients were on acenocoumarol. A multivariable logistic regression analysis showed that patients on acenocoumarol had more comorbidities (i.e., ≥3, odds ratio (OR) 1.443, 95% confidence interval (CI) 1.081-1.927, = 0.013). The mean TiTR was lower in the acenocoumarol than in the warfarin group (56.1 ± 19.2% vs. 61.6 ± 19.4%, < 0.001). A higher prevalence of TiTR (<60%, <65%, or <70%) was found in acenocoumarol users than in warfarin ones ( < 0.001 for all comparisons). Acenocoumarol use was associated with low TiTR regardless of the cutoff used at multivariable analysis. A lower TiTR on acenocoumarol was found in all subgroups of patients analyzed according to sex, hypertension, diabetes, age, valve site, atrial fibrillation, and INR range. In conclusion, anticoagulation quality was consistently lower in MPHV patients on acenocoumarol compared to those on warfarin.
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http://dx.doi.org/10.3390/molecules26051425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961992PMC
March 2021

Thromboembolism, mortality, and bleeding in 2,435,541 atrial fibrillation patients with and without cancer: A nationwide cohort study.

Cancer 2021 Feb 25. Epub 2021 Feb 25.

Service de Cardiologie, Centre Hospitalier Universitaire Trousseau et EA7505, Faculté de Médecine, Université François Rabelais, Tours, France.

Background: The number of patients with atrial fibrillation (AF) and cancer is rapidly increasing in clinical practice. The impact of cancer on clinical outcomes in this patient population is unclear, as is the performance of the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol) and CHA DS -VASc (Congestive Heart Failure, Hypertension, Age ≥ 75 years, Diabetes Mellitus, Stroke or Transient Ischemic Attack, Vascular Disease, Age 65 to 74 Years, Sex Category) scores.

Methods: This was an observational, retrospective cohort study including 2,435,541 adults hospitalized with AF. The authors investigated the incidence rates (IRs) of all-cause and cardiovascular mortality, ischemic stroke, major bleeding, and intracranial hemorrhage (ICH) according to the presence of cancer and cancer types.

Results: Overall, 399,344 (16.4%) had cancer, with the most common cancers being metastatic, prostatic, colorectal, lung, breast, and bladder. During a mean follow-up of 2.0 years, cancer increased all-cause mortality (hazard ratio [HR], 2.00; 95% confidence interval [CI], 1.99-2.01). The IR of ischemic stroke was higher with pancreatic cancer (2.8%/y), uterine cancer (2.6%/y), and breast cancer (2.6%/y), whereas it was lower with liver/lung cancer (1.9%/y) and leukemia/myeloma (2.0%/y), in comparison with noncancer patients (2.4%/y). Cancer increased the risk of major bleeding (HR, 1.27; 95% CI, 1.26-1.28) and ICH (HR, 1.07; 95% CI, 1.05-1.10). Leukemia, liver cancer, myeloma, and metastatic cancers showed the highest IRs for major bleeding/ICH. Major bleeding and ICH rates progressively increased with the HAS-BLED score, which showed generally good predictivity with C indexes > 0.70 for all cancer types. The CHA DS -VASc score's predictivity was slightly lower in AF patients with cancer.

Conclusions: Cancer increased all-cause mortality, major bleeding, and ICH risk in AF patients. The association between cancer and ischemic stroke differed among cancer types, and in some types, the risk of bleeding seemed to exceed the thromboembolic risk.
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http://dx.doi.org/10.1002/cncr.33470DOI Listing
February 2021

Sex-based difference in anticoagulated patients with mechanical prosthetic heart valves and long-term mortality risk.

Int J Clin Pract 2021 Feb 3:e14064. Epub 2021 Feb 3.

I Clinica Medica, Atherothrombosis Centre, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Background: Vitamin K antagonists (VKAs) reduce thromboembolism in patients with mechanical prosthetic heart valves (MPHV). It is unclear whether a sex-based difference in MPHV patients regarding valve site, anticoagulation quality, and mortality risk does exist.

Methods: We analysed 2111 MPHV patients from the nationwide PLECTRUM study promoted by the Italian Federation of Anticoagulation Clinics (FCSA). We analysed the site of MPHV, anticoagulation quality, as assessed by the time in therapeutic range (TiTR), and mortality risk in women and men.

Results: The mean age of the patients was 56.8 ± 12.3 years. Women were older with a lower prevalence of ischemic heart disease and smoking habit and a higher prevalence of atrial fibrillation at baseline. Aortic MPHV was more frequent in men (74.7% vs 43.3%, P < .001), whereas mitral (41.1% vs 17.6%, P < .001) and mitro-aortic (15.6% vs 7.7%, P < .001) MPVH in women. The association between female sex and mitral/mitro-aortic site remained at multivariable logistic regression analysis (Odds Ratio 3.623, 95% Confidence Interval [CI] 2.947-4.455, P < .001). Regarding anticoagulation quality, women showed lower mean TiTR (63.0 ± 19.4 vs 57.5 ± 19.2, P < .001), and a higher proportion of TiTR < 60% (54.9% vs 43.3%, P < .001). During a mean follow-up of 123 months (21 665 pt-years), 152 deaths occurred (0.7%/year); 83 in the aortic (0.63%/year) and 69 in the mitral/mitro-aortic (0.81%/year) group. At multivariable Cox proportional hazard regression analysis, female sex was not associated with mortality (HR 0.953, 95%CI 0.678 1.340, P = .783).

Conclusions: Female sex is independently associated with mitral/mitro-aortic MPHV. Despite a lower TiTR in women, mortality risk did not differ between the two groups.
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http://dx.doi.org/10.1111/ijcp.14064DOI Listing
February 2021

Real-world safety and efficacy of direct oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of 605 771 patients.

Eur Heart J Cardiovasc Pharmacother 2021 Apr;7(FI1):f11-f19

Department of Clinical, Internal, Anesthesiological, and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, Rome 00161, Italy.

Aims: To analyse the safety and efficacy of direct oral anticoagulants (DOACs) in real-world studies including atrial fibrillation (AF) patients.

Methods And Results: Systematic review and meta-analysis of observational studies including AF patients on DOACs. Primary endpoints: any, major, gastrointestinal (GI), intracranial haemorrhage (ICH), and haemorrhagic stroke (HS). Secondary endpoints: ischaemic stroke (IS), systemic embolism (SE), myocardial infarction (MI), and all-cause of death. A set of pair-wise meta-analyses using a random effect model and a random effect network meta-analysis under a Bayesian framework were performed. Prospero registration number: CRD42019137111. We included 21 studies with 605 771 AF patients. Apixaban was associated with lower major and GI bleeding compared with Rivaroxaban [hazard ratio (HR) 2.0, 95% confidence interval (CI) 1.6-2.5] and Dabigatran (HR 1.6, 95% CI 1.3-2.1). The latter drug performed better than Rivaroxaban (HR 1.2, 95% CI 1.0-1.5). Dabigatran and Apixaban had a similar association with HS, but Apixaban performed better than Rivaroxaban (HR 1.8, 95% CI 1.1-3.0). Apixaban had a similar association with Rivaroxaban and Dabigatran for ICH, the latter drug performing better than Rivaroxaban (HR 1.3, 95% CI 1.0-1.7). Rankograms showed that Apixaban was likely to be the first-choice treatment in relation to any (65%) major (100%) and GI bleeding (100%) followed by Dabigatran (46%, 100%, 99%, respectively). Dabigatran and Apixaban had similar rank as first choice for ICH (44% and 55%) and HS (52% and 48%). DOACs showed similar association with IS/SE, MI, all-cause of death.

Conclusions: Analysis of real-world studies shows significant differences for safety among DOACs.
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http://dx.doi.org/10.1093/ehjcvp/pvab002DOI Listing
April 2021

The Atrial fibrillation Better Care (ABC) pathway and cardiac complications in atrial fibrillation: a potential sex-based difference. The ATHERO-AF study.

Eur J Intern Med 2021 Mar 6;85:80-85. Epub 2021 Jan 6.

Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, United Kingdom; Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark.

Background: An integrated care approach is recommended to optimize management of patients with atrial fibrillation (AF). The impact of the Atrial fibrillation Better Care (ABC) pathway on major adverse cardiac events (MACE), which are the main causes of death in AF, has not been explored.

Material And Methods: We investigated the association between ABC compliance and MACE incidence in 1157 (2690 patient-years) nonvalvular AF patients from the ATHERO-AF study. A subgroup analysis by sex and high cardiovascular risk patients as defined by a 2MACE score ≥3 was performed.

Results: Overall, 428 (37%) patients composed the ABC-compliant group. During a median follow up of 23 (IQR 12-37) months, 64 MACE occurred (2.38%/year). Kaplan Meier curve analysis showed a higher rate of MACE in ABC non-compliant group compared to the ABC-compliant (log-rank test p=0.006). The risk of MACE increased by the number of non-fulfilled ABC criteria. On multivariable Cox proportional hazard regression analysis, the ABC non-compliance was associated with an increased risk of MACE (Hazard ratio (HR) 2.244, 95% Confidence Interval (95%CI) 1.129-4.462). Men were more likely to have suboptimal anticoagulation control (group A), while uncontrolled symptoms were more frequent in women. The association between non-ABC and MACE was more evident in men than women (HR 3.647, 95%CI 1.294-10.277) and in patients with 2MACE score ≥3 (HR 1.728, 95%CI 1.209-2.472).

Conclusion: An integrated care ABC approach is associated with a reduced risk of MACE in the AF population, especially in men and in patients at high risk of MACE.
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http://dx.doi.org/10.1016/j.ejim.2020.12.011DOI Listing
March 2021

Long-Term Risk of Major Adverse Cardiac Events in Atrial Fibrillation Patients on Direct Oral Anticoagulants.

Mayo Clin Proc 2021 03 9;96(3):658-665. Epub 2020 Dec 9.

I Clinica Medica, Atherothrombosis Center, Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy; Mediterranea Cardiocentro, Naples, Italy.

Objective: To determine the association between direct oral anticoagulant (DOAC) use and risk of major adverse cardiac events (MACEs) in patients with atrial fibrillation (AF).

Patients And Methods: This study is a single-center prospective observational cohort study including 2366 outpatients with non-valvular AF on treatment with DOACs or vitamin K antagonists (VKAs) from February 2008 for patients on VKA and September 2013 for patients on novel oral anticoagulants. The primary endpoint was the incidence of MACE including fatal and non-fatal myocardial infarction (MI), cardiac revascularization, and cardiovascular death.

Results: The mean age was 75.1±9.0 years; 44.7% were women. During a mean follow-up of 33.3±21.9 months (6567 patients/years) 133 MACEs occurred (2.03%/year): 79 MI/cardiac revascularization and 54 cardiovascular deaths. Of these, 101 were on VKAs (2.42%/year) and 32 on DOACs (1.34%/year; log-rank test P=.040). This difference was evident also considering MI alone (1.53%/year and 0.63%/year in the VKA and DOAC group, respectively, log-rank test P=.009). At multivariable Cox proportional hazard regression analysis, use of DOACs was associated with a lower risk of MACE (hazard ratio, 0.636; 95% CI, 0.417 to 0.970; P=.036) and MI (hazard ratio, 0.497; 95% CI, 0.276 to 0.896; p=.020). Sensitivity analysis showed that this association was consistent in younger patients (<75 years), in patients with anemia, and in those without chronic obstructive pulmonary disease and heart failure. We also found that both dabigatran and apixaban/rivaroxaban were associated with a lower rate of MACE, with similar efficacy between full and low doses.

Conclusion: DOACs are associated with a lower risk of MACE in patients with AF independently from dosage.
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http://dx.doi.org/10.1016/j.mayocp.2020.06.057DOI Listing
March 2021

Relation of Atrial Fibrillation to Angiographic Characteristics and Coronary Artery Disease Severity in Patients Undergoing Percutaneous Coronary Intervention.

Am J Cardiol 2021 02 18;141:1-6. Epub 2020 Nov 18.

Department of Clinical Internal, Anesthesiologic, and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Patients with atrial fibrillation (AF) have an increased risk of coronary artery disease (CAD) compared to patients without. Angiographic characteristics, clinical presentation and severity of CAD according to the presence of AF have been poorly described. We performed a retrospective study of 303 consecutive patients (mean age 69.6 ± 10.8 years; 23.1% women) with and without AF undergoing percutaneous coronary intervention. Data on (1) type of CAD presentation, (2) coronary involvement, and (3) number of diseased coronary vessels (≥70%/luminal narrowing) were collected. CHADS-VASc and 2 major adverse cardiac event (MACE) scores were calculated. Presentation of CAD was ST-segment elevation myocardial infarction (STEMI) in 37.6% of patients, non-STEMI- unstable angina in 55.1%, and other in 7.3%. Non-STEMI-unstable angina was more common in AF (69.6% vs 46.6%, p <0.001), while STEMI was more in the non-AF (22.3% vs 46.6%, p <0.001) group. Left anterior descending artery (LAD) was the most common diseased vessel (70.6%) followed by right coronary artery (RCA, 56.4%) and obtuse marginal artery (36.6%). Patients with AF had a significantly lower RCA involvement (47.3% vs 61.8%, p = 0.016), with a trend for LAD (64.3% vs 74.3%, p = 0.069). At multivariable logistic regression analysis, AF remained inversely associated with RCA involvement (odds ratio [OR] 0.541, 95% confidence interval [CI] 0.335 to 0.874, p = 0.012) and with ≥3 vessel CAD (OR 0.470, 95% CI 0.272 to 0.810, p = 0.007). The 2MACE score was associated with diseased LAD (OR 1.301, 95% CI 1.103 to 1.535, p = 0.002) and with ≥3 vessel CAD (OR 1.330, 95% CI 1.330 to 1.140, p <0.001). In conclusion, patients with AF show lower RCA involvement and generally less severe CAD compared to non-AF ones. The 2MACE score was higher in LAD obstruction and identified patients with severe CAD.
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http://dx.doi.org/10.1016/j.amjcard.2020.11.006DOI Listing
February 2021

Inositol and Non-Alcoholic Fatty Liver Disease: A Systematic Review on Deficiencies and Supplementation.

Nutrients 2020 Nov 3;12(11). Epub 2020 Nov 3.

Department of Oncology and Hemato-oncology, Postgraduate School of Clinical Pharmacology, University of Milan, 20129 Milan, Italy.

Liver lipid accumulation is a hallmark of non-alcoholic fatty liver disease (NAFLD), broadly associated with insulin resistance. Inositols (INS) are ubiquitous polyols implied in many physiological functions. They are produced endogenously, are present in many foods and in dietary supplements. Alterations in INS metabolism seems to play a role in diseases involving insulin resistance such as diabetes and polycystic ovary syndrome. Given its role in other metabolic syndromes, the hypothesis of an INS role as a supplement in NAFLD is intriguing. We performed a systematic review of the literature to find preclinical and clinical evidence of INS supplementation efficacy in NAFLD patients. We retrieved 10 studies on animal models assessing Myoinosiol or Pinitol deficiency or supplementation and one human randomized controlled trial (RCT). Overall, INS deficiency was associated with increased fatty liver in animals. Conversely, INS supplementation in animal models of fatty liver reduced hepatic triglycerides and cholesterol accumulation and maintained a normal ultrastructural liver histopathology. In the one included RCT, Pinitol supplementation obtained similar results. Pinitol significantly reduced liver fat, post-prandial triglycerides, AST levels, lipid peroxidation increasing glutathione peroxidase activity. These results, despite being limited, indicate the need for further evaluation of INS in NAFLD in larger clinical trials.
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http://dx.doi.org/10.3390/nu12113379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694137PMC
November 2020

Atrial fibrillation pattern, left atrial diameter and risk of cardiovascular events and mortality. A prospective multicenter cohort study.

Int J Clin Pract 2020 Oct 20:e13771. Epub 2020 Oct 20.

I Clinica Medica, Atherothrombosis Centre, Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Background: There are conflicting evidence on the association between atrial fibrillation (AF) pattern, such as persistent/permanent (Pers/Perm) and paroxysmal (PAF) AF and risk of ischemic events. We investigated if left atrial diameter (LAd) may affect the risk of cardiovascular outcomes according to AF pattern.

Methods: Prospective multicenter observational including 1,252 non-valvular AF patients (533 PAF and 719 Pers/Perm AF). Study endpoints were cardiovascular events (CVEs), major adverse cardiac events (MACE) and CV death. LA anteroposterior diameter (LAd) was obtained by transthoracic echocardiography.

Results: Pers/Perm AF patients had a higher proportion of LAd above median than PAF (≥44 mm, 59.5% vs 37.5% respectively, P < .001). In a mean follow-up of 42.2 ± 31.0 months (4,315 patients/year) 179 CVEs (incidence rate [IR] 4.2%/year), 133 MACE (IR 3.1%/year), and 97 CV deaths (IR 2.2%/year) occurred. Compared to patients with LAd below median, those with LAd above the median had a higher rate of CVEs (log-rank test, P < .001), MACE (log-rank test P < .001), and CV death (log-rank test P < .001). Multivariable Cox regression analysis showed that LAd above the median was associated with CVEs, (HR 1.569, 95% CI 1.129-2.180, P = .007) MACE (HR 1.858, 95% CI 1.257-2.745, P = .002) and CV death (HR 2.106, 95% CI 1.308-3.390, P = .002). The association between LAd and outcomes was evident both in PAF and Pers/Perm AF patients. No association between AF pattern and outcomes was found.

Conclusion: LAd is a simple parameter that can be obtained in virtually all AF patients and can provide prognostic information on the risk of CVEs, MACE and CV death regardless of AF pattern.
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http://dx.doi.org/10.1111/ijcp.13771DOI Listing
October 2020

Direct oral anticoagulants and advanced liver disease: A systematic review and meta-analysis.

Eur J Clin Invest 2021 Mar 27;51(3):e13397. Epub 2020 Sep 27.

Dipartimento di Scienze della Salute, Medicina 2 ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milano, Italy.

Background: Direct oral anticoagulants (DOACs) are recommended for stroke prevention in patients with atrial fibrillation (AF) or for treatment of deep vein thrombosis, although some concerns about safety and efficacy were raised on the use of these drugs in patients with advanced liver disease (ALD). We want to investigate the association of DOACs use with the bleeding and ischaemic risk.

Material And Methods: We performed a systematic review and metanalysis of clinical studies retrieved from PubMed (via MEDLINE) and Cochrane (CENTRAL) databases addressing the impact of DOACs therapy on bleeding events including intracranial haemorrhage (ICH), gastrointestinal and major bleeding. Secondary end points were all-cause death, ischaemic stroke/systemic embolism (IS/SE) and recurrence/progression of vein thrombosis (rDVT).

Results: 12 studies were included in the meta-analysis: a total of 43 532 patients with ALD or cirrhosis, of whom 27 574 (63.3%) were on treatment with DOACs and 15 958 were in warfarin/low molecular weight heparin. DOACs reduced the incidence of major bleeding by 61% (pooled Hazard Ratio [HR] 0.39, 95% Confidence Interval [CI] 0.21-0.70), ICH by 52% (HR 0.48, 95% CI 0.40-0.59), while no difference in the reduction of any and gastrointestinal bleeding were observed. DOACs reduced also rDVT by 82% (HR 0.18, 95%CI 0.06-0.57), but did not reduce death and IS/SE. No difference was shown according to oesophageal varices and Child Pugh score in the meta-regression analysis between warfarin/heparin and DOACs performed on each outcome.

Conclusions: DOACs are associated with a lower incidence of bleeding and may be an attractive therapeutic option in patients with cirrhosis.
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http://dx.doi.org/10.1111/eci.13397DOI Listing
March 2021

Features of severe COVID-19: A systematic review and meta-analysis.

Eur J Clin Invest 2020 Oct 29;50(10):e13378. Epub 2020 Aug 29.

I Clinica Medica, Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Background: To systematically review clinical and biochemical characteristics associated with the severity of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease (COVID-19).

Materials And Methods: Systematic review of observational studies from PubMed, ISI Web of Science, SCOPUS and Cochrane databases including people affected by COVID-19 and reporting data according to the severity of the disease. Data were combined with odds ratio (OR) and metanalysed. Severe COVID-19 was defined by acute respiratory distress syndrome, intensive care unit admission and death.

Results: We included 12 studies with 2794 patients, of whom 596 (21.33%) had severe disease. A slightly higher age was found in severe vs non-severe disease. We found that prevalent cerebrovascular disease (odds ratio [OR] 3.66, 95% confidence interval [CI] 1.73-7.72), chronic obstructive pulmonary disease (OR: 2.39, 95% CI 1.10-5.19), prevalent cardiovascular disease (OR: 2.84, 95% CI 1.59-5.10), diabetes (OR: 2.78, 95% CI 2.09-3.72), hypertension (OR: 2.24, 95% CI 1.63-3.08), smoking (OR: 1.54, 95% CI 1.07-2.22) and male sex (OR: 1.22, 95% CI 1.01-1.49) were associated with severe disease. Furthermore, increased procalcitonin (OR: 8.21, 95% CI 4.48-15.07), increased D-Dimer (OR: 5.67, 95% CI 1.45-22.16) and thrombocytopenia (OR: 3.61, 95% CI 2.62-4.97) predicted severe infection.

Conclusion: Characteristics associated with the severity of SARS-CoV-2 infection may allow an early identification and management of patients with poor outcomes.
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http://dx.doi.org/10.1111/eci.13378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435565PMC
October 2020

Family History of Atrial Fibrillation and Risk of Cardiovascular Events: A Multicenter Prospective Cohort Study.

Circ Arrhythm Electrophysiol 2020 09 27;13(9):e008477. Epub 2020 Jul 27.

I Clinica Medica, Atherothrombosis Center, Department of Clinical, Internal Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy (D.P., D.M., F.V., P.P.).

Background: To investigate the association between family history of atrial fibrillation (AF) with cardiovascular events (CVEs), major adverse cardiac events (MACE), and cardiovascular mortality.

Methods: Multicenter prospective observational cohort study including 1722 nonvalvular AF patients from February 2008 to August 2019 in Italy. Family history of AF was defined as the presence of AF in a first-degree relative: mother, father, sibling, or children. Primary outcome was a composite of CVEs including fatal/nonfatal ischemic stroke and myocardial infarction, and cardiovascular death. Second, we analyzed the association with major adverse cardiac event.

Results: Mean age was 74.6±9.4 years; 44% of women. Family history of AF was detected in 368 (21.4%) patients, and 3.5% had ≥2 relatives affected by AF. Age of AF onset progressively decreased from patients without family history of AF, compared with those with single and multiple first-degree affected relatives (<0.001). During a mean follow-up of 23.7 months (4606 patients/y) 145 CVEs (3.15%/y), 98 major adverse cardiac event (2.13%/y), and 57 cardiovascular deaths (0.97%/y) occurred. After adjustment for cardiovascular risk factors, family history of AF was associated with a higher risk of CVEs (hazard ratio, 1.524 [95% CI, 1.021-2.274], =0.039), major adverse cardiac event (hazard ratio, 1.917 [95% CI, 1.207-3.045], =0.006), and cardiovascular mortality (hazard ratio, 2.008 [95% CI, 1.047-3.851], =0.036). Subgroup analysis showed that this association was modified by age, sex, and prior ischemic heart disease.

Conclusions: In a cohort of elderly patients with a high atherosclerotic burden, family history of AF is evident in >20% of patients and was associated with an increased risk for CVEs and mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01882114.
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http://dx.doi.org/10.1161/CIRCEP.120.008477DOI Listing
September 2020

Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Advanced Liver Disease: An Exploratory Meta-Analysis.

Hepatol Commun 2020 Jul 7;4(7):1034-1040. Epub 2020 May 7.

I Clinica Medica Atherothrombosis Center Department of Clinical Internal, Anesthesiologic, and Cardiovascular Sciences Sapienza University of Rome Rome Italy.

Direct oral anticoagulants (DOACs) have had a positive impact in preventing cardioembolic stroke in patients with atrial fibrillation (AF) who were associated with lower bleeding complications; however, data on subjects with concomitant advanced liver diseases (ALDs) are poor. This meta-analysis evaluates bleeding and thromboembolic complications in patients with coexisting AF and ALD who were treated with DOACs or vitamin K antagonists (VKAs). We performed a meta-analysis of randomized controlled trials and observational studies identified by the PubMed and Embase databases using a combination of the following keywords: "direct oral anticoagulants," "advanced liver disease," "cirrhosis," "bleeds," "stroke." No time restriction was applied to the research. Two physicians reviewed data on outcome measures and assessed the quality rating. The main outcome was major bleeding, and the secondary outcomes were bleedings (all, intracranial, and gastrointestinal) and ischemic strokes. A total of four studies (one prospective, three retrospective) were identified involving 3,483 subjects with AF and ALD; of these, 1,547 were on VKAs and 1,936 on DOACs. Advanced liver disease was defined as liver cirrhosis or fibrosis-4 score >3.25. Compared to VKA use, DOAC use was associated with reduced risk for major bleedings (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.44-0.77;  < 0.001), total bleedings (HR, 0.45; 95% CI, 0.36-0.55;  < 0.05), intracranial hemorrhage (HR, 0.51; 95% CI, 0.32-0.80;  < 0.004), and gastrointestinal bleedings (HR, 0.61; 95% CI, 0.42-0.88;  < 0.008). Efficacy analysis showed no significant difference between VKA- and DOAC-treated patients (HR, 0.83; 95% CI, 0.58-1.15;  = 0.31). In patients with AF and ALD, the safety and efficacy profile of DOACs did not appear to differ from those with AF without ALD.
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http://dx.doi.org/10.1002/hep4.1513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327201PMC
July 2020

Cancer-specific ischemic complications in elderly patients with atrial fibrillation: Data from the prospective ATHERO-AF study.

Int J Cancer 2020 12 11;147(12):3424-3430. Epub 2020 Jul 11.

Department of Clinical, Internal, Anesthesiologic, and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Cancer may complicate the clinical course of nonvalvular atrial fibrillation (AF) but its association with cardiovascular events (CVEs) remains unclear. We performed a prospective cohort study including 2092 consecutive AF patients on vitamin K antagonists. Principal endpoint was the occurrence of CVEs including fatal/nonfatal myocardial infarction and ischemic stroke/transient ischemic attack and cardiovascular death. Secondary endpoints were major adverse cardiac events (MACEs) and thromboembolism (TE). Mean age was 73.7 ± 9.1 years and 42.1% were women; 367 (17.5%) patients had cancer: 21% gastrointestinal (GI), 10% respiratory, 28% genitourinary and 41% had other localization. Cancer patients were older but with similar comorbidities than those without. During a mean of 35.9 months, 203 CVEs occurred (incidence rate [IR] = 3.24 per 100 patient-years): 133 MACEs (IR = 2.12 per 100 patient-years) and 70 TE (IR = 1.12 per 100 patient-years). Multivariable Cox proportional hazards regression analysis showed an association between GI cancer and MACE occurrence (hazard ratio [HR] = 3.22, 95% confidence interval [CI] = 1.59-6.52, P = .001) and between respiratory cancer and TE (HR = 3.37, 95% CI = 1.30-8.75, P = .013). These associations were confirmed at competing risk analysis. In conclusion, AF patients with cancer have specific vascular outcomes according to cancer site, as indicated by the higher risk of MACE and TE in patients with gastrointestinal and respiratory cancer, respectively.
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http://dx.doi.org/10.1002/ijc.33179DOI Listing
December 2020

Association of different oral anticoagulants use with renal function worsening in patients with atrial fibrillation: A multicentre cohort study.

Br J Clin Pharmacol 2020 12 7;86(12):2455-2463. Epub 2020 Jun 7.

Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Aims: To investigate the decline of estimated glomerular filtration rate (eGFR) in patients with atrial fibrillation (AF) treated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs).

Methods: Multicentre prospective cohort study including 1667 patients with nonvalvular AF. The eGFR was assessed by the CKD-EPI formula at baseline and during follow-up. The primary endpoint of the study was the median annual decline of eGFR according to VKA (n = 743) or NOAC (n = 924) use. As secondary endpoints, we analysed the transition to eGFR <50 mL/min/1.73 m and the eGFR class worsening.

Results: Median age was 73.7 ± 9.1 years and 43.3% were women. VKA-treated patients showed an eGFR decline of -2.11 (interquartile range [IQR] -5.68/-0.62), which was -0.27 (IQR -9.00/4.54, P < 0.001 vs VKAs), -1.21 (IQR -9.98/4.02, P = 0.004 vs VKAs) and -1.32 (IQR -8.70/3.99, P = 0.003 vs VKAs) in patients on dabigatran, rivaroxaban and apixaban, respectively. Transition to eGFR <50 mL/min/1.73 m was lower in dabigatran- and apixaban-treated patients: odds ratio (OR) 0.492, 95% confidence interval (CI) 0.298-0.813, P = 0.006 and OR 0.449, 95% CI 0.276-0.728, P = 0.001, respectively. A lower rate of eGFR class worsening was found in all groups of NOACs compared to VKAs. No difference between full and reduced dose of NOAC was found. Subgroup analysis showed that the association between NOAC and eGFR changes was markedly reduced in diabetic patients.

Conclusion: Patients prescribed NOACs showed a lower decline of renal function compared to those prescribed VKAs. This effect was partially lost in patients with diabetes.
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http://dx.doi.org/10.1111/bcp.14350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688543PMC
December 2020

Statins and Major Adverse Limb Events in Patients with Peripheral Artery Disease: A Systematic Review and Meta-Analysis.

Thromb Haemost 2020 May 5;120(5):866-875. Epub 2020 May 5.

Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Italy.

Background:  Statins are guidelines recommended in patients with peripheral artery disease (PAD) for the prevention of cardiovascular (CV) events. Comprehensive meta-data on the impact of statins on major adverse limb events (MALE) in PAD patients are lacking. We examined the association of statin use with MALE in patients with PAD.

Methods:  We performed a systematic review (registered at PROSPERO: number CRD42019137111) and metanalysis of studies retrieved from PubMed (via MEDLINE) and Cochrane (CENTRAL) databases addressing the impact of statin on MALE including amputation and graft occlusion/revascularization. Secondary endpoints were all-cause death, composite CV endpoints, CV death, and stroke.

Results:  We included 51 studies with 138,060 PAD patients, of whom 48,459 (35.1%) were treated with statins. The analysis included 2 randomized controlled trials, 20 prospective, and 29 retrospective studies. Overall, 11,396 MALE events, 21,624 deaths, 4,852 composite CV endpoints, 4,609 CV deaths, and 860 strokes were used for the analysis. Statins reduced MALE incidence by 30% (pooled hazard ratio [HR]: 0.702; 95% confidence interval [CI]: 0.605-0.815) and amputations by 35% (HR: 0.654; 95% CI: 0.522-0.819), all-cause mortality by 39% (pooled HR: 0.608, 95% CI: 0.543-0.680), CV death by 41% (HR: 0.594; 95% CI: 0.455-0.777), composite CV endpoints by 34% (pooled HR: 0.662; 95% CI: 0.591-0.741) and ischemic stroke by 28% (pooled HR: 0.718; 95% CI: 0.620-0.831).

Conclusion:  Statins reduce the incidence of MALE, all-cause, and CV mortality in patients with PAD. In PAD, a high proportion of MALE events and deaths could be prevented by implementing a statin prescription in this patient population.
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http://dx.doi.org/10.1055/s-0040-1709711DOI Listing
May 2020

Determinants of low-quality warfarin anticoagulation in patients with mechanical prosthetic heart valves. The nationwide PLECTRUM study.

Br J Haematol 2020 08 20;190(4):588-593. Epub 2020 Feb 20.

I Clinica Medica, Atherothrombosis Centre, Department of Clinical Internal, Anaesthetic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Quality of warfarin therapy in patients with a mechanical prosthetic heart valve (MPHV) has been barely investigated. We analysed determinants of low time in the therapeutic range (TiTR <60%) in 2111 patients with MPHVs from the nationwide PLECTRUM study by the Italian Federation of Anticoagulation Clinics. Overall, 48·5% of patients had a TiTR of < 60%. At logistic regression analysis, arterial hypertension (odds ratio [OR] 1·502, P < 0·001), diabetes (OR 1·732, P < 0·001), heart failure (OR 1·484, P = 0·004), mitral site (vs. aortic) (OR 1·399, P = 0·006), international normalised ratio (INR) ranges of 2·5-3·5 (OR 2·575, P < 0·001) and 3·0-4·0 (OR 8·215, P < 0·001) associated with TiTR < 60%. TiTR is substantially suboptimal in MPHV patients, particularly in higher INR ranges.
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http://dx.doi.org/10.1111/bjh.16528DOI Listing
August 2020

Seronegative antiphospholipid syndrome: refining the value of "non-criteria" antibodies for diagnosis and clinical management.

Haematologica 2020 03 30;105(3):562-572. Epub 2020 Jan 30.

I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombotic manifestations and/or pregnancy-related complications in patients with persistently high antiphospholipid antibodies (aPL), the most common being represented by anticardiolipin antibodies (aCL), anti-beta 2 glycoprotein-I (aβ2GPI), and lupus anticoagulant (LAC). A growing number of studies have showed that, in some cases, patients may present with clinical features of APS but with temporary positive or persistently negative titers of aPL. For these patients, the definition of seronegative APS (SN-APS) has been proposed. Nevertheless, the negativity to classic aPL criteria does not imply that other antibodies may be present or involved in the onset of thrombosis. The diagnosis of SN-APS is usually made by exclusion, but its recognition is important to adopt the most appropriate anti-thrombotic strategy to reduce the rate of recurrences. This research is in continuous development as the clinical relevance of these antibodies is far from being completely clarified. The most studied antibodies are those against phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, vimentin/cardiolipin complex, and annexin A5. Moreover, the assays to measure the levels of these antibodies have not yet been standardized. In this review, we will summarize the evidence on the most studied non-criteria aPL, their potential clinical relevance, and the antithrombotic therapeutic strategies available in the setting of APS and SN-APS.
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http://dx.doi.org/10.3324/haematol.2019.221945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049333PMC
March 2020

Multiple Arterial Thrombosis in Seronegative Antiphospholipid Syndrome: Need for New Diagnostic Criteria?

Eur J Case Rep Intern Med 2019 23;6(10):001180. Epub 2019 Sep 23.

Department of Internal Medicine and Medical Specialties, I Clinica Medica, Atherothrombosis Centre, Sapienza University of Rome, Rome, Italy.

Background: Antiphospholipid syndrome (APS) is defined as thromboembolic complications and/or pregnancy morbidity in the presence of persistent increased titres of antiphospholipid antibodies. Nevertheless, some patients with clinical signs suggestive of APS are negative for diagnostic antibodies and may be classified as having seronegative-APS (SN-APS). Among the 'non-diagnostic' antibodies, a few studies have suggested that the IgG anti-vimentin/cardiolipin antibodies (AVA/CL) may be associated with risk of thrombosis.

Aims: The aim of this case report is to encourage the assessment of non-conventional antibodies in APS.Patient and methods: We report the case of a 69-year-old male patient with rapid onset of apparently unexplained multiple exclusively arterial thrombotic events in both coronary and peripheral vascular beds.

Results: The patient did not meet the diagnostic criteria for APS but was positive for AVA/CL, which result persisted on further testing at 3 and 6 months.

Discussion: Ongoing research has revealed the existence of non-criteria antibodies which may be relevant for the diagnosis of SN-APS and should be included in the classification criteria for the disease.

Learning Points: In patients with unexplained multiple thrombosis without the conventional antibodies of antiphospholipid syndrome, the assessment of non-conventional antibodies should be considered.IgG anti-vimentin/cardiolipin antibodies may be associated with risk of thrombosis.Arterial thrombosis could be the only manifestation of antiphospholipid syndrome.
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http://dx.doi.org/10.12890/2019_001180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822671PMC
September 2019

Serum albumin and risk of cardiovascular events in primary and secondary prevention: a systematic review of observational studies and Bayesian meta-regression analysis.

Intern Emerg Med 2020 01 11;15(1):135-143. Epub 2019 Oct 11.

I Clinica Medica, Atherothrombosis Centre, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161, Roma, Italy.

The predictive role of serum albumin (SA) has been evaluated in primary prevention studies. We want to assess the association of SA with the subsequent risk of cardiovascular events (CVE) in primary and secondary prevention studies. We performed a systematic review and Bayesian meta-regression analysis. Studies were identified by PubMed and EMBASE database using a combination of the following terms and MeSH terms: "serum albumin", "myocardial infarction, "cardiovascular events", "percutaneous coronary intervention" and "coronary restenosis". No time restriction of the research was applied. Two experienced physicians reviewed data on outcome measures and assessed the quality rating. The main outcomes were CVE including myocardial infarction, coronary heart disease, percutaneous coronary intervention and coronary restenosis. 15 studies of SA and CVE were identified involving 65,077 subjects with a mean age of 57.89 ± 6.05 years and a mean follow-up of 9.4 (±5.56) years. Subjects under SA cut-off of 3.8 g/dL had a combined hazard ratio (HR) for CVE of 2.16 [95% confidence interval (CI) 1.93-2.45]. An increased risk for CVE was also evident using SA as a continuous variable (HR = 1.89, 95% CI 1.5-2.39). Females and males had a similar risk for CVE (HR 2.46, 95% CI 1.92-3.16, and HR 1.46, 95% CI 1.27-1.69, respectively). We found a similar risk of CVE between primary and secondary prevention studies (HR 1.79, 95% CI 1.5-2.17, and HR 2.47, 95% CI 2.24-2.75, respectively). Low SA levels are associated with an increased risk of CVE, not only in subjects free from CVE, but also in patients who already experienced a CVE.
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http://dx.doi.org/10.1007/s11739-019-02204-2DOI Listing
January 2020

Relationship of Antiphospholipid Antibodies to Risk of Dementia: A Systematic Review.

J Alzheimers Dis 2019 ;69(2):561-576

I Clinica Medica, Atherothrombosis Center, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.

Antiphospholipid antibodies (aPL) are well-known risk factors for venous and arterial thrombosis, but their association with cognitive dysfunction has not been widely investigated in the general population and in patients with primary and secondary antiphospholipid syndrome (APS). We performed a systematic review searching MEDLINE via PubMed and Cochrane (CENTRAL) databases for observational studies reporting on the association between aPL and dementia in the general population, in subjects carrying aPL, in patients with cognitive disorder/dementia, and in primary and secondary APS. Prevalence of anticardiolipin (aCL) IgG ranged from 5.9% to 31.1% in the general population, with aCL titers being more elevated in subjects with functional decline of cognitive functions or with neurological alterations as detected by imaging. The prevalence of aPL ranged from 6.0 to 56.6% in patients with vascular dementia. Regarding patients with primary and secondary APS, a severe cognitive deficit has been described in up to 60% of patients, 33.3% of systemic lupus erythematosus (SLE)-APS and 22.2% of SLE patients without aPL. Five studies included patients with primary APS with divergent results, while 18 studies investigated the association between aPL and cognitive impairment in patients with SLE. Of these, 14 reported a positive association between aPL, mostly aCL and LAC, and cognitive impairment while little evidence on anti β2-Glycoprotein I exists. Mechanisms leading to cognitive dysfunction are not well characterized and may include vascular aPL-induced micro and macro-thrombosis and immune-mediated neuronal toxicity pathways in the cerebral district.
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http://dx.doi.org/10.3233/JAD-181294DOI Listing
September 2020

Tailored Practical Management of Patients With Atrial Fibrillation: A Risk Factor-Based Approach.

Front Cardiovasc Med 2019 12;6:17. Epub 2019 Mar 12.

I Clinica Medica, Atherothrombosis Centre, Department of Internal Medicine and Medical Specialties of Sapienza University, Rome, Italy.

The management of antithrombotic therapy for thromboprophylaxis in patients with atrial fibrillation (AF) has been recently evolved by the progressive replacement of vitamin K antagonists with the non-vitamin K antagonist oral anticoagulants (NOACs). However, while these drugs are effective in reducing ischemic stroke/systemic embolism, a still high rate of cardiovascular events is present in the AF population. A tailored integrated approach to patients with AF is therefore necessary to reduce both thromboembolic events and cardiovascular disease. This approach should consist in the assessment of individual risk factors for ischemic and bleeding events in order to choose the most appropriate anticoagulant treatment according to patient's characteristics and preference. To this purpose, several risk scores have been developed and validated to stratify thromboembolic and hemorrhagic risk. This review provides an individual-based strategy for the management of patients with AF, from a risk-factor based approach to a tailored prescription and monitoring of NOACs. In particular, we reported an updated practical management strategy for AF patients in specific clinical situations such as those (1) experiencing a major bleeding, (2) requiring a switch to another antithrombotic regimen, (3) restarting anticoagulation after acute ischemic stroke, (4) suffering from an acute coronary artery disease (acute coronary syndrome or undergoing cardiac revascularization).
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http://dx.doi.org/10.3389/fcvm.2019.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422871PMC
March 2019

Update and Unmet Needs on the Use of Nonvitamin K Oral Anticoagulants for Stroke Prevention in Patients With Atrial Fibrillation.

Curr Probl Cardiol 2021 Mar 27;46(3):100410. Epub 2019 Feb 27.

The landscape of stroke prevention in patients with atrial fibrillation (AF) is rapidly changing after the introduction of nonvitamin K oral anticoagulants (NOACs) that are replacing in many countries the use of vitamin K antagonists in virtue of their similar efficacy and better safety. The European Heart Rhythm Association has proposed a new classification for AF patients with valvular heart disease (VHD), which has clinical implications for the most appropriate choice of antithrombotic strategy. Furthermore, a growing body of evidence is available on the use of NOACs in patients with VHD. Beyond VHD, several other factors may help tailoring the antithrombotic therapy to the characteristics of patients. Thus, a new risk factors-based approach to improve the management of AF patients, namely Atrial fibrillation Better Care (ABC) pathway has been recently proposed. This includes "A" avoid stroke by adequate anticoagulant therapy, "B" better control of symptoms related to AF, and "C" optimal management of comorbidities focusing on modifiable cardiovascular risk factors. Another recent update regards the use of NOACs in patients undergoing myocardial revascularization, where the association of NOACs with antiplatelet offers a new safe option in the first period after the procedure. Finally, there are still some patients in whom NOACs have not been systematically studied, and the clinician has to decide whether to prescribe or not NOACs balancing the risk of bleeding and stroke. This review aims to summarize the most recent evidence to consider when choosing an anticoagulant therapy in AF patients.
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http://dx.doi.org/10.1016/j.cpcardiol.2019.02.002DOI Listing
March 2021

Integrated Care Management of Patients With Atrial Fibrillation and Risk of Cardiovascular Events: The ABC (Atrial fibrillation Better Care) Pathway in the ATHERO-AF Study Cohort.

Mayo Clin Proc 2019 07 11;94(7):1261-1267. Epub 2018 Dec 11.

Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, United Kingdom; Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Denmark. Electronic address:

Objective: To investigate the impact on cardiovascular events (CVEs) in a real-world population of patients with atrial fibrillation (AF) by implementing the Atrial fibrillation Better Care (ABC: A, Avoid stroke with anticoagulation; B, better symptom management; C, Cardiovascular and comorbidity risk management) pathway.

Patients And Methods: This prospective single-center cohort study included 907 consecutive patients with nonvalvular AF on vitamin K antagonists from February 2008 to December 2016. The A, B, and C groups were defined as follows: "A" by a Time in Therapeutic Range ≥65%; "B" by a European Heart Rhythm Association (EHRA) symptom scale I-II, and "C" as optimized cardiovascular comorbidity management. Primary end point was a composite outcome of CVEs.

Results: During a median follow-up of 36.9 months (interquartile range [IQR] 20.0-57.5; 3022 patient-years), 118 CVEs occurred (3.9% per year; 95% confidence interval [CI], 3.2-4.7). Symptomatic patients (EHRA III-IV) had a higher risk of CVEs compared with those in EHRA I (hazard ratio [HR], 2.73, 95% CI, 1.61-4.63, P<.001). Optimally managed patients in the ABC group (n=198) had a lower risk of CVEs (1.8 [95% CI, 0.9-3.0] vs 4.5% [95% CI, 3.7-5.5] per year, P=.001) compared with those presenting with at least 1 suboptimal ABC factor (HR, 0.40, 95% CI, 0.22-0.74, P=.003). This association was evident using multivariate Cox proportional regression analysis (HR, 0.44, 95% CI, 0.24-0.80, P=.007).

Conclusion: Integrated care management according to the ABC pathway resulted in a significantly lower rate of CVEs, suggesting a clear benefit of a holistic approach to optimize the management of patients with AF.

Trial Registration: clinicaltrials.gov Identifier: NCT01882114.
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http://dx.doi.org/10.1016/j.mayocp.2018.10.022DOI Listing
July 2019

Silybin and metabolic disorders.

Intern Emerg Med 2019 01 17;14(1):1-3. Epub 2018 Oct 17.

Department of Internal Medicine and Medical Specialties, I Clinica Medica, Atherothrombosis Centre, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.

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http://dx.doi.org/10.1007/s11739-018-1968-xDOI Listing
January 2019

Hazelnut and cocoa spread improves flow-mediated dilatation in smokers.

Intern Emerg Med 2018 Dec 20;13(8):1211-1217. Epub 2018 Jul 20.

Department of Internal Medicine and Medical Specialties, I Clinica Medica, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.

Hazelnut and cocoa spread is an Italian product containing cocoa and hazelnut. Several epidemiological studies suggest that cocoa and hazelnuts cocoa exert beneficial cardiovascular effects. To investigate whether in smokers, hazelnut and cocoa spread elicits artery dilatation via down-regulation of oxidative stress. Flow-mediated dilatation (FMD), oxidative stress (as assessed by serum isoprostanes excretion, Nox2 activation and NO bioavailability) and antioxidant status [as assessed by vitamin E levels, plasma total polyphenols and HO breaking down activity (HBA)] were studied in 20 smokers in a crossover, single-blind study. Patients were randomly allocated to 60 g of Hazelnut and cocoa spread or 60 g of milk chocolate (≤ 35% cocoa). FMD, serum isoprostanes, Nox2 activation, NOx, vitamin E, HBA and total polyphenols were assessed at baseline and 2 h after chocolate ingestion. After Hazelnut and cocoa spread intake, FMD and NOx significantly increased (from 4.3 ± 2.8 to 8.0 ± 3.2%, p < 0.001 and from 23.1 ± 5.5 to 32.0 ± 12.6 µM, p = 0.016, respectively); conversely, serum isoprostanes and Nox2 activation significantly decreased (from 302.8 ± 59.8 to 240.7 ± 90.8 pmol/l, p = 0.03 and from 25 ± 4.4 to 22.6 ± 3.2, p = 0.03, respectively). After Hazelnut and cocoa spread intake, serum total polyphenols, vitamin E and HBA significantly increased (from 133.8 ± 49.7 to 202.5 ± 69.5 mg/l GAE, p = 0.001; from 3.56 ± 1.4 to 4.5 ± 1.0 μmol/mmol cholesterol, p = 0.002 and from 63.3 ± 13.2 to 74.2 ± 12.4%, p = 0.003, respectively). No changes in the above variables were observed after milk chocolate intake. A linear correlation analysis shows that Δ (expressed by difference of values between before and after chocolate intake) of FMD correlates with Δ of total polyphenols and Δ of vitamin E. This study shows that Hazelnut and cocoa spread improves FMD with a mechanism potentially involving downregulation of oxidative stress and eventually increased NO generation in smokers.
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http://dx.doi.org/10.1007/s11739-018-1913-zDOI Listing
December 2018

Oxidative stress and cardiovascular disease: new insights.

Kardiol Pol 2018 14;76(4):713-722. Epub 2018 Mar 14.

Sapienza University. Department of Internal Medicine and Medical Specialities, Viale del Policlinico, 00166 Rome, Italy.

The role of oxidative stress in the onset and progression of atherosclerosis and its impact on the development of cardiovascular events has been widely described. Thus, increased oxidative stress has been described in several atherosclerotic risk factors, such as hypertension, dyslipidaemia, peripheral artery disease, metabolic syndrome, diabetes, and obesity. Among others, specific oxidative pathways involving both pro-oxidant and antioxidant enzymes seem to play a major role in the production of reactive oxidant species (ROS), such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, myeloperoxidase, superoxide dismutase, and glutathione peroxidase. In this review, we will discuss: 1) the most relevant enzyme systems involved in the formation and detoxification of ROS, 2) the relationship between oxidative stress and cardiovascular risk, and 3) therapeutic implications to modulate oxidative stress.
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http://dx.doi.org/10.5603/KP.a2018.0071DOI Listing
December 2018

Relationship of PCSK9 and Urinary Thromboxane Excretion to Cardiovascular Events in Patients With Atrial Fibrillation.

J Am Coll Cardiol 2017 Sep;70(12):1455-1462

I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy. Electronic address:

Background: Soluble proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to be predictive of cardiovascular events (CVEs) in patients who are at high cardiovascular risk. No data on the effect of PCSK9 levels in patients with atrial fibrillation (AF) are available.

Objectives: This study investigated the association between PCSK9 and CVEs in AF as well as the relationship between PCSK9 and urinary 11-dehydro-thromboxane B (11-dh-TxB), a marker of platelet activation.

Methods: We conducted a prospective, single-center cohort study, including 907 patients with AF treated with vitamin K antagonists (3,865 patient-years), to assess CVEs, including fatal and nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. At admission, plasma PCSK9 and urinary 11-dh-TxB (n = 852) were measured. The population was divided into tertiles of PCSK9 for the analysis.

Results: The mean age of patients was 73.5 ± 8.2 years, and 43.0% were women. At follow-up, 179 CVEs (4.6%/year) occurred: 43 (15.3%), 49 (15.5%), and 87 (28.0%) in the first, second, and third tertiles of PCSK9, respectively (log-rank test p = 0.009). Patients with CVEs had higher median PCSK9 compared with those without (1,500 pg/ml [IQR: 1,000 to 2,300 pg/ml] vs. 1,200 pg/ml [IQR: 827 to 1,807 pg/ml], respectively; p < 0.001). Multivariable Cox regression analysis showed that the third versus the first tertile of PCSK9 (hazard ratio: 1.640; 95% confidence interval: 1.117 to 2.407; p = 0.012), female sex, age, diabetes, smoking, heart failure, previous cerebrovascular and cardiac events, digoxin use, and total cholesterol to high-density lipoprotein cholesterol ratio were associated with CVEs. In 682 patients not treated with antiplatelet therapy, circulating PCSK9 and 11-dh-TxB were significantly correlated (Spearman's rho: 0.665; p < 0.001).

Conclusions: Plasma PCSK9 levels are associated with an increased risk of CVEs in patients with AF. The direct correlation between PCSK9 and 11-dh-TxB suggests PCSK9 as a mechanism potentially implicated in platelet activation.
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http://dx.doi.org/10.1016/j.jacc.2017.07.743DOI Listing
September 2017

Gut-Derived Serum Lipopolysaccharide is Associated With Enhanced Risk of Major Adverse Cardiovascular Events in Atrial Fibrillation: Effect of Adherence to Mediterranean Diet.

J Am Heart Assoc 2017 Jun 5;6(6). Epub 2017 Jun 5.

I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy

Background: Gut microbiota is emerging as a novel risk factor for atherothrombosis, but the predictive role of gut-derived lipopolysaccharide (LPS) is unknown. We analyzed (1) the association between LPS and major adverse cardiovascular events (MACE) in atrial fibrillation (AF) and (2) its relationship with adherence to a Mediterranean diet (Med-diet).

Methods And Results: This was a prospective single-center study including 912 AF patients treated with vitamin K antagonists (3716 patient-years). The primary end point was a composite of MACE. Baseline serum LPS, adherence to Med-diet (n=704), and urinary excretion of 11-dehydro-thromboxane B (TxB, n=852) were investigated. Mean age was 73.5 years; 42.9% were women. A total of 187 MACE (5.0% per year) occurred: 54, 59, and 74 in the first, second, and third tertile of LPS, respectively (log-rank test =0.004). Log-LPS (hazard ratio 1.194, =0.009), age (hazard ratio 1.083, <0.001), and previous cerebrovascular (hazard ratio 1.634, =0.004) and cardiac events (hazard ratio 1.822, <0.001) were predictors of MACE. In the whole cohort, AF (versus sinus rhythm) (β 0.087, =0.014) and low-density lipoprotein cholesterol (β 0.069, =0.049) were associated with circulating LPS. Furthermore, Med-diet score (β -0.137, <0.001) was predictive of log-LPS, with fruits (β -0.083, =0.030) and legumes (β -0.120, =0.002) negatively associated with log-LPS levels. Log-LPS and log-TxB were highly correlated (r=0.598, <0.001). Log-LPS (β 0.574, <0.001) and Med-diet score (β -0.218, <0.001) were significantly associated with baseline urinary excretion of TxB.

Conclusions: In this cohort of AF patients, LPS levels were predictive of MACE and negatively affected by high adherence to Med-diet. LPS may contribute to MACE incidence in AF by increasing platelet activation.
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http://dx.doi.org/10.1161/JAHA.117.005784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669181PMC
June 2017

Is There an Interplay Between Adherence to Mediterranean Diet, Antioxidant Status, and Vascular Disease in Atrial Fibrillation Patients?

Antioxid Redox Signal 2016 11 30;25(14):751-755. Epub 2016 Sep 30.

1 Department of Internal Medicine and Medical Specialties, I Clinica Medica, Atherothrombosis Centre, Sapienza University of Rome , Rome, Italy .

Mediterranean Diet (Med-Diet) is associated with reduced incidence of vascular events (VEs) in atrial fibrillation (AF), but the mechanism accounting for its beneficial effect is only partially known. We hypothesized that Med-Diet may reduce VEs by improving antioxidant status, as assessed by glutathione peroxidase 3 (GPx3) and superoxide dismutase (SOD). We performed a prospective cohort study investigating the relationship between adherence to Med-Diet, serum baseline GPx3 and SOD activities, and the occurrence of VEs in 690 AF patients. GPx3 activity was directly associated with Med-Diet score (B = 0.192, p < 0.001) and inversely with age (B = -0.124, p = 0.001), after adjustment for potential confounders; Med-Diet weakly affected SOD levels. During a mean follow-up of 46.1 ± 28.2 months, 89 VEs were recorded; patients with VEs had lower GPx3 levels compared with those without VEs (p = 0.002); and no differences regarding SOD activity were found. Multivariable Cox regression analysis showed that age (Hazard ratio [HR]:1.065, p < 0.001), logGPx3 (above median, HR: 0.629, p < 0.05), and Med-Diet score (HR: 0.547, p < 0.05) predicted VEs. Med-Diet favorably modulates antioxidant activity of GPx3 in AF, resulting in reduced VEs rate. We hypothesize that the modulation of GPx3 levels by Med-Diet could represent an additional nutritional strategy to prevent VEs in AF patients. Antioxid. Redox Signal. 25, 751-755.
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http://dx.doi.org/10.1089/ars.2016.6839DOI Listing
November 2016