Left ventricular volumes and function in successful and failed His-BundLe Pacing. A comparative prospective study.

INTRODUCTION: Initial data suggest that His Bundle Pacing (HBP) could preserve long-term cardiac structure and function better than Right Ventricular Pacing (RVP), but evidence is limited. METHODS: We studied consecutive patients with baseline ejection fraction (EF) ≥ 50% who underwent HBP attempt, either successful (HBP group) or failed (RVP group). Two-dimensional (2D) and three-dimensional (3D) echocardiography were carried out at baseline and after 6 months of ventricular pacing burden > 20%. RESULTS: Among 68 patients, 40 underwent successful HBP, and 28 RVP. The HBP and RVP groups did not differ for age, sex and pacing indication. At baseline, the HBP and RVP groups did not differ for 2D EF (62% vs. 62%), 3D EF (60% vs. 63%), 2D (-19% vs. -19%) and 3D global longitudinal strain (GLS) (-15% vs. -16%). After 6 months, 2D EF (-3.86%) and 3D EF (-5.71%) significantly decreased in the RVP group and did not change in the HBP group (p for interaction .006 and <.001, respectively). 2D GLS (3.08%) and 3D GLS (2.22%) significantly increased in the RVP group, but did not change in the HBP group (p for interaction .013 and <.016, respectively). Pacing induced cardiomyopathy (PICM) (EF drop ≥ 10% and EF < 50%) occurred in 14% (RVP) versus 0% (HBP) of patients (p = .025). CONCLUSIONS: Successful HBP was superior to RVP in preserving LV systolic function despite a high ventricular pacing burden, and was less frequently associated with PICM.

Hyperuricemia increases the risk of cardiovascular mortality associated with very high HdL-cholesterol level.

BACKGROUND AND AIMS: Whether the association between very high HDL-cholesterol levels and cardiovascular mortality (CVM) is modulated by some facilitating factors is unclear. Aim of the study was to investigate whether the risk of CVM associated with very high HDL-cholesterol is increased in subjects with hyperuricemia. METHODS AND RESULTS: Multivariable Cox analyses were made in 18,072 participants from the multicentre URRAH study stratified by sex and HDL-cholesterol category. During a median follow-up of 11.4 years there were 1307 cases of CVM. In multivariable Cox models a J-shaped association was found in the whole population, with the highest risk being present in the high HDL-cholesterol group [>80 mg/dL, adjusted hazard ratio (HR), 1.28; 95%CI, 1.02-1.61; p = 0.031)]. However, a sex-specific analysis revealed that this association was present only in women (HR, 1.34; 95%CI, 1.02-1.77; p = 0.034) but not in men. The risk of CVM related to high HDL-cholesterol was much greater in the women with high uric acid (>0.30 mmol/L, HR 1.61; 95%CI, 1.08-2.39) than in those with low uric acid (HR, 1.17; 95%CI, 0.80-1.72, p for interaction = 0.016). In women older than 70 years with hyperuricemia the risk related to high HDL-cholesterol was 1.83 (95%CI, 1.19-2.80, p < 0.005). Inclusion of BMI in the models weakened the strength of the associations. CONCLUSION: Our data indicate that very high HDL-cholesterol levels in women are associated with CVM in a J-shaped fashion. The risk of CVM is increased by concomitant hyperuricemia suggesting that a proinflammatory/oxidative state can enhance the detrimental cardiovascular effects associated with high HDL-cholesterol.

Therapy of Type 2 diabetes: more gliflozines and less metformin?

Metformin is a frequently used anti-diabetic drug. In addition to the well-known modulating properties on glyco-metabolic control, metformin reduces cardiovascular (CV) risk partly independently of its anti-hyperglycaemic effect. The use of 'new' anti-diabetic drugs, inhibitors of the renal Na-glucose co-transporter (SGLTs-I or 'gliflozines') and GLP-1 receptor agonists (GLP1-RAs), has further contributed to challenge the strictly 'gluco-centric' view of diabetic CV disease. Several controlled trials have demonstrated that the cardio-renal benefits of gliflozines and GLP1-RAs are present regardless of the presence of metformin as 'background' therapy. The impact on the 'cardio-renal continuum' exerted by SGLTs-I was also noted in non-diabetic patients with heart failure and reduced or preserved ventricular function and different levels of renal function. These drugs reduced re-hospitalization, CV mortality, and progression to end-stage renal disease. These clinical acquisitions, implemented by Scientific Societies, have led to a change in the therapeutic approach to diabetic cardio-renal disease. Although metformin still represents a valid therapeutic option to be offered particularly to 'naïve' diabetic patients without previous cardio-renal events, SGLTs-I and/or GLP1-RAs emerge as 'first-line' drugs in diabetic patients with previous CV events, or at high CV risk, without having to request 'on board' metformin therapy.

Soluble CD40 ligand and outcome in patients with coronary artery disease undergoing percutaneous coronary intervention.

OBJECTIVES: CD40 ligand (CD40L), a transmembrane glycoprotein belonging to the tumor necrosis factor family and expressed by a variety of cells, is involved in the basic mechanisms of inflammation, atherosclerosis and thrombosis. Some studies suggest that the soluble form of CD40L (sCD40L) is a predictor of major cardiovascular events and mortality in a variety of clinical settings, but data from literature are conflicting. METHODS: We studied consecutive patients with acute (ACS) or chronic (CCS) coronary syndrome who underwent percutaneous coronary artery intervention (PCI). Blood samples for sCD40L dosage were taken at baseline immediately before PCI. We tested the relation between sCD40L and pre-specified outcome measures consisting of new ACS, clinical restenosis and all-cause mortality. We recruited 3,841 patients (mean age 64 ± 11 years, 79% men) with ACS (n=2,383) or CCS (n=1,458). RESULTS: During a mean follow-up of two years (±0.6 years), 642 patients developed ACS, 409 developed restenosis (≥70% of at least one of the previously treated coronary segments) and 175 died. For each 1-standard deviation increase in sCD40L (0.80 ng/mL), the hazard ratios (HRs) for ACS, restenosis, and mortality were 1.11 (95% confidence interval [CI]: 1.05 to 1.18, p<0.0001), 1.10 (95% CI: 1.02 to 1.19, p=0.010), and 1.00 (95% CI: 0.86 to 1.16, p=0.983), respectively. In multivariable Cox regression models with adjustment for several potential confounders including age, acute or chronic coronary syndrome, multi-vessel disease, stent placement, diabetes, previous coronary events and dyslipidemia, sCD40L remained an independent predictor of ACS and coronary restenosis. There were no interactions between sCD40L and acute or chronic coronary syndrome or stent placement. CONCLUSIONS: Among patients with ACS or CCS who undergo PCI, higher levels of sCD40L predict an increased risk of acute coronary events and coronary restenosis, but not of mortality.

Serum uric acid levels threshold for mortality in diabetic individuals: The URic acid Right for heArt Health (URRAH) project.

BACKGROUND AND AIM: The URRAH (URic acid Right for heArt Health) Study has identified cut-off values of serum uric acid (SUA) predictive of total mortality at 4.7 mg/dl, and cardiovascular (CV) mortality at 5.6 mg/dl. Our aim was to validate these SUA thresholds in people with diabetes. METHODS AND RESULTS: The URRAH subpopulation of people with diabetes was studied. All-cause and CV deaths were evaluated at the end of follow-up. A total of 2570 diabetic subjects were studied. During a median follow-up of 107 months, 744 deaths occurred. In the multivariate Cox regression analyses adjusted for several confounders, subjects with SUA ≥5.6 mg/dl had higher risk of total (HR: 1.23, 95%CI: 1.04-1.47) and CV mortality (HR:1.31, 95%CI:1.03-1.66), than those with SUA <5.6 mg/dl. Increased all-cause mortality risk was shown in participants with SUA ≥4.7 mg/dl vs SUA below 4.7 mg/dl, but not statistically significant after adjustment for all confounders. CONCLUSIONS: SUA thresholds previously proposed by the URRAH study group are predictive of total and CV mortality also in people with diabetes. The threshold of 5.6 mg/dl can predict both total and CV mortality, and so is candidate to be a clinical cut-off for the definition of hyperuricemia in patients with diabetes.

Cardiac complications of COVID-19 vaccination: now we know more.

The proliferation of good quality observational studies on the potential adverse effects of COVID-19 vaccination has greatly increased our knowledge on myocarditis and pericarditis, and also, more recently, on arterial hypertension. According to some recent studies, the incidence of a significant increase in blood pressure after COVID-19 vaccination is about 3.2% (95% CI: 1.62-6.21). The incidence of serious hypertensive emergencies or stage III hypertension has been reported as 0.6%. It is well known that the 'spike protein' of the Sars-CoV-2 virus, the synthesis of which is induced by vaccines, binds to ACE2 receptors, inducing their migration towards the inside of the cell. This would result in a lack of ACE2 activity on cell surfaces and therefore a relative deficiency of angiotensin1-7 with a relative excess of angiotensin II, which could explain, at least in part, the blood pressure increases. Regarding myo-pericarditis, there is evidence that the advantages of COVID-19 vaccination over non-vaccination remain preponderant in terms of prevented hospitalizations and serious complications of COVID-19, compared with the risk of developing myocarditis. In the age group most at risk of COVID-19 vaccine myocarditis (12-29 years), for every 100 000 vaccinated, compared to about four more cases of myocarditis we have 56 fewer hospitalizations, 13.8 admissions to intensive care and 0.6 fewer deaths. Several studies have shown that post vaccine myocarditis/pericarditis are generally short-lasting phenomena with favourable clinically course.

Certainties fading away: ß-blockers do not worsen chronic obstructive pulmonary disease.

For many years, ß-blockers have been considered contraindicated in patients with heart failure (HF) and in those with bronchial asthma or even chronic obstructive pulmonary disease (COPD) although without clear evidence of asthma. Today, despite overwhelming evidence of the usefulness of ß-blockers, especially in HF with reduced left ventricular ejection fraction (HFrEF), and in ischaemic heart disease, some reluctance persists in using these drugs when COPD coexists. Such resistance is due to the fear that a possible worsening of bronchospasm induced by ß-blockers could induce negative effects greater than the benefits. The Guidelines of the European Society of Cardiology clearly suggest that: (i) implantation of a cardiac defibrillator (ICD) are not contraindicated in COPD without clear evidence of bronchial asthma; (ii) ß-blockers are only 'relatively' contraindicated when there is certainty of bronchial asthma with a documented bronchodilator response to the ß2 stimulant. Therefore, bronchial asthma is not an absolute contraindication to ß-blockers. The cardiologist should not limit the diagnosis of COPD to clinical suspicion, but should rely on a spirometry examination associated with any bronchodilation tests. In any case, selective ß1 blockers are preferred, starting at a basic dose, which ensure a better dilator response to bronchodilators and in any case cause less bronchospasm than non-selective ß-blockers. Unfortunately, there is still some reluctance to the use of ß-blockers in patients with COPD associated with HF, which should be eliminated.

Hypertension and Atrial Fibrillation: Doubts and Certainties From Basic and Clinical Studies.

Hypertension and atrial fibrillation (AF) are 2 important public health priorities. Their prevalence is increasing worldwide, and the 2 conditions often coexist in the same patient. Hypertension and AF are strikingly related to an excess risk of cardiovascular disease and death. Hypertension ultimately increases the risk of AF, and because of its high prevalence in the population, it accounts for more cases of AF than other risk factors. Among patients with established AF, hypertension is present in about 60% to 80% of individuals. Despite the well-known association between hypertension and AF, several pathogenetic mechanisms underlying the higher risk of AF in hypertensive patients are still incompletely known. From an epidemiological standpoint, it is unclear whether the increasing risk of AF with blood pressure (BP) is linear or threshold. It is uncertain whether an intensive control of BP or the use of specific antihypertensive drugs, such as those inhibiting the renin-angiotensin-aldosterone system, reduces the risk of subsequent AF in hypertensive patients in sinus rhythm. Finally, in spite of the observational evidence suggesting a progressive relation between BP levels and the risk of thromboembolism and bleeding in patients with hypertension and AF, the extent to which BP should be lowered in these patients, including those who undergo catheter ablation, remains uncertain. This article summarizes the main basic mechanisms through which hypertension is believed to promote AF. It also explores epidemiological data supporting an evolutionary pathway from hypertension to AF, including the emerging evidence favoring an intensive BP control or the use of drugs, which inhibit the renin-angiotensin-aldosterone system to reduce the risk of AF. Finally, it examines the impact of non-vitamin K antagonist oral anticoagulants compared with warfarin in relation to hypertension.

Fragmented QRS as an early predictor of left ventricular systolic dysfunction in healthy individuals: a nested case-control study in the era of speckle tracking echocardiography.

BACKGROUND: Several studies addressed the association between fragmented QRS (fQRS) on 12-lead EKG and left ventricular (LV) dysfunction in patients with a variety of cardiovascular disorders. We tested such association in healthy individuals. METHODS: Out of 500 healthy participants without -overt cardiovascular disease from the Shiraz Heart Study cohort, we identified 20 subjects with fQRS (cases) and 20 peers without fQRS (controls). Global LV longitudinal strain (GLS) was measured by speckle tracking echocardiography in the two groups. Comparison was made between case and control groups by using chi-square or independent sample t-test or ANOVA. RESULTS: Age, gender, ejection fraction, LV volume and dimensions did not differ between the case and the control groups. Overall, 14 subjects out of 40 had reduced GLS (≤20%) and 10 of them (25%) had fQRS. GLS was significantly lower in the group with fQRS than in the control group (19.9 ± 1.8 vs 21.4 ± 1.6; p = 0.009). CONCLUSIONS: Healthy subjects with fQRS present regional LV systolic dysfunction, assessed by GLS, in the presence of a normal ejection fraction. These data suggest that fQRS may be a promising tool to identify apparently healthy subjects with regional LV systolic dysfunction.

The revolution of the anti-diabetic drugs in cardiology.

Beginning in December 2008, under the auspices of Food and Drug Administration, numerous controlled clinical trial were planned, and in part completed, concerning the cardiovascular (CV) effects of hypoglycaemic drug in patients with Type 2 diabetes mellitus. At least 9 studies have been concluded, 13 are still open, and 4 have been initiated and closed ahead of time. Of the nine completed studies, three concerned inhibitor of the dipeptidyl peptidase 4 (inhibitors of DPP-4), four the glucagon-like peptide 1 agonist (GLP-1 agonist), and two the inhibitor of sodium-glucose co-transporter-2 (inhibitors of SGLT-2). Only four studies demonstrated the superiority, and not the mere 'non-inferiority', of the anti-diabetic drugs compared to placebo, in addition to standard treatment, in terms of reduction of the primary endpoint (CV death, non-fatal myocardial infarction, and non-fatal stroke). Two of the four studies regarded GLP-1 analogues (liraglutide and semaglutide), and two inhibitors of SGLT-2 (empaglifozin and canaglifozin). As a whole, these studies provided solid data supporting major beneficial CV effects of anti-diabetic drugs. During the next 3-4 years, an equal number of studies will be completed and published, so we will soon have the 'final word' on this issue. In the meantime, the clinical cardiologist should become familiar with these drugs, selecting the patients able to gain the best clinical advantage from this treatment, also by establishing a close relationship with the diabetologist.

Severity of COVID-19: The importance of being hypertensive.

The novel respiratory Syndrome Coronavirus-2 (SARS-CoV-2) caused a cluster of pneumonia cases in China at the end of 2019. After few months, it led to a pandemic that has spread throughout most countries of the world (https://coronavirus.jhu.edu/map.html).

Detrimental Impact of Chronic Obstructive Pulmonary Disease in Atrial Fibrillation: New Insights from Umbria Atrial Fibrillation Registry.

Background and objectives: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Among extra-pulmonary manifestations of COPD, atrial fibrillation (AF) is commonly observed in clinical practice. The coexistence of COPD and AF significantly affects the risk of cardiovascular morbidity and mortality. Nonetheless, the mechanisms explaining the increased risk of vascular events and death associated to the presence of COPD in AF are complex and not completely understood. We analyzed data from an Italian network database to identify markers and mediators of increased vascular risk among subjects with AF and COPD. Materials and Methods: Cross-sectional analysis of the Umbria Atrial Fibrillation (Umbria-FA) Registry, a multicenter, observational, prospective on-going registry of patients with non-valvular AF. Of the 2205 patients actually recruited, 2159 had complete clinical data and were included in the analysis. Results: the proportion of patients with COPD was 15.6%. COPD patients had a larger proportion of permanent AF when compared to the control group (49.1% vs. 34.6%, p < 0.0001) and were more likely to be obese and current smokers. Other cardiovascular risk factors including chronic kidney disease (CKD), peripheral artery disease and subclinical atherosclerosis were more prevalent in COPD patients (all p < 0.0001). COPD was also significantly associated with higher prevalence of previous vascular events and a history of anemia (all p < 0.0001). The thromboembolic and bleeding risk, as reflected by the CHA2DS2VASc and HAS-BLED scores, were higher in patients with COPD. Patients with COPD were also more likely to have left ventricular (LV) hypertrophy at standard ECG than individuals forming the cohort without COPD (p = 0.018). Conclusions: AF patients with COPD have a higher risk of vascular complications than AF patients without this lung disease. Our analysis identified markers and mediators of increased risk that can be easily measured in clinical practice, including LV hypertrophy, CKD, anemia, and atherosclerosis of large arteries.

Glomerular hyperfiltration is a predictor of adverse cardiovascular outcomes.

The association between glomerular hyperfiltration and cardiovascular events is not well known. To investigate whether glomerular hyperfiltration is independently associated with risk of adverse outcome we analyzed 8794 participants, average age 52 years enrolled in 8 prospective studies. Of these, 89% had hypertension. Using the 5th and 95th percentiles of the age- and sex-specific quintiles of CKD-EPI-calculated estimated glomerular filtration rate (eGFR), we identified three participant groups with low, high and normal eGFR. The ambulatory pulse pressure interval was wider and nighttime blood pressure fall was smaller in both the low and high than in the normal eGFR participants. During a mean follow-up of 6.2 years, there were 722 cardiovascular events. Crude event rates were significantly higher for both high (1.8 per 100-person-year) and low eGFR groups (2.1 per 100 person-year) as compared with group with normal eGFR (1.2 per 100 person-year). In multivariable Cox models including age, sex, average 24-hour blood pressure, smoking, diabetes, and cholesterol, both high eGFR (hazard ratio 1.5 (95% confidence interval 1.2-2.1) and low eGFR (2.0 [1.5-2.6]) participants had a significantly higher risk of cardiovascular events as compared to those with normal eGFR. Addition of body mass index to the multivariable survival model did not change the magnitude of hazard estimates. Thus, glomerular hyperfiltration is a strong and independent predictor of cardiovascular events in a large multiethnic population of predominantly hypertensive individuals. Our findings support a U-shaped relationship between eGFR and adverse outcome.

Dabigatran vs. warfarin in relation to the presence of left ventricular hypertrophy in patients with atrial fibrillation- the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) study.

Aim: We tested the hypothesis that left ventricular hypertrophy (LVH) interferes with the antithrombotic effects of dabigatran and warfarin in patients with atrial fibrillation (AF). Methods and results: This is a post-hoc analysis of the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) Study. We defined LVH by electrocardiography (ECG) and included patients with AF on the ECG tracing at entry. Hazard ratios (HR) for each dabigatran dose vs. warfarin were calculated in relation to LVH. LVH was present in 2353 (22.7%) out of 10 372 patients. In patients without LVH, the rates of primary outcome were 1.59%/year with warfarin, 1.60% with dabigatran 110 mg (HR vs. warfarin 1.01, 95% confidence interval (CI) 0.75-1.36) and 1.08% with dabigatran 150 mg (HR vs. warfarin 0.68, 95% CI 0.49-0.95). In patients with LVH, the rates of primary outcome were 3.21%/year with warfarin, 1.69% with dabigatran 110 mg (HR vs. warfarin 0.52, 95% CI 0.32-0.84) and 1.55% with 150 mg (HR vs. warfarin 0.48, 95% CI 0.29-0.78). The interaction between LVH status and dabigatran 110 mg vs. warfarin was significant for the primary outcome (P = 0.021) and stroke (P = 0.016). LVH was associated with a higher event rate with warfarin, not with dabigatran. In the warfarin group, the time in therapeutic range was significantly lower in the presence than in the absence of LVH. Conclusions: LVH was associated with a lower antithrombotic efficacy of warfarin, but not of dabigatran, in patients with AF. Consequently, the relative benefit of the lower dose of dabigatran compared to warfarin was enhanced in patients with LVH. The higher dose of dabigatran was superior to warfarin regardless of LVH status. Clinical trial registration: http:www.clinicaltrials.gov. Unique identifier: NCT00262600.

Clinical value of ambulatory blood pressure: evidence and limits.

This article reviews the clinical value of ambulatory blood pressure (BP) vis-à-vis the traditional BP measurements taken in the physician's office or in the hospital. Mention is initially made that longitudinal studies conducted in the general population or in hypertensive cohorts have shown that ambulatory BP provides a more accurate prediction of outcome than office BP. Namely, that (1) the risk of cardiovascular events increases in a less steep fashion with office than with 24-hour mean BP, (2) the 24-hour BP-dependent prediction is maintained after adjustment for office BP values, and (3) among individuals with normal office BP, those with increased ambulatory BP (masked hypertension) have an increased prevalence of organ damage, a more frequent unfavorable metabolic profile and a higher risk of new onset sustained hypertension, diabetes mellitus, and cardiovascular events than those with normal ambulatory BP. It is further mentioned, however, that more recently similar observations have been made for individuals with high office but normal ambulatory BP (white coat hypertension) suggesting a complementary role of out-of-office and office BP values in the determination of patients' prognosis. The evidence in favor of an independent prognostic value also of some within 24-hour BP phenomena (night BP reduction or absolute values, short-term BP variations, and morning BP surge) is then critically appraised for its elements of strength and weakness. Finally, whether the clinical advantages of ambulatory BP make this approach necessary for all patients with hypertension is discussed. The conclusion is that this is at present still premature because crucial evidence pro or against routine use of this approach in untreated and treated hypertensives is not yet available. It will be crucial for future studies to determine whether, compared with a treatment guided by office BP, a treatment tailored on ambulatory BP allows to improve prevention or regression of organ damage as well as protection from major cardiovascular complications to a degree that justifies the complexity and cost of the procedure.

Comparison of Oral Anticoagulants for Stroke Prevention in Nonvalvular Atrial Fibrillation: A Multicriteria Decision Analysis.

BACKGROUND: Decision on the most appropriate oral anticoagulation therapy for stroke prevention in patients with nonvalvular atrial fibrillation is difficult because multiple treatment options are available, and these vary in their clinical effects and relevant nonclinical characteristics. OBJECTIVES: To use a multicriteria decision analysis (MCDA) to compare the oral anticoagulants apixaban, dabigatran, edoxaban, rivaroxaban, and vitamin K antagonist (VKAs; specifically warfarin) in patients with nonvalvular atrial fibrillation. METHODS: We identified the evaluation criteria through a targeted literature review and clinical judgment. The final evaluation model included nine clinical events and four other criteria. We ranked possibly fatal clinical event criteria on the basis of the differences in risks of fatal events and the corresponding window of therapeutic opportunity, as observed in clinical trials. Clinical judgment was used to rank other criteria. Full criteria ranking was used to calculate centroid weights, which were combined with individual treatment performances to estimate the overall value score for each treatment. RESULTS: Using such an MCDA, dabigatran yielded the highest overall value, approximately 6% higher than that of the second-best treatment, apixaban. Dabigatran also had the highest first-rank probability (0.72) in the probabilistic sensitivity analysis. Rivaroxaban performed worse than the other non-VKA oral anticoagulants, but better than VKAs (with both having 0.00 first-rank probability). The results were insensitive to changes in model structure. CONCLUSIONS: When all key oral anticoagulant value criteria and their relative importance are investigated in an MCDA, dabigatran appears to rank the highest and warfarin the lowest.

ANMCO Position Paper: direct oral anticoagulants for stroke prevention in atrial fibrillation: clinical scenarios and future perspectives.

It is now 4 years since the introduction of the new direct oral anticoagulants into clinical practice. Therefore, the Italian Association of Hospital Cardiologists (ANMCO) has deemed necessary to update the previous position paper on the prevention of thrombo-embolic complications in patients with non-valvular atrial fibrillation, which was published in 2013. All available scientific evidence has been reviewed, focusing on data derived from both clinical trials and observational registries. In addition, all issues relevant to the practical clinical management of oral anticoagulation with the new direct inhibitors have been considered. Specific clinical pathways for optimal use of oral anticoagulation with the new directly acting agents are also developed and proposed for clinical implementation. Special attention is finally paid to the development of clinical algorithms for medium and long-term follow-up of patients treated with new oral direct anticoagulants.