[The IN-HF Registry: the history and the scientific production for the Italian cardiology community]. / Il programma IN-HF: la storia e la produzione scientifica a favore della comunità cardiologica italiana.

The Italian Network on Congestive Heart Failure (IN-CHF) project, later known as IN-HF Online, was launched in 1995 to provide the Italian cardiology community with a digital tool, standardized across the country, for managing outpatients with heart failure (HF), that enabled the creation of a database for clinical, educational and scientific purposes. During its almost three decades of activity, this observational research program has achieved highly positive scientific results. Indeed, IN-HF fostered professional relationships among individuals working in different centers, established a cultural network for the care of HF patients, periodically updated on the scientific advances, and allowed the assessment of several clinical, epidemiological, and prognostic features. These findings have been published in numerous national and international journals, as summarized in the present overview.

Clinical characteristics, treatment, trajectories and outcome of patients with dilated cardiomyopathy in a national heart failure registry.

BACKGROUND: Available data on the clinical characteristics and prognosis of patients with heart failure (HF) due to dilated cardiomyopathy (DCM) derive mainly from tertiary care centres for cardiomyopathies or from drug trial sub-studies, which may entail a referral bias. METHODS: From 2008 to 2021, we enrolled in a nationwide HF Registry 1886 DCM patients and 3899 with ischemic heart disease (IHD). RESULTS: Patients with DCM were younger, more often female, had more commonly recent onset HF, left bundle branch block, and showed higher LV end-diastolic volume and lower LVEF than IHD. With respect to IHD, DCM patients received more often mineralocorticoid receptor antagonists, renin angiotensin system inhibitors and betablockers, the latter more commonly at doses ≥50% of target, and triple guideline-directed medical therapy (GDMT) (adjusted OR 1.411, 95% CI 1.247-1.595, p < .0001). During one-year follow-up, 819 patients (14.2%) died or were hospitalized for HF [187 (9.9%) DCM, 632 (16.2%) IHD]; DCM was associated with lower risk of the combined end-point (adjusted HR 0.745, 95% CI 0.625- 0.888, p = .0011). Among the 1954 patients with 1-year echocardiograms available, 1483 had LVEF≤40% at baseline; of these,166 (30.6%) DCM and 165 (17.5%) IHD improved their LVEF to >40% (p < .0001). DCM aetiology was associated with higher likelihood of LVEF improvement (adjusted OR 1.722, 95% CI 1.328 -2.233, p < .0001). CONCLUSIONS: DCM patients have a different clinical profile, greater uptake of GDMT and better outcomes than IHD subjects. A comprehensive management approach is needed to further address the risk of unfavorable outcomes in DCM.

[Pulmonary hypertension associated with left heart diseases: pathophysiology, diagnosis, treatment]. / Ipertensione polmonare associata ad insufficienza cardiaca: fisiopatologia, diagnosi, terapia.

Pulmonary hypertension (PH) is a common complication of diseases affecting the left heart, mostly found in patients suffering from heart failure. Left atrial hypertension is the initial driver of post-capillary PH. However, several mechanisms may lead in a subset of patients to structural changes in the pulmonary vessels with development of a pre-capillary component. The right ventricle may be frequently affected, leading to right ventricular failure and a worse outcome. The differential diagnosis of PH associated with left heart disease vs pulmonary arterial hypertension (PAH) is challenging in patients with cardiovascular comorbidities, risk factors for PAH and/or a preserved left ventricular ejection fraction. Multidimensional clinical phenotyping is needed to identify patients in whom hemodynamic confirmation is deemed necessary, that may be completed by provocative testing in the cath lab. In contrast with PAH, management of PH associated with left heart disease should focus on the treatment of the underlying condition. There is currently no approved therapy for PH associated with left heart disease: some PAH-specific treatments have led to an increase in adverse events in these patients.

ORal anticoaGulants in diAbetic and Nondiabetic patients with nOn-valvular atrial fibrillatioN (ORGANON).

BACKGROUND: Diabetes represents a pro-thrombotic condition. OBJECTIVES: The primary objective was to evaluate the effects of Vitamin K Antagonist (VKA) compared to direct oral anticoagulants (DOACs) in diabetic and nondiabetic patients with non-valvular atrial fibrillation, newly diagnosed. The secondary objective was to evaluate the effects on the risk of bleeding. METHODS: We enrolled 300 patients with newly diagnosed atrial fibrillation. One hundred and sixteen patients were taking warfarin, 31 acenocumarol, 22 dabigatran, 80 rivaroxaban, 34 apixaban, and 17 edoxaban. We evaluated: anthropometric parameters, glycated hemoglobin (HbA1c), fasting and post-prandial glucose (FPG, and PPG), lipid profile, Lp(a), small and dense low-density lipoprotein (SD-LDL), oxidized LDL (Ox-LDL), I-troponin (I-Tn), creatinine, transaminases, iron, red blood cells (RBC); hemoglobin (Hb), platelets (PLT), fibrinogen, D-dimer, anti-thrombin III, C-reactive protein (Hs-CRP), Metalloproteinases-2 (MMP-2), Metalloproteinases-9 (MMP-9), and incidence of bleeding. RESULTS: We did not record any differences among nondiabetic patients between VKA and DOACs. However, when we considered diabetic patients, we found a slight, but significant improvement of triglycerides and SD-LDL. As regards incidence of bleeding, minor bleeding was more frequent in VKA diabetic group compared to DOACs diabetic group; furthermore, the incidence of major bleeding was higher with VKA in nondiabetic and diabetic group, compared to patients with DOACs. Among DOACs, we recorded a higher incidence of bleeding (minor and major) with dabigatran compared to rivaroxaban, apixaban and edoxaban in nondiabetic and diabetic patients. CONCLUSION: DOACs seem to be metabolically favourable in diabetic patients. Regarding incidence of bleeding, DOACs with the exception of dabigatran, seem better than VKA in diabetic patients.

New paradigm for the management of cardio-nephro-metabolic syndrome: multidisciplinary approach and role of telemedicine.

Heart failure (HF), type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) are some of the most important health problems of this century, and these three conditions often coexist, one worsening the prognosis of the other two. No disease is more important than the others in the composition of risk, which is significantly increased by their overlap. Thus, it would be more appropriate to refer to this cluster as cardio-nephro-metabolic syndrome. The aim of this review is to promote the development of an integrated multidisciplinary approach to the treatment of HF, T2DM and CKD in a perspective of paradigm shift from an individual management among different specialists to a shared one. Nowadays, this is achievable thanks to telemedicine and optimized therapy consisting in the new drugs with pleiotropic effect available today. The need is to have technological solutions, which also include telemedicine, for the management of patients affected by all three diseases to consider their fragility, sometimes due to a wrong, partial, or incomplete treatment. Multicentric, multidisciplinary trials on cardio-nephro-metabolic syndrome and new telemedicine/telemonitoring technologies could help place the chronic and fragile patient at the center of such multidimensionally integrated care.

[Ten questions on cardiac magnetic resonance in patients with heart failure: from etiological diagnosis to prognostic stratification]. / Dieci quesiti in tema di risonanza magnetica cardiaca nel paziente con scompenso cardiaco: dalla diagnosi eziologica alla stratificazione prognostica.

Cardiac magnetic resonance (CMR) imaging has progressively become part of the imaging methods recommended in patients with heart failure. CMR represents the gold standard for assessing volumes, function, biventricular kinetics and providing tissue characterization through scans with and without contrast medium. In patients with heart failure with reduced ejection fraction (HFrEF) and ischemic dilated cardiomyopathy, CMR allows to search for viability, accurately estimate volumes and ejection fraction. It can assess scar extent for predicting response to cardiac resynchronization therapy and for establishing an indication for implanting a defibrillator in borderline cases. In patients with HFrEF and non-ischemic dilated cardiomyopathy, CMR helps to identify specific etiological subgroups and to estimate the arrhythmic risk beyond ejection fraction. In patients with heart failure with preserved ejection fraction, CMR offers the possibility of diagnosing specific phenotypes, including sarcomeric hypertrophic cardiomyopathy, amyloidosis or Fabry disease, and adds prognostic information. Both clinical and scientific interest in this imaging method is constantly expanding; the clinicians dealing with heart failure cannot fail to know the technique, the indications and all the potential that CMR can offer.

[Heart failure with improved ejection fraction: practical guidance for the clinician]. / Lo scompenso cardiaco con frazione di eiezione migliorata: indicazioni gestionali per il clinico.

Heart failure with improved ejection fraction (HFimpEF) represents a nosological entity that has recently been recognized and has little evidence from the literature. Available data indicate an increasing incidence of this patient group, consistent with the progressive improvement and implementation of medical therapy of heart failure with reduced ejection fraction (HFrEF). Furthermore, it is important to underline that the therapy itself should not be suspended after ejection fraction recovery, to avoid the recurrence of worse systolic dysfunction and patient outcomes. Only recently a randomized clinical study has been published, which enrolled also this patient subgroup, the DELIVER trial. Other data will soon become available, given the interest of the scientific community for this subgroup of patients, whose best management remains controversial. Since many studies suggest that the probability of myocardial recovery in HFrEF patients might be as high as 40%, depending on the case series taken into account, whereas the time to recovery might even be 12 months, the appropriate timing of device implantation, such as the defibrillator, in this setting deserves careful consideration.

Combined Neuro-Humoral Modulation and Outcomes in Patients with Chronic Heart Failure and Mildly Reduced or Preserved Ejection Fraction.

Pharmacotherapy of chronic heart failure with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF) remains challenging. We aimed to assess whether combined neuro-humoral modulation (NHM) (renin−angiotensin system inhibitors, betablockers, mineralocorticoid receptor antagonists) was differentially associated with outcome according to phenotype and age groups. Between 1999 and 2018 we recruited in a nationwide cardiology registry 4707 patients (HFmrEF n = 2298, HFpEF n = 2409) from three age groups: <65, 65−79 and 80+ years old. We analyzed clinical characteristics and 1 year all-cause mortality/cardiovascular hospitalization according to none/single, any double, or triple NHM. Prescription rates of no/single and triple NHM were 25.1% and 26.7% for HFmrEF; 36.5% and 17.9% for HFpEF patients, respectively. Older age was associated with higher prescription of no/single NHM in HFmrEF (ptrend = 0.001); the reverse was observed among HFpEF (ptrend = 0.005). Triple NHM increased over time in both phenotypes (all p for trend < 0.0001). Compared to no/single NHM, triple, but not double, NHM was associated with better outcomes in both HFmrEF (HR 0.700, 95%CI 0.505−0.969, p = 0.032) and HFpEF (HR 0.700, 95%CI 0.499−0.983, p = 0.039), with no interaction between NHM treatment and age groups (p = 0.58, p = 0.80, respectively). In a cardiology setting, among HF outpatients with EF > 40%, triple NHM treatment increased over time and was associated with better patient outcomes.

The PONTE (PDTA FOR INTEGRATED FOLLOW-UP TERRITORY HOSPITAL OF THE PATIENT WITH CARDIAC HEART FAILURE) (BRIDGE) Heart Failure project: increased adherence to guideline-recommended therapies through web-based shared clinical database.

The aim of this study was to evaluate the effects on the adherence of drug prescription to the guideline recommendations of a chronic care model based on the close interaction between hospital and local healthcare district cardiologists through a shared web-based database. From 2018 to 2021, patients hospitalized for an episode of acute decompensated heart failure (HF) (de novo or worsening) in cardiology wards from the healthcare district of Bari, Italy, were enrolled. The follow-up programme was based on a first visit after discharge within 1 month; patients were therefore addressed to the local health district cardiologist outpatient clinics when not requiring further invasive investigations and haemodynamically stable and followed-up with at least one visit every 6 months. In order to share in-hospital patients' data with outpatient clinics, at discharge, they were entered in a web-based database accessible for all cardiologists and centres participating in the Ponte Project. The group of patients affected by HF with reduced ejection fraction (HFrEF) were considered for the analyses. Drug prescription rates at 1-year follow-up were analysed as endpoint, as well as the re-admission for HF worsening. Out of 1200 HF patients enrolled in the project until December 2021, 56% were affected by HFrEF. At 1-year follow-up, 91% of patients were assuming beta-blockers, 86% mineralocorticoid receptor antagonists, 98% angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists/neprilysin angiotensin receptor antagonists, and 13% ARNI. Compared to patients enrolled before 2020, ARNI prescription increased in 2021 (60% vs. 13%, respectively, P < 0.001). In 30% of patients, ARNI were prescribed before hospital discharge. Furthermore, in 10% of the population (most diabetics), sodium-glucose cotransporter 2 inhibitors were also prescribed. The implementation of the PONTE project was associated with an improved adherence to guidelines recommendations.

Incidence of cardiovascular events in patients with chronic myeloid leukaemia treated with tyrosine kinase inhibitors.

BACKGROUND: The introduction of imatinib and tyrosine kinase inhibitors as therapeutic strategy for Philadelphia chromosome-positive chronic myeloid leukaemia (CML) has represented an important step forward for treatment of this disease. The aim of this study was therefore to evaluate the incidence of cardiovascular adverse events (CVEs) in patients affected by CML treated with TKI in an observational prospective study. METHODS: All consecutive patients affected by CML and treated with TKI in our Institution were enrolled in the study from February 2005 to September 2018 with a clinical, laboratory and instrumental follow-up. RESULTS: Sixty-one consecutive patients were enrolled, 29 with imatinib, 15 with nilotinib, 11 with dasatinib, 3 with bosutinib and 3 with ponatinib. Neither patients in therapy with bosutinib nor with nilotinib had CVE during follow-up. Incidence rates per person/year were 0 for bosutinib and nilotinib, 0.15 for dasatinib, 0.19 for imatinib and 1.69 for ponatinib (Log Rank p < 0.05); differences in terms of incidence of adverse outcomes remained significant also after multivariate correction. CONCLUSIONS: In patients with CML treated with TKIs, therapy with ponatinib was associated with a higher risk of CVE than other TKIs. The lowest incidence of CVE was associated with bosutinib and nilotinib.

Meta-analysis study on direct oral anticoagulants vs warfarin therapy in atrial fibrillation and PCI: Dual or triple approach?

BACKGROUND: Dual antiplatelet therapy and anticoagulants may be required in the case of coexistence of coronary artery disease and atrial fibrillation (AF) undergoing (PCI), with associated increased bleeding rates. The introduction of direct oral anticoagulants (DOACs), however, significantly reduced the incidence of bleeding complications in this clinical setting of patients. We therefore sought to assess whether the recent publication of the AUGUSTUS and ENTRUST-AF PCI studies significantly impacted current evidence on the use of DOACs in AF patients treated with PCI. METHODS: We performed a meta-analysis of randomized controlled studies enrolling patients with nonvalvular AF undergoing PCI. We assessed pooled estimates of risk ratios (RRs) and 95%CIs for any bleeding (AB), cardiovascular events (CVE), and death at follow-up: 12,542 patients have been included in the analysis. We particularly analyzed data comparing dual anti-thrombotic therapy (DOAC plus single anti-platelet therapy) with triple (DOAC plus dual anti-platelet therapy). RESULTS: When compared with patients receiving standard triple therapy with warfarin, patients receiving DOACs had a significantly lower risk of AB (RR 0.65; 95% CI, 0.61-0.70, p < 0.00001) and of MB (RR 0.63; 95% CI, 0.53-0.73, p < 0.00001). The risk of cardiovascular events and mortality were comparable between DOAC and VKA groups (RR 1.05, 95% CI 0.93-1.18, RR 1.14, 95% CI 0.94-1.37, respectively, p n.s.). Similar results were observed comparing triple therapy vs dual therapy. CONCLUSIONS: DOACs are safer than and as effective as warfarin when used in patients with AF undergoing PCI; dual therapy with DOACs is comparable to triple therapy in terms of safety and efficacy.

Lower Major Bleeding Rates with Direct Oral Anticoagulants in Catheter Ablation of Atrial Fibrillation: an Updated Meta-analysis of Randomized Controlled Studies.

INTRODUCTION: Catheter ablation (CA) of atrial fibrillation (AF) is an important rhythm control strategy for patients with drug-refractory AF. We aimed to perform an updated meta-analysis of direct oral anticoagulants (DOACs) vs vitamin K antagonists (VKAs) as uninterrupted anticoagulation in patients undergoing AF ablation to assess safety and efficacy of DOAC, after the publication of recent data on edoxaban in CA of AF. METHODS: We performed a meta-analysis of RCTs enrolling patients undergoing AF ablation. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% CIs for thromboembolic events, major bleeding (MB), and non-major bleeding (NMB). RESULTS: A total of 2118 patients have been included in the analysis. Compared with patients receiving VKA, patients receiving DOACs had a lower, although non-significant, risk of thromboembolic events (RR, 0.40; 95% CI, 0.09-1.76; P = 0.23). MB rates in patients treated with DOACs were statistically significantly lower than VKA (RR, 0.61; 95% CI, 0.39-0.93, P = 0.02). The incidence of NMB was not significantly different (RR, 0.98; 95% CI, 0.83-1.57, p n.s.). CONCLUSIONS: In a meta-analysis of RCTs, an uninterrupted DOACs strategy for CA of AF appears to be superior to uninterrupted VKA in terms of safety; a non-significant trend favoring DOACs in terms of efficacy is also evident.

Early diagnosis, clinical management, and follow-up of cardiovascular events with ponatinib.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by neoplastic transformation of pluripotent cells due to a typical cytogenetic and molecular mutation known as Philadelphia (Ph) chromosome. In 2001, the introduction of the tyrosine kinasis inhibitor (TKI) imatinib as a therapeutic strategy for CML with PH chromosome mutation represented an important step towards treatment of these patients, and nowadays, this drug represents the gold therapeutic standard in this clinical setting. A second generation of TKIs (dasatinib, nilotinib, and bosutinib) showed an effective action in all patients with mutations resistant to imatinib. Ponatinib is a third-generation TKI and is the only inhibitor with activity against T3151 mutation. The impact of ponatinib on cardiovascular events was first evaluated in the PACE trial. We therefore report and discuss most relevant evidence currently available on cardiovascular events associated with the use of ponatinib. Though many exams can be used for diagnosis and follow-up of this kind of cardiotoxicity, echocardiography seems to have a pivotal role thanks to its feasibility, availability, and low cost.

Direct oral anticoagulants more effective than low-molecular-weight heparin for venous thrombo-embolism in cancer: an updated meta-analysis of randomized trials.

In the recent past, low-molecular-weight heparin (LMWH) was the first choice in the treatment of cancer related venous thrombo-embolism (VTE). Evidence supporting the preferential use of direct anticoagulants (DOACs) in patients with cancer, instead, is less robust so far. We therefore aimed to assess in an updated meta-analysis of randomized controlled trials whether the use of DOACs may be associated with a more favorable profile when compared to LMWH. We performed a meta-analysis of RCTs enrolling patients with VTE and cancer. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% CIs for recurrence of VTE, major bleeding, and mortality comparing subjects treated with DOACs with those with LMWH. After study selection, three RCTs (HOKUSAI-Cancer, SELECT-D and ADAM-VTE) were included for the analysis with an overall population of 1739 patients. DOACs patients had a lower incidence of 6-month recurrent VTE when compared to LMWHs (RR 0.56, 95% CI 0.40-0.79; p < 0.001). Incidence of major bleeding was not significantly different between DOACs and LMWH treated patients (RR 1.56, 95% CI 0.95-2.47, p = n.s.), and mortality rates were comparable (RR 1.03, 95% CI 0.91-2.47, p = n.s.). In a meta-analysis of RCTs therapy with DOACs was superior to LMWH in terms of efficacy and lower recurrence of VTE with a comparable safety profile in terms of bleeding events and complications.

[PEGASUS or COMPASS? A guide for a wise clinical choice.] / PEGASUS o COMPASS? Una guida per una scelta clinica oculata.

The recent publication of the PEGASUS and COMPASS studies could have a great influence on the clinical management of patients with stable ischemic heart disease. In the presence of possible eligibility for both approaches, a practical tool based on inclusion/exclusion criteria of the two studies could be useful for clinical decision of ideal treatment for suitable patients. We therefore report a simple nomogram helpful in identifying the treatment indicated on the base of patient's characteristics.

Budget impact analysis of PCSK9 inhibitors costs from a community payers' perspective in Apulia, Italy.

Introduction: Despite established clinical efficacy of PCSK9 inhibitors (PCSK9i) in reducing cardiovascular events, their cost still represents a big matter of debate. We therefore sought to estimate possible impact of PCSK9i therapy from a community taxpayers' perspective with a budget impact analysis based on data coming from two randomised trials (FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab)). Methods: The analysis focused on Apulia region, South-Eastern Italy (4 million inhabitants). Costs per cardiovascular event saved were calculated from randomised trials data and annually indexed per Apulia's inhabitants. Results: On the base of actual cost in Apulia, individual costs per saved adverse event ranged from €0.12 to €0.78, with just €1 annually spent per Apulia's inhabitant, 2-8.3 events could be avoided thanks to the use of PCSK9i.When considering high-risk subgroups (baseline cholesterol levels >100 mg/dL, multivessel coronary disease), the annual cost per Apulia's inhabitant for one death avoided was more than halved to €0.19 and the cost for a saved major adverse cardiovascular event was €0.07. With €1 annually spent per Apulia's inhabitant, 10.9-15 major adverse cardiovascular events and 5.3 deaths could be saved. Conclusions: When considered from a large taxpayers' community perspective, relevant costs per cardiovascular event saved with PCSK9i may turn into very small individual costs per year. The selection of high-risk subgroups may further reduce individual costs.

Malignancies and outcome in Takotsubo syndrome: a meta-analysis study on cancer and stress cardiomyopathy.

Takotsubo syndrome (TTS) can be induced by a large variety of physical/emotional triggers; several cases, however, are related to either an overt or occult malignancy, as shown in retrospective studies and case reports. The aim of this study was therefore to evaluate the clinical outcome of patients with TTS and cancer in a meta-analysis study. In June 2018, a Pubmed systematic research was conducted for studies assessing outcome in patients with TTS and cancer. We assessed Mantel-Haenszel pooled estimates of risk ratios (RRs) and 95% confidence intervals (CIs) for adverse events at follow-up. After paper retrieval, four studies were included in the meta-analysis, with a total of 123,563 patients. The prevalence of current or previous malignancy among patients admitted with TTS was 6.7% (8258 patients). When compared to control patients, patients with cancer showed an increased risk of clinical events (RR 3.24, 95% CI 3.04-3.45, p < 0.01). The risk of in-hospital events was significantly higher in the cancer group (RR 2.08 95% CI, 1.50-2.87, p < 0.01) and was mainly due to higher need for respiratory support (RR 1.67, 95% CI, 1.58-1.77, p < 0.01). The risk of adverse events at follow-up was also higher in the cancer group (RR 3.30, 95% CI 3.09-3.51, p < 0.01). Cancer, either history or active, is associated with an increased risk of adverse events in TTS.

Fenofibrate and Dyslipidemia: Still a Place in Therapy?

Dyslipidemia is one of the major cardiovascular risk factors, but beyond statin treatment-which represents the cornerstone of therapy-a relevant practical uncertainty regards the use of fibrate derivatives. In the lack of successful results from the main cardiovascular trials, guidelines recommend the use of peroxisome proliferator-activated receptor agonists in selected cases, i.e. patients with true atherogenic dyslipidemia. However, recent observations indicate that fenofibrate treatment may provide a reliable complementary support against residual cardiovascular risk. We therefore summarize current evidence on fenofibrate, seeking to provide an updated interpretation of recent studies in the field.