[ANMCO/SIC Consensus statement on pulmonary arterial hypertension]. / Documento di consenso ANMCO/SIC sull'ipertensione arteriosa polmonare.

Pulmonary hypertension (PH) is a frequent pathological condition worldwide, mainly secondary to cardiovascular and respiratory diseases, with a poor prognosis. Pulmonary arterial hypertension (PAH) is a rare form that affects the arterial pulmonary vasculature. PH and PAH are characterized by non-specific symptoms and a progressive increase of pulmonary vascular resistance that results in progressive, sometimes irreversible, right ventricular dysfunction. In recent years, a growing medical and social commitment on this disease allowed more accurate diagnosis in shorter times. However, the gap between guidelines and clinical practice remains a challenge for all medical doctors involved in the disease management. Considering the needs to share and describe diagnostic and therapeutic pathways, to measure the results obtained and to address the economical and organizational problems of this disease, all involved figures should collaborate to improve its prognostic impact and health expenses. In this consensus document, the PH experts of the Italian Association of Hospital Cardiologists (ANMCO) together with those of the Italian Society of Cardiology (SIC), address 1) definition, classification and unmet needs of PH and PAH; 2) classification and characteristics of centers involved in the diagnosis and treatment of the disease; 3) proposal of organization of a diagnostic-therapeutic pathway, based on robust and recent scientific evidence.

[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.

Acute pulmonary embolism and cancer: findings from the COPE study.

BACKGROUND: Patients with acute venous thromboembolism associated with cancer have an increased risk of recurrences and bleeding in the long term. RESEARCH QUESTION: To describe the clinical features and short-term course of patients with acute pulmonary embolism (PE) and active cancer, previous cancer or no cancer. STUDY DESIGN AND METHODS: Patients with acute PE included in COPE-prospective, multicentre study of adult patients with acute, symptomatic, objectively diagnosed PE-were classified as having active cancer, previous cancer, or no cancer. RESULTS: Overall, 832 patients had active cancer, 464 with previous cancer and 3660 patients had no cancer at the time of acute PE. The most prevalent primary sites of active cancer were urogenital (23.0%), gastrointestinal (21.0%), and lung (19.8%), with a high prevalence of metastatic disease (57.6%) and ongoing anticancer treatment (16.2%). At discharge, a direct oral anticoagulant was used in 43.1%, 78.8%, and 82.0% of patients with active cancer, previous cancer, and no cancer, respectively. Rates of death in-hospital and at 30 days were higher in patients with active cancer compared to patients with previous cancer and no cancer (7.9% vs. 4.3% vs. 2.2% and 13.8% vs. 5.2% vs. 2.6%, respectively). Rates of major bleeding were 4.8%, 2.6%, and 2.4%, respectively. Among patients with active cancer, lung or metastatic cancer were independent predictors of death; brain, hematological or gastrointestinal cancer had the highest risk of major bleeding. INTERPRETATION: Among patients with acute PE, those with active cancer have high risks for death or major bleeding within 30 days. These risks vary based on primary site of cancer. CLINICAL TRIAL REGISTRATION: clinicaltrial.gov identifier: NCT03631810.

Contemporary anticoagulant treatment strategies in patients with acute pulmonary embolism at different risk for death.

INTRODUCTION: Availability of new treatment strategies for patients with acute pulmonary embolism (PE) have changed clinical practice with potential influence in short-term patients' outcomes. We aimed at assessing contemporary anticoagulation strategies and mortality in patients with acute PE included in the prospective, non-interventional, multicentre, COntemporary management of PE study. MATERIALS AND METHODS: Anticoagulant treatment at admission, during hospital-stay, at discharge and at 30-day are described in the overall population and by clinical severity. RESULTS: Overall, 5158 patients received anticoagulant treatment (99%); during the hospital-stay, 2298 received completely parenteral, 926 completely oral and 1934 parenteral followed by oral anticoagulation (1670 DOACs, 264 VKAs). Comorbidities and PE severity influenced the choice of in-hospital anticoagulation. The use of completely parenteral and completely oral anticoagulation varied based on PE severity. In patients treated with thrombolysis, DOACs were used in 46.4% and 80.1% during the hospital stay and at discharge, respectively. Death at 30 days occurred in 34.6% of patients not receiving anticoagulant treatment and in 1.5, 1.3, 3.4 and 8.1% of patients receiving completely oral, sequential with DOACs, sequential with VKAs and completely parenteral regimens, respectively. Increased mortality in patients receiving completely parenteral anticoagulation persisted after adjustment for PE severity. Completely oral anticoagulation was effective and safe also in patients at intermediate-high risk of death. CONCLUSIONS: Contemporary anticoagulation for acute PE includes parenteral agents in over 90% of patients; DOACs are used in the large majority of PE patients at discharge and their early use seems effective and safe also in selected intermediate-risk patients. TRIAL REGISTRATION NUMBER: NCT03631810.

Focus on the Most Common Paucisymptomatic Vasculopathic Population, from Diagnosis to Secondary Prevention of Complications.

Middle-aged adults can start to be affected by some arterial diseases (ADs), such as abdominal aortic or popliteal artery aneurysms, lower extremity arterial disease, internal carotid, or renal artery or subclavian artery stenosis. These vasculopathies are often asymptomatic or paucisymptomatic before manifesting themselves with dramatic complications. Therefore, early detection of ADs is fundamental to reduce the risk of major adverse cardiovascular and limb events. Furthermore, ADs carry a high correlation with silent coronary artery disease (CAD). This study focuses on the most common ADs, in the attempt to summarize some key points which should selectively drive screening. Since the human and economic possibilities to instrumentally screen wide populations is not evident, deep knowledge of semeiotics and careful anamnesis must play a central role in our daily activity as physicians. The presence of some risk factors for atherosclerosis, or an already known history of CAD, can raise the clinical suspicion of ADs after a careful clinical history and a deep physical examination. The clinical suspicion must then be confirmed by a first-level ultrasound investigation and, if so, adequate treatments can be adopted to prevent dreadful complications.

Focus on the Prevention of Acute Limb Ischemia: Centrality of the General Practitioner from the Point of View of the Internist.

The thrombotic mechanism, being common to peripheral arterial disease (PAD), acute myocardial infarction (AMI), and stroke, is responsible for the highest number of deaths in the western world. However, while much has been done for the prevention, early diagnosis, therapy of AMI and stroke, the same cannot be said for PAD, which is a negative prognostic indicator for cardiovascular death. Acute limb ischemia (ALI) and chronic limb ischemia (CLI) are the most severe manifestations of PAD. They both are defined by the presence of PAD, rest pain, gangrene, or ulceration and we consider ALI if symptoms last less than 2 weeks and CLI if they last more than 2 weeks. The most frequent causes are certainly atherosclerotic and embolic mechanisms and, to a lesser extent, traumatic or surgical mechanisms. From a pathophysiological point of view, atherosclerotic, thromboembolic, inflammatory mechanisms are implicated. ALI is a medical emergency that puts both limb and the patient's life at risk. In patients over age 80 undergoing surgery, mortality remains high reaching approximately 40% as well as amputation approximately 11%. The purpose of this paper is to summarize the scientific evidence on the possibilities of primary and secondary prevention of ALI and to raise awareness among doctors involved in the management of ALI, in particular by describing the central role of the general practitioner.

[Anticoagulation therapy during pulmonary embolism follow-up in clinical practice]. / Gestione della terapia anticoagulante nel follow-up dell'embolia polmonare nella pratica clinica.

Patients with pulmonary embolism are a heterogeneous population and, after the acute phase and the first 3-6 months, the main issue is whether to continue, and hence how long and at what dose, or to stop anticoagulation therapy. In patients with venous thromboembolism (VTE), direct oral anticoagulants (DOACs) are the recommended treatment (class I, level of evidence B in the latest European guidelines), and in most cases, an "extended" or "long-term" low-dose therapy is warranted. This paper aims to provide a practical management tool to the clinician dealing with pulmonary embolism follow-up: from the evidence behind the most used exams (D-dimer, ultrasound Doppler of the lower limbs, imaging tests, recurrence and bleeding risk scores), and the use of DOACs in the extended phase, to six real clinical scenarios with the relative management in the acute phase and at follow-up. Lastly, a practical algorithm is shown to deal with anticoagulation therapy in the follow-up of VTE patients in a simple, schematic, and pragmatic way.

Contemporary Management and Clinical Course of Acute Pulmonary Embolism: The COPE Study.

BACKGROUND: New diagnosis, risk stratification, and treatment strategies became recently available for patients with acute pulmonary embolism (PE) leading to changes in clinical practice and potentially influencing short-term patients' outcomes. RESEARCH QUESTION: The COntemporary management of PE (COPE) study is aimed at assessing the contemporary clinical management and outcomes in patients with acute symptomatic PE. STUDY DESIGN AND METHODS: Prospective, noninterventional, multicenter study. The co-primary study outcomes, in-hospital and 30-day death, were reported overall and by risk categories according to the European Society of Cardiology (ESC) and American Heart Association guidelines. RESULTS: Among 5,213 study patients, PE was confirmed by computed tomography in 96.3%. In-hospital, 289 patients underwent reperfusion (5.5%), 92.1% received parenteral anticoagulants; at discharge, 75.6% received direct oral anticoagulants and 6.7% vitamin K antagonists. In-hospital and 30-day mortalities were 3.4 and 4.8%, respectively. In-hospital death occurred in 20.3% high-risk patients (n = 177), in 4.0% intermediate-risk patients (n = 3,281), and in 0.5% low-risk patients (n = 1,702) according to ESC guidelines. Further stratification in intermediate-high and intermediate-low risk patients did not reach statistical significance, but intermediate-risk patients with sPESI > 0 alone had lower mortality compared to those with one or both among right ventricular dilation at echocardiography or increased troponin. Death or clinical deterioration occurred in 1.5, 5.0, and 9.4% of patients at low, intermediate-low, and intermediate-high risk for death according to ESC guidelines. CONCLUSION: For the majority of patients with PE, contemporary initial management includes risk stratification and treatment with direct oral anticoagulants. In-hospital mortality remains high in intermediate and high-risk patients calling for and informing research focused on its reduction. TRIAL REGISTRATION NUMBER: NCT03631810.

Mean arterial pressure predicts 48 h clinical deterioration in intermediate-high risk patients with acute pulmonary embolism.

AIMS: We assess the prognostic role of mean arterial pressure (MAP) for 48 h clinical deterioration in intermediate-high risk pulmonary embolism (PE) patients after admission. METHODS AND RESULTS: A post hoc analysis of intermediate-high-risk PE and intermediate-low-risk PE patients enrolled in the Italian Pulmonary Embolism Registry (IPER) (Trial registry: ClinicalTrials.gov; No.: NCT01604538) was performed. Clinical deterioration within 48 h was defined as patient worsening from a stable to an unstable haemodynamic condition, need of catecholamine infusion, endotracheal intubation, or cardiopulmonary resuscitation. Of 450 intermediate-high risk PE patients (mean age 71.4 ± 13.8 years, 298 males), 40 (8.8%) experienced clinical deterioration within 48 h from admission. Receiver operating characteristic analysis established the optimal cut-off value for MAP, as a predictor of 48 h clinical deterioration, ≤81.5 mmHg [area under curve (AUC) of 0.77 ± 0.3] with sensitivity, specificity, positive predictive value, and negative predictive value were 77.5, 95.0, 63.2, and 97.7%, respectively. Multivariate Cox regression analysis showed that independent risk factors for 48 h clinical deterioration were age [hazard ratio (HR): 1.26, 95% confidence interval (CI): 1.19-1.28, P < 0.0001], history of heart failure (HR: 1.76, 95% CI: 1.72-1.81, P < 0.0001), simplified Pulmonary Embolism Severity Index (HR: 1.52, 95% CI: 1.49-1.58, P = 0.001), systemic thrombolysis (HR: 0.54, 95% CI: 0.30-0.65, P < 0.0001), and a MAP of ≤81.5 mmHg at admission (HR: 3.25, 95% CI: 1.89-5.21, P < 0.0001). The deteriorating group had a significantly higher risk of 30-day mortality (HR: 2.61, 95% CI: 2.54-2.66, P < 0.0001) compared with the non-deteriorating group. CONCLUSION: The mean arterial pressure appears to be a useful, bedside, and non-invasive prognostic tool potentially capable of promptly identifying intermediate-high risk PE patients at higher risk of 48 h clinical deterioration.

[ANMCO Position paper: Cardiovascular disease in women - prevention, diagnosis, treatment and organization of care]. / Position paper ANMCO: Malattie cardiovascolari nella donna ­ prevenzione, diagnosi, terapia e organizzazione delle cure.

Cardiovascular diseases are still the main cause of death among women despite the improvements in treatment and prognosis achieved in the last 30 years of research. The determinant factors and causes have not been completely identified but the role of "gender" is now recognized. It is well known that women tend to develop cardiovascular disease at an older age than men, and have a high probability of manifesting atypical symptoms not often recognized. Other factors may also co-exist in women, which may favor the onset of specific cardiac diseases such as those with a sex-specific etiology (differential effects of estrogens, pregnancy pathologies, etc.) and those with a different gender expression of specific and prevalent risk factors, inflammatory and autoimmune diseases and cancer. Whether the gender differences observed in cardiovascular outcomes are influenced by real biological differences remains a matter of debate.This ANMCO position paper aims at providing the state of the research on this topic, with particular attention to the diagnostic aspects and to care organization.

[Pulmonary hypertension: pre- or post-capillary? The role of provocative tests in the cath lab]. / Ipertensione polmonare pre-capillare o post-capillare? Il ruolo dei test provocativi in sala di emodinamica.

The discrimination between heart failure with preserved ejection fraction (HFpEF) and pulmonary arterial hypertension (PAH) requires a multiparametric approach, eventually culminating in right heart catheterization. Solving this differential diagnosis is crucial in order to properly tailor patient treatment, with relevant clinical implications. However, it is not uncommon to be confronted with patients at intermediate or high risk of having HFpEF whose pulmonary artery wedge pressure (PAWP) falls in a grey zone in between 13 and 15 mmHg. In these patients, a provocative test in the cath lab might be considered, with the aim of unmasking an occult form of HFpEF with non-overt hemodynamic manifestations, or to definitely exclude it.Saline load and physical exercise can be viewed as the most suitable provocative tests seeking to help for the differential diagnosis in this specific patient population. Although normative values for the hemodynamic response to these maneuvers have been proposed, supporting evidence is still preliminary or equivocal. In this paper, we will review the pathophysiological background for the application of provocative tests in the cath lab, as well as methodological and interpretative aspects to discriminate between HFpEF and PAH, highlighting strengths and weaknesses of fluid load and physical exercise.

Contemporary clinical management of acute pulmonary embolism: the COPE study.

BACKGROUND: New management, risk stratification and treatment strategies have become available over the last years for patients with acute pulmonary embolism (PE), potentially leading to changes in clinical practice and improvement of patients' outcome. METHODS: The COntemporary management of Pulmonary Embolism (COPE) is a prospective, non-interventional, multicentre study in patients with acute PE evaluated at internal medicine, cardiology and emergency departments in Italy. The aim of the COPE study is to assess contemporary management strategies in patients with acute, symptomatic, objectively confirmed PE concerning diagnosis, risk stratification, hospitalization and treatment and to assess rates and predictors of in-hospital and 30-day mortality. The composite of death (either overall or PE-related) or clinical deterioration at 30 days from the diagnosis of PE, major bleeding occurring in hospital and up to 30 days from the diagnosis of PE and adherence to guidelines of the European Society of Cardiology (ESC) are secondary study outcomes. Participation in controlled trials on the management of acute PE is the only exclusion criteria. Expecting a 10-15%, 3% and 0.5% incidence of death for patients with high, intermediate or low-risk PE, respectively, it is estimated that 400 patients with high, 2100 patients with intermediate and 2500 with low-risk PE should be included in the study. This will allow to have about 100 deaths in study patients and will empower assessment of independent predictors of death. CONCLUSIONS: COPE will provide contemporary data on in-hospital and 30-day mortality of patients with documented PE as well as information on guidelines adherence and its impact on clinical outcomes. TRAIL REGISTRATION: NCT number: NCT03631810.

How lower doses of direct oral anticoagulants are interpreted in clinical practice: a national survey of the Italian Atherosclerosis, Thrombosis and Vascular Biology (ATVB) Study Group.

AIM: To evaluate the current interpretation of the lower doses of direct oral anticoagulants (DOAC) dabigatran, apixaban, edoxaban and rivaroxaban in nonvalvular atrial fibrillation. METHODS: A questionnaire of 14 statements to which the possible answers were fully agree/partially agree/partially disagree/fully disagree or yes/no was prepared within the board of the Italian Atherosclerosis, Thrombosis and Vascular Biology Study Group and forwarded to individual Italian physicians. RESULTS: A total of 620 complete questionnaires were received from nearly all the Italian regions and physicians of various medical specialists, either enabled or not for the prescription of DOAC. A wide agreement was found as regards the pharmacological, as well as clinical consequences of the administration of the lower dose of factor-Xa inhibitors both in patients with and without clinical and/or laboratory criteria requiring dose reduction. Wide agreement was also found as regards the presence of moderate kidney insufficiency in selecting the dose of DOAC. Instead, more debated were issues regarding the proportionality between dabigatran dose and plasma concentration and selection of dabigatran dose, as well as the role of measuring drug plasma concentration and/or determine the anticoagulant activity of factor-Xa inhibitors when used at the lower dose. CONCLUSION: The interpretation of the lower doses of DOAC in current Italian clinical practice appears largely correct and shared. Because of the persistence of some residual uncertainties, essentially regarding dabigatran, however, continuous educational effort still appears warranted.

[HCF-ANMCO/AICPR/GIEC/ITAHFA/SICOA/SICP/SIMG/SIT Cardiological Societies Council Consensus document: Anticoagulant therapy in venous thromboembolism and atrial fibrillation of the patient with cancer. Current knowledge and new evidence]. / Documento di consenso della Consulta delle Società Cardiologiche HCF-ANMCO/AICPR/GIEC/ITAHFA/SICOA/SICP/SIMG/SIT: La terapia anticoagulante nel tromboembolismo venoso e nella fibrillazione atriale del paziente con cancro. Le attuali conoscenze e le nuove evidenze.

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

[ANMCO Position paper: Pulmonary circulation diseases and COVID-19]. / Position paper ANMCO: Malattie del circolo polmonare e COVID-19.

The new coronavirus disease 2019 (COVID-19), which is causing hundreds of thousands of deaths worldwide, is complex and can present with a multi-organ localization. One of its worst complications is an interstitial pneumonia with acute respiratory failure also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which requires non-invasive or invasive ventilation. A severe coagulopathy with poor prognosis is found in 5-10% of cases. SARS-CoV-2 is manifesting as a multi-dimensional disease and, recently, unique co-existing pathophysiological and clinical aspects are being defined: (i) an increased immune and inflammatory response with the activation of a cytokine storm and consequent coagulopathy, which promote both venous thromboembolic events and in situ thrombosis localized in small arterioles and pulmonary alveolar capillaries; (ii) a high intrapulmonary shunt, which often accounts for the severity of respiratory failure, due to reduced hypoxic pulmonary vasoconstriction with pulmonary neo-angiogenetic phenomena. Furthermore, the high incidence of venous thromboembolism in COVID-19 patients admitted to the intensive care unit and the autoptic findings of in situ micro-thrombosis at the pulmonary vascular level, suggest that in this disease coagulopathy, unlike septic disseminated intravascular coagulation, is driven towards a hyper-thrombogenic state, giving rise to a debate (with ongoing studies) about the preventive use of anticoagulant doses of heparin to reduce mortality. The aim of this position paper from the Italian Association of Hospital Cardiologists (ANMCO) is to highlight the main implications that COVID-19 infection has on the pulmonary circulation from a pathophysiological, clinical and management point of view.

[Proposal for a standardized discharge letter after hospital stay for acute pulmonary embolism]. / Proposta di una lettera di dimissione standardizzata dopo ospedalizzazione per embolia polmonare acuta.

Pulmonary embolism represents the third leading cause of cardiovascular mortality in developed countries. It requires, in most cases, hospital treatment and always a structured follow-up program. Therefore, at the time of discharge, the communication and the transfer of information from the specialist to the general practitioner, through the discharge letter, represents a crucial opportunity. The aim is to improve the quality of the transmitted content, including information regarding initial assessment, procedures during hospitalization, residual risks, discharge treatments, therapeutic goals and follow-up plan in accordance with the latest guidelines. The discharge letter after hospitalization for pulmonary embolism must include personalized information, especially regarding the anticoagulant regimen in the specific onset setting. Finally, the follow-up program should be accurately described. A standardized discharge letter template, accompanied by some final notes addressed to the general practitioner and patient, could represent a useful tool to improve the quality and time of transmission of information between health professionals after pulmonary embolism.

[Diagnostic and therapeutic models for the management of acute pulmonary embolism: an issue of local available resources]. / Modelli diagnostici e terapeutici nel trattamento dell'embolia polmonare acuta: una questione di risorse locali.

Acute pulmonary embolism (PE) still represents the third leading cause of cardiovascular mortality in developed countries. In this regard, the last European guidelines offer important suggestions on the management of the disease in daily clinical practice but, at the same time, they do not take into account the feasibility of the recommendations according to the local available resources, including the presence or lack of adequate healthcare facilities (cardiological intensive care unit, cath-lab) or specialists (cardiologist available on a 24 h basis, interventional cardiologist, cardiac surgeon, etc.) all over the day. In the real clinical practice, those recommendations should be adapted to the local available resources. The aim of this document is to provide some suggestions regarding the diagnosis and treatment of acute PE, according to the possible available resources in different local circumstances.