Guideline-Directed Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Incident Cancer.

BACKGROUND: It has been postulated that cancer hampers the delivery of guideline-directed medical therapy (GDMT) for heart failure (HF). However, few data are available in this regard. METHODS: We performed a retrospective analysis from the HF Outpatient Clinic of the IRCCS Ospedale Policlinico San Martino in Genova, Italy. All HF patients evaluated between 2010 and 2019, with a left ventricular ejection fraction <50% and at least two visits ≥3 months apart with complete information about GDMT were included in the study. We assessed the prescription of GDMT-in particular, beta-blockers (BB), renin-angiotensin system inhibitors (RASi), and mineralocorticoid antagonists (MRA)-at the time of the last HF evaluation and compared it between patients with and without incidental cancer. For those with incidental cancer, we also evaluated modifications of GDMT comparing the HF evaluations before and after cancer diagnosis. RESULTS: Of 464 HF patients, 39 (8%) had incidental cancer. There were no statistical differences in GDMT between patients with and without incidental cancer at last evaluation. In the year following cancer diagnosis, of 33 patients with incidental cancer on BB, none stopped therapy, but two had a down-titration to a dosage <50%; of 27 patients on RASi, two patients stopped therapy and three had a down-titration to a dosage <50%; of 19 patients on MRA, four stopped therapy. CONCLUSIONS: Although HF patients with incidental cancer may need to have GDMT down-titrated at the time of cancer diagnosis, this does not appear to significantly hinder the delivery of HF therapies during follow-up.

Frequency, characteristics and risk assessment of pulmonary arterial hypertension with a left heart disease phenotype.

AIM: To obtain real-world evidence about the features and risk stratification of pulmonary arterial hypertension (PAH) with a left heart disease (LHD) phenotype (PAH-LHD). METHODS AND RESULTS: By reviewing the records of consecutive incident PAH patients at 7 tertiary centers from 2001 to 2021, we selected 286 subjects with all parameters needed to determine risk of death at baseline and at first follow-up with COMPERA and COMPERA 2.0 scores. Fifty seven (20%) had PAH-LHD according to the AMBITION definition. Compared with no-LHD ones, they were older, had higher BMI, more cardiovascular comorbidities, higher E/e' ratio and left atrial area, but lower BNP concentrations and better right ventricular function and pulmonary hemodynamics. Survival was comparable between PAH-LHD and no-LHD patients, although the former were less commonly treated with dual PAH therapy. Both COMPERA and COMPERA 2.0 discriminated all-cause mortality risk of PAH-LHD at follow-up, but not at baseline. Risk profile significantly improved during follow-up only when assessed by COMPERA 2.0. At multivariable analysis with low-risk status as reference, intermediate-high and high-risk, but not LHD phenotype, were associated with higher hazard of all-cause mortality. Results were comparable in secondary analyses including patients in the last 10 years and atrial fibrillation and echocardiographic abnormalities as additional criteria for PAH-LHD. CONCLUSIONS: In real life, PAH-LHD patients are frequent, have less severe disease and are less likely treated with PAH drug combinations than no-LHD. The COMPERA 2.0 model may be more appropriate to evaluate their mortality risk during follow-up and how it is modulated by therapy.

Direct Oral Anticoagulants for Cancer-Associated Venous Thromboembolism.

PURPOSE OF REVIEW: To present the randomized controlled trial (RCT) evidence and highlight the areas of uncertainty regarding direct oral anticoagulants (DOAC) for cancer-associated venous thromboembolism (CAT). RECENT FINDINGS: In the last years, four RCTs have shown that rivaroxaban, edoxaban, and apixaban are at least as effective as low-molecular-weight heparin (LMWH) for the treatment of both incidental and symptomatic CAT. On the other hand, these drugs increase the risk of major gastrointestinal bleeding in patients with cancer at this site. Another two RCTs have demonstrated that apixaban and rivaroxaban also prevent CAT in subjects at intermediate-to-high risk commencing chemotherapy, albeit at the price of higher likelihood of bleeding. By contrast, data are limited about the use DOAC in individuals with intracranial tumors or concomitant thrombocytopenia. It is also possible that some anticancer agents heighten the effects of DOAC via pharmacokinetic interactions, up to making their effectiveness-safety profile unfavorable. Leveraging the results of the aforementioned RCTS, current guidelines recommend DOAC as the anticoagulants of choice for CAT treatment and, in selected cases, prevention. However, the benefit of DOAC is less defined in specific patient subgroups, in which the choice of DOAC over LMWH should be carefully pondered.

Diagnostic yield and predictive value on left ventricular remodelling of genetic testing in dilated cardiomyopathy.

AIMS: We assessed the diagnostic yield of genetic testing and the relationship of left ventricular (LV) reverse remodelling (LVRR) with the presence of DNA pathogenic (P) or likely pathogenic (LP) variants in patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: From 680 outpatients followed at the Heart Failure Outpatient Clinic of our institution, we selected subjects with a diagnosis of DCM as defined by LV ejection fraction (LVEF) ≤40% and LV dilatation not explained by coronary artery disease or other causes. All patients were offered genetic investigation of 42 disease-associated DCM genes with next-generation sequencing. Seventy patients fulfilled the definition of DCM and 66 underwent genetic investigation. We identified 18 P/LP variants in 16 patients, with a diagnostic yield of 24%. The most common variants were truncating TTN variants (n = 7), followed by LMNA (n = 3), cytoskeleton Z-disc (n = 3), ion channel (n = 2), motor sarcomeric (n = 2), and desmosomal (n = 1) genes. After a median follow-up of 53 months (inter-quartile range 20-111), patients without P/LP variants exhibited higher systolic and diastolic blood pressure, lower plasma brain natriuretic peptide levels, and a larger extent of LVRR, as reflected by the increase in LVEF (+14% vs. +1%, P = 0.0008) and decrease in indexed LV end-diastolic diameter (-6.5 vs. -2 mm/m2 , P = 0.03) compared with patients with P/LP variants. CONCLUSIONS: Our results confirm the high diagnostic yield of genetic testing in selected DCM patients and suggest that identification of P/LP variants in DCM portends poorer LVRR in response to guideline-directed medical therapy.

Performance of risk stratification scores and role of comorbidities in older vs younger patients with pulmonary arterial hypertension.

BACKGROUND: Risk scores are important tools for the prognostic stratification of pulmonary arterial hypertension (PAH). Their performance and the additional impact of comorbidities across age groups is unknown. METHODS: Patients with PAH enrolled from 2001 to 2021 were divided in ≥65 years old vs <65 years old patients. Study outcome was 5-year all-cause mortality. French Pulmonary Hypertension Network (FPHN), FPHN noninvasive, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL 2.0) risk scores were calculated and patients categorized at low, intermediate and high risk. Number of comorbidities was calculated. RESULTS: Among 383 patients, 152 (40%) were ≥65 years old. They had more comorbidities (number of comorbidities 2, IQR 1-3, vs 1, IQR 0-2 in <65 years patients). Five-year survival was 63% in ≥65 vs 90% in <65 years. Risk scores correctly discriminated the different classes of risk in the overall cohort and in the older and younger groups. REVEAL 2.0 showed the best accuracy in the total cohort (C-index 0.74, standard error-SE- 0.03) and older (C-index 0.69, SE 0.03) patients, whereas COMPERA 2.0 performed better in younger patients (C-index 0.75, SE 0.08). Number of comorbidities was associated with higher 5-year mortality, and consistently increased the accuracy of risk scores, in younger but not in older patients. CONCLUSIONS: Risk scores have similar accuracy in the prognostic stratification of older vs younger PAH patients. REVEAL 2.0 had the best performance in older patients and COMPERA 2.0 had it in younger patients. Comorbidities increased the accuracy of risk scores only in younger patients.

Left Heart Disease Phenotype in Elderly Patients with Pulmonary Arterial Hypertension: Insights from the Italian PATRIARCA Registry.

Pulmonary arterial hypertension (PAH) in the elderly is often associated with left heart disease (LHD), prompting concerns about the use of pulmonary vasodilators. The PATRIARCA registry enrolled ≥70 year-old PAH or chronic thromboembolic pulmonary hypertension (CTEPH) patients at 11 Italian centers from 1 December 2019 through 15 September 2022. After excluding those with CTEPH, post-capillary PH at the diagnostic right heart catheterization (RHC), and/or incomplete data, 23 (33%) of a total of 69 subjects met the criteria proposed in the AMBITION trial to suspect LHD. Diabetes [9 (39%) vs. 6 (13%), p = 0.01] and chronic kidney disease [14 (61%) vs. 12 (26%), p = 0.003] were more common, and the last RHC pulmonary artery wedge pressure [14 ± 5 vs. 10 ± 3 mmHg, p < 0.001] was higher and pulmonary vascular resistance [5.56 ± 3.31 vs. 8.30 ± 4.80, p = 0.02] was lower in LHD than non-LHD patients. However, PAH therapy was similar, with 13 (57%) and 23 (50%) subjects, respectively, taking two oral drugs. PAH medication patterns remained comparable between LHD and non-LHD patients also when the former [37, 54%] were identified by atrial fibrillation and echocardiographic features of LHD, in addition to the AMBITION criteria. In this real-world snapshot, elderly PAH patients were treated with pulmonary vasodilators, including combinations, despite a remarkable prevalence of a LHD phenotype.

The paradox of pulmonary arterial hypertension in Italy in the COVID-19 era: is risk of disease progression around the corner?

OBJECTIVE: The coronavirus disease 2019 (COVID-19) outbreak has led to significant restrictions on routine medical care. We conducted a multicentre nationwide survey of patients with pulmonary arterial hypertension (PAH) to determine the consequences of governance measures on PAH management and risk of poor outcome in patients with COVID-19. MATERIALS AND METHODS: The present study, which included 25 Italian centres, considered demographic data, the number of in-person visits, 6-min walk and echocardiographic test results, brain natriuretic peptide/N-terminal pro-brain natriuretic peptide test results, World Health Organization functional class assessment, presence of elective and non-elective hospitalisation, need for treatment escalation/initiation, newly diagnosed PAH, incidence of COVID-19 and mortality rates. Data were collected, double-checked and tracked by institutional records between March 1 and May 1, 2020, to coincide with the first peak of COVID-19 and compared with the same time period in 2019. RESULTS: Among 1922 PAH patients, the incidences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 were 1.0% and 0.46%, respectively, with the latter comparable to that in the overall Italian population (0.34%) but associated with 100% mortality. Less systematic activities were converted into more effective remote interfacing between clinicians and PAH patients, resulting in lower rates of hospitalisation (1.2% versus 1.9%) and related death (0.3% versus 0.5%) compared with 2019 (p<0.001). A high level of attention is needed to avoid the potential risk of disease progression related to less aggressive escalation of treatment and the reduction in new PAH diagnoses compared with 2019. CONCLUSION: A cohesive partnership between healthcare providers and regional public health officials is needed to prioritise PAH patients for remote monitoring by dedicated tools.

Mechanical circulatory support in patients with cardiogenic shock not secondary to cardiotomy: a network meta-analysis.

To compare the efficacy and safety of different mechanical circulatory support (MCS) devices in CS. A total of 24 studies (7 randomized controlled trials-RCTs-and 17 non-RCTs) involving 11,117 patients were entered in a Bayesian network meta-analysis. The primary endpoint was 30-day mortality. Secondary endpoints were stroke and bleeding (requiring transfusion and/or intracranial and/or fatal). Compared with no MCS, extra-corporeal membrane oxygenation (ECMO) reduced 30-day mortality when used both alone (OR 0.37, 95% CrI 0.15-0.90) and together with the micro-axial pump Impella (OR 0.13, 95% CrI 0.02-0.80) or intra-aortic balloon pump (IABP) (OR 0.19, 95% CrI 0.05-0.63), although the relevant articles were affected by significant publication bias. Consistent results were obtained in a sensitivity analysis including only studies of CS due to myocardial infarction. After halving the weight of studies with a non-RCT design, only the benefit of ECMO + IABP on 30-day mortality was maintained (OR 0.22, 95% CI 0.057-0.76). The risk of bleeding was increased by TandemHeart (OR 13, 95% CrI 3.50-59), Impella (OR 5, 95% CrI 1.60-18), and IABP (OR 2.2, 95% CrI 1.10-4.4). No significant differences were found across MCS strategies regarding stroke. Although limited by important quality issues, the studies performed so far indicate that ECMO, especially if combined with Impella or IABP, reduces short-term mortality in CS. MCS increases the hazard of bleeding.

Sacubitril/valsartan in real-life European patients with heart failure and reduced ejection fraction: a systematic review and meta-analysis.

AIMS: We systematically reviewed the European real-world evidence (RWE) about sacubitril-valsartan for heart failure with reduced ejection fraction. METHODS AND RESULTS: Twenty-one articles, including 16 952 subjects, were identified until 31 October 2020. Taking as reference the PARADIGM-HF cohort, few baseline characteristics were presented in >80% of these studies, most often with high heterogeneity. In random-effects model meta-analysis, age was higher (mean difference +3.84, 95% CI 1.92-5.76), ischaemic aetiology (OR 0.76, 95% CI 0.64-0.91), hypertension (OR 0.55, 95% CI 0.37-0.82), and diabetes (OR 0.77, 95% CI 0.64-0.92) were less common, and the use of mineralocorticoid receptor antagonists was more frequent (OR 3.54, 95% CI 2.27-5.53) in real-life than in PARADIGM-HF. Other clinical and medical features were presented in 19-76% of the selected publications and suggested more severe heart failure with reduced ejection fraction. Sacubitril-valsartan was titrated to 97/103 mg b.i.d. in 35% (95% CI 23-47) and discontinued in 12.8% (95% CI 7.4-18.3) patients. When reported, the incidence of hyperkalaemia (six studies, no. 1076), all-cause mortality (five studies, no. 684), and any hospitalization (three studies, no. 390) was 12 (95% CI 5-19)/100 person-year, 8 (95% CI 4-12)/100 person-year, and 24 (95% CI 5-42)/100 person-year, respectively. Knowledge contribution, a metric measuring the proportion of RWE provided by each article based on the number of reported variables and the sample size, was 58.8% and 13.6% for the two biggest investigations (12 082 and 2037 patients), and <5% for all others (most with <100 subjects). CONCLUSIONS: Limited-quality RWE indicates that there are important differences between European patients prescribed sacubitril-valsartan and the PARADIGM-HF population, including the frequency of target dose achievement.

Cancer and atrial fibrillation: Epidemiology, mechanisms, and anticoagulation treatment.

Cancer patients are at an increased risk of developing atrial fibrillation (AF) and thrombosis. However, the management of anticoagulation in patients with both diseases may be challenging, and data on these patients are lacking. We summarize the current evidence on the incidence and prevalence of cancer in AF and vice versa and provide some practical considerations on the management of oral anticoagulation in specific clinical situations. Low-molecular weight heparins are not approved for thromboprophylaxis in AF, and management of warfarin can be difficult. The use of direct oral anticoagulants may be particularly attractive for their rapid onset/offset action and lower bleeding risk.

Multiparametric vs. Inferior Vena Cava-Based Estimation of Right Atrial Pressure.

Background: Right atrial pressure (RAP) can be estimated by echocardiography from inferior vena cava diameter and collapsibility (eRAPIVC), tricuspid E/e' ratio ( eRAP E / e ' ), or hepatic vein flow (eRAPHV). The mean of these estimates (eRAPmean) might be more accurate than single assessments. Methods and Results: eRAPIVC, eRAP E / e ' , eRAPHV (categorized in 5, 10, 15, or 20 mmHg), eRAPmean (continuous values) and invasive RAP (iRAP) were obtained in 43 consecutive patients undergoing right heart catheterization [median age 69 (58-75) years, 49% males]. There was a positive correlation between eRAPmean and iRAP (Spearman test r = 0.66, P < 0.001), with Bland-Altman test showing the best agreement for values <10 mmHg. There was also a trend for decreased concordance between eRAPIVC, eRAP E / e ' , eRAPHV, and iRAP across the 5- to 20-mmHg categories, and iRAP was significantly different from eRAP E / e ' and eRAPHV for the 20-mmHg category (Wilcoxon signed-rank test P = 0.02 and P < 0.001, respectively). The areas under the curve in predicting iRAP were nonsignificantly better for eRAPmean than for eRAPIVC at both 5-mmHg [0.64, 95% confidence interval (CI) 0.49-0.80 vs. 0.70, 95% CI 0.53-0.87; Wald test P = 0.41] and 10-mmHg (0.76, 95% CI 0.60-0.92 vs. 0.81, 95% CI 0.67-0.96; P = 0.43) thresholds. Conclusions: Our data suggest that multiparametric eRAPmean does not provide advantage over eRAPIVC, despite being more complex and time-consuming.

Very short vs. long dual antiplatelet therapy after second generation drug-eluting stents in 35 785 patients undergoing percutaneous coronary interventions: a meta-analysis of randomized controlled trials.

AIM: To provide an updated assessment of the efficacy-safety profile of very short (1 or 3 months) dual antiplatelet therapy (DAPT) compared with long (12 months) DAPT in patients undergoing percutaneous coronary interventions (PCIs). METHODS AND RESULTS: Seven randomized controlled trials (RCTs) comparing very short vs. long DAPT in 35 785 patients undergoing PCI were selected. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint trial-defined major bleeding through at least 1 year. Compared with longer duration, very short DAPT yielded comparable rates of MACE [odds ratio (OR) 0.93, 95% confidence interval (CI) 0.84-1.03, P = 0.19], all-cause mortality (OR 0.92, 95% CI 0.80-1.06, P = 0.25), myocardial infarction (OR 1.01, 95% CI 0.88-1.15, P = 0.91), stroke (OR 1.04, 95% CI 0.72-1.50, P = 0.83), stent thrombosis (OR 1.05, 95% CI 0.80-1.37, P = 0.73), target vessel revascularization (OR 0.99, 95% CI 0.82-1.18, P = 0.89), and comparable net clinical benefit (OR 0.92, 95% CI 0.84-1.01, P = 0.08). Very short DAPT was associated with reduced rates of major bleeding (OR 0.61, 95% CI 0.40-0.94, P = 0.03) or any bleeding (OR 0.65, 95% CI 0.47-0.90, P = 0.009). Subgroup analyses showed consistent results for 1 vs. 3 month DAPT and for aspirin vs. P2Y12 inhibitor monotherapy following very short DAPT. CONCLUSIONS: Compared with long DAPT, very short DAPT did not increase the odds of ischaemic complications, while reducing the odds of major or any bleeding by over 30%.

How to Monitor Cardiac Complications of Immune Checkpoint Inhibitor Therapy.

Immune-checkpoint inhibitors (ICIs) represent a successful paradigm in the treatment of cancer. ICIs elicit an immune response directed against cancer cells, by targeting the so-called immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Such response, however, is not entirely tumor-specific and may result in immune-related adverse events (irAEs), involving a number of organs and systems. Cardiovascular (CV) irAEs are rare, although potentially severe. In particular, several cases of ICI-related myocarditis with life-threatening course have been reported: the possibility of fulminant cases, thus, requires a high level of awareness among both oncologists and cardiologists. Aggressive work-up and management of symptomatic patients taking ICIs is fundamental for early recognition and initiation of specific immunosuppressive therapies. Notably, myocarditis occurs within few weeks from ICIs initiation, offering opportunity for a targeted screening. Troponin testing is the cornerstone of this screening, yet uncertainties remain regarding timing and candidates. Moreover, troponins positivity should be carefully interpreted. We herein review the main aspects of ICI-related myocarditis and suggest a practical approach. In particular, we focus on the opportunities that a baseline CV evaluation offers for subsequent management by collecting clinical and instrumental data, essential for the interpretation of troponin results, for differential diagnosis and for the formulation of a diagnostic and therapeutic workup.

[One-year follow-up of Italian patients with atrial fibrillation treated with edoxaban in ETNA-AF Europe]. / Dati di un anno di follow-up dei pazienti italiani con fibrillazione atriale trattati con edoxaban nello studio ETNA-AF Europe.

BACKGROUND: The ongoing prospective, single-arm, observational, phase 4 ETNA-AF Europe study is collecting real-world data about the safety and, secondarily, the effectiveness and therapeutic adherence of newly prescribed edoxaban for non-valvular atrial fibrillation in Europe. METHODS: At the end of enrollment in 2018, 13 980 subjects were included, of whom 3509 were Italian. Of them, 3341 (95.2%) had follow-up data available at 1 year. RESULTS: Their mean age was 75 ± 9.3 years, with 56.9% being ≥75 years old. The CHA2DS2-VASc score was ≥4 in 1380 (41.3%) patients. Overall, 662 patients (19.7%) were judged as "frail" by the investigators. Edoxaban 30 mg/day was given to 1048 (31.4%) subjects, who were older with more comorbidities and a lower estimated creatinine clearance than those prescribed the 60 mg/day dose. Overall, the rates of bleeding and thromboembolic events were low: major bleeding was 1.63%/year, intracranial hemorrhage 0.16%/year, stroke or systemic embolism 0.50%/year and all-cause mortality 3.72%/year. Rates were higher in subjects ≥75 years or with a CHA2DS2-VASc score ≥4 and in frail individuals. Remarkably, there was a trend for no increase in intracranial bleeding with more advanced age. CONCLUSIONS: These findings confirm the favorable safety and effectiveness profile of edoxaban in atrial fibrillation patients in routine clinical care in Italy.