Pharmacoutilization and adherence to sacubitril/valsartan in real world: the REAL.IT study in HFrEF.

AIMS: The current European Society of Cardiology (ESC) guidelines provide clear indications for the treatment of acute and chronic heart failure (HF). Nevertheless, there is a constant need for real-world evidence regarding the effectiveness, adherence, and persistence of drug therapy. We investigated the use of sacubitril/valsartan for the treatment of HF with reduced ejection fraction in real-world clinical practice in Italy. METHODS AND RESULTS: An observational, retrospective, non-interventional cohort study based on electronic medical records from nine specialized hospital HF centres in Italy was carried out on patients with prescription of sacubitril/valsartan. Overall, 948 patients had a prescription of sacubitril/valsartan, with 924 characterized over 6 months and followed up for 12 months. Pharmacoutilization data at 1 year of follow-up were available for 225 patients {mean age 69.7 years [standard deviation (SD) = 10.8], 81.8% male}. Of those, 398 (45.2%) reached the target dose of sacubitril/valsartan of 97/103 mg in a mean time of 6.9 (SD = 6.2) weeks. Blood pressure and hypotension in 61 patients (65%) and worsening of chronic kidney disease in 10 patients (10.6%) were the main reasons for not reaching the target dose. Approximatively 50% of patients had a change in sacubitril/valsartan dose during follow-up, and 158 (70.2%) were persistent with the treatment during the last 3 months of follow-up. A sensitivity analysis (persistence during the last 4 months of follow-up) showed persistence for 162 patients (72.0%). Adherence data, available for 387 patients, showed full adherence for 205 (53%). Discontinuation (102/717 patients, 14.2%) was mainly due to hypotension and occurred after a mean time of 34.3 (SD = 28.7) weeks. During follow-up, out of 606 patients with available data, 434 patients (71.6%) had an HF add-on drug or drugs concomitant with sacubitril/valsartan. HF-related hospitalization during follow-up was numerically higher in non-persistent (16/67 patients, 23.9%) vs. patients persistent to sacubitril/valsartan (30/158, 19%) (P = 0.405). CONCLUSIONS: Real-world data on the use of sacubitril/valsartan in clinical practice in Italy show a rapid titration to the target dose, high therapeutic adherence enabling a good level of therapeutic management in line with ESC guidelines for patients with reduced ejection fraction.

Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction: Real-World Experience from Italy (the REAL.IT Study).

Sacubitril/valsartan reduces heart failure (HF)-related hospitalizations and cardiovascular mortality in PARADIGM-HF and has become a foundational treatment for HF with reduced ejection fraction (HFrEF). However, data of its routine real-world use are limited, and evidence from Italian settings is lacking. The REAL.IT study aimed to characterize the demographics, pharmacotherapy, clinical characteristics and outcomes of sacubitril/valsartan-treated Italian patients with HFrEF. Electronic medical records of patients initiating sacubitril/valsartan from October 2016 to June 2019 at nine specialized hospital outpatient HF centers across Italy were reviewed. Overall, 924 adults (mean age 64.5 years, 84.6% male) were included. At baseline, 38.7% had an ischemic HF etiology, 45.9% hypertension, 23.2% atrial fibrillation, 25.4% diabetes mellitus, 26.1% an implantable cardioverter-defibrillator and 31.9% coronary artery bypass grafting. There were no clear patterns of patient selection over time. During follow-up, NYHA class improved in 37.5% of patients after a mean of 5.3 ± 3.8 months; 36.1% and 16.7% of patients were in NYHA class III during characterization and after one year of follow-up, respectively. Left ventricular ejection fraction (LVEF) improved ≥5% in 56.3% of patients at one year; 39.7% had ≥30% reduction of N-terminal pro-B-type natriuretic peptide; 2.2% had hyperkalemia during characterization and 2.6% during follow-up; and 3.8% had hypotension during characterization and 12% during follow-up. A total of 50 (5.8%) of patients had device implantation (ICD/CRT) during follow-up. HF-related hospitalization was recorded in 19.6% of patients during follow-up; 3.8% of patients died, approximately 1.3% from cardiovascular causes. Our real-world data confirm the favorable effectiveness and tolerability of sacubitril/valsartan observed in pivotal randomized controlled trials.

Association between Very Low-Density Lipoprotein Cholesterol (VLDL-C) and Carotid Intima-Media Thickness in Postmenopausal Women Without Overt Cardiovascular Disease and on LDL-C Target Levels.

BACKGROUND: atherosclerotic process inexorably advances in patients reaching low-density lipoprotein cholesterol (LDL-C) targets. An attractive hypothesis is that lipoprotein particles (very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL)), could contribute to residual risk. The present study aims to investigate the relationship between carotid intima-media thickness (IMT) and different lipoprotein subfractions in a cohort of healthy postmenopausal women. METHODS: 75 postmenopausal women, at LDL-C target levels without overt cardiovascular disease, underwent biochemical analyses (including subfraction assay of plasma lipoproteins) and carotid ultrasound examination. RESULTS: a statistically significant correlation between VLDL and carotid IMT (p < 0.001) was found. No significant correlation was found between carotid IMT and LDL-C (p = 0.179), IDL-C (p = 0.815), high-density lipoprotein (HDL) (p = 0.855), and LDL score (p = 0.240). Moreover, IMT is significantly correlated to LDL particle diameter (p = 0.044). After adjusting for age, systolic blood pressure, body mass index, smoking habits, glucose plasma concentration, and Lipoprotein(a) (Lpa) levels, multivariate analysis showed that women in the third tertile of VLDL-C, compared with those in the first tertile, were significantly associated to the highest IMT (p = 0.04). CONCLUSIONS: in this cohort of postmenopausal women, VLDL-C was significantly associated to carotid IMT, independent of main cardiovascular risk factors. These findings pave the way for targeting circulating concentrations of VLDL-C to reduce cardiovascular events in patients with target LDL-C levels.

The Effects of Sacubitril/Valsartan on Clinical, Biochemical and Echocardiographic Parameters in Patients with Heart Failure with Reduced Ejection Fraction: The "Hemodynamic Recovery".

BACKGROUND: Sacubitril/valsartan has been shown to be superior to enalapril in reducing the risks of death and hospitalization for heart failure (HF). However, knowledge of the impact on cardiac performance remains limited. We sought to evaluate the effects of sacubitril/valsartan on clinical, biochemical and echocardiographic parameters in patients with heart failure and reduced ejection fraction (HFrEF). METHODS: Sacubitril/valsartan was administered to 205 HFrEF patients. RESULTS: Among 230 patients (mean age 59 ± 10 years, 46% with ischemic heart disease) 205 (89%) completed the study. After a follow-up of 10.49 (2.93 ± 18.44) months, the percentage of patients in New York Heart Association (NYHA) class III changed from 40% to 17% (p < 0.001). Median N-Type natriuretic peptide (Nt-proBNP) decreased from 1865 ± 2318 to 1514 ± 2205 pg/mL, (p = 0.01). Furosemide dose reduced from 131.3 ± 154.5 to 120 ± 142.5 (p = 0.047). Ejection fraction (from 27± 5.9% to 30 ± 7.7% (p < 0.001) and E/A ratio (from 1.67 ± 1.21 to 1.42 ± 1.12 (p = 0.002)) improved. Moderate to severe mitral regurgitation (from 30.1% to 17.4%; p = 0.002) and tricuspid velocity decreased from 2.8 ± 0.55 m/sec to 2.64 ± 0.59 m/sec (p < 0.014). CONCLUSIONS: Sacubitril/valsartan induce "hemodynamic recovery" and, consistently with reduction in Nt-proBNP concentrations, improve NYHA class despite diuretic dose reduction.

Effects of ivabradine and ranolazine in patients with microvascular angina pectoris.

Patients with microvascular angina (MVA) often have persistence of symptoms despite full classical anti-ischemic therapy. In this study, we assessed the effect of ivabradine and ranolazine in MVA patients. We randomized 46 patients with stable MVA (effort angina, positive exercise stress test [EST], normal coronary angiography, coronary flow reserve <2.5), who had symptoms inadequately controlled by standard anti-ischemic therapy, to ivabradine (5 mg twice daily), ranolazine (375 mg twice daily), or placebo for 4 weeks. The Seattle Angina Questionnaire (SAQ), EuroQoL scale, and EST were assessed at baseline and after treatment. Coronary microvascular dilation in response to adenosine and to cold pressor test and peripheral endothelial function (by flow-mediated dilation) were also assessed. Both drugs improved SAQ items and EuroQoL scale compared with placebo (p <0.01 for all), with ranolazine showing some more significant effects compared with ivabradine, on some SAQ items and EuroQoL scale (p <0.05). Time to 1-mm ST-segment depression and EST duration were improved by ranolazine compared with placebo. No effects on coronary microvascular function and on flow-mediated dilation were observed with drugs or placebo. In conclusion, ranolazine and ivabradine may have a therapeutic role in MVA patients with inadequate control of symptoms in combination with usual anti-ischemic therapy.

[Did household parental smoking attitude change over the last 15 years? A survey among primary school children in the city of Agrigento, Italy]. / È cambiato qualcosa nelle abitudini dei genitori fumatori in ambito domestico negli ultimi 15 anni? Indagine epidemiologica tra gli alunni della città di Agrigento.

BACKGROUND: Exposure of children to passive tobacco smoking in the household setting has been demonstrated to cause respiratory diseases. Early atherosclerosis has also been demonstrated in young people previously exposed to passive tobacco smoking. Functional damage can initiate at the fetal age due to maternal smoking, with a tendency towards over-time progress. To date only scant data are available about indoor parental smoking attitudes and their changes after campaigns against smoke and risk factors in exposed youths. Questionnaires are useful tools in order to search for information on cigarette smoking and parental household lifestyle. In this study, we asked pupils of primary schools for providing information on their relatives' every 5 years throughout the period 1994-2009. METHODS: A multiple-choice answer questionnaire about sharing household parental smoking was administered to all primary school children (mean age 10.5 ± 0.5 years) of the city of Agrigento (Sicily, Italy). RESULTS: A total of 2221 questionnaires were collected from 637 children in 1994, 687 in 1999, 516 in 2004, and 381 in 2009. Important findings show a significant reduction in both smoking parents and exposure to passive tobacco smoking (from 64% in 1994 to 45% in 2009, p<0.00001). In 2009, 22% of mothers and 39% of fathers resulted to be smokers in the household setting yet. CONCLUSIONS: In agreement with the 2011 Italian DOXA survey on the general population, the present study demonstrates a negative trend in the prevalence of household smoker parents (predominantly mothers) and exposure of children to passive tobacco smoking. These results likely reflect such a greater awareness about smoke-related risks in children, and the effectiveness of medical campaigns against cardiovascular risk factors as well.

Differential effects of heart rate reduction by atenolol or ivabradine on peripheral endothelial function in type 2 diabetic patients.

OBJECTIVE: To assess whether reduction of heart rate (HR) has beneficial effects on endothelial function in patients with type 2 diabetes mellitus (T2DM). DESIGN: Randomised, double-blind, placebo-controlled study. SETTING: University hospital. PATIENTS: 66 T2DM patients without overt cardiovascular disease. INTERVENTIONS: Patients were randomised to receive for 4 weeks, in addition to their standard therapy, one of the following treatments: atenolol (25 mg twice daily), ivabradine (5 mg twice daily) or placebo (1 tablet twice daily). MAIN OUTCOME MEASURES: Systemic endothelial function, assessed by flow-mediated dilation (FMD); endothelium-independent vasodilation, assessed by nitrate-mediated dilation (NMD); cardiac autonomic function, assessed by HR variability (HRV). RESULTS: 61 patients completed the study (19, 22 and 20 patients in atenolol, ivabradine and placebo groups, respectively). Compared with baseline, HR was similarly reduced by atenolol (87±13 vs 69±9 bpm) and ivabradine (86±12 to 71±9 bpm), but not by placebo (82±10 vs 81±9 bpm) (p<0.001). FMD improved at follow-up in the atenolol group (4.8±1.7 vs 6.4±1.9%), but not in the ivabradine group (5.2±2.5 vs 4.9±2.2%) and in the placebo group (4.8±1.5 vs 4.7±1.7%) (p<0.01). NMD did not change significantly in any group. HRV parameters did not change in the placebo group; they, instead, consistently increased in the atenolol, whereas a mild increase in SDNNi was only observed in the ivabradine group. A significant correlation was found in the atenolol group between HR and FMD changes (r=-0.48; p=0.04). CONCLUSIONS: Despite a comparable reduction in HR, atenolol, but not ivabradine, improved FMD in T2DM patients suggesting that changes in HR are by themselves unlikely to significantly improve endothelial function.

Cardiopulmonary Exercise Testing in Patients with Chronic Heart Failure: Prognostic Comparison from Peak VO2 and VE/VCO2 Slope.

BACKGROUND: Cardiopulmonary exercise testing with ventilatory expired gas analysis (CPET) has proven to be a valuable tool for assessing patients with chronic heart failure (CHF). The maximal oxygen uptake (peak V02) is used in risk stratification of patients with CHF. The minute ventilation-carbon dioxide production relationship (VE/VCO2 slope) has recently demonstrated prognostic significance in patients with CHF. METHODS: Between January 2006 and December 2007 we performed CPET in 184 pts (146 M, 38 F, mean age 59.8 +/- 12.9 years), with stable CHF (96 coronary artery disease, 88 dilated cardiomyopathy), in NYHA functional class II (n.107) - III (n.77), with left ventricular ejection fraction (LVEF) /= 35.6 and 25% in those with VE/VCO2 slope < 35.6 (log rank chi2: 67.03, p < 0.0001) and 66% in patients with peak VO2 12.2 ml/kg/min (log rank chi2: 50.98, p < 0.0001). One-year cardiac-related hospitalization was 77% in patients with VE/VCO2 slope >/= 32.5 and 23% in those with VE/VCO2 slope < 32.5 (log rank chi2: 133.80, p < 0.0001) and 63% in patients with peak VO2 12.3 ml/kg/min (log rank chi2: 72.86, p < 0.0001). The VE/VCO2 slope was demonstrated with receiver operating characteristic curve analysis to be equivalent to peak VO2 in predicting cardiac-related mortality (0.89 vs. 0.89). Although area under the receiver operating characteristic curve for the VE/VCO2 slope was greater than peak VO2 in predicting cardiac-related hospitalization (0.88 vs 0.82), the difference was no statistically significant (p = 0.13). CONCLUSION: These results add to the present body of knowledge supporting the use of CPET in CHF patients. The VE/VCO2 slope, as an index of ventilatory response to exercise, is an excellent prognostic parameter and improves the risk stratification of CHF patients. It is easier to obtain than parameters of maximal exercise capacity and is of equivalent prognostic importance than peak VO2.

Exercise induced atrio-ventricular (AV) block during nuclear perfusion stress testing: a case report.

BACKGROUND: Exercise causes enhanced sympathetic discharge and results in physiologic tachycardia. However, in some patients with a diseased conduction system resulting from acute ischemia, exercise can precipitate heart block. METHODS AND RESULTS: In this report we describe a 51 years old male patient with transient advanced degree atrioventricular (AV) block developed during recovery from exercise stress testing, resolved after the administration of atropine. Nuclear perfusion imaging demostrated stress-induced ischemia of the inferior-apical segments, and recovery of perfusion in the images obtained at rest. Coronarography showed critical stenosis of the right coronary artery, which was treated by percutaneous coronary intervention (PCI) and drug eluting stent (DES) deployment. CONCLUSION: Nuclear myocardial perfusion imaging provides noninvasive evidence that transient ischemia of the infero-apical segment can result in advanced degree AV block in patient with critical severe right coronary disease.

Safety and feasibility of atropine added in patients with sub-maximal heart rate during exercise myocardial perfusion SPECT.

BACKGROUND: Failure to reach 80% of maximal predicted heart rate (HR) during exercise may render a myocardial perfusion single photon emission computed tomography (SPECT) study non-diagnostic for ischemia detection. We sought to investigate the injection of atropine in patients who fail to achieve 80% of age-predicted HR during exercise performed for myocardial perfusion SPECT (MPS), defining its safety and efficacy to raise HR to adequate levels as well as its effect on MPS interpretation. METHODS AND RESULTS: Between January 2002 and December 2004, we studied 3,150 consecutive patients (2,253 men and 897 women, mean age 55 +/- 6 years) who were referred to a single office-based nuclear cardiology laboratory for MPS using SPECT imaging. One milligram of atropine was administered to patients that were unable to continue because of fatigue before reaching minimal HR, without an ischemic response (group A, n = 397). The scintigraphic results for group A were compared with those of patients who spontaneously achieved target HR (group B, n = 2,753). In group A, mean HR before atropine injection was 119.5 +/- 13.6 beats per minute (bpm), and it increased up to 137.3 +/- 13.5 bpm after drug administration, with an incremental of 17.8 +/- 6.9 bpm (P < 0.0001). The mean percentage of age-related HR achieved in this group was 83.5 +/- 8.1%. In 302 of this patients (76.1%) more than 80% of their aged-related HR (86.9 +/- 5.1%) was attained. No major adverse effects occurred. When groups A and B were compared, baseline and peak HR, rate pressure product, and maximal metabolic equivalents achieved were higher in group B. There were no significant differences in the percentage of total positive perfusion studies between both groups: 210/397 patients (52.9%) in group A and 1,342/2,753 patients (48.7%) in group B (P = 0.39). Ischemia or ischemia plus scar was found in 112/397 patients (28.2%) in group A and in 923/2,753 patients (33.5%) of group B (P = 0.14). CONCLUSION: Atropine added to exercise stress testing in patients who cannot achieve their 80% age-related HR is a safe, well-tolerated, and feasible method for MPS.

[Efficacy and safety of non-invasive positive pressure ventilation therapy in acute pulmonary edema]. / Efficacia e sicurezza della terapia con ventilazione a pressione positiva non invasiva nell'edema polmonare acuto.

BACKGROUND: Non-invasive positive pressure ventilation (NIPPV) is an effective treatment for acute respiratory failure in patients with chronic obstructive pulmonary disease. We assessed the efficacy and safety of this therapy in acute cardiogenic pulmonary edema (ACPE). METHODS: In addition to routine therapy consisting of oxygen, nitrates and diuretics, 60 patients (39 male, 21 female, mean age 72.5 +/- 15.8 years) were started on full mask NIPPV using a Sullivan VPAP II ventilator delivering pressure support 15 cm H2O, PEEP 5 cm H2O, FiO2 100%. Pressure support were titrated to achieve oxygen saturation (SaO2) > 95%. Physiological measurements were obtained in the first 2 h and at 3 h, 4 h, and 10 h. Outcome measures included arterial blood gas (ABG), Borg dyspnea score, vital signs, and need for endotracheal intubation (ETI). RESULTS: Initial mean values on FiO2 100% by non nonrebreather mask: pH 7.11 +/- 0.25, paCO2 67.7 +/- 17.5 mmHg, paO2 71.5 +/- 29.7 mmHg, SaO2 83 +/- 12%, lactate concentrations 4.7 +/- 2.3 mmol/L, Borg score 8.6 +/- 1.3, respiratory rate (RR) 41 +/- 7. At 60 minutes of NIPPV, improvement was statistically significant: pH 7.35 +/- 0.18 (difference 0.24; p < 0.0001), paCO2 43 +/- 13 mmHg (difference 24.7; p < 0.0001), paO2 102 +/- 10 mmHg (difference 30.5; p < 0.0001), SaO2 99 +/- 5% (difference 16; p < 0.0001), lactate concentrations 1.2 +/- 0.8 (difference 3.5; p < 0.0001) Borg score 3.6 +/- 0.9 (difference 5; p < 0.0001), RR 24.6 +/- 5 (difference 17.1; p < 0.0001). NIPPV duration ranged from 40 minutes to 24 hours (median 3 hours, 30 minutes). Fifty-six patients (93.4%) improved allowing cessation of NIPPV. ETI was required in four (6.6%) of 60 patients. There were non complications of NIPPV. CONCLUSION: In this study of acute cardiogenic pulmonary edema, NIPPV is an effective treatment and may help prevent ETI.

Relationship between exercise-induced ST segmental depression and myocardial ischemia assessed by technetium-99m tetrofosmin SPECT imaging in patients with inferior Q wave myocardial infarction.

BACKGROUND: ST segment depression (STD) is a standard electrocardiographic sign of myocardial ischemia. Although STD may represent reciprocal changes in patients with previous myocardial infarction, studies of reciprocal changes during exercise testing are scarce. METHODS: From December 1999 to December 2000, 160 patients (119 males, 41 females, mean age 54 +/- 8 years), undergoing, maximal or symptom-limited exercise treadmill test (Bruce-protocol), myocardial perfusion scintigraphy using technetium-99m tetrofosmin single photon emission computed tomography (SPECT) imaging, within 30 days of an uncomplicated inferior Q wave myocardial infarction. The location of STD at the electrocardiogram (ECG) was defined as anterior (V1-4), high lateral (I, aVL), and lateral (V5-6). Ischemia was defined as reversible perfusion abnormalities. RESULTS: STD occurred in anterior leads in 29 patients (18.1%), in the lateral leads in 41 patients (25.6%), in the high lateral leads in 20 patients (12.5%). In 70 patients (43.8%) no significant STD occurred during the exercise test. ST segment elevation occurred in 28 patients (17.5%) in inferior leads. High lateral STD was associated with inferior ST elevation in 16 patients (80%), whereas only eight patients (19.5%) with lateral STD and nine patients (31%) with anterior STD were associated with inferior ST elevation. Ischemia was detected in 63 of 90 patients (70%) with and in 10 of 70 patients (14.3%) without STD (p < 0.0001). Patients with high lateral STD had a higher prevalence of fixed perfusion defects in the inferior wall (95 vs. 27.8%) and in posterolateral wall (75 vs. 18.9%) compared with other patients (p = 0.003 and 0.002, respectively). Ischemia was more prevalent in patients with lateral STD than without (87.8 vs. 14.3%, p < 0.0001). CONCLUSION: In patients with inferior Q wave, the presence of exercise-induced STD in lateral and anterior leads appears to be a sign of myocardial ischemia, and may require invasive evaluation; on the other hand, the presence of STD in high lateral leads should be recognized as a reciprocal change for ST elevation in the inferior leads, and may not be an indication for invasive evaluation.