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1.
N Engl J Med ; 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31475794

RESUMO

BACKGROUND: The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS: We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS: There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).

2.
Heart Fail Rev ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31489515

RESUMO

In recent years, several studies have shown the usefulness and clinical relevance of left ventricular global longitudinal systolic strain (GLS) in different cardiovascular diseases. In line with this, the role of GLS in patients with heart failure with preserved ejection fraction (HFpEF) has achieved great importance in this predominant form of heart failure in the last years. In this regard, GLS has shown to be not only a sensitive parameter to detect subtle myocardial abnormalities but also a parameter of clinical and prognostic relevance in patients with HFpEF. In this review, we analyze the current evidence concerning the clinical relevance of GLS in patients with HFpEF and we discuss the potential usefulness of GLS in this complex and heterogeneous condition for which so far no effective therapy exists.

6.
Eur J Heart Fail ; 21(7): 852-861, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31116485

RESUMO

Functional mitral regurgitation (FMR) is associated with poor outcomes in patients with heart failure (HF). However, it is not clear whether FMR is just a consequence of left ventricular (LV) remodelling or a factor contributing to cardiomyopathy progression. There will be more clarity about this controversy when the effects of FMR correction on outcomes will be shown. FMR correction can be performed surgically or, more often, percutaneously with the MitraClip procedure. MitraClip is the most widely used device with more than 70 000 implants performed to date. Observational studies suggest that MitraClip treatment of FMR is safe and associated with improved symptoms, quality of life and functional status in HF patients. Two recently randomized controlled clinical trials have investigated the impact of MitraClip on the outcomes of HF patients: Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) and Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT). Both trials randomized patients to MitraClip plus guideline-directed medical therapy (GDMT) or GDMT alone. No reduction in the primary endpoint of all-cause mortality or HF hospitalizations was shown in MITRA-FR, whereas a significant reduction in HF hospitalizations (primary endpoint) as well as in mortality alone were shown in COAPT. The aim of this review is to summarize the pathophysiology, prevalence, prognostic role and management of FMR, focusing on the differences between MITRA-FR and COAPT and trying to provide possible explanations for the diverging results. We speculate that the two trials should be interpreted as complementary rather than opposite. Patients with severe FMR (effective regurgitant orifice area > 30 mm2 ) despite maximum tolerated GDMT (including cardiac resynchronization therapy), and without too advanced cardiomyopathy seem to be the best candidates for MitraClip treatment. MITRA-FR and COAPT provide us a long awaited 'proof of concept': FMR may be considered a leading actor in cardiomyopathy progression rather than a mere marker of severity.

7.
Eur J Heart Fail ; 21(8): 998-1007, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31134724

RESUMO

AIMS: To assess tolerability and optimal time point for initiation of sacubitril/valsartan in patients stabilised after acute heart failure (AHF). METHODS AND RESULTS: TRANSITION was a randomised, multicentre, open-label study comparing two treatment initiation modalities of sacubitril/valsartan. Patients aged ≥ 18 years, hospitalised for AHF were stratified according to pre-admission use of renin-angiotensin-aldosterone system inhibitors and randomised (n = 1002) after stabilisation to initiate sacubitril/valsartan either ≥ 12-h pre-discharge or between Days 1-14 post-discharge. Starting dose (as per label) was 24/26 mg or 49/51 mg bid with up- or down-titration based on tolerability. The primary endpoint was the proportion of patients attaining 97/103 mg bid target dose after 10 weeks. Median time of first dose of sacubitril/valsartan from the day of discharge was Day -1 and Day +1 in the pre-discharge group and the post-discharge group, respectively. Comparable proportions of patients in the pre- and post-discharge initiation groups met the primary endpoint [45.4% vs. 50.7%; risk ratio (RR) 0.90; 95% confidence interval (CI) 0.79-1.02]. The proportion of patients who achieved and maintained for ≥ 2 weeks leading to Week 10, either 49/51 or 97/103 mg bid was 62.1% vs. 68.5% (RR 0.91; 95% CI 0.83-0.99); or any dose was 86.0% vs. 89.6% (RR 0.96; 95% CI 0.92-1.01). Discontinuation due to adverse events occurred in 7.3% vs. 4.9% of patients (RR 1.49; 95% CI 0.90-2.46). CONCLUSIONS: Initiation of sacubitril/valsartan in a wide range of heart failure with reduced ejection fraction patients stabilised after an AHF event, either in hospital or shortly after discharge, is feasible with about half of the patients achieving target dose within 10 weeks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02661217.

11.
Artigo em Inglês | MEDLINE | ID: mdl-30649303

RESUMO

Aims: We evaluated the 1-year clinical events, pharmacologic management and quality of life in a contemporary cohort of stable coronary artery disease (CAD) patients managed by cardiologists. Methods and Results: START (STable Coronary Artery Diseases RegisTry) was a prospective, observational, nationwide study that enrolled 5070 stable CAD patients over 3 months in 183 cardiology centers in Italy. At 1 year, 4790 (94.5%) patients had data on vital status. Death occurred in 107 (2.2%) patients and the cause of death was cardiovascular in 41 (38.3%) of cases. Among the 4775 patients with follow-up data on clinical events available, a hospitalization due to cardiovascular and non-cardiovascular causes occurred in 523 (11.0%) and in 231 (4.8%) of cases, respectively. Over 60% of patients reported as "no problems" in all domains (61.4-84.5%) of the EuroQoL quality of life 5D-5L questionnaire. Among the 3239 patients with clinical visit/telephone interview at follow-up, in whom optimal medical therapy (OMT; aspirin or thienopyridine, ß-blocker, and statin) was prescribed at enrollment, 2971 (91.7%) were still receiving OMT at follow-up. At multivariable analysis, only increasing age (OR 0.98; 95% CI 0.97-0.99; p = 0.04) resulted as independent negative predictor of OMT persistence at 1 year from enrolment. Conclusions: In this large, contemporary registry, stable CAD patients managed by cardiologists presented a high rate of clinical events at 1 year. Nevertheless, the persistence to OMT and quality of life appeared reasonable.

12.
Eur J Heart Fail ; 21(2): 208-217, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30632680

RESUMO

AIMS: Exercise-derived parameters, specifically peak exercise oxygen uptake (peak VO2 ) and minute ventilation/carbon dioxide relationship slope (VE/VCO2 slope), have a pivotal prognostic value in heart failure (HF). It is unknown how the prognostic threshold of peak VO2 and VE/VCO2 slope has changed over the last 20 years in parallel with HF prognosis improvement. METHODS AND RESULTS: Data from 6083 HF patients (81% male, age 61 ± 13 years), enrolled in the MECKI score database between 1993 and 2015, were retrospectively analysed. By enrolment year, four groups were generated: group 1 1993-2000 (n = 440), group 2 2001-2005 (n = 1288), group 3 2006-2010 (n = 2368), and group 4 2011-2015 (n = 1987). We compared the 10-year survival of groups and analysed how the overall risk (cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation) changed over time according to peak VO2 and VE/VCO2 slope and to major clinical and therapeutic variables. At 10 years, a progressively higher survival from group 1 to group 3 was observed, with no further improvement afterwards. A 20% risk for peak VO2 15 mL/min/kg (95% confidence interval 16-13), 9 (11-8), 4 (4-2) and 5 (7-4) was observed in group 1, 2, 3, and 4, respectively, while the VE/VCO2 slope value for a 20% risk was 32 (37-29), 47 (51-43), 59 (64-55), and 57 (63-52), respectively. CONCLUSIONS: Heart failure prognosis improved over time up to 2010 in a HF population followed by experienced centres. The peak VO2 and VE/VCO2 slope cut-offs identifying a definite risk progressively decreased and increased over time, respectively. The prognostic threshold of peak VO2 and VE/VCO2 slope must be updated whenever HF prognosis improves.


Assuntos
Previsões , Insuficiência Cardíaca/fisiopatologia , Consumo de Oxigênio/fisiologia , Ventilação Pulmonar/fisiologia , Progressão da Doença , Teste de Esforço , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Testes de Função Respiratória , Estudos Retrospectivos
14.
Int J Cardiol ; 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30420146

RESUMO

Sacubitril/valsartan represents the first of a new class of drugs able to act as a neprilysin inhibitor and as an angiotensin receptor blocker. This double inhibition has the advantage of concomitantly blocking a pro-fibrotic/pro-hypertrophic mechanism (angiotensin receptor blocker component) while stimulating an anti-fibrotic/anti-hypertrophic mechanism (neprilysin inhibitor component). Furthermore, the novel drug has natriuretic and diuretic properties, better preserves renal function, provides better blood pressure control as compared to renin angiotensin system inhibitors, and improves ventricular-arterial coupling. Consequently, sacubitril/valsartan provides greater target organ protection than angiotensin receptor blocker therapy alone, including cardiac, vascular, and renal protection. Up to now, this drug does not have an indication in patients with heart failure with preserved ejection fraction (HFpEF). However, its complex mechanism of action and previous experimental and clinical data seem to suggest its possible success in HFpEF. In this review we highlight and discuss the rationale, clinical insights, and perspectives behind the use of sacubitril/valsartan in HFpEF, specifically referring to its possible efficacy in pathophysiologic mechanisms, such as myocardial hypertrophy, fibrosis, and ischemia, renal dysfunction, impaired ventricular-arterial coupling, which are all tightly related to elevated left ventricular end diastolic pressure, a common hallmark for this multifaceted syndrome.

15.
Artigo em Inglês | MEDLINE | ID: mdl-30452784

RESUMO

The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose. Patients were treated for 2 weeks with either placebo (n = 12) or 4 different doses of fulacimstat (5 mg twice daily, n = 9; 10 mg twice daily, n = 9; 25 mg twice daily, n = 10; 50 mg once daily, n = 9). Fulacimstat was safe and well tolerated at all examined doses. There were no clinically relevant effects on vital signs or potassium levels compared with placebo treatment. Mean plasma concentrations of fulacimstat increased with the administered dose and reached exposures predicted to be therapeutically active. The safety profile and the absence of effects on blood pressure or heart rate in a chronic patient population having similar comorbidities and receiving similar comedication as patients after acute MI support future clinical trials with fulacimstat in patients after acute MI.

16.
G Ital Cardiol (Rome) ; 19(10): 568-590, 2018 Oct.
Artigo em Italiano | MEDLINE | ID: mdl-30281045

RESUMO

Sacubitril/valsartan, the first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is the first medication to demonstrate a mortality benefit in patients with chronic heart failure and reduced ejection fraction (HFrEF) since the early 2000s. Sacubitril/valsartan simultaneously suppresses renin-angiotensin-aldosterone system activation through blockade of angiotensin II type 1 receptors and enhances the activity of vasoactive peptides including natriuretic peptides, through inhibition of neprilysin, the enzyme responsible for their degradation. In the landmark PARADIGM-HF trial, patients with HFrEF treated with sacubitril/valsartan had a 20% reduction in the primary composite endpoint of cardiovascular death or heart failure hospitalization, a 20% lower risk of cardiovascular death, a 21% to 20% lower risk of a first heart failure hospitalization, and a 16% to 20% lower risk of death from any cause, compared with subjects allocated to enalapril (all p<0.001).Following the trial, new international guidelines endorsed sacubitril/valsartan as a class I recommendation for the management of patients with HFrEF who remain symptomatic despite optimal medical management. In Italy, sacubitril/valsartan is reimbursed by the National Health Service since March 2017 within criteria set by the Italian Medicines Agency subject to patient inclusion in a dedicated monitoring registry. Although numerous post-hoc analyses of the original trial suggested that the benefits of this innovative medication may extend across a variety of subgroups, many questions do not yet have an evidence-based answer.In this position paper, we discuss the current role of sacubitril/valsartan in the management of chronic HFrEF, treatment eligibility and the modulating role of patients' characteristics. Moreover, we address concerns elicited by the PARADIGM-HF study and shortcomings of this novel drug, to clarify the place of this new therapy in the context of global care of heart failure in Italy. Our aim is to provide clinical cardiologists with a concise and practical guidance on when and how to use sacubitril/valsartan, to assist clinicians in closing the gap between scientific innovation and real-world experience.

17.
Artigo em Inglês | MEDLINE | ID: mdl-30244510

RESUMO

BACKGROUND: Iatrogenic hemorrhagic pericardial tamponade (IHPT) represents a life-threating condition requiring emergency pericardiocentesis. In this clinical context, reinfusion of pericardial blood can stabilize the patient and sustain hemodynamic conditions. AIMS AND METHODS: We reviewed all cases of IHPT occurred at our hospital over a 10 years span. In all patient autologous blood reinfusion through a femoral vein was performed. RESULTS: In our clinical experience of 30 consecutive patients with hemorrhagic cardiac tamponade, this technique was successful to limit blood transfusions, to prevent further clinical worsening and bridge patients with intractable bleeding, to cardiac surgery. No major adverse reactions were directly related to blood autotransfusion. CONCLUSION: In the complex clinical scenario of acute tamponade occurring during catheter-based cardiac procedures, autotransfusion of pericardial blood through a femoral vein is safe and effective. It can be a useful trick up the sleeve of the interventional cardiologist.

18.
Eur J Heart Fail ; 20(11): 1540-1548, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30225956

RESUMO

BACKGROUND: Mild asymptomatic left ventricular systolic dysfunction (ALVSD) may be associated with incident heart failure (HF). However, this gray zone group needs incremental risk refinement. We hypothesized that diastolic dysfunction (DD) may refine HF and death risk prediction in mild ALVSD. METHODS AND RESULTS: Among 4047 subjects aged ≥55/≤80 years followed by 10 general practitioners in northern Italy, the DAVID-Berg study prospectively enrolled 623 asymptomatic outpatients at increased risk for HF. Baseline evaluation included clinical visit, N-terminal pro B-type natriuretic peptide, and echocardiogram. Based on left ventricular ejection fraction (LVEF) and DD, subjects were classified as: control group (normal LVEF, n = 459, 76%), mild ALVSD (LVEF ≥40%/<53%) without DD (n = 89, 15%) and with DD (n = 54, 9%). Subjects with LVEF <40% or without full echocardiographic data were excluded from the analysis (n = 21). Mean age of the population was 69 ±7 years, 56% were men, mostly hypertensive, mean LVEF was 61%. During a median follow-up of 5.7 years, 88 subjects (15%) experienced HF/death events (59 HF events and 29 deaths). Compared to the control group, mild ALVSD was associated with a higher risk of incident HF/death (hazard ratio 1.80, 95% confidence interval 1.10-2.93, adjusted P = 0.019) according to the Cox proportional hazards model. However, this higher risk was present only in subjects with combined DD (P = 0.005) and not in those without it (P = 0.30). Results were consistent even considering the individual components of the primary outcome. CONCLUSION: In a high-risk population, an echocardiographic exam is normally performed to assess systolic dysfunction. Our data underline the importance of also relying on DD to risk stratify mild ALVSD. Mild ALVSD might be a predictor of adverse events mainly in subjects with combined DD, though further studies are needed to confirm these results.

19.
Int J Cardiol ; 273: 141-146, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30098827

RESUMO

BACKGROUND: The usefulness of ß-blockers in heart failure (HF) patients with permanent atrial fibrillation (AF) has been questioned. METHODS AND RESULTS: We analyzed data from HF patients (958 patients (801 males, 84%, age 67 ±â€¯11 years)) with AF enrolled in the MECKI score database. We evaluated prognosis (composite of cardiovascular death, urgent heart transplant, or left ventricular assist device) of patients receiving ß-blockers (n = 777, 81%) vs. those not treated with ß-blockers (n = 181, 19%). We also analyzed the role ß1-selectivity and the role of daily ß-blocker dose. To account for different HF severity, Kaplan-Meier survival curves were normalized for relevant confounding factors and for treatment strategies. Dose was available in 629 patients. Median follow-up was 1312 (577-2304) days in the entire population, 1203 (614-2420) and 1325 (569-2300) days in patients not receiving and receiving ß-blockers. 224 (23%, 54/1000 events/year), 163 (21%, 79/1000 events/year), and 61 (34%, 49/1000 events/year) events were recorded, respectively. At 10-year patients treated with ß-blockers had a better outcome (HR 0.447, p < 0.01) with no effects as regards ß1selective drugs (53%) vs. ß1-ß2 blockers (47%). Survival improved in parallel with ß-blocker dose increase (HR 0.296, 0.496, 0.490 for the high, medium, and low dose vs. no ß-blockers, p < 0.0001). CONCLUSION: HF patients with AF taking a ß-blocker have a better outcome (with a survival improvement in parallel with daily dose but no differences as regards ß1 selectivity) but this does not mean that ß-blockers improve outcomes in these patients as we cannot control for all the potential confounders associated with ß-blocker use.

20.
Circ Heart Fail ; 11(7): e004962, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29980595

RESUMO

BACKGROUND: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. METHODS AND RESULTS: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), ß-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease. CONCLUSIONS: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

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