Michele Senni

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

Background— Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results— We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74–0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52–0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro–B-type natriuretic peptide and troponin) versus enalapril. Conclusions— Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes

The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimal study designs, or inadequate statistical power. Many novel agents are in various stages of research and development for potential use in patients with HF-PEF. To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials. This paper represents a synthesis of a workshop held in Bergamo, Italy, and it examines new and emerging therapies in the context of specific, targeted HF-PEF phenotypes where positive clinical benefit may be detected in clinical trials. Specific considerations related to patient and endpoint selection for future clinical trials design are also discussed.

Developing Therapies for Heart Failure with Preserved Ejection Fraction: Current State and Future Directions

The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting.

Use of echocardiography in the management of congestive heart failure in the community

OBJECTIVES We evaluated the use and the impact of echocardiography in patients receiving an initial diagnosis of congestive heart failure in Olmsted County, Minnesota, in 1991. BACKGROUND The American College of Cardiology/American Heart Association clinical practice guidelines recommend echocardiography in all patients with suspected congestive heart failure. No data are available on use and impact of echocardiography in management of congestive heart failure in a community. METHODS The medical records linkage system of the Rochester Epidemiology Project was used to identify all 216 patients who satisfied the Framingham criteria for congestive heart failure. Of these, 137 (63%) underwent echocardiography within 3 weeks before or after the episode of congestive heart failure (Echo group), and the other 79 patients constitute the No-Echo group. RESULTS The No-Echo group patients were older (p=0.022), were more likely to be female (p=0.072), had milder symptoms (p=0.001) and were less often hospitalized at diagnosis (p=0.001). Fewer patients in the No-Echo group were treated with angiotensin-converting enzyme inhibitors (p=0.001). Advanced age (> or = 80 years), lower New York Heart Association functional class, absence of a fourth heart sound on examination, absence of cardiomegaly or signs of congestive heart failure on chest radiography and absence of known valve disease were independently related to the decision not to obtain an echocardiogram. Survival after adjustment for age, functional class and gender was lower in the No-Echo group than the Echo group (risk ratio=0.607, p=0.017). CONCLUSIONS The underuse of echocardiography appears to be associated with poorer survival and underuse of angiotensin-converting enzyme inhibitor therapy.

Influence of mitral regurgitation repair on survival in the surgical treatment for ischemic heart failure trial.

Background— Whether mitral valve repair during coronary artery bypass grafting (CABG) improves survival in patients with ischemic mitral regurgitation (MR) remains unknown. Methods and Results— Patients with ejection fraction ⩽35% and coronary artery disease amenable to CABG were randomized at 99 sites worldwide to medical therapy with or without CABG. The decision to treat the mitral valve during CABG was left to the surgeon. The primary end point was mortality. Of 1212 randomized patients, 435 (36%) had none/trace MR, 554 (46%) had mild MR, 181 (15%) had moderate MR, and 39 (3%) had severe MR. In the medical arm, 70 deaths (32%) occurred in patients with none/trace MR, 114 (44%) in those with mild MR, and 58 (50%) in those with moderate to severe MR. In patients with moderate to severe MR, there were 29 deaths (53%) among 55 patients randomized to CABG who did not receive mitral surgery (hazard ratio versus medical therapy, 1.20; 95% confidence interval, 0.77–1.87) and 21 deaths (43%) among 49 patients who received mitral surgery (hazard ratio versus medical therapy, 0.62; 95% confidence interval, 0.35–1.08). After adjustment for baseline prognostic variables, the hazard ratio for CABG with mitral surgery versus CABG alone was 0.41 (95% confidence interval, 0.22–0.77; P=0.006). Conclusion— Although these observational data suggest that adding mitral valve repair to CABG in patients with left ventricular dysfunction and moderate to severe MR may improve survival compared with CABG alone or medical therapy alone, a prospective randomized trial is necessary to confirm the validity of these observations. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00023595.

Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure

The prevalence of patients with concomitant heart failure (HF) and diabetes mellitus (DM) continues to increase with the general aging of the population. In patients with chronic HF, prevalence of DM is 24% compared with 40% in those hospitalized with worsening HF. Patients with concomitant HF and DM have diverse pathophysiologic, metabolic, and neurohormonal abnormalities that potentially contribute to worse outcomes than those without comorbid DM. In addition, although stable HF outpatients with DM show responses that are similar to those of patients without DM undergoing evidence-based therapies, it is unclear whether hospitalized HF patients with DM will respond similarly to novel investigational therapies. These data support the need to re-evaluate the epidemiology, pathophysiology, and therapy of HF patients with concomitant DM. This paper discusses the role of DM in HF patients and underscores the potential need for the development of targeted therapies.

Acute heart failure patient profiles, management and in-hospital outcome: results of the Italian Registry on Heart Failure Outcome.

Registries and surveys improve knowledge of the ‘real world’. This paper aims to describe baseline clinical profiles, management strategies, and the in‐hospital outcome of patients admitted to hospital for an acute heart failure (AHF) episode.

Left ventricular systolic and diastolic function after pericardiectomy in patients with constrictive pericarditis: Doppler echocardiographic findings and correlation with clinical status.

OBJECTIVES The study assessed changes in left ventricular systolic and diastolic function after pericardiectomy in patients with constrictive pericarditis and correlated postoperative Doppler echocardiographic findings with clinical status. BACKGROUND Despite the efficacy of pericardiectomy, some patients with constrictive pericarditis fail to improve postoperatively. Data on serial evaluation of systolic and diastolic function after pericardiectomy and its relation to clinical status are not available. METHODS From 1985 to 1995, a total of 58 patients with constrictive pericarditis underwent pericardiectomy and had at least one follow-up Doppler echocardiographic study with a respirometer: 23 patients had one examination within 3 months postoperatively, 19 had a study within 3 months and another one more than 3 months postoperatively, and 16 had one study more than 3 months postoperatively. RESULTS In the early postoperative period, diastolic function was normal in 17 patients (40.5%), restrictive in 17 (40.5%), and constrictive in 8 (19%). Among 19 patients who had serial Doppler echocardiography, in 2 patients with restrictive physiology and 5 with constrictive physiology the results had become normal, and 1 patient who had had constrictive physiology had restrictive findings. In late follow-up, left ventricular end-diastolic diameter increased compared with preoperative measurement (p = 0.0009). Diastolic filling pattern at late follow-up was normal in 20 patients (57%), restrictive in 12 (34%) and constrictive in 3 (9%). There was a significant relationship between diastolic filling patterns and symptomatic status (chi2 = 20.9, p < 0.0001). Patients with persistent abnormal diastolic filling on Doppler echocardiography had had symptoms for a longer time preoperatively than did patients with normal diastolic physiology (p = 0.0471). CONCLUSIONS Diastolic filling characteristics remain abnormal in a substantial number of patients with constrictive pericarditis after pericardiectomy. These abnormalities may resolve gradually but can persist. Diastolic filling abnormalities after pericardiectomy correlate well with clinical symptoms and tend to occur in patients who have had symptoms longer preoperatively. This finding supports the recommendation that pericardiectomy be performed promptly in symptomatic patients with constrictive pericarditis.

Predicting heart failure outcome from cardiac and comorbid conditions: The 3C-HF score☆

BACKGROUND Prognostic stratification in heart failure (HF) is crucial to guide clinical management and treatment decision-making. Currently available models to predict HF outcome have multiple limitations. We developed a simple risk stratification model, based on routinely available clinical information including comorbidities, the Cardiac and Comorbid Conditions HF (3C-HF) Score, to predict all-cause 1-year mortality in HF patients. METHODS We recruited in a cohort study 6274 consecutive HF patients at 24 Cardiology and Internal Medicine Units in Europe. 2016 subjects formed the derivation cohort and 4258 the validation cohort. We entered information on cardiac and comorbid candidate prognostic predictors in a multivariable model to predict 1-year outcome. RESULTS Median age was 69 years, 35.8% were female, 20.6% had a normal ejection fraction, and 65% had at least one comorbidity. During 5861 person-years follow-up, 12.1% of the patients met the study end-point of all-cause death (n=750) or urgent transplantation (n=9). The variables that contributed to outcome prediction, listed in decreasing discriminating ability, were: New York Heart Association class III-IV, left ventricular ejection fraction <20%, no beta-blocker, no renin-angiotensin system inhibitor, severe valve heart disease, atrial fibrillation, diabetes with micro or macroangiopathy, renal dysfunction, anemia, hypertension and older age. The C statistic for 1-year all-cause mortality was 0.87 for the derivation and 0.82 for the validation cohort. CONCLUSIONS The 3C-HF score, based on easy-to-obtain cardiac and comorbid conditions and applicable to the 1-year time span, represents a simple and valuable tool to improve the prognostic stratification of HF patients in daily practice.

Fibrinogen is an independent marker for thoracic aortic atherosclerosis.

The fibrinogen level is an independent risk factor for coronary events and stroke, but no detailed data are available concerning fibrinogen and atherosclerotic disease of the thoracic aorta. This prospective study using multiplane transesophageal echocardiography examined the relation between atherosclerotic thoracic aortic plaque and fibrinogen level. One-hundred forty-eight patients (65 +/- 11 years) with valvular heart disease underwent multiplane transesophageal echocardiography and coronary angiography. We measured plasma fibrinogen level for each patient and recorded the following cardiovascular risk factors: age, sex, systemic hypertension, history of smoking, hypercholesterolemia, diabetes mellitus, body mass index, and family history of coronary artery disease (CAD). Patients with thoracic aortic plaque had a higher level of plasma fibrinogen (p = 0.0001), were older (p = 0.0001), and had significantly more risk factors: history of smoking (p = 0.009), hypertension (p = 0.008), hypercholesterolemia (p = 0.0001), diabetes mellitus (p = 0.01), and family history of CAD (p = 0.003). Multivariate logistic regression analysis of fibrinogen level and risk factors revealed 4 independent predictors of thoracic aortic plaque: fibrinogen, age, hypercholesterolemia, and history of smoking. Fibrinogen was also an independent predictor of CAD. There was a relation between fibrinogen levels and the severity of aortic atherosclerosis (r = 0.46; p = 0.0001) and the severity of CAD (r = 0.30; p = 0.0001). This prospective study indicates that fibrinogen is an independent marker for thoracic aortic plaque related to the severity of thoracic aortic atherosclerosis and confirms that fibrinogen constitutes an independent marker for CAD related to the severity of angiographically evaluated coronary atherosclerosis.