S. А. Boytsov

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.).

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.

Background: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (&gt;40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone–system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. Methods: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), &gt;22.5% to 32.5% (n=3987), &gt;32.5% to 42.5% (n=3143), &gt; 42.5% to 52.5% (n=1427), &gt; 52.5% to 62.5% (n=2166), and &gt;62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. Results: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone–system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78–0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76–0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77–0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81–0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P =0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. Conclusions: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone–system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).

In the frame of Multicenter observational study ECVD-RF (Epidemiology of Cardiovascular Diseases and their Risk Factors in Regions of Russian Federation) by the unique protocol the investigation of representative selections of adult population at the age of 25-64 y.o. of 11 regions RF (n=18305, including males, n=6919 and females n=11386): Volgograd, Vologda, Voronezh, Ivanovo, Kemerovo, Orenburg, Samara, Tomsk, Tyumen, Saint-Petersburg and Northern Osetia-Alania. The prevalence of the following risk factors (RF) of cardiovascular diseases is evaluated: high blood pressure — 33,8%, obesity — 29,7%, high total cholesterol — 57,6%, high glucose level or diabetes — 4,6%, smoking (tobacco consumption) — 25,7%, insufficient (low) level of physical activity — 38,8%, excessive salt consumption — 49,9% and insufficient vegetables and fruits consumption — 41,9%. Gender differences and an increase with the age of the parameters mentioned are described. The absence of a epidemiologic monitoring system at the Federal level leads to an impossibility of clear conclusions on the RF dynamics in Russian population. While comparing the ECVD-RF study with previous epidemiological studies we can just cautiously suppose the existence in 21st age of negative dynamics of one RF (obesity, dyslipidemia) and positive dynamics of the others (smoking).

Aim. To study prevalence of arterial hypertension (AH), mean values of systolic and diastolic blood pressure (SBP, DBP), awareness of patients about their disease, medication consumption (MC) and efficacy of treatment in several regions of Russia. Material and methods. Representative selections were made in 9 regions of Russia: men (n=5563), women (n=9737) of 25–64 y.o., studied in 2012–2013 with the response 80%. Systematic stratified multilevel random selection was formed with localilty criteria (Kisch method). The Questionnaire on the presence of AH included: awareness of the patient about his disease, drug intake. BP measurement was performed on the right arm by automatic tonometer Omron in sitting position after 5 minutes resting. The mean value of two measurements was used. BP defined as SBP ≥140 mmHg, DBP ≥90 mmHg, or if the patient had taken antihypertensive therapy. Efficacy of treatment — the part of patients (in %) who reached target BP. Control group — part of patients (in %) with BP &lt;140/90 mmHg. Statistic data calculation was done with computer-based statistic software — SAS with standardising by age stratification of Europe. Results. Mean SBP and DBP were 130,7±0,1 mmHg and 81,6±0,1 mmHg respectively. Prevalence of AH — 44%, higher in men (p&lt;0,001). Prevalence of AH was higher in rural area citizens in men — 51,8% vs 47,5% (р&lt;0,02) and in women — 42,9% vs 40,2% (р&lt;0,05). Awareness was 67,5% in men, 78,9% in women. Medications were taken by 60,9% of women and 39,5% of men. Effectively treated were 53,5% of women and 41,4% of men. With the age the part of effectively treated decreases (p&lt;0,0005). BP is under control only in 1/3 of women and 14,4% of men. Conclusion. The role of AH as one of the main modifiable risk factors of cardiovascular diseases is proved, however it is depressing that the percent of controlled AH is low. BP control is the main task of outpatient surveillance at every local outpatient department, where now less than a half of those affected are being observed.