Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF.

AIMS: Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM-HF. METHODS AND RESULTS: The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1-Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N-terminal pro-brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA ≥8.6 mg/dL) compared with Q1 (<5.4 mg/dL) were younger (62.8 vs. 64.2 years), more often male (88.7% vs. 63.1%), had lower systolic blood pressure (119 vs. 123 mmHg), lower eGFR (57.4 vs. 76.6 mL/min/1.73 m2 ), and greater diuretic use. Higher SUA was associated with a higher risk of the primary outcome (adjusted hazard ratios) Q5 vs. Q1 = 1.28 [95% confidence intervals (1.09-1.50), P = 0.003], cardiovascular death [1.44 (1.11-1.77), P = 0.001], HF hospitalization [1.37 (1.11-1.70), P = 0.004], and all-cause mortality [1.36 (1.13-1.64), P = 0.001]. Compared with enalapril, sacubitril/valsartan reduced SUA by 0.24 (0.17-0.32) mg/dL over 12 months (P < 0.0001). Sacubitril/valsartan improved outcomes, irrespective of SUA concentration. CONCLUSION: Serum uric acid concentration was an independent predictor of worse outcomes after multivariable adjustment in patients with HFrEF. Compared with enalapril, sacubitril/valsartan reduced SUA and improved outcomes irrespective of SUA.

Atherogenic index of plasma is positively associated with the risk of all-cause death in elderly women : A 10-year follow-up.

BACKGROUND: The blood concentrations of total cholesterol and low-density lipoprotein (LDL) do not predict survival in patients older than 60 years. The atherogenic index of plasma (AIP) is a logarithm of the triacylglycerol to high-density lipoprotein (HDL) ratio and a surrogate for the concentration of small dense LDL. It might be a better reflection of the risk of all-cause death in elderly patients. METHODS: We conducted a prospective observational study of patients with arterial hypertension older than 60 years. The concentrations of total cholesterol, LDL, HDL and triacylglycerol were measured at the time of the recruitment and the patients were observed for 10 years. Cox regression analysis was performed to assess the effects of lipoproteins and AIP on survival. RESULTS: A total of 500 patients were recruited and 473 of them (226 men, 247 women) either died or successfully completed the 10-year follow-up and were included in the analysis. The AIP was positively associated, while HDL concentration was negatively associated with the risk of all-cause death adjusted for age, smoking habits, statin use, history of diabetes mellitus, myocardial infarction, stroke and peripheral artery occlusive disease (PAOD) in elderly women but not in men. The LDL, total cholesterol, triacylglycerol and non-HDL concentrations were not associated with the risk of death in both sexes. CONCLUSIONS: The AIP is positively associated with the risk of all-cause death in elderly women with arterial hypertension independent of age, smoking habits, statin therapy and comorbidities.

Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial.

BACKGROUND: The angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) reduced cardiovascular morbidity and mortality compared with enalapril in patients with heart failure (HF) and reduced ejection fraction (EF) in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. We evaluated the influence of EF on clinical outcomes and on the effectiveness of sacubitril/valsartan compared with enalapril. METHODS AND RESULTS: Eight thousand three hundred ninety-nine patients with New York Heart Association class II to IV HF with reduced EF [left ventricular EF (LVEF) ≤40%] were randomized to sacubitril/valsartan 97/103 mg twice daily versus enalapril 10 mg twice daily and followed for a median of 27 months. The primary study end point was cardiovascular death or HF hospitalization. LVEF was assessed at the sites and recorded on case report forms. We related LVEF to study outcomes and assessed the effectiveness of sacubitril/valsartan across the LVEF spectrum. The mean LVEF in PARADIGM-HF, reported by sites, was 29.5 (interquartile range, 25-34). The risk of all outcomes increased with decreasing LVEF. Each 5-point reduction in LVEF was associated with a 9% increased risk of cardiovascular death or HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.05-1.13; P<0.001), a 9% increased risk for CV death (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14), a 9% increased risk in HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14) and a 7% increased risk in all-cause mortality (hazard ratio, 1.07; 95% confidence interval, 1.03-1.12) in adjusted analyses. Sacubitril/valsartan was effective across the LVEF spectrum, with no evidence of heterogeneity, when modeled either in tertiles (P interaction=0.87) or continuously (P interaction=0.95). CONCLUSIONS: In patients with HF and reduced EF enrolled in PARADIGM-HF, LVEF was a significant and independent predictor of all outcomes. Sacubitril/valsartan was effective at reducing cardiovascular death and HF hospitalization throughout the LVEF spectrum. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

[Present and future in the management of venous vascular diseases]. / Súcasnost a budúcnost v manazmente vénových vaskulárnych chorôb.

The prevalence and the incidence of chronic and acute venous vascular disease has been shown to be globally very high, in both industrialized and developing countries. Chronic venous diseases of lower extremities are being an integral part of the third millennium's deadly angiopandemy, at the present time. The rate of the most severe cases with advanced stage of venous failure is approximately twice as high in the population (2.1 %) as has been assumed so far. Among venoactive drugs (VAD), micronized purified flavonoid fraction (MPFF) of diosmin hesperidin remains the agent with the highest degree of recommendation and it also indicated to pharmacotherapeutical support of leg ulcer healing, along with sulodexide and pentoxifylline. Compressive sclerotherapy, liquid or foam, is a safe and effective invasive method to treat telangiectasias, reticular varicose veins and subcutaneous varicose veins. Direct oral anticoagulants (DOAC) represent one of the therapeutic and preventive options of deep venous thrombosis (DVT) and of venous thromboembolism (VTE) with a limitation in patients with malignant conditions and in pregnancy. The most effective is triple simultaneous pharmaco-kinezio-mechano-phlebothromboemboloprophylaxis. Superficial vein thromboses longer than 5 cm are indicated to anticoagulant therapy too.

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.

[Mesenterointestinocolonovascular arterial ischemic disease: guidelines of the angiology section of Slovak Medical Chamber (AS SMC, 2013)]. / Mezentériointestinokolonovaskulárna artériová ischemická choroba Odporúcania Sekcie angiológov Slovenskej lekárskej komory (2013).

Organovascular arterial ischemic diseases (cardiovascular, cerebrovascular, extremitovascular, renovascular, genitovascular, pulmovascular, mesenterovascular, dermovascular, oculovascular, otovascular, stomatovascular etc.) are an important manifestations of systemic atherosclerosis and other arterial diseases of vascular system (arteriolosclerosis/arteriolonecrosis; diabetic macroangiopathy; diabetic microangiopathy; Mönckeberg´s mediosclerosis/mediocalcinosis; arteritis - vasculitis; syndromes of arterial compression; fibromuscular dysplasia; cystic adventitial degeneration; arterial thrombosis; arterial embolism/thromboembolism; traumatic and posttraumatic arteriopathies; physical arteriopathies; chemical and toxic arteriopathies; iatrogenic arterial occlusions; dissection of aorta and of arteries; coiling; kinking; complicated arterial aneurysms; arteriovenous fistula, rare vascular diseases). Key clinical-etiology-anatomy-pathophysiology (CEAP) aspects of the mesenteriovascular arterial ischemic diseases are discussed in this article (project Vessels).

Effect of a plant sterol, fish oil and B vitamin combination on cardiovascular risk factors in hypercholesterolemic children and adolescents: a pilot study.

BACKGROUND: Assessment of cardiovascular disease (CVD) risk factors can predict clinical manifestations of atherosclerosis in adulthood. In this pilot study with hypercholesterolemic children and adolescents, we investigated the effects of a combination of plant sterols, fish oil and B vitamins on the levels of four independent risk factors for CVD; LDL-cholesterol, triacylglycerols, C-reactive protein and homocysteine. METHODS: Twenty five participants (mean age 16 y, BMI 23 kg/m2) received daily for a period of 16 weeks an emulsified preparation comprising plant sterols esters (1300 mg), fish oil (providing 1000 mg eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA)) and vitamins B12 (50 µg), B6 (2.5 mg), folic acid (800 µg) and coenzyme Q10 (3 mg). Atherogenic and inflammatory risk factors, plasma lipophilic vitamins, provitamins and fatty acids were measured at baseline, week 8 and 16. RESULTS: The serum total cholesterol, LDL- cholesterol, VLDL-cholesterol, subfractions LDL-2, IDL-1, IDL-2 and plasma homocysteine levels were significantly reduced at the end of the intervention period (p<0.05). The triacylglycerols levels decreased by 17.6%, but did not reach significance. No significant changes in high sensitivity C-reactive protein, HDL-cholesterol and apolipoprotein A-1 were observed during the study period. After standardisation for LDL cholesterol, there were no significant changes in the levels of plasma γ-tocopherol, ß-carotene and retinol, except for reduction in α-tocopherol levels. The plasma levels of n-3 fatty acids increased significantly with the dietary supplementation (p<0.05). CONCLUSIONS: Daily intake of a combination of plant sterols, fish oil and B vitamins may modulate the lipid profile of hypercholesterolemic children and adolescents. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89549017.

Lipoprotein profile in patients who survive a stroke.

OBJECTIVE: In the subjects, who survived a stroke, an atherogenic lipoprotein profile phenotype B, was identified and a predominance of atherogenic lipoproteins of the lipoprotein families, VLDL and LDL, in the lipoprotein spectrum, was confirmed. The higher total cholesterol, triglycerides, and low HDL concentrations were accompanied by high serum levels of small dense LDL - strong atherogenic subfractions of the LDL family. High LDL2 also contributes to the creation of the atherogenic lipoprotein profile. Conversely, decreased serum concentration of LDL1 suggests, that the LDL1 subfraction does not contribute to the creation of an atherogenic lipoprotein profile of specific individuals, i.e., those who survived a stroke. MATERIALS AND METHODS: A quantitative analysis of serum lipoproteins in a group of stroke patients, and in a group of healthy normolipidemic volunteers, without signs of clinically manifested impairment of the cardiovascular system, was performed. For the analysis of plasma lipoproteins, an innovative electrophoresis method was used, on polyacrylamide gel (PAG) - the Lipoprint LDL system, (Quantimetrix corp., CA, USA). With regard to lipids, total cholesterol and triglycerides in serum were analyzed with an enzymatic CHOD PAP method (Roche Diagnostics, FRG). A new parameter, the score for anti-atherogenic risk (SAAR), was calculated as the ratio between non-atherogenic to atherogenic serum lipoproteins in examined subjects. RESULTS: An atherogenic lipoprotein profile phenotyp B was identified in the individuals who survived a stroke. There were increased concentrations of total cholesterol, triglycerides (p<0.001), and atherogenic lipoproteins: VLDL (p<0.001), total LDL, LDL2 (p<0.0001) and LDL3-7 (p<0.01), in the group of stroke patients, compared to the control group. The LDL1 subfraction, like HDL, was decreased and did not contribute to the formation of the atherogenic lipoprotein spectrum in stroke-surviving individuals. Therefore, it can be assumed that the LDL1 subfraction is not an atherogenic part of the LDL family, which was usually considered to be an atherogenic lipoprotein part of the lipoprotein spectrum. Decreased SAAR values - score of anti-atherogenic risk, was confirmed in the stroke surviving individuals, compared to the controls, with high statistical significance (p<0.0001). CONCLUSIONS: The advantages of this new method include: (i) Identification of an atherogenic and a non-atherogenic lipoprotein profile, in the serum of examined individuals. (ii) Identification of an atherogenic normopidemic lipoprotein profile; phenotype B in subjects who survived a stroke. (iii) Introduction of new risk measure, the score for anti-atherogenic risk (SAAR), to estimate the atherogenic risk of examined individuals. (iv) Declaration of an atherogenic lipoprotein profile is definitive when small dense LDL are present in serum. It is valid for hyperlipidemia and for normolipidemia as well. (v) Selection of optimal therapeutic measures, including removal of atherogenic lipoproteins, as a part of a complex therapeutic approach, and the secondary prevention of a relapsing ischemic cerebral-vascular event.

Atherogenic normolipidemia - a new phenomenon in the lipoprotein profile of clinically healthy subjects.

OBJECTIVE: The identification of an atherogenic and a non-atherogenic lipoprotein profile, athero phenotype B vs. non-athero phenotype A, in a group of healthy normolipidemic subjects reveals a new clinical phenomenon in lipoprotein profiles, an atherogenic normolipidemia. Individuals with atherogenic normolipidemia are at increased risk to develop premature atherothrombosis and experience a sudden cardiovascular event. METHODS: A quantitative analysis of non-atherogenic and atherogenic lipoproteins in plasma in a group of healthy normolipidemic volunteers who had no clinical signs of cardiovascular system impairment was performed. An innovative electrophoresis method on polyacrylamide gel (PAG) (Lipoprint LDL System, USA) was used for the analysis of plasma lipoproteins. With regard to lipids, total cholesterol and triglycerides in plasma were analyzed with an enzymatic method, CHOD PAP (Roche Diagnostics, FRG). Prostacyclin and thromboxane A2 were analyzed with an ELISA analysis (DRG USA). A new parameter, the score for anti-atherogenic risk (SAAR), was calculated as the ratio between non-atherogenic to atherogenic plasma lipoproteins in examined subjects. RESULTS: There was a high concentration of LDL3-7 subfraction (p<0.0001) and a slowly increasing triglyceride concentration (p<0.05) in the atherogenic subgroup. The non-atherogenic subgroup of healthy subjects was characterized by high SAAR scores, as well as a low concentration of LDL3-7 subfractions (p<0.0001). Other statistically significant differences between the atherogenic and non-atherogenic subgroup, including total cholesterol, prostanoid parameters (prostacyklin, thromboxane A2), and lipoproteins values, were not confirmed. CONCLUSIONS: The advantages of this new method include: (i) identification of an atherogenic and a nonatherogenic lipoprotein profile in an individual's plasma (ii) identification of an atherogenic normolipidemic lipoprotein profile in plasma (iii) introduction of a new risk measure, the score for anti-atherogenic risk (SAAR), for an estimation of a patient's atherogenic risk of atherothrombosis development. (iv) the presence of small dense LDL in plasma is decisive for declaration of an atherogenic lipoprotein profile. It is valid for hyperlipidemia and for normolipidemia as well.

Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study.

BACKGROUND: LCZ696 is a first-in-class inhibitor of the angiotensin II receptor and neprilysin. We aimed to establish whether the dual actions of LCZ696 lead to further lowering of blood pressure, compared with the angiotensin-receptor blocker valsartan. METHODS: 1328 patients aged 18-75 years with mild-to-moderate hypertension were randomly assigned (double-blind) to 8 weeks' treatment in one of eight groups: 100 mg (n=156 patients), 200 mg (n=169), or 400 mg (n=172) LCZ696; 80 mg (n=163), 160 mg (n=166), or 320 mg (n=164) valsartan; 200 mg AHU377 (n=165); or placebo (n=173). The primary endpoint was the mean difference across the three single-dose pairwise comparisons of LCZ696 versus valsartan (100 mg vs 80 mg, 200 mg vs 160 mg, and 400 mg vs 320 mg) in mean sitting diastolic blood pressure during the 8-week treatment period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00549770. FINDINGS: 1215 patients completed the 8-week treatment period. The average reduction in mean sitting diastolic blood pressure across the doses of LCZ696 versus the appropriate comparator dose of valsartan showed significantly greater reductions with LCZ696 (mean reduction: -2.17 mm Hg, 95% CI -3.28 to -1.06; p<0.0001). The reduction in mean sitting diastolic blood pressure was significantly different for 200 mg LCZ696 versus 160 mg valsartan (-2.97 mm Hg, 95% CI -4.88 to -1.07, p=0.0023) and for 400 mg LCZ696 versus 320 mg valsartan (-2.70 mm Hg, -4.61 to -0.80, p=0.0055). LCZ696 was well tolerated and no cases of angio-oedema were reported; only three serious adverse events occurred during the 8-week treatment period, of which none was judged to be related to the study drug, and no patients died. INTERPRETATION: Compared with valsartan, dual-acting LCZ696 provides complementary and fully additive reduction of blood pressure, which suggests that the drug holds promise for treatment of hypertension and cardiovascular disease. FUNDING: Novartis.