May 2019 at a Glance: Epidemiology, Drug Effects On Biomarkers, Adverse Events With LVAD

Treatment of cardiomyopathies is continuously evolving.1, 2 All the aspects of heart failure (HF) diagnosis and treatment in different cardiomyopathies are covered in a position statement in this issue of the Journal.3 Geographical differences may be associated with different patient characteristics and outcomes.4-6 Dewan et al.7 compared the patients enrolled in Asia and in Western countries in two large trials with similar design. The analysis included 13 174 patients with HF and reduced ejection fraction (HFrEF). Compared with patients in Western Europe and America, Asian patients were younger and less likely to be on diuretics and devices. The rate of cardiovascular death/HF hospitalization was higher in Asia (e.g. Taiwan 17.2, China 14.9 per 100 patient-years) than in Western Europe (10.4) and North America (12.8). The adjusted risk of cardiovascular death was higher in many Asian countries than in Western Europe, except Japan, and the risk of HF hospitalization was lower in India and in the Philippines, but significantly higher in China, Japan, and Taiwan.7 Translation of the results of clinical trials to real-world clinical practice is always an issue and this is occurring also with sacubitril/valsartan.8 Wachter et al.9 analysed sacubitril/valsartan prescription patterns, from January 2016 to June 2017, in 26 191 patients in Germany. Two-thirds of patients started treatment with the lowest dose but only 41% of them had dose up-titration in the following 6 months. In contrast, 10% of the patients who started with the highest dose were then down-titrated. The mean daily diuretic dose decreased by 25% after initiation. High compliance and persistence rates were observed across different doses. Prior dose of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) had only minor impact on the first angiotensin receptor–neprilysin inhibitor dose, compliance and persistence.9 In a study conducted in 73 patients with chronic HFrEF, switching from ACEI or ARB to sacubitril/valsartan improved symptoms and echocardiographic parameters, and caused a dose-dependent decrease in soluble neprilysin (NEP) activity.10 NEP inhibition was associated with an increase in its substrates such as atrial natriuretic peptide (ANP), substance P, and glucagon-like peptide 1. Cardiac troponin and soluble ST2 levels, biomarkers not directly related to NEP metabolism, also decreased. ANP increased by approximately four-fold but there was no change in plasma brain natriuretic peptide (BNP) and plasma BNP activity, and only a mild decrease in N-terminal proBNP (NT-proBNP) concentrations. These data confirm a pleiotropic favourable effect of sacubitril/valsartan11 and suggest that ANP, rather than BNP, changes play a major role amongst natriuretic peptides.10 Wessler et al.12 related the short-term placebo-corrected drug or device effect on BNP or NT-proBNP plasma levels and the longer-term effect on clinical outcomes in 19 trials. No correlation was observed between therapy-induced placebo-corrected changes in BNP or NT-proBNP levels and the effect on all-cause mortality or on mortality or HF hospitalizations. Thus, short-term intervention-induced changes in BNP/NT-proBNP levels are not valid surrogates of treatment effects on mortality or morbidity in HFrEF patients trials.12 Spot urinary sodium measurements can predict the response to diuretic therapy.13-15 Biegus et al.14 related spot urinary sodium measurements during the first 48 h of acute HF treatment with indices of decongestion, renal function, and prognosis. Overall, spot urinary sodium increased from baseline in the sample taken after 6 h and returned to baseline thereafter. Patients with a decrease or no change from baseline of urinary sodium in the 6 and 48 h samples had a lower weight loss during hospitalization, a poorer diuretic response, a significant increase in the urinary levels of tubular damage biomarkers and a higher all-cause mortality at 1 year. Grodin et al.16 calculated plasma volume status in 3414 patients with HF and preserved ejection fraction (HFpEF) enrolled in the Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist Trial (TOPCAT). Overall, 9% of patients had an increased plasma volume status and this was associated with poorer outcomes with an approximately 11%, 14%, and 12% higher risk for the primary composite endpoint, all-cause death, and HF hospitalization for each 5% increase in plasma volume status, respectively. The association with HF hospitalizations remained significant also after multivariable adjustment for natriuretic peptides. The clinical features, predictors, and long-term prognosis of pacing-induced cardiomyopathy were assessed in a retrospective analysis of 618 pacemaker patients who had initially a normal left ventricular (LV) ejection fraction and no history of HF.17 Pacing-induced cardiomyopathy occurred in 87 patients (14.1%), with a decrease in ejection fraction from 60.5% to 40.1% during a median follow-up of 4.7 years. Baseline left bundle branch block, wider paced QRS duration and higher ventricular pacing percentage were independent predictors of pacing-induced cardiomyopathy. These patients had a higher risk of all-cause death or HF admission, compared with the others.17 Haemocompatibility-related adverse events (HRAEs), generally defined as non-surgical bleeding, thromboembolic events, pump thrombosis, or neurological events are among the most important complications in patients with LV assist device (LVAD).18, 19 In this study, 51 of 83 patients (61%) had optimized haemodynamics at rest and during exercise with low ventricular filling pressure and cardiac index > 2.2 L/min/m2 following LVAD speed adjustment. The 1-year survival free of any HRAE was of 75% in these patients, vs. 44% of those with non-optimized haemodynamics. Thus, optimal haemodynamics with LVAD predicts also freedom from HRAEs.20