This study investigated whether sacubitril/valsartan or valsartan are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in two experimental models of pre-hypertension induced by continuous light (24 hours/day) exposure or by chronic lactacystin treatment, and how this potential protection interferes with the renin-angiotensin-aldosterone system (RAAS). Nine groups of three-month-old male Wistar rats were treated for six weeks as follows: untreated controls (C), sacubitril/valsartan (ARNI), valsartan (Val), continuous light (24), continuous light plus sacubitril/valsartan (24+ARNI) or valsartan (24+Val), lactacystin (Lact), lactacystin plus sacubitil/valsartan (Lact+ARNI) or plus valsartan (Lact+Val). Both the 24 and Lact groups developed a mild but significant systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, as well as LV systolic and diastolic dysfunction. Yet, no changes in serum renin-angiotensin were observed either in the 24 or Lact groups, though aldosterone was increased in the Lact group compared to the controls. In both models, sacubitril/valsartan and valsartan reduced elevated SBP, LV hypertrophy and fibrosis and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan and valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7 in the 24 and Lact groups and reduced aldosterone in the Lact group. We conclude that both continuous light exposure and lactacystin treatment induced normal-to-low serum renin-angiotensin models of pre-hypertension, whereas aldosterone was increased in lactacystin-induced pre-hypertension. The protection by ARNI or valsartan in the hypertensive heart in either model was related to the Ang II blockade and the protective Ang 1-7, while in lactacystin-induced pre-hypertension this protection seems to be additionally related to the reduced aldosterone level.

• MeSH
• acetylcystein analogy a deriváty   MeSH
• aldosteron MeSH
• aminobutyráty * MeSH
• bifenylové sloučeniny farmakologie   MeSH
• fibróza MeSH
• fixní kombinace léků MeSH
• hypertenze * farmakoterapie   MeSH
• hypertrofie levé komory srdeční MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• prehypertenze * MeSH
• renin-angiotensin systém MeSH
• renin MeSH
• srdeční selhání * MeSH
• tepový objem MeSH
• tetrazoly farmakologie   terapeutické užití   MeSH
• valsartan farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• sakubitril/valsartan,
• MeSH
• aminobutyráty terapeutické užití   MeSH
• diastolické srdeční selhání * farmakoterapie   MeSH
• fixní kombinace léků MeSH
• lidé MeSH
• randomizované kontrolované studie jako téma MeSH
• tetrazoly terapeutické užití   MeSH
• valsartan terapeutické užití   MeSH
• Check Tag
• lidé MeSH

AIMS: Diabetes mellitus is associated with worse outcomes and lower attainment of disease-modifying therapies in patients with heart failure with reduced ejection fraction (HFrEF). This post hoc analysis of TRANSITION compared the patterns of tolerability and uptitration of sacubitril/valsartan in patients with HFrEF stabilized after hospital admission due to acute decompensated HF depending on the presence or absence of diabetes as a co-morbidity. METHODS: TRANSITION, a randomized, open-label study compared sacubitril/valsartan initiation pre-discharge vs. post-discharge (up to14 days) in 991 patients hospitalized for acutely decompensated HFrEF. The impact of diabetes status on tolerability and safety was studied at 10-week and 26-week post-randomization. RESULTS: Among the 991 patients analysed at baseline, 460 (46.4%) had diabetes and exhibited a higher risk profile. At 10 weeks, sacubitril/valsartan target dose (97/103 mg bid) was achieved in a similar proportion of patients in each subgroup, when initiated pre-discharge or post-discharge respectively [diabetes subgroup: 47% (n = 105/226) vs. 50% (n = 115/228); relative risk ratio (RRR), 0.923; P = 0.412; non-diabetes subgroup: 45% (n = 119/267) vs. 51% (n = 133/261); RRR, 0.878; P = 0.155]. The proportions of patients achieving and maintaining either 49/51 mg or 97/103 mg bid [diabetes subgroup: 61.1% (n = 138/226) vs. 67.5% (n = 154/228); RRR, 0.909; P = 0.175; non-diabetes subgroup: 62.9% [n = 168/267] vs 69.3% [n = 181/261]; RRR, 0.906; P = 0.118] or any dose for ≥2 weeks leading to Week 10 [diabetes subgroup: 85% (n = 192/226) vs. 88.2% (n = 201/228); RRR, 0.966; P = 0.356; non-diabetes subgroup: 86.9% (n = 232/267) vs. 90.8% (n = 237/261); RRR, 0.963; P = 0.215] were also similar in each subgroup, when initiated pre-discharge or post-discharge, respectively. At 10 weeks, hypotension and renal dysfunction rates were similar, although hyperkalaemia was higher among patients with diabetes (15.9% vs. 9.5%). The rate of permanent discontinuation due to adverse events was similar in the diabetes and non-diabetes subgroups at 10 weeks, respectively: pre-discharge (7.5% vs. 7.1%) or post-discharge (5.7% vs. 4.2%). Similar patterns of uptitration and tolerability were observed at 26 weeks. Cardiac biomarkers including NT-proBNP (P < 0.005) and hs-TnT (P < 0.005) reduced significantly from baseline levels in both subgroups at Weeks 4 and 10; however, the response was greater among patients without diabetes. Mortality (diabetes vs. non-diabetes subgroups: 3.3% vs 4.0%; P = 0.438) and HF rehospitalization (diabetes vs. non-diabetes subgroups: 36.3% vs. 33.0%; P = 0.295) did not differ between the groups at 26 weeks. CONCLUSIONS: Despite a higher risk profile among patients with diabetes, sacubitril/valsartan initiation either before or shortly after discharge in hospitalized patients with HFrEF resulted in comparable rates of dose up-titration and tolerability as in those without diabetes.

• MeSH
• aminobutyráty terapeutické užití   MeSH
• antagonisté receptorů pro angiotenzin terapeutické užití   MeSH
• bifenylové sloučeniny terapeutické užití   MeSH
• diabetes mellitus * MeSH
• lidé MeSH
• následná péče MeSH
• propuštění pacienta MeSH
• srdeční selhání * MeSH
• tepový objem fyziologie   MeSH
• tetrazoly terapeutické užití   MeSH
• valsartan terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

• Klíčová slova
• cenobamát,
• MeSH
• antikonvulziva farmakologie   terapeutické užití   MeSH
• chlorfenoly farmakologie   terapeutické užití   MeSH
• karbamáty farmakologie   terapeutické užití   MeSH
• lidé MeSH
• randomizované kontrolované studie jako téma MeSH
• refrakterní epilepsie * farmakoterapie   MeSH
• tetrazoly farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

• Klíčová slova
• sacubitril-valsartan, studie PARADIGM-HF, ARNI,
• MeSH
• aminobutyráty terapeutické užití   MeSH
• blokátory receptorů AT1 pro angiotensin II terapeutické užití   MeSH
• hypotenze farmakoterapie   MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• neprilysin * antagonisté a inhibitory   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• systolické srdeční selhání * farmakoterapie   MeSH
• tetrazoly terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• novinové články MeSH

x

x

• Klíčová slova
• Cenobamát,
• MeSH
• antikonvulziva * farmakologie   škodlivé účinky   terapeutické užití   MeSH
• chlorfenoly farmakologie   terapeutické užití   MeSH
• epilepsie farmakoterapie   MeSH
• farmakokinetika MeSH
• karbamáty farmakologie   terapeutické užití   MeSH
• lékové interakce MeSH
• lidé MeSH
• tetrazoly farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

• Klíčová slova
• cenobamát,
• MeSH
• antikonvulziva aplikace a dávkování   terapeutické užití   MeSH
• chlorfenoly farmakologie   terapeutické užití   MeSH
• epilepsie * diagnóza   farmakoterapie   MeSH
• karbamáty farmakologie   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• tetrazoly farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

During year 2020, we learned new options to better stratify patients with heart failure and preserved left ventricular ejection fraction (HFpEF) (A), the clinical benefit of three new drugs to improve prognosis of patient with heart failure and reduced left ventricular ejection fraction (HFrEF): empagliflozin, vericiguat and omecamtiv mecarbil (B), the potential benefit of a broader utilization of recommended drugs for HFrEF in patients with left ventricular ejection fraction higher than 40% (C), and the potential added clinical benefit of a comprehensive use of recommended drugs for HFrEF (D) in a year marked by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic (central cartoon). Reprinted or adapted from: (A) Selvaraj et al.,23 (B) Packer et al.,115 Armstrong et al.,126 and Teerlink et al.,132 (C) Böhm et al.,100 (D) Vaduganathan et al.139 (Graphical Abstract - see in original.)

• MeSH
• antagonisté receptorů pro angiotenzin terapeutické užití   MeSH
• biologické markery MeSH
• kardiomyopatie diagnóza   terapie   MeSH
• lidé MeSH
• neprilysin terapeutické užití   MeSH
• srdeční selhání * diagnóza   terapie   MeSH
• tetrazoly terapeutické užití   MeSH
• Check Tag
• lidé MeSH

AIMS: The PARADIGM-HF and PARAGON-HF trials tested sacubitril/valsartan against active controls given renin-angiotensin system inhibitors (RASi) are ethically mandated in heart failure (HF) with reduced ejection fraction and are used in the vast majority of patients with HF with preserved ejection fraction. To estimate the effects of sacubitril/valsartan had it been tested against a placebo control, we made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in HF across the full range of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45-0.65] for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 48% (95% CI 35-58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF ≥ 45%), the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 29% (95% CI 7-46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64-0.82), first HF hospitalization (RR 0.67, 95% CI 0.58-0.78), cardiovascular death (RR 0.76, 95% CI 0.64-0.89), and all-cause death (RR 0.83, 95% CI 0.71-0.96); all P < 0.02. CONCLUSION: This putative placebo analysis reinforces the treatment benefits of sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.

• MeSH
• aminobutyráty terapeutické užití   MeSH
• antagonisté receptorů pro angiotenzin * terapeutické užití   MeSH
• fixní kombinace léků MeSH
• funkce levé komory srdeční MeSH
• lidé MeSH
• srdeční selhání * farmakoterapie   MeSH
• tepový objem MeSH
• tetrazoly terapeutické užití   MeSH
• valsartan MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Studie PARAGON‑HF sledovala léčbu kombinací sakubitril/valsartan u nemocných se srdečním selháním se zachovanou ejekční frakcí (heart failure with preserved ejection fraction, HFpEF). Pacienti byli randomizováni k léčbě sakubitril/valsartanem, nebo valsartanem samotným. Terapie sakubitril/valsartanem nevedla u nemocných s chronickým HFpEF k signifikantnímu poklesu rizika hospitalizací pro srdeční selhání a ke snížení kardiovaskulární mortality, avšak trend k vyšší klinické účinnosti ve srovnání se samotným valsartanem se zdá být nepochybný.

PARAGON‑HF study evaluated the treatment with sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF). Patients were randomised to treatment with sacubitril/valsartan or valsartan alone. The therapy with sacubitril/valsartan did not lead to significant decrease in risk of hospitalisations for heart failure and decrease in cardiovascular mortality in patients with chronic HfpEF. However, the trend towrds higher clinical efficacy in comparison with valsartan alone is unquestionable.

• Klíčová slova
• sakubitril/valsartan, studie PARAGON-HF,
• MeSH
• aminobutyráty terapeutické užití   MeSH
• antihypertenziva terapeutické užití   MeSH
• diastolické srdeční selhání farmakoterapie   mortalita   MeSH
• fixní kombinace léků MeSH
• lidé MeSH
• tetrazoly terapeutické užití   MeSH
• valsartan terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• randomizované kontrolované studie MeSH