Efficacy and safety of bicyclol for treating patients with antituberculosis drug-induced liver injury.

BACKGROUND: Bicyclol was used for treating idiosyncratic acute drug-induced liver injury (DILI) in a phase II trial. This study was aimed at evaluating the efficacy and safety of bicyclol 25 and 50 mg thrice a day (TID) for treating acute DILI caused by anti-TB drugs in the light of the trial results.METHODS: We analysed clinical data of patients with TB drug-induced DILI in the trial database. The primary endpoint was reduction in serum alanine aminotransferase (ALT) levels after 4 weeks of treatment compared to baseline.RESULTS: Overall, 148 patients were included, with respectively 48, 52 and 48 patients included in the control (456 mg polyene phosphatidylcholine TID), high-dose (50 mg bicyclol TID) and low-dose (25 mg bicyclol TID) groups. ALT levels decreased by respectively â-"149.0 (IQR â-"299.3 to â-"98.3 (), â-"225.5 (IQR â-"309.3 to â-"181.8 ) and â-"242.5 (IQR â-"364.8 to â-"153.8) U/L in the control, high-dose and low-dose groups (P < 0.001). The ALT normalisation rates at weeks 1, 2, 4, 6 and 8 were higher in the high- and low-dose groups, while adverse events and serious adverse events were similar across groups.CONCLUSIONS: Bicyclol (25 and 50 mg TID) is effective and safe in treating anti-TB DILI, and bicyclol 50 mg TID showed higher efficacy.

The real-world safety of sacubitril / valsartan among older adults (≥75): A pharmacovigilance study from the FDA data.

BACKGROUND: Heart failure is a major cause of morbidity and mortality among older adults. Sacubitril-Valsartan (Sac/Val) has been shown to improve patients' outcomes; however, its safety profile among older adults has not been adequately examined. We therefore aimed to examine its safety profile among this population. METHODS: We conducted a retrospective pharmacovigilance study utilizing the FDA's database of safety reports (FAERS). We employed disproportionality analysis comparing Sac/Val to angiotensin receptor blockers (ARBs). We aim to evaluate the reporting of pre-defined adverse events associated with Sac/Val (hypotension, acute kidney injury (AKI), hyperkalemia and angioedema) in two age groups: adults (< 75 years) and older adults (≥ 75). For each subgroup, we calculated reporting odds ratio (ROR) and compared them by calculating P for interaction. RESULTS: The FAERS database encompassed 18,432 unique reports of Sac/Val. Of them, 12,630 (68.5%) subjects were adults (< 75 years), and 5802 (31.5%) were older adults (≥ 75 years), with a median age (IQR) of 68 (59-77). When compared to ARBs, Sac/Val was associated with higher reporting of hypotension, lower reporting of acute kidney injury (AKI) and hyperkalemia, and similar reporting of angioedema. Notably, we did not observe a significant interaction between the age subgroups and the risk estimates (AKI: Pinteraction = 0.72, hyperkalemia: Pinteraction = 0.94, hypotension: Pinteraction = 0.31, and angioedema: Pinteraction = 0.61). CONCLUSIONS: In this postmarking study, none of the prespecified adverse events was reported more frequently in older adults. These findings provide reassurance for safety use of Sac/Val in older adults.

Surgery after sonidegib treatment achieves complete response in locally advanced basal cell carcinoma of the face.

Basal cell carcinoma accounts for 75% of skin cancers worldwide and is the most common malignancy in Caucasians. Since chronic ultraviolet exposure is the major risk factor for its development, sun-exposed areas such as the face are frequently affected. The gold-standard treatment is surgical excision. Radiotherapy may be considered in selected cases such as unresectable primary tumors. In some patients, when the risk of a significant functional/cosmetic deficit advises against both surgery and radiotherapy, target therapy (hedgehog pathway inhibitors) can be administered alone or in a neoadjuvant setting, to reduce the tumor size and make it eligible for surgery. Vismodegib as a neoadjuvant treatment before surgery has been investigated in a single, multicentre, open-label, phase II trial (VISMONEO); however, sonidegib has not yet been evaluated in this setting. We report the cases of two patients with locally advanced basal cell carcinoma of the face who achieved complete remission with sonidegib followed by a more limited surgical excision than would have been needed without target therapy.

Efficacy and Safety Comparative of Sacubitril/Valsartan vs. Olmesartan in the Treatment of hypertension: A Meta-analysis of RCTs.

BACKGROUND: Sacubitril/valsartan (LCZ696) is a widely used drug for hypertension in Asia, popular for its efficacy and safety. However, there has been no comprehensive literature review comparing it with olmesartan. This meta-analysis compared the antihypertensive and adverse effects of sacubitril/valsartan and olmesartan. METHODS: We conducted a comprehensive search of Pubmed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov databases to identify eligible randomized controlled trials (RCTs). The data were then analyzed and processed using Revman 5.4 and Stata SE14 software. RESULTS: Six RCTs with 4,127 patients were identified, showing that LCZ696 had better blood pressure control than olmesartan; mean sitting systolic and diastolic blood pressure, sitting pulse pressure, 24-hour ambulatory systolic blood pressure, and 24-hour ambulatory diastolic blood pressure were significantly decreased with LCZ696 compared with olmesartan. No significant difference between LCZ696 and olmesartan was observed in the occurrence of the majority of adverse events, with a decreased probability of headache in patients with sacubitril/valsartan compared with olmesartan. The subgroup analysis showed treatment with 400 mg/d LCZ696 was better than olmesartan in reducing serious adverse events. CONCLUSIONS: Sacubitril/valsartan was better than olmesartan in controlling blood pressure in patients with hypertension, with relatively higher safety.

Association of Heart Failure Patients With and Without Sacubitril-Valsartan Use With Incident Cancer Risk.

ABSTRACT: This study was to evaluate the association between heart failure (HF) patients with and without sacubitril-valsartan use with incident cancer risk. This study consisted of 18,072 patients receiving sacubitril-valsartan and 18,072 control group participants. In the Fine and Gray model, which extends the standard Cox proportional hazards regression model, we estimated the relative risk of developing cancer between the sacubitril-valsartan cohort and the non-sacubitril-valsartan cohort by using subhazard ratios (SHRs) and 95% confidence intervals (CIs). The incidence rates of cancer were 12.02 per 1000 person-years for the sacubitril-valsartan cohort and 23.31 per 1000 person-years for the non-sacubitril-valsartan cohort. Patients receiving sacubitril-valsartan had a significantly lower risk of developing cancer with an adjusted SHR of 0.60 (0.51, 0.71). Sacubitril-valsartan users were less to be associated with the development of cancer.

Safety and tolerability of Sacubitril/Valsartan in heart failure patient with reduced ejection fraction.

BACKGROUND: Angiotensin receptor blocker and a neprilysin inhibitor (ARNI) has emerged as an innovative therapy for patients of heart failure with reduced ejection fraction (HFrEF). The purpose of this study was to assess the safety and tolerability of Sacubitril/Valsartan in patient with HFrEF in Pakistani population. METHODS: This proof-of-concept, open label non-randomized clinical trial was conducted at a tertiary care cardiac center of Karachi, Pakistan. Patients with HFrEF were prescribed with Sacubitril/Valsartan and followed for 12 weeks for the assessment of safety and tolerability. Safety measures included incidence of hypotension, renal dysfunction, hyperkalemia, and angioedema. RESULTS: Among the 120 HFrEF patients, majority were male (79.2%) with means age of 52.73 ± 12.23 years. At the end of 12 weeks, four (3.3%) patients died and eight (6.7%) dropped out of the study. In the remaining 108 patients, 80.6% (87) of the patients were tolerant to the prescribed dose. Functional class improved gradually with 75.0% (81) in class I and 24.1% (26) in class II, and only one (0.9%) patient in class III at the end of 12 weeks. Hyperkalemia remains the main safety concern with incidence rate of 21.3% (23) followed by hypotension in 19.4% (21), and renal dysfunction in 3.7% (4) of the patients. CONCLUSIONS: Sacubitril/Valsartan therapy in HFrEF patients is safe and moderately tolerated among the Pakistani population. It can be used as first line of treatment for these patients. TRIAL REGISTRATION: NCT05387967. Registered 24 May 2022-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05387967.

Effects of Sacubitril-Valsartan in Patients With Various Types of Heart Failure: A Meta-analysis.

ABSTRACT: We performed a meta-analysis investigating the efficacy and adverse effects of sacubitril-valsartan in various types of heart failure including more recent studies and a larger sample size. We conducted an electronic search through Cochrane, Web of Science, PubMed, and Embase. Included studies were randomized controlled trials analyzing the efficacy of sacubitril-valsartan compared with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) in patients with heart failure. Fourteen trials were included. Pooled estimates were analyzed using RevMan 5.4.1. The odds ratio (OR) of hospitalization from worsening heart failure that compared sacubitril-valsartan with control was 0.70 (95% CI, 0.51-0.97; P = 0.03) in patients with heart failure with reduced ejection fraction (HFrEF) with a relative risk reduction (RRR) of 24.3% and absolute risk reduction (ARR) of 3.4%. In patients with heart failure with midrange (HFmEF) and preserved (HFpEF) ejection fraction, the OR was 0.80 (95% CI, 0.71-0.90; P = 0.0001) with RRR of 14.5% and ARR of 3.3%. There was a significant reduction in cardiovascular deaths (OR = 0.79; 95% CI, 0.70-0.89; P = <0.0001) and all-cause mortality (OR = 0.84; 95% CI, 0.75-0.94; P = 0.002) in patients with HFrEF, with no significant differences in patients with HFmEF and HFpEF. Hospitalization rate was significantly reduced in patients taking sacubitril-valsartan across all analyzed cohorts. Sacubitril-valsartan significantly reduced the risk of all-cause mortality and cardiovascular death in patients with HFrEF but not in patients with HFmEF/HFpEF. These findings support sacubitril-valsartan use in reducing hospitalization of patients with HFmEF and HFpEF. More studies should be performed to further analyze the efficacy of sacubitril-valsartan in patients with HFmEF/HFpEF.

Updated insights on dementia-related risk of sacubitril/valsartan: A real-world pharmacovigilance analysis.

AIM: Sacubitril/valsartan is a new cardiovascular agent characterized by its dual inhibition on the reninangiotensin system (RAS) and the neprilysin. As neprilysin also involved itself in the degradation of amyloid-ß, there is an ongoing concern about the effect of sacubitril/valsartan on cognition, especially in case of long-term administration. METHODS: The FDA Adverse Event Reporting System (FAERS) was mined between 2015Q3 and 2022Q4 to analyze the association between sacubitril/valsartan and adverse events (AEs) involving dementia. Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) with "broad" and "narrow" preferred terms (PTs) relevant to dementia was applied to systematically search demented AE reports. The Empirical Bayes Geometric Mean (EBGM) from Multi-Item Gamma Poisson Shrinker (MGPS) and proportional reporting ratio with Chi-square (PRR, χ2 ) were used to calculate the disproportionality. RESULTS: We filtered the query for indication and identified 80,316 reports with heart failure indication in FAERS during the analytical period. Among all the reports, sacubitril/valsartan was listed as primary suspected or secondary suspected drug in 29,269 cases. No significantly elevated reporting rates of narrow dementia were evident with sacubitril/valsartan. The EBGM05 for narrow dementia-related AEs associated with sacubitril/valsartan was 0.88 and the PRR (χ2 ) was 1.22 (2.40). Similarly, broad demented complications were not over-reported in the heart failure patients administrated with sacubitril/valsartan (EBGM05 1.11; PRR 1.31, χ2 109.36). CONCLUSION: The number of dementia-related cases reported to FAERS generate no safety signal attributable to sacubitril/valsartan in patients with heart failure for now. Further follow-ups are still warranted to address this question.

Candesartan Cilexetil Attenuates Arrhythmogenicity Following Pressure Overload in Rats via the Modulation of Cardiac Electrical and Structural Remodeling and Calcium Handling Dysfunction.

Background Cardiac hypertrophy is associated with abnormal electrophysiology and increased arrhythmia risk. This study assessed whether candesartan cilexetil, an angiotensin II type 1 receptor blocker, could suppress arrhythmogenecity by attenuating cardiac electrical remodeling and calcium mishandling in rats with pressure-overload hypertrophy. Methods and Results Male Sprague-Dawley rats were randomly subjected to abdominal aorta banding or sham procedure and received either candesartan cilexetil (3.0 mg/kg per day) or vehicle by gavage for 5 weeks. Pressure overload was characterized by compensated left ventricular (LV) hypertrophy and fibrosis, increased LV pressure and its decay time, and prolonged corrected QT interval, all of which were attenuated by candesartan cilexetil treatment. Candesartan cilexetil-treated banded rat hearts displayed shorter QT intervals and lower vulnerability to atrial and ventricular tachyarrhythmias than vehicle-treated banded hearts. Candesartan cilexetil prevented banding-induced prolonged action potential duration and reduced the occurrence of triggered activity in LV papillary muscles. In addition, the prolonged time to 50% cell relengthening and calcium transient decay time were normalized in LV myocytes from candesartan cilexetil-treated banded rats, along with a normalization of decreased SERCA2a (sarco[endo]plasmic reticulum calcium-ATPase) expression in LV tissues. Furthermore, candesartan cilexetil normalized depressed transient outward potassium current densities and protein and mRNA levels of both voltage-gated potassium 4.2 and 4.3 channel subunits (Kv4.2 and Kv4.3) in banded rats. Conclusions Candesartan cilexetil protects the heart from pressure overload-induced adverse electrical remodeling by preserving potassium channel densities. In addition, calcium handling and its molecular regulation also improved after treatment. These beneficial effects may contribute to a lower susceptibility to arrhythmias in hearts from candesartan cilexetil-treated pressure-overloaded rats.

Effectiveness and safety of sacubitril/valsartan for patients with hypertension and heart failure in the real-world setting: A retrospective study in China.

WHAT IS KNOWN AND OBJECTIVE: Hypertension (HP) is associated with heart failure (HF). Sacubitril/valsartan (sac/val) has been approved for primary HP by China Food and Drug Administration (CFDA) in June 2021. The present study aimed to provide evidence on the effectiveness and safety of sac/val in Chinese patients complicated with HP and HF. METHODS: This retrospective study was conducted on adult patients diagnosed with HP and HF and treated with sac/val between July 2020 and December 2020. The potential risk factors for the discontinuation events caused by sac/val-related adverse events (AEs) were explored. The data, including blood pressure (BP), cardiac indicators, corresponding values on echocardiographic parameters, unplanned visits, and AEs throughout 3-12 months, were collected. RESULTS AND DISCUSSION: A total of 446 eligible patients were included in this study. The discontinuation events of sac/val were mainly attributed to its AEs (hypotension, hyperkalemia, and deterioration in kidney function). Univariate analysis revealed that history of chronic kidney disease, atrial fibrillation, higher values of serum creatinine, serum uric acid, serum N-terminal pro B-type natriuretic peptide, and lower estimated glomerular filtration rate were potential risk factors for discontinuation. Patients who maintained sac/val therapy throughout 3-12 months showed significantly improved values of clinical BP, cardiac indicators, and echocardiographic parameters compared to those at baseline (p < 0.0001). WHAT IS NEW AND CONCLUSION: Sac/val was effective on BP and improved cardiac function in patients complicated with HP and HF. The physicians should focus on patients with renal dysfunction to take timely precautions to improve tolerability for sac/val.

Effects of sacubitril/valsartan on glycemia in patients with diabetes and heart failure: the PARAGON-HF and PARADIGM-HF trials.

BACKGROUND: Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. METHODS: We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. RESULTS: Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: - 0.24%, 95% CI - 0.33 to - 0.16%, P < 0.001). Numerically, new insulin treatment was initiated less often in the sacubitril/valsartan group than in the valsartan group, but the difference was not statistically significant (12.8% vs. 16.1%; HR: 0.80, 95% CI 0.62-1.02, P = 0.07). Hypoglycemia adverse event reports were low, but more frequent in those receiving sacubitril/valsartan than in the valsartan group (4.2% vs. 2.6%; HR: 1.64, 95% CI 1.05-2.56, P = 0.030). In a pooled analysis of PARAGON-HF and PARADIGM-HF, the effect of sacubitril/valsartan on change in HbA1c was not significantly modified by LVEF (Pinteraction = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63-0.89, P = 0.001), compared with enalapril or valsartan. CONCLUSIONS: Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration ClinicalTrials.gov NCT01920711.

A pilot study of vidofludimus calcium for treatment of primary sclerosing cholangitis.

The purpose of this pilot study was to explore the efficacy, safety, and tolerability of vidofludimus calcium (VC) in the treatment of primary sclerosing cholangitis (PSC). This was a single-arm open-label pilot study with a cohort of 18 patients with PSC. Study patients received VC for a period of 6 months. The study was undertaken at two sites, Mayo Clinic, Rochester, MN, and Mayo Clinic, Phoenix, AZ. The primary endpoint of the study was improvement of serum alkaline phosphatase (ALP) at the end of the study. Secondary endpoints included assessment of other liver biomarkers (bilirubin, alanine aminotransferase, and aspartate aminotransferase). Of 18 patients enrolled, 11 completed the 6 months of study treatment. Patients who completed treatment versus those who did not were similar other than a significantly higher direct bilirubin at baseline in the group that completed treatment (mean ± SD, 0.4 ± 0.3 versus 0.1 ± 0.1, p = 0.04). By intent to treat analysis, the primary outcome was met in 16.7% (3/18) of patients. By per-protocol analysis, including only patients who completed treatment, normalization of ALP occurred in 27.7% (3/11) at week 24 (95% confidence interval, 6.0% to 61.0%). VC was well tolerated with no drug-related serious adverse events. Conclusion: This proof of concept study provides support for further exploration of VC in patients with PSC.

Effects of Sacubitril/Valsartan on resistant hypertension and myocardial work in hemodialysis patients.

Growing evidences have confirmed the effect of Sacubitril/Valsartan (SV) on antihypertension and cardiac protection in general population. However, there was no prospective study about the effect and safety of SV on resistant hypertension and myocardial work in hemodialysis patients. In this single-center, prospective, before-after study, enrolled patients were endured with resistant hypertension for more than 6 months. Participants were initially instructed to take SV 50 mg twice daily, and the dosage was gradually increased up to 100 mg twice daily. The primary outcomes were blood pressure (BP) control, N-terminal pro-B-type natriuretic peptide (NT-proBNP), myocardial work (MW), fatigue and life quality. In addition, the adverse events were also recorded in this cohort. A total of 18 patients (34-64 years old) was finally enrolled and completed in this study. The SV-based regimen provided significantly mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) reductions from baseline (-20.7/-8.3 mm Hg), respectively. The cardiac remodeling parameters were partially improved. Compared to the baseline, NT-proBNP was significantly reduced at week 4 (8119.50 [3710.75, 29300] pg/ml to 7216.50 [4124.75, 17455.00] pg/ml, p = .046), which was much lower at week 12 (3130.50 [2244.50, 9565.70] pg/ml, p = .037). Global MW index was higher at week 12 compared to the baseline (p = .026). MW efficiency was also improved accordingly compared to the baseline, even though the statistical difference was not significant (p = .226). Life quality and fatigue were improved at week 12 compared to the baseline (all p = .000). There was no serious adverse events were observed. SV safely and effectively controlled resistant hypertension and improved MW as well as life quality in hemodialysis patients.

Efficacy and safety of sacubitril/valsartan in an outpatient setting: A single-center real-world retrospective study in HFrEF patients with focus on possible predictors of clinical outcome.

BACKGROUND: Currently, data on sacubitril/valsartan therapy from the real-world settings are scarce and the predictors of a good clinical responsiveness to this drug are unknown. OBJECTIVES: To assess efficacy and safety profile of sacubitril/valsartan and to identify predictors for a better clinical outcome. MATERIAL AND METHODS: Clinical, laboratory and echocardiographic data of 95 chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) were retrospectively analyzed. A good efficacy of sacubitril/valsartan was defined as the fulfilment of at least 2 of the following criteria: improvement of left ventricular ejection fraction (LVEF) or functional status, and reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels or hospitalization rates. RESULTS: Under sacubitril/valsartan, major improvements were observed in LVEF, the New York Heart Association (NYHA) class, NT-proBNP levels, and hospitalization rates. Patients with a good efficacy of sacubitril/valsartan were characterized by initially worse LVEF (median (interquartile range (IQR)): 29.0% (23.0-33.0%) compared to 32.0% (28.5-38.0%) with more frequent nonischemic etiology (65.4% compared to 41.9%) and hospitalizations for CHF/month (0.016 (0.004-0.057) compared to 0.000 (0.000-0.012)), lower cholesterol (42.3% compared to 65.1%), higher C-reactive protein (CRP) levels at baseline (0.5 mg/L (0.5-1.0 mg/L) compared to 0.5 mg/L (0.5-0.5 mg/L)), and a shorter timespan between CHF diagnosis and the start of sacubitril/valsartan treatment (66.0 (11.0-127.0) compared to 111 (73.0-211.0) months) (p < 0.05 each). In a multivariate Cox analysis, only the last 2 parameters were shown to be independent predictors of good clinical responsiveness to sacubitril/valsartan (hazard ratio (HR) = 1.263, 95% confidence interval (95% CI) = [1.048; 1.521]; HR = 0.992, 95% CI = [0.987; 0.997], p < 0.05, respectively). CONCLUSIONS: Sacubitril/valsartan improved LVEF, NYHA class, NT-proBNP levels, and hospitalization rates, mostly without relevant side effects. The independent predictors of a good clinical efficacy were higher CRP levels at baseline and a shorter delay between CHF diagnosis and the initialization of sacubitril/valsartan therapy.

Effects and Safety of Sacubitril/Valsartan for Patients with Myocardial Infarction: A Systematic Review and Meta-Analysis.

Patients who develop heart failure (HF) after an acute myocardial infarction (AMI) are at higher risk of adverse fatal and nonfatal outcomes. Studies have shown sacubitril/valsartan can further reduce the risk of cardiovascular death or hospitalization for heart failure by 20% compared with enalapril. At the same time, its tolerance and safety are better. However, the current evidence regarding the efficacy of sacubitril/valsartan in patients with heart failure after acute myocardial infarction is controversial. To assess the effect of sacubitril/valsartan on heart failure after acute myocardial infarction, we conducted a systematic review of the literature and a meta-analysis of existing randomized clinical trials. Meta-analysis of randomized controlled trails is used where data are collected from PubMed, the Cochrane library, Embase, and Web of Science. Data about sacubitril/valsartan were available from 5 studies. Forest plots showed that the sacubitril/valsartan group had a 299% higher value of sacubitril/valsartan to the control group (MD = 2.99%, 95% CI: 2.01, 3.96, I 2 = 78%, P < 0.00001, Figure 2), and the difference was statistically significant. Forest plots showed that the sacubitril/valsartan group had a 531% lower value of LVEF to the control group (MD = -5.31%, 95% CI: -7.36, -3.26, I 2 = 91%, P < 0.00001, Figure 2), and the difference was statistically significant. Forest plots showed that the sacubitril/valsartan group had a 133% lower value of NT-proBNP to the control group (MD = -1.33%, 95% CI: -1.54, -1.12, I 2 = 96%, P < 0.00001, Figure 3). Forest plots showed that the sacubitril/valsartan group had a 49% lower risk of heart failure to the control group (MD = 0.49, 95% CI: 0.27, 0.89, I 2 = 0%, P=0.02, Figure 3). The patients in experimental showed an obviously lower OR of MACE (OR = 0.47, 95% CI: 0.27, 0.82, P=0.007, Figure 3). The data were statistically significant. We have observed that for patients with heart failure after acute myocardial infarction, early administration of sacubitril/valsartan can significantly reduce the incidence of heart rate, left ventricular ejection fraction, NT-proBNP, and MACE. Our meta-analysis suggests that taking sacubitril/valsartan is relatively safe and effective, especially if started early after acute myocardial infarction.

Diarrhoea with the angiotensin receptor neprilysin inhibitor sacubitril + valsartan: A pharmacovigilance study.

Diarrhoea is an adverse drug reaction of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril + valsartan. It was also described with olmesartan and more recently with other angiotensin receptor blockers. The study was performed to compare diarrhoea reports in pharmacovigilance databases with sacubitril + valsartan and valsartan. The study used reports of diarrhoea with the ARNI sacubitril + valsartan registered: first in the French PharmacoVigilance Database (FPVD) and second in Vigibase®, the WHO Global Individual Case Safety Report database. After description of the main characteristics, disproportionality analyses were performed. Results are reported as reporting odds ratios (ROR) with 95% confidence interval. We found 29 reports of diarrhoea with sacubitril + valsartan in the FPVD and 686 in Vigibase®. With sacubitril + valsartan, diarrhoea occurred more frequently in males around 70 years with a median delay of 3 days. With valsartan, diarrhoea occurred more frequently in females around 68 years with a median delay of 0.5 days. In the FPVD, a significant association was found with sacubitril + valsartan in comparison with valsartan alone before (ROR = 8.78 [5.19-14.85]) and after (ROR = 11.19 [5.89-21.25]) exclusion of concomitant drugs known to be associated with diarrhoea. A significant association was also found in Vigibase® after adjustment on age, sex, reporter and its location (ROR = 1.31 [1.14-1.50]). Diarrhoea reported with sacubitril + valsartan has marked differences in gender, delay of occurrence and frequency of reporting in comparison with diarrhoea with valsartan. From a pharmacodynamic point of view, these results suggest a specific role of sacubitril in diarrhoea.

Pharmacokinetics and Safety of a Single Dose and Multiple Doses of Allisartan Isoproxil, an Angiotensin II Receptor Blocker, in Healthy Chinese People.

Allisartan isoproxil (AI) is a blocker of the angiotensin II type 1 receptor. We evaluated the safety and pharmacokinetics of single- and multiple-dose AI in healthy Chinese individuals. Participants were assigned to receive AI or placebo. Plasma concentration of EXP3174 (carboxylic acid derivative) was measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental methods. Twelve subjects were enrolled, and the ratio of men to women was 5:1. Main pharmacokinetic parameters of EXP3174 after single and multiple doses of AI were a mean maximum concentration in plasma (Cmax ) of 2242 ± 1037 ng/mL and median time to reach Cmax (Tmax ) of 3.5 hours (2.5-8 hours). The median Tmax, at steady state was 4.0 hours (1.5-8 hours). The mean Cmax at steady state (Cmax, SS ) was 2047 ± 1050 ng/mL. In terms of EXP3174, there was no significant difference in the Cmax, SS , area under the curve from time zero to 24 hours of quantifiable concentration at steady state (AUC0-24 SS ), and AUC0-72 after multiple doses of AI. Serious adverse events did not occur. These data suggest that AI is safe and well tolerated in healthy Chinese individuals at a single dose of 480 or 480 mg once daily for 7 days.

Low- vs high-dose ARNI effects on clinical status, exercise performance and cardiac function in real-life HFrEF patients.

PURPOSE: Only a few studies are available on dose-related effects of sacubitril/valsartan (angiotensin receptor neprilysin inhibition (ARNI)) in real-life patients with heart failure and reduced ejection fraction (HFrEF). We sought to investigate clinical and functional effects in real-life HFrEF patients receiving ARNI at a different cumulative dose. METHODS: This was an observational study in consecutive outpatients admitted for HFrEF from October 2017 to June 2019. The PARADIGM criteria were needed for enrolment. ARNI was uptitrated according to blood pressure, drug tolerability, renal function and kaliemia. At least 10-month follow-up was required in each patient. Clinical assessment, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, 6-min walk test and strain echocardiography were performed in each patient on a regular basis during the observational period. At the end of the study, patients were divided into two groups based on the median yearly dose of the ARNI medication. RESULTS: A total of 90 patients, 64 ± 11 years, 82% males, were enrolled. The cut-off dose was established in 75 mg BID, and the study population was divided into group A (≤ 75 mg), 52 patients (58%), and group B (> 75 mg), 38 patients (42%). The follow-up duration was 12 months (range 11-13). NYHA class, KCCQ score and 6MWT performance ameliorated in both groups, with a quicker time to benefit in group B. The proportion of patients walking > 350 m increased from 21 to 58% in group A (p < 0.001), and from 29 to 82% in group B (p < 0.001). A positive effect was also disclosed in the left ventricular remodelling, strain deformation and diastolic function. CONCLUSION: One-year ARNI treatment was effective in our real-life HFrEF patient population, leading to clinical and functional improvement in both study groups, slightly greater and with a shorter time to benefit in group B.

Are Post Hoc Analyses on Subgroups Sufficient to Support New Treatment Algorithms of Heart Failure? The Case of SGLT2 Inhibitors Associated with Sacubitril/Valsartan.

The use of sodium glucose cotransporter 2 inhibitors (SGLT2i) in heart failure (HF) with reduced ejection fraction (HFrEF) has been strongly supported by the results of recent randomized clinical trials. Upon this evidence, international recommendations and consensus documents propose the inclusion of SGLT2i among the first-line classes for HFrEF management. Subsequent analyses of treatment subgroups have been performed to investigate the effects of SGLT2i in patients treated with first-line classes including sacubitril/valsartan (Sac/Val), showing a consistent reduction of cardiovascular outcomes with a good safety profile of SGLT2i in combination with the other classes. Accordingly, SGLT2i are recommended also in combination with Sac/Val. This association, however, may require caution before being translated into guideline-directed medical therapy in clinical practice, since the proportion of patients receiving Sac/Val and SGLT2i in the available studies was poorly represented. In order to support an effective and safe sequencing or a simultaneous initiation of these 2 drug classes, pragmatic and real-world clinical studies would be helpful.