Acute quadruple extremity compartment syndrome due to angio-oedema after polypharmacy overdose including olmesartan medoxomil, telmisartan and vildagliptin.

This case report describes a rare manifestation of acute compartment syndrome (ACS) involving all four extremities, precipitated by angio-oedema in a middle-aged woman who consumed an overdose of multiple medications: nifedipine, azelnidipine, amlodipine besylate, olmesartan medoxomil, telmisartan, esaxerenone and vildagliptin. She presented with haemodynamic instability, necessitating intubation. Despite stabilising haemodynamic parameters within 24 hours, she manifested escalating extremity oedema. At 52 hours after ingestion, mottled skin was observed, along with necrotic alterations in the swollen hands and compartment pressures exceeding 30 mm Hg in all extremities. ACS was diagnosed, leading to fasciotomies. The aetiology is postulated to be drug-induced angio-oedema, possibly intensified by the concurrent overdose of olmesartan medoxomil, telmisartan and vildagliptin, each of which has a risk of angio-oedema even at standard dosages. This scenario is a very rare case caused by drug-induced angio-oedema, which underscores the importance of vigilant monitoring to detect ACS in patients with progressing limb oedema.

CandeSpartan Study: Candesartan Spanish Response-prediction and Tolerability study in migraine.

INTRODUCTION: Effectiveness of candesartan in migraine prevention is supported by two randomized controlled trials. We aimed to assess the effectiveness, tolerability, and response predictors of candesartan in the preventive treatment of migraine. METHODS: Observational, multicenter, prospective cohort study. The 50%, 75% and 30% responder rates, between weeks 8-12 and 20-24, were compared with the baseline. Treatment emergent adverse effects were systematically evaluated. Response predictors were estimated by multivariate regression models. RESULTS: Eighty-six patients were included, 79.1% females, aged 39.5 (inter-quartile range [IQR] 26.3-50.3), with chronic migraine (43.0%), medication overuse headache (55.8%) and a median of two (inter-quartile range: 0.75-3) prior preventive treatments. At baseline patients had 14 (10-24) headache and 8 (5-11) migraine days per month. The 30%, 50% and 75% responder rates were 40%, 34.9% and 15.1% between weeks 8-12, and 48.8%, 36%, and 18.6% between weeks 20-24. Adverse effects were reported by 30 (34.9%) and 13 (15.1%) patients between weeks 0-12 and 12-24, leading to discontinuation in 15 (17.4%) patients. Chronic migraine, depression, headache days per month, medication overuse headache, and daily headache at baseline predicted the response between weeks 20-24. CONCLUSION: Candesartan effectiveness and tolerability in migraine prevention was in line with the clinical trials' efficacy.Trial registration: The study protocol is registered in ClinicalTrials.gov (NCT04138316).

Effects of the valsartan recall on heart failure patients: A nationwide analysis.

BACKGROUND: Valsartan is commonly used for cardiac conditions. In 2018, the Food and Drug Administration recalled generic valsartan due to the detection of impurities. Our objective was to determine if heart failure patients receiving valsartan at the recall date had a greater likelihood of unfavorable outcomes than patients using comparable antihypertensives. METHODS: We conducted a cohort study of Optum's de-identified Clinformatics® Datamart (July 2017-January 2019). Heart failure patients with commercial or Medicare Advantage insurance who received valsartan were compared to persons who received non-recalled angiotensin receptor blockers (ARBs) and angiotensin converting enzyme-inhibitors (ACE-Is) for 1 year prior and including the recall date. Outcomes included a composite for all-cause hospitalization, emergency department (ED), and urgent care (UC) use and a measure of cardiac events which included hospitalizations for acute myocardial infarction and hospitalizations/ED/UC visits for stroke/transient ischemic attack, heart failure or hypertension at 6-months post-recall. Cox proportional hazard models with propensity score weighting compared the risk of outcomes between groups. RESULTS: Of the 87 130 adherent patients, 15% were valsartan users and 85% were users of non-recalled ARBs/ACE-Is. Valsartan use was not associated with an increased risk of all-cause hospitalization/ED/UC use six-months post-recall (HR 1.00; 95% CI 0.96-1.03), compared with individuals taking non-recalled ARBs/ACE-Is. Similarly, cardiac events 6-months post-recall did not differ between individuals on valsartan and non-recalled ARBs/ACE-Is (HR 1.04; 95% CI 0.97-1.12). CONCLUSIONS: The valsartan recall did not affect short-term outcomes of heart failure patients. However, the recall potentially disrupted the medication regimens of patients, possibly straining the healthcare system.

Safety and efficacy of candesartan versus valsartan combined with amlodipine on peripheral and central blood pressure.

INTRODUCTION: "Amlodipine/valsartan" or "amlodipine/candesartan" combinations represent two effective antihypertensive agents with complementary mechanisms of action. Nevertheless, a study has yet to be done to evaluate the effect of amlodipine/candesartan on central blood pressure and compare it with amlodipine/valsartan combination. To see how "amlodipine plus candesartan combination" reduces peripheral and central blood pressure compared to the most studied combination, "amlodipine plus valsartan". MATERIAL AND METHODS: Eighty-six patients were randomized in an open-label, prospective study by 1:1 ratio to two groups. Group I (n=42) received the amlodipine and valsartan combination, and group II (n=44) received the amlodipine and candesartan combination. Peripheral and central blood pressure (CBP) was measured at baseline, at 6 and 12 weeks of follow-up. DISCUSSION: Both treatment groups reduced peripheral systolic, diastolic, and mean blood pressure. There was no significant difference between and within both groups. The amlodipine/candesartan combination showed more reduction in peripheral systolic blood pressure (PSBP) after 12 weeks of treatment (p=<0.001). Both groups decreased CBP without significant differences between groups. The amlodipine/candesartan combination showed additional efficacy in decreasing CSBP after 12 weeks (p=<0.001). The two treatment groups did not exert significant efficacy in lowering heart rate (HR) and augmentation index% (AIx%). CONCLUSION: To conclude, the amlodipine 10mg/candesartan 16mg combination was non-inferior to the amlodipine 10mg/valsartan 160mg combination in terms of reducing peripheral and CBP over time.

Effect of sacubitril valsartan on heart failure with mid-range or preserved ejection fraction in patients on maintenance hemodialysis: real-world experience in a single-center, prospective study.

BACKGROUND: This study aimed to evaluate the effect of sacubitril valsartan (SV) on heart failure (HF) hospitalization and cardiovascular mortality in patients on hemodialysis with HF with preserved ejection fraction (EF; HFpEF). METHODS: This single-center, prospective study enrolled 155 stable hemodialysis patients with EF > 40% who were followed up for 12 months. Fifty-nine patients were treated with SV; the others were matched for EF (57.89 ± 9.35 vs. 58.00 ± 11.82, P = 0.9) at a ratio of 1:1 and included as controls. The target dosage of SV was 200 mg/day. RESULTS: Twenty-three (23/155; 14.84%) had HF with mid-range EF (HFmrEF), while 132 (85.16%) had HFpEF. After SV treatment, the peak early diastolic transmitral flow velocity/peak early diastolic mitral annular tissue velocity(E/e') improved from 17.19 ± 8.74 to 12.80 ± 5.52 (P = 0.006), the left ventricular (LV) end-diastolic diameter decreased from 53.14 ± 7.67 mm to 51.56 ± 7.44 mm (P = 0.03), and the LV mass index decreased from 165.7 ± 44.6 g/m2 to 154.8 ± 24.0 g/m2 (P = 0.02). LVEF (P = 0.08) and LV global longitudinal strain (P = 0.7) did not change significantly. The composite outcome of first and recurrent HF hospitalization or cardiovascular death showed no difference between group. However, the Acute Dialysis Quality Initiative Workgroup (ADQI) HF class improved in 39 and 15 patients and worsened in 1 and 11 patients in the SV and control groups, respectively (P < 0.001). Age, diabetes mellitus, and pulmonary arterial pressure were independent risk factors for HF hospitalization and cardiovascular mortality in patients with HFpEF. CONCLUSIONS: SV improved LV hypertrophy, diastolic function, and the ADQI class for HF; however, it failed to reduce the composite endpoints of HF hospitalization and cardiovascular disease-related mortality over 12 months of follow-up in patients on maintenance hemodialysis with EF of > 40%.

Effect of angiotensin receptor neprilysin inhibitor on physical activity in patients with heart failure with reduced ejection fraction, monitored by implantable electronic device home monitoring.

AIMS: Angiotensin receptor neprilysin inhibitor (ARNI) therapy is a cornerstone in the treatment of heart failure with reduced ejection fraction (HFrEF), with significant improvement in mortality as well as morbidity and quality of life. However, maximal ARNI doses often result in hypotension. Recent studies with 'real world' experience suggest that lower doses of ARNI are as effective as higher doses.In order to evaluate the symptomatic effect of low-dose ARNI in HFrEF patients, we analyzed physical activity data obtained via home monitoring of patients with cardiac implantable electronic devices (CIEDs). METHODS: We retrospectively analyzed physical activity data obtained from HFrEF patients with CIED-active home monitoring during the years 2021-2022. Patients with ARNI therapy were further divided into subgroups according to the administered dose. Low-dose ARNI included doses of up to 24/26 mg sacubitril/valsartan daily. Intermediate dose and high dose included doses of 72/78-120/130 mg/day, and 144/156-194/206 mg/day, respectively. RESULTS: A total of 122 patients had home monitoring-compatible CIEDs and HFrEF during the study period. Sixty-four of these patients were treated with ARNI. Administration of low-dose ARNI resulted in a 20% increase in daily activity when compared with patients without ARNI treatment ( P  = 0.038). Change in physical activity of patients in the intermediate-dose and high-dose groups was not significant. Younger patients, patients with cardiac resynchronization therapy, and patients without diabetes mellitus were more physically active. CONCLUSION: Low-dose ARNI had a beneficial effect on physical activity in HFrEF patients. MH via CIED provided real-life objective data for patients' follow-up.

Efficacy and safety of Qingda granule versus valsartan capsule in Chinese grade 1 hypertensive patients with low-moderate risk: A randomized, double-blind, double dummy, non-inferiority, multi-center trial.

BACKGROUND: The efficacy and safety of Qingda granule (QDG) in managing blood pressure (BP) among grade 1 hypertensive patients with low-moderate risk remain uncertain. METHODS: In the randomized, double-blind, double dummy, non-inferiority and multicenter trial, 552 patients with grade 1 hypertension at low-moderate risk were assigned at a ratio of 1:1 to receive either QDG or valsartan for 4 weeks, followed up by a subsequent 4 weeks. RESULTS: Post-treatment, clinic systolic/diastolic BPs (SBP/DBP) were reduced by a mean change of 9.18/4.04 mm Hg in the QDG group and 9.85/5.05 mm Hg in the valsartan group (SBP P = 0.47, DBP P = 0.16). Similarly, 24-hour, daytime and nighttime BPs were proportional in both groups (P > 0.05) after 4 weeks treatment. After discontinuing medications for 4 weeks, the mean reduction of clinic SBP/DBP were 0.29/0.57 mm Hg in the QDG group compared to -1.59/-0.48 mm Hg in the valsartan group (SBP P = 0.04, DBP P = 0.04). Simultaneously, the 24-hour SBP/DBP were reduced by 0.9/0.31 mm Hg in the QDG group and -1.66/-1.08 mm Hg in the valsartan group (SBP P = 0.006, DBP P = 0.02). And similar results were observed regarding the outcomes of daytime and nighttime BPs. There was no difference in occurrence of adverse events between two groups (P > 0.05). CONCLUSION: QDG proves to be efficacious for grade 1 hypertension at a low-to-medium risk, even after discontinuation of the medication for 4 weeks. These findings provide a promising option for managing grade 1 hypertension and suggest the potential for maintaining stable BP through intermittent administration of QDG. TRIAL REGISTRATION: ChiCTR2000033890.

Use of sacubitril/valsartan early after CABG.

BACKGROUND: Heart failure (HF) remains a major public health problem with a high mortality and morbidity worldwide. Currently, there is no optimal revascularisation strategy for patients with ischaemic cardiomyopathy despite suggestions that coronary artery bypass graft (CABG) may be superior to medical therapy in improving survival. However, CABG may be associated with substantial risk in HF subjects. We therefore aimed to evaluate the safety and efficacy of the early initiation of sacubitril/valsartan in haemodynamically stabilised patients with HF with reduced ejection fraction (HFrEF) after early CABG. METHODS: This was an open-label study in which ~80 patients after CABG were randomised either to the early or late initiation of the sacubitril-valsartan. The study included patients >40 years with left ventricular ejection fraction <45% and New York Heart Association (NYHA) class II-IV at the early stage after CABG. Patients underwent intervention, the starting dose of sacubitril/valsartan (24/26 mg or 49/51 mg two times per day). The follow-up took place every 4 weeks except the first visit, which took place in 2 weeks after initiation. The primary endpoint assessed the key safety outcomes, the secondary endpoints were: the quality of life measured, the N-terminal pro-B-type natriuretic peptide (NT-proBNP) changes and 6 min walk test (6MWT). RESULTS: In total, 83 patients were screened and 77 patients were enrolled. The majority of patients (84.4%) were in the NYHA class III at randomisation. The number of patients who discontinued the study was low in both groups (2.5%, 5.2%), and renal function, hyperkalaemia and symptomatic hypotension rarely seen in both groups did not differ significantly. The improvement in quality of life and distance at the 6MWT in both groups was significant (p<0.001). The NT-proBNP concentration decreased in both groups, the significant reduction was in the early group (p<0.001) versus the postdischarge group. CONCLUSIONS: The early initiation of sacubitril/valsartan in patients after CABG with HFrEF is safe and effective. Adverse events and permanent discontinuation were low. The NT-proBNP concentration reduced significantly with the early in-hospital initiation.

The efficacy and safety of sacubitril/valsartan in chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: Sacubitril/valsartan, a new pharmacological class of angiotensin receptor neprilysin inhibitor, is beneficial to heart failure through blocking the degradation of natriuretic peptides and inhibiting renin-angiotensin-aldosterone system (RAAS) activation which also relate to the pathophysiologic mechanisms of chronic kidney disease (CKD). However, its effects on CKD remain unclear. To assess the efficacy and safety of sacubitril/valsartan for patients with CKD, we performed this meta-analysis. METHODS: The Embase, PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sacubitril/valsartan with ACEI/ARBs in patients with CKD whose estimated glomerular filtration rate (eGFR) was below 60 mL/min/1.73 m2. We adopted the Cochrane Collaboration tool for assessing the risk of bias. The effect size was estimated using the odds ratio (OR) with 95% confidence interval (CI). RESULTS: Six trials with a total of 6217 patients with CKD were included. In terms of cardiovascular events, sacubitril/valsartan attenuated the risk of cardiovascular death or heart failure hospitalization (OR: 0.68, 95% CI 0.61-0.76, P < 0.00001, I2 = 43%). With respect to renal function, sacubitril/valsartan prevented the incidence of serum creatinine (Scr) elevation among patients with CKD (OR: 0.79, 95% CI 0.67-0.95, P = 0.01, I2 = 0%). Subgroup analysis about eGFR demonstrated that with long follow-up, sacubitril/valsartan significantly decreased the number of patients with more than 50% reduction in eGFR compared with ACEI/ARBs (OR: 0.52, 95% CI 0.32-0.84, P = 0.008, I2 = 9%). In patients with CKD, the incidence of end-stage renal disease (ESRD) was reduced with sacubitril/valsartan treatment, despite no statistically significant difference between the two groups (OR: 0.59, 95% CI 0.29-1.20, P = 0.14, I2 = 0%). As for the safety, we found that sacubitril/valsartan was associated with the occurrence of hypotension (OR: 1.71, 95% CI 1.15-2.56, P = 0.008, I2 = 51%). However, there was no trend towards increasing the risk of hyperkalemia in patients who received sacubitril/valsartan (OR: 1.09, 95% CI 0.75-1.60, P = 0.64, I2 = 64%). CONCLUSION: This meta-analysis indicated that sacubitril/valsartan improved renal function and conferred effective cardiovascular benefits in patients with CKD, without serious safety issues being observed. Thus, sacubitril/valsartan may be a promising option for patients with CKD. Certainly, further large-scale randomized controlled trials are needed to confirm these conclusions. SYSTEMATIC REVIEW REGISTRATION: [ https://inplasy.com/inplasy-2022-4-0045/ ], identifier [INPLASY202240045].

Application of eligibility criteria from DAPA-HF, EMPEROR-Reduced, and PARADIGM-HF trials to a population with heart failure with reduced ejection fraction at a specialized cardiology Clinic in Medellin, Colombia: A retrospective cohort study.

INTRODUCTION: The evidence supporting pharmacological heart failure treatment relies on randomized clinical trials with stringent inclusion and exclusion criteria. OBJECTIVES: Assess the eligibility of outpatients with chronic heart failure for the trials DAPA-HF, EMPEROR-reduced, and PARADIGM-HF, while exploring potential differences among study populations. METHODS: By reviewing medical records, we determined the eligibility rate for each study and evaluated the incidence of heart failure hospitalizations and all-cause mortality during this period. RESULTS: A total of 446 patients were included in the cohort. Approximately 75% would be ineligible for the trials, mainly because of their comorbidities. Ineligible patients had a higher all-cause mortality, but a similar incidence of hospitalization. CONCLUSION: Approximately 1 in 4 patients from a heart failure clinic in Medellin, Colombia would meet the eligibility criteria for the DAPA-HF, EMPEROR-reduced, and PARADIGM-HF trials. These findings highlight the need to complement randomized clinical trials with real-world data.

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.

A meta-analysis investigating the efficacy and adverse events linked to sacubitril-valsartan in various heart failure subtypes.

BACKGROUND: Sacubitril-valsartan, an inhibitor of the angiotensin receptor neprilysin (ARNi), has been purported to exhibit superiority over angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in individuals diagnosed with heart failure. HYPOTHESIS: This paper gives an updated meta-analysis comparing the efficacy and safety of sacubitril-valsartan to that of standard treatment for different types of heart failure. RESULTS: The meta-analysis comprised a total of nine randomized controlled trials (RCTs), incorporating data from a substantial sample size of 15 939 patients. The study observed a decrease in overall mortality and mortality related to cardiovascular causes among patients in the heart failure with reduced ejection fraction (HFrEF) category who were treated with sacubitril-valsartan. However, no statistically significant variation in this outcome was seen among patients with heart failure with preserved ejection fraction and HFmrEF. Patients who were administered sacubitril-valsartan had a notably elevated likelihood of experiencing hypotension. Nevertheless, no significant disparities were observed in terms of other adverse events among the various treatment groups. CONCLUSION: Current meta-analysis provide support for use of sacubitril-valsartan in decreasing mortality in patients with HFrEF. However, more numbers of studies are required to draw a definite conclusion on other benefits associated with sacubitril-valsartan use over standard treatment of ACE inhibitors and ARBs.

From statistical inference to machine learning: A paradigm shift in contemporary cardiovascular pharmacotherapy.

AIMS: Heart failure with reduced ejection fraction (HFrEF) poses significant challenges for clinicians and researchers, owing to its multifaceted aetiology and complex treatment regimens. In light of this, artificial intelligence methods offer an innovative approach to identifying relationships within complex clinical datasets. Our study aims to explore the potential for machine learning algorithms to provide deeper insights into datasets of HFrEF patients. METHODS: To this end, we analysed a cohort of 386 HFrEF patients who had been initiated on sodium-glucose co-transporter-2 inhibitor treatment and had completed a minimum of a 6-month follow-up. RESULTS: In traditional frequentist statistical analyses, patients receiving the highest doses of beta-blockers (BBs) (chi-square test, P = .036) and those newly initiated on sacubitril-valsartan (chi-square test, P = .023) showed better outcomes. However, none of these pharmacological features stood out as independent predictors of improved outcomes in the Cox proportional hazards model. In contrast, when employing eXtreme Gradient Boosting (XGBoost) algorithms in conjunction with the data using Shapley additive explanations (SHAP), we identified several models with significant predictive power. The XGBoost algorithm inherently accommodates non-linear distribution, multicollinearity and confounding. Within this framework, pharmacological categories like 'newly initiated treatment with sacubitril/valsartan' and 'BB dose escalation' emerged as strong predictors of long-term outcomes. CONCLUSIONS: In this manuscript, we not only emphasize the strengths of this machine learning approach but also discuss its potential limitations and the risk of identifying statistically significant yet clinically irrelevant predictors.

Left ventricular reverse remodeling following initiation of sacubitril/valsartan for heart failure with reduced ejection fraction and low blood pressure.

Sacubitril/valsartan has become an important first-line drug for symptomatic heart failure (HF) patients, especially with left ventricular (LV) ejection fraction (LVEF) < 50%. However, the impact of sacubitril/valsartan on cardiovascular outcomes, especially LV reverse remodeling for such patients with low blood pressure, remains uncertain. We retrospectively studied 164 HF patients with LVEF < 50% who were treated with sacubitril/valsartan from two institutions. Echocardiography was performed before and 9.5 ± 5.1 months after initiation of maximum tolerated dose of sacubitril/valsartan. The maximum tolerated dose of sacubitril/valsartan was lower for the low blood pressure group (≤ 100 mmHg in systole) than for the non-low blood pressure group (> 100 mmHg in systole) (165 ± 106 mg vs. 238 ± 124 mg, P = 0.017). As expected, significant LV reverse remodeling was observed in the non-low blood pressure group after initiation of sacubitril/valsartan. It was noteworthy that significant LV reverse remodeling was also observed in the low blood pressure group after initiation of sacubitril/valsartan (LV end-diastolic volume: 177.3 ± 66.0 mL vs. 137.7 ± 56.1 mL, P < 0.001, LV end-systolic volume: 131.6 ± 60.3 mL vs. 94.6 ± 55.7 mL, P < 0.001, LVEF: 26.8 ± 10.3% vs. 33.8 ± 13.6%, P = 0.015). Relative changes in LV volumes and LVEF after initiation of sacubitril/valsartan were similar for the two groups. In conclusion, significant LV reverse remodeling occurred after initiation of sacubitril/valsartan, even in HF patients with LVEF < 50% and systolic blood pressure ≤ 100 mmHg.

Predicting Hospital Readmissions in Patients Receiving Novel-Dose Sacubitril/Valsartan Therapy: A Competing-Risk, Causal Mediation Analysis.

Backgrounds: Our study aimed to identify and predict patients with heart failure (HF) taking novel-dose Sacubitril/Valsartan (S/V) at risk for all-cause readmission, as well as investigate the possible role of left ventricular reverse remodeling (LVRR). Methods and results: There were 464 patients recruited from December 2017 to September 2021 in our hospital with a median follow-up of 660 days (range, 17-1494). Competing risk analysis with Gray's Test showed statistically significant differences in all-cause readmission (p-value< .001) across the three different dose groups. Models 1 and 2 were developed based on the results of univariable competing risk analysis, least absolute shrinkage and selection operator approach, backward stepwise regression, and multivariable competing risk analysis. The internal verification (data-splitting method) indicated that Model 1 had better discrimination, calibration, and clinical utility. The corresponding nomogram showed that patients aged 75 years and above, or taking the lowest-dose S/V (≤50 mg twice a day), or diagnosed with ventricular tachycardia, or valvular heart disease, or chronic obstructive pulmonary disease, or diabetes mellitus were at the highest risk of all-cause readmission. In the causal mediation analysis, LVRR was considered as a critical mediator that negatively affected the difference of novel-dose S/V in readmission. Conclusions: A significant association was detected between novel-dose S/V and all-cause readmission in HF patients, in part negatively mediated by LVRR. The web-based nomogram could provide individual prediction of all-cause readmission in HF patients receiving novel-dose S/V. The effects of different novel-dose S/V are still needed to be explored further in the future.

[Effects of sacubitril/valsartan in patients with cancer therapy-related heart failure].

AIM: To evaluate the effect of Sacubitril/Valsartan (S/V) on the functional status, systolic and diastolic function of the left ventricle (LV), tolerability of therapy and to determine predictors of its effectiveness in patients with cancer therapy-related heart failure (СTRHF). MATERIALS AND METHODS: Forty patients 58 [46; 65.5] years of age with HF associated with anthracycline-containing cancer therapy were enrolled. Clinical examination, echocardiography, and assessment of potassium and creatinine levels were performed at baseline and after 6 months of S/V therapy. RESULTS: NYHA functional class (FC) improvement was observed in 22 (64.7%) patients. Radiation therapy (RT) decreased (OR 0.091; 95% CI 0.01-0.83; p=0.03) while baseline low LV EF increased (OR 9.0; 95% CI 1.78-45.33; p=0.008) the odds of FC improvement. LV EF increased from 37.3 [30; 42.5] % to 45 [38; 48] % (p<0.0001) and exceeded 50% in 7 (20.6%) patients. The odds of LV EF recovery increased when S/V therapy was initiated ≤1 year after anthracycline therapy (OR 10.67; 95% CI 1.57-72.67; p=0.0016) and decreased in patients with the history of RT (OR 0.14; 95% CI 0.02-0.89; p=0.0037) and in patients over 58 years (OR 0.07; 95% CI 0.01-0.68; p=0.022). LV diastolic function improvement included E/e' descent from 13.6 [10; 18.3] to 8.9 [6.9; 13.7] (p=0.0005), and decrease in diastolic dysfunction grade in 18 (45%) patients (p=0.0001). No significant change in serum potassium (4.45 [4.2; 4.8] versus 4.5 [4.3; 4.8]; p=0.5) and creatinine (75.4 [67.6; 85.1] versus 75.5 [68.2; 98.3]; p=0.08) levels were observed. CONCLUSION: S/V therapy is associated with improvement of EF, systolic and diastolic LV function, demonstrates a favorable tolerability profile in patients with СTRHF. Lack of RT and low baseline LV EF increased the odds of LV EF improvement; lack of RT, early (≤1 year) start of treatment after discontinuation of anthracycline therapy, and age <58 years increased the odds of LV EF recovery.

Risk of myocardial infarction, heart failure, and cerebrovascular disease with the use of valsartan, losartan, irbesartan, and telmisartan in patients.

There is a lack of studies comparing the risk of cardio-cerebrovascular disease between angiotensin receptor blockers (ARBs) of different half-lives. We aimed to compare the risks of myocardial infarction (MI), heart failure (HF), and cerebrovascular disease with the use of valsartan, losartan, irbesartan, and telmisartan with different half-lives in a national claim-based retrospective cohort of patients aged ≥ 40 years with hypertension. To establish a cohort exposed to valsartan, losartan, irbesartan, or telmisartan, we performed propensity score (PS) matching and used an as-treated approach to evaluate exposure. The Cox regression model was employed to calculate hazard ratios, which were based on the incidence rate for each newly occurring event of MI, heart failure, or cerebrovascular disease. These hazard ratios were calculated to compare the risk of MI, heart failure, and cerebrovascular disease associated with valsartan, losartan, and irbesartan in comparison to telmisartan. A PS-matched cohort of 148,229 patients was established for each of valsartan, losartan, irbesartan, or telmisartan. The matched cohort analysis showed that the adjusted hazard ratio (aHRs, 95% confidence interval) for MI was higher for valsartan use (1.39, 1.33-1.45) and losartan use (1.10, 1.05-1.15) but lower for irbesartan use (0.90, 0.86-0.94) compared with the reference (telmisartan). The aHRs for HF were not different among these ARBs (angiotensin receptor blockers). The aHR for cerebrovascular disease was lower for valsartan use (0.85, 0.83-0.87) and losartan use (0.80, 0.78-0.82) but higher for irbesartan use (1.11, 1.09-1.13) compared with the reference. We found differences in the risk of MI and cerebrovascular disease with the use of different ARBs compared to telmisartan use. Valsartan, and losartan with a short half-life, which showed a higher risk of MI, had a lower risk of cerebrovascular disease. Conversely, irbesartan with a long half-life, which showed a lower risk of MI, had a higher risk of cerebrovascular disease.

Efficacy and Safety of Sacubitril/Valsartan in Japanese Patients With Heart Failure According to Baseline Systolic Blood Pressure　- Results From a Subgroup Analysis of the PARALLEL-HF Study.

BACKGROUND: Lower systolic blood pressure (SBP) is known to be associated with poor prognosis in heart failure (HF). We evaluated the efficacy and safety of sacubitril/valsartan according to baseline SBP tertiles in Japanese patients from the PARALLEL-HF study.Methods and Results: In all, 223 patients were stratified into tertiles according to baseline SBP (≤114 mmHg: n=75; >114 and ≤130 mmHg: n=76; and >130 mmHg: n=72). Patients with lower SBP (≤114 mmHg) had the highest median N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations at baseline (P=0.0184). No significant difference was observed between sacubitril/valsartan and enalapril for the composite outcome of cardiovascular death and HF hospitalization across SBP tertiles (P-interaction=0.2682). Although the P-interaction value was not significant (0.2106), a greater reduction in NT-proBNP with sacubitril/valsartan compared with enalapril was observed in patients with SBP >130 mmHg (P=0.0076). The incidence of hypotension-related events and reduction or discontinuation of treatment due to hypotension-related events was higher in the lower SBP subgroup, and these events were more frequent in the sacubitril/valsartan than enalapril group. CONCLUSIONS: The efficacy of sacubitril/valsartan compared with enalapril was consistent across baseline SBP tertiles in Japanese patients from the PARALLEL-HF study. Hypotension-related events were more common in patients treated with sacubitril/valsartan with lower SBP.

Sacubitril/Valsartan in Heart Failure with Hypertension Patients: Real-World Experiences on Different Ages, Drug Doses, and Renal Functions.

INTRODUCTION: Hypertension is a significant risk factor in heart failure for worldwide patients. More than half of hypertensive patients suffer from heart failure. Recently, sacubitril/valsartan (sac/val) has been approved as an antihypertensive agent in China and Japan. Additionally, it is not approved for treating hypertension in Europe or the USA. AIM: To accumulate more real-world experiences to investigate the effectiveness and optimize clinical medication of sac/val in hypertensive patients with heart failure. METHODS: We retrospectively enrolled adult patients diagnosed with hypertension (HTN) and heart failure (HF) and newly treated with sac/val. The baseline characteristics and clinical outcomes were retrospectively extracted from electronic medical records (EMR) in three centers. The efficacy and safety of sac/val were first analyzed in all enrolled patients. Stratified analyses were conducted in patients with different ages (≥ 65, < 65), maximum tolerated doses (≥ 200 mg/days, < 200 mg/days), and renal functions (e-GFR ≥ 60 ml/min/1.73 m2, < 60 ml/min/1.73 m2). RESULTS: Overall, 794 patients diagnosed with both HF and HTN were included in our study. During follow-up, significant reductions were found in blood pressure (BP) (SBP 12.8 ± 21.2 mmHg, P < 0.001, DBP 7.1 ± 16.5 mmHg, P < 0.001), and cardiac biomarkers (cardiac troponin 1.78 ± 19.1 ng/mL, P < 0.001, NT-proBNP 1403 ± 6937 pg/mL, P < 0.001) from baseline. In stratification analyses, the lower dosage group earned a higher BP control rate (83.4% vs. 75.6%, P = 0.025) and an overall improvement rate of cardiac indicators (61.3% vs. 48.0%, P = 0.002). The younger patients' group had significantly less cumulative hazard of recurrent cerebral-cardiovascular events than the elder group (log-rank P value < 0.001). Patients with renal dysfunction were observed with more AE incidences. CONCLUSIONS: Sac/val could reduce BP and improve cardiac structural and functional parameters in hypertensive patients with HF, even with less than target doses. However, more attention should be paid to older patients and renal dysfunction patients when using sac/val because of additional risks in adverse events.