Pharmacological Research Progress of Novel Antihypertensive Drugs.

Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely ß-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.

Hemodynamic Changes in Intrarenal Blood Flow are Associated With Poor Prognosis in Patients With Acute Decompensated Heart Failure.

AIM: To evaluate a potential role of different patterns of intrarenal blood flow using Doppler ultrasound as a part of determining the severity of venous congestion, predicting impairment of renal function and an unfavorable prognosis in patients with acute decompensated chronic heart failure (ADCHF). MATERIAL AND METHODS: This prospective observational single-site study included 75 patients admitted in the intensive care unit for ADCHF. Upon admission all patients underwent bedside renal venous Doppler ultrasound to determine the blood flow pattern (continuous, biphasic, monophasic). In one hour after the initiation of intravenous diuretic therapy, sodium concentration was measured in a urine sample. The primary endpoint was the development of acute kidney injury (AKI). The secondary endpoints were the development of diuretic resistance (a need to increase the furosemide daily dose by more than 2 times compared with the baseline), decreased natriuretic response (defined as urine sodium concentration less than 50-70 mmol/l), and in-hospital death. RESULTS: According to the data of Doppler ultrasound, normal renal blood flow was observed in 40 (53%) patients, biphasic in 21 (28%) patients, and monophasic in 14 (19%) patients. The monophasic pattern of intrarenal blood flow was associated with the highest incidence of AKI: among 14 patients in this group, AKI developed in 100% of cases (OR 3.8, 95% CI: 2.5-5.8, p<0.01), while among patients with normal and moderate impairment of renal blood flow, there was no significant increase in the risk of developing AKI. The odds of in-hospital death were increased 25.77 times in patients with monophasic renal blood flow (95% CI: 5.35-123.99, p<0.001). Patients with a monophasic intrarenal blood flow pattern were also more likely to develop diuretic resistance compared to patients with other blood flow patterns (p<0.001) and had a decreased sodium concentration to less than 50 mmol/l (p<0.001) in a spot urine test obtained one hour after the initiation of furosemide administration. CONCLUSION: Patients with monophasic intrarenal blood flow are at a higher risk of developing AKI, diuretic resistance with decreased natriuretic response, and in-hospital death.

Acetazolamide As A Valuable Addition to Acute Heart Failure?

Consider IV Acetazolamide in addition to standard IV loop diuretic therapy in patients hospitalized for acute decompensated heart failure.1.

[Acute heart failure (AHF)].

INTRODUCTION: Acute heart failure (AHF) is a frequent cause for emergency consultations, leads to long hospital stays and is characterized by high mortality and rehospitalization rates, with the first months after hospitalization having the highest risk («vulnerable phase¼). The clinical presentation is usually characterized by fluid accumulation. Over the last three decades, few advances have been achieved in the treatment of AHF, as most studies with diuretics or vasodilators failed to show positive effects in terms of mortality and rehospitalization rates. In this context, the treatment of AHF must have an integrative approach, consisting of rapid correction of systemic congestion on the one hand, and specific therapies for the precipitating factors, the underlying cardiac pathology, and non-cardiac comorbidities on the other. Recently, it has been shown that a rapid and intensive up-titration of oral heart failure medical therapy during and immediately after hospitalization can improve the prognosis during the vulnerable phase after AHF. In this article, the principles of optimization and personalization of diuretic therapy and oral heart failure medication during hospitalization and the early outpatient phase after AHF are discussed.

Preoperative use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and diuretics increases the risk of dehydration after ileostomy formation: population-based cohort study.

BACKGROUND: Readmission rates following ileostomy formation are high. Dehydration and consecutive renal failure are common causes of readmission, potentially pronounced by drugs affecting the homeostasis. The aim of the study was to assess the risk of dehydration after ileostomy formation in patients treated with angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) or diuretics. METHOD: This nationwide population-based cohort study used data derived from the Colorectal Cancer Data Base of several Swedish healthcare registers. The study included all patients operated on with elective anterior resection and temporary ileostomy for rectal cancer clinically staged I-III in Sweden in 2007-2016. Exposure was at least two dispensations of ACEI, ARB or diuretics within 1 year prior to surgery. Outcome was 90-day readmission due to dehydration including acute renal failure. RESULTS: In total, 3252 patients were included with 1173 (36.1%) exposed to ACEI, ARB or diuretics. The cumulative incidence for 90-day readmission due to dehydration was 29.0% (151 of 520) for exposed versus 13.8% (98 of 712) for unexposed. The proportion of readmissions due to any reason was 44.3% (520 of 1173) for exposed compared to 34.2% (712 of 2079) for unexposed. The incidence rate ratio for readmission due to dehydration was 2.83 (95% c.i. 2.21 to 3.63, P < 0.001). The hazard rate ratio was 2.45 (95% c.i. 1.83 to 3.27, P < 0.001) after adjusting for age, gender and comorbidity. CONCLUSION: Medication with ACEI, ARB or diuretics defines a vulnerable patient group with increased risk of readmission due to dehydration after ileostomy formation.

Comparison of preventive effects of combined furosemide and mannitol versus single diuretics, furosemide or mannitol, on cisplatin-induced nephrotoxicity.

Cisplatin (CDDP)-induced nephrotoxicity is a common dose-limiting toxicity, and diuretics are often administered to prevent nephrotoxicity. However, the efficacy and optimal administration of diuretics in preventing CDDP-induced nephrotoxicity remain to be established. This study aimed to evaluate the efficacy of combining furosemide and mannitol to prevent CDDP-induced nephrotoxicity. This was a post-hoc analysis of pooled data from a multicenter, retrospective, observational study, including 396 patients who received one or two diuretics for CDDP-based chemotherapy, compared using propensity score matching. Multivariate logistic regression analyses were used to identify risk factors for nephrotoxicity. There was no significant difference in the incidence of nephrotoxicity between the two groups (22.2% vs. 28.3%, P = 0.416). Hypertension, CDDP dose ≥ 75 mg/m2, and no magnesium supplementation were identified as risk factors for nephrotoxicity, whereas the use of diuretics was not found to be a risk factor. The combination of furosemide and mannitol showed no advantage over a single diuretic in preventing CDDP-induced nephrotoxicity. The renal function of patients receiving CDDP-based chemotherapy (≥ 75 mg/m2) and that of those with hypertension should be carefully monitored. Magnesium supplementation is important for these patients.

Evaluation of renal sodium handling in heart failure with preserved ejection fraction: A pilot study.

The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo-responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B-type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank-sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo-responsiveness to NPs.

Renal Sodium Avidity in Heart Failure.

BACKGROUND: Increased renal sodium avidity is a hallmark feature of the heart failure syndrome. SUMMARY: Increased renal sodium avidity refers to the inability of the kidneys to elicit potent natriuresis in response to sodium loading. This eventually causes congestion, which is a major contributor to hospital admissions and mortality in heart failure. KEY MESSAGES: Important novel concepts such as the renal tamponade hypothesis, accelerated nephron loss, and the role of hypochloremia, the sympathetic nervous system, inflammation, the lymphatic system, and interstitial sodium buffers are involved in the pathophysiology of renal sodium avidity. A good understanding of these concepts is crucially important with respect to treatment recommendations regarding dietary sodium restriction, fluid restriction, rapid up-titration of guideline-directed medical therapies, combination diuretic therapy, natriuresis-guided diuretic therapy, use of hypertonic saline, and ultrafiltration.

Urinary Cell Cycle Arrest Biomarkers and Diuretic Efficiency in Acute Heart Failure.

INTRODUCTION: This study aimed to evaluate the association between the NephroCheck® test AKIRisk® score, diuretic efficiency (DE), and the odds of worsening kidney function (WKF) within the first 72 h of admission in patients hospitalized for acute heart failure (AHF). METHODS: The study prospectively enrolled 125 patients admitted with AHF. NephroCheck® test was obtained within the first 24 h of admission. DE was defined as net fluid urine output per 40 mg of furosemide equivalents. RESULTS: The median AKIRisk® score was 0.11 (IQR 0.06-0.34), and 38 (30.4%) patients had an AKIRisk® score >0.3. The median cumulative DE at 72 h was 1,963 mL (IQR 1317-3,239 mL). At 72 h, a total of 10 (8%) patients developed an absolute increase in sCr ≥0.5 mg/dL (WKF). In a multivariable setting, there was an inverse association between the AKIRisk® score and DE within the first 72 h. In fact, the highest the AKIRisk® score (centered at 0.3), the higher the likelihood of poor DE (below the median) and WKF at 72 h (odds ratio [OR] 2.04; 95%; CI: 1.02-4.07; p = 0.043, and OR 3.31, 95% CI: 1.30-8.43; p = 0.012, respectively). CONCLUSION: In patients with AHF, a higher NephroCheck® AKIRisk® score is associated with poorer DE and a higher risk of WKF at 72 h. Further research is needed to confirm the role of urinary cell cycle arrest biomarkers in the AHF scenario.

Characteristics, Risk Factors, and Outcomes in Acute Kidney Injury Patients: A Retrospective Cross-Sectional Study, Palestine.

Background: Acute kidney injury (AKI) is a major medical problem affecting patients' quality of life and healthcare costs. Objectives: This study evaluated the severity, risk factors, and outcomes of patients diagnosed with acute kidney injury (AKI), including community-acquired AKI (CA-AKI) and hospital-acquired AKI (HA-AKI), who were admitted to tertiary institutions in Palestine. Methods: This retrospective cross-sectional study was conducted at multiple tertiary care hospitals in Palestine by reviewing patient charts from January 2020 to March 2023. The study included all patients aged ≥18 years who were admitted to the hospital and diagnosed with AKI at admission (CA-AKI) or who developed AKI 48 hours after admission (HA-AKI). Patients with incomplete medical records and those with no reported creatinine levels during their stay, pregnant women, kidney transplant patients, and end-stage renal disease patients were excluded. Data were analyzed using SPSS v22.0. The incidence of AKI in each group was compared using the chi-squared test. Results: This study included 259 participants. HA-AKI was present in 27.3% of the patients, while CA-AKI was 72.7%. The most common stage among patients was stage 3 (55.7%, HA-AKI) (42.9%, CA-AKI), and the most common comorbidity contributing to AKI was CKD. NSAIDs, ACE-I/ARBs, and DIURETICs were the most nephrotoxic drugs contributing to AKI. Patients with hyperphosphatemia, hyperkalemia, severe metabolic acidosis, or stage 3 AKI require renal replacement therapy. In addition, our findings revealed a significant association among AKI mortality, age, and heart disease. Conclusion: CA-AKI was more prevalent than HA-AKI in Palestinian patients admitted for AKI. Risk factors for AKI included diabetes, CKD, and medications (antibiotics, NSAID, diuretics, and ACE-I/ARB). Preventive measures, medication management, and disease state management are necessary to minimize AKI during hospital admission or in the community.

Risk factors for erectile dysfunction in diabetes mellitus: a systematic review and meta-analysis.

Background: Previous studies have established that diabetes mellitus (DM) markedly raises the risk of developing erectile dysfunction (ED). Despite extensive investigations, the risk factors associated with ED in diabetic men have yet to be unequivocally determined, owing to incongruent and inconclusive results reported in various studies. Objective: The objective of this systematic review and meta-analysis was to assess the risk factors for ED in men with DM. Methods: A comprehensive systematic review was conducted, encompassing studies published in the PubMed, Scopus and Embase databases up to August 24th, 2023. All studies examining the risk factors of ED in patients with DM were included in the analysis. To identify significant variations among the risk factors, odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were employed. The risk of bias was evaluated using the Newcastle-Ottawa Scale(NOS) for longitudinal studies and the Agency for Healthcare Research and Quality Scale(AHRQ) for cross-sectional studies. Results: A total of 58 studies, including a substantial participant pool of 66,925 individuals diagnosed with DM, both with or without ED, were included in the meta-analysis. Mean age (OR: 1.31, 95% CI=1.24-1.37), smoking status (OR: 1.32, 95% CI=1.18-1.47), HbA1C (OR: 1.44, 95% CI=1.28-1.62), duration of DM (OR: 1.39, 95% CI=1.29-1.50), diabetic neuropathy (OR: 3.47, 95% CI=2.16-5.56), diabetic retinopathy (OR: 3.01, 95% CI=2.02-4.48), diabetic foot (OR: 3.96, 95% CI=2.87-5.47), cardiovascular disease (OR: 1.92, 95% CI=1.71-2.16), hypertension (OR: 1.74, 95% CI=1.52-2.00), microvascular disease (OR: 2.14, 95% CI=1.61-2.85), vascular disease (OR: 2.75, 95% CI=2.35-3.21), nephropathy (OR: 2.67, 95% CI=2.06-3.46), depression (OR: 1.82, 95% CI=1.04-3.20), metabolic syndrome (OR: 2.22, 95% CI=1.98-2.49), and diuretic treatment (OR: 2.42, 95% CI=1.38-4.22) were associated with increased risk factors of ED in men with DM. Conclusion: Our study indicates that in men with DM, several risk factors for ED have been identified, including mean age, HbA1C, duration of DM, diabetic neuropathy, diabetic retinopathy, diabetic foot, cardiovascular disease, hypertension, microvascular disease, vascular disease, nephropathy, depression, metabolic syndrome, and diuretic treatment. By clarifying the connection between these risk factors and ED, clinicians and scientific experts can intervene and address these risk factors, ultimately reducing the occurrence of ED and improving patient management.

Combination of diuretics for acute heart failure: a protocol for a systematic review of randomised clinical trials with network meta-analysis and trial sequential analysis.

INTRODUCTION: Acute heart failure (AHF) is a critical, costly condition with high mortality rates, affecting millions annually. Despite advances in cardiovascular care, AHF treatment lacks robust evidence. AHF commonly manifests with sudden heart failure symptoms such as pulmonary congestion, and the pathophysiology involves fluid overload. Initial treatment is based on intravenous diuretics typically, but the optimal combination of drugs remains uncertain. METHODS AND ANALYSIS: We will systematically review randomised controlled trials enrolling patients with AHF and volume overload undergoing in-hospital diuretic treatment. We aim to investigate any diuretic intervention. Our search strategy includes the following databases: Embase, Medline, Latin American and Caribbean Health Sciences Literature, Web of Science and the Cochrane Central Register of Controlled Trials. The primary outcome is all-cause mortality. Secondary outcomes are serious adverse events, hospital readmission and kidney failure. Study results reported at the most extended follow-up will be used for all outcomes. If appropriate, we will conduct meta-analysis, trial sequential analysis and network meta-analysis. ETHICS AND DISSEMINATION: No ethics approval is required for this study. The results will be published in a peer-reviewed journal in this field. PROSPERO REGISTRATION NUMBER: CRD42023463979.

Initiation and continuation of pharmacological therapies in patients hospitalized for heart failure in Japan.

Currently, the utilization patterns of medications for heart failure (HF) after worsening HF events remain unelucidated in Japan. Here, we conducted a retrospective cohort study evaluating the changes in HF drug utilization patterns in 6 months before and after hospitalizations for HF. The adherence to newly initiated HF medications was evaluated based on the proportion of days covered (PDC) and persistence as continuous treatment episodes among new users. The study included 9091 patients hospitalized for HF between January 2016 and September 2019, including 2735 (30.1%) patients who were newly prescribed at least one HF medication after hospitalization. Despite increases in the use of foundational HF therapy (beta-blockers, angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers, or mineralocorticoid receptor antagonists), 35.6% and 7.6% of patients were treated with the HF foundational monotherapy or diuretics alone after hospitalization, respectively. The mean PDC of newly initiated HF medications ranged from 0.57 for thiazide diuretics to 0.77 for sodium-glucose cotransporter-2 inhibitors. Continuous use of HF medications during the first year after initiation was observed in 30-60% of patients. The mean PDC and one-year continuous HF medication use were consistently lower in patients aged ≥ 75 years and in patients with a history of HF hospitalization for all HF medication classes except for tolvaptan and digoxin. Despite the guideline recommendations of HF pharmacotherapy, both treatment and adherence were suboptimal after HF hospitalization, especially in vulnerable populations such as older patients and those with prior HF hospitalizations.

Efficacy and Safety of Dapagliflozin in Patients With Acute Heart Failure.

BACKGROUND: The primary goals during acute heart failure (AHF) hospitalization are decongestion and guideline-directed medical therapy (GDMT) optimization. Unlike diuretics or other GDMT, early dapagliflozin initiation could achieve both AHF goals. OBJECTIVES: The authors aimed to assess the diuretic efficacy and safety of early dapagliflozin initiation in AHF. METHODS: In a multicenter, open-label study, 240 patients were randomized within 24 hours of hospital presentation for hypervolemic AHF to dapagliflozin 10 mg once daily or structured usual care with protocolized diuretic titration until day 5 or hospital discharge. The primary outcome, diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose, was compared across treatment assignment using a proportional odds model adjusted for baseline weight. Secondary and safety outcomes were adjudicated by a blinded committee. RESULTS: For diuretic efficiency, there was no difference between dapagliflozin and usual care (OR: 0.65; 95% CI: 0.41-1.02; P = 0.06). Dapagliflozin was associated with reduced loop diuretic doses (560 mg [Q1-Q3: 260-1,150 mg] vs 800 mg [Q1-Q3: 380-1,715 mg]; P = 0.006) and fewer intravenous diuretic up-titrations (P ≤ 0.05) to achieve equivalent weight loss as usual care. Early dapagliflozin initiation did not increase diabetic, renal, or cardiovascular safety events. Dapagliflozin was associated with improved median 24-hour natriuresis (P = 0.03) and urine output (P = 0.005), expediting hospital discharge over the study period. CONCLUSIONS: Early dapagliflozin during AHF hospitalization is safe and fulfills a component of GDMT optimization. Dapagliflozin was not associated with a statistically significant reduction in weight-based diuretic efficiency but was associated with evidence for enhanced diuresis among patients with AHF. (Efficacy and Safety of Dapagliflozin in Acute Heart Failure [DICTATE-AHF]; NCT04298229).