Therapeutic potential of ramipril, losartan, and spironolactone against sepsis-associated liver tissue injury induced by cecal ligation and puncture in rats.

OBJECTIVE: Sepsis-associated liver injury is responsible for the high morbidity and mortality rates seen with septic shock. Activation of the renin-angiotensin-aldosterone system (RAAS) is an essential counteractive mechanism during the hypotensive phase of sepsis; however, excessive activation is associated with exaggerated pro-oxidant and inflammatory response, which aggravates organ damage. This study aimed to evaluate the effect of RAAS inhibition on sepsis-induced liver damage. MATERIALS AND METHODS: The cecal ligation and puncture (CLP) model was employed as a model of sepsis. Rats were divided into five groups: sham-operated, vehicle-treated septic rats, septic rats treated with ramipril in a dose of 10 mg/kg, septic rats treated with losartan in a dose of 20 mg/kg, and finally septic rats treated with spironolactone in a dose of 25 mg/kg. Rats received the treatment one hour after induction. Twenty-four hours later, rats were euthanized, and serum samples and liver tissue were collected to evaluate liver function and hepatic oxidative, anti-oxidative, inflammatory, and apoptotic markers. The microscopic integrity of the hepatic tissue was also assessed. RESULTS: The results of our study showed that all the treatments used ameliorated sepsis-induced liver injury. This was reflected by improved liver function parameters and histopathological appearance of liver tissue. Treatment with ramipril, losartan, or spironolactone reduced tissue malondialdehyde (MDA), nitric oxide, activated caspase-3, and TNF-α. Moreover, these drugs increased hepatic reduced-glutathione (GSH) levels, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) expression. CONCLUSIONS: Administration of ramipril, losartan, or spironolactone after CLP produced a hepatoprotective effect in rats, possibly by reducing oxidative stress, inflammation, and apoptosis.

Clinical trial design for assessing hypertension medications: are critical circadian chronopharmacological principles being taking into account?

INTRODUCTION: Clinical hypertension trials typically rely on homeostatic principles, including single time-of-day office blood pressure (BP) measurements (OBPM), rather than circadian chronopharmacological principles, including ambulatory monitoring (ABPM) done around-the-clock to derive the asleep systolic BP (SBP) mean and sleep-time relative SBP decline - jointly the strongest prognosticators of cardiovascular disease (CVD) risk and true definition of hypertension - to qualify participants and assess outcomes. AREAS COVERED: Eight chronopharmacological elements are indispensable for design and conduct of hypertension medication trials, mainly those on ingestion-time differences in effects, and also a means of rating quality of investigations. Accordingly, we highlight the findings and shortcomings of: (i) 155 such ingestion-time trials, 83.9% finding at-bedtime/evening treatment more beneficial than conventional upon-awakening/morning treatment; (ii) HOPE and ONTARGET CVD outcomes investigations assessing in the former add-on ramipril at-bedtime and in the latter telmisartan, ramipril, or both in combination in the morning; and (iii) pragmatic TIME CVD outcomes trial. EXPERT OPINION: Failure to incorporate chronopharmacological principals - including ABPM to derive asleep SBP and SBP dipping to qualify subjects as hypertensive and assess CVD risk - results in deficient study design, dubious findings, and unnecessary medical controversy at the expense of advances in patient care.

Repurposing fexofenadine as a promising candidate for diabetic kidney disease: randomized clinical trial.

PURPOSE: Diabetic kidney disease (DKD) is a devastating complication of diabetes mellitus. Inflammation and histamine are potentially involved in the disease progression. This study aimed to evaluate the role of fexofenadine in patients with DKD. METHODS: From January 2020 to February 2022, out of 123 patients screened for eligibility, 61 patients completed the study. Patients were randomized into two groups, the fexofenadine group (n = 30): received ramipril plus fexofenadine, and the control group (n = 31): received ramipril only for six months. Changes in urinary albumin to creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were considered primary outcomes. Measurements of urinary cyclophilin A, monocyte chemoattractant protein-1 (MCP-1), 8-hydroxy-2' deoxyguanosine (8-OHdG), and podocalyxin (PCX) were considered secondary outcomes. The study was prospectively registered on clinicaltrial.gov on January 13, 2020, with identification code NCT04224428. RESULTS: At the end of the study, fexofenadine reduced UACR by 16% (95% CI, - 23.4% to - 9.3%) versus a noticeable rise of 11% (95% CI, 4.1% to 17.8%) in UACR in the control group, (p < 0.001). No significant difference in eGFR was revealed between the two groups. However, the control group showed a significant decrease of - 3.5% (95% CI, - 6.6% to - 0.3%) in eGFR, compared to its baseline value. This reduction was not reported in the fexofenadine group. Fexofenadine use was associated with a significant decline in MCP-1, 8-OHdG, and PCX compared to baseline values. CONCLUSION: Fexofenadine is a possible promising adjuvant therapy in patients with DKD. Further large-scale trials are needed to confirm our preliminary results.

Sacubitril/valsartan compared to ramipril in high-risk post-myocardial infarction patients stratified according to use of mineralocorticoid receptor antagonists: Insight from the PARADISE MI trial.

AIM: It is unknown whether safety and clinical endpoints by use of sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor [ARNI]) are affected by mineralocorticoid receptor antagonists (MRA) in high-risk myocardial infarction (MI) patients. The aim of this study was to examine whether MRA modifies safety and clinical endpoints by use of sacubitril/valsartan in patients with a MI and left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion. METHODS AND RESULTS: Patients (n = 5661) included in the PARADISE MI trial (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) were stratified according to MRA. Primary outcomes in this substudy were worsening heart failure or cardiovascular death. Safety was defined as symptomatic hypotension, hyperkalaemia >5.5 mmol/L, or permanent drug discontinuation. A total of 2338 patients (41%) were treated with MRA. Safety of ARNI compared to ramipril was not altered significantly by ± MRA, and both groups had similar increase in symptomatic hypotension with ARNI. In patients taking MRA, the risk of hyperkalaemia or permanent drug discontinuation was not significantly altered by ARNI (p > 0.05 for all comparisons). The effect of ARNI compared with ramipril was similar in those who were and were not taking MRA (hazard ratio [HR]MRA 0.96, 95% confidence interval [CI] 0.77-1.19 and HRMRA- 0.87, 95% CI 0.71-1.05, for the primary endpoint; p = 0.51 for interaction [Clinical Endpoint Committee adjudicated]); similar findings were observed if investigator-reported endpoints were evaluated (p = 0.61 for interaction). CONCLUSIONS: Use of a MRA did not modify safety or clinical endpoints related to initiation of ARNI compared to ramipril in the post-MI setting in patients with LVSD and/or congestion.

Evaluation of the efficacy of hydro-alcoholic extract of Evolvulus alsinoides L. for the treatment of primary hypertension - A randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Evolvulus alsinoides L. (Sankhaholi) has been traditionally used in Unani (Greco-Arabic) medicine to treat diverse cardiovascular disorders. Notably, preclinical and clinical investigations have substantiated its remarkable potential as an antihypertensive agent. AIM OF THE STUDY: The aim of this study was to compare the efficacy of hydroalcoholic extract of Evolvulus alsinoides L. and ramipril in treating hypertension using a higher dose of the test drug within the recommended limit. MATERIALS AND METHODS: In this open-label randomized controlled trial, 57 participants (29 in the test group, 28 in the control group) completed the 42-day study. The test group received 630 mg of dried hydro-alcoholic extract of Evolvulus alsinoides L. in capsule form orally once daily, while the control group received 5 mg of Ramipril orally once daily. Participants in both groups were advised to adhere to the Dietary Approaches to Stop Hypertension (DASH) eating plan in terms of diet and lifestyle adjustments recommended by JNC-8. The primary outcome measures were changes in systolic and diastolic blood pressure as well as changes in plasma levels of hsCRP and IL6. Secondary outcome measures included changes in symptoms such as palpitations, giddiness, headaches, fatigue and shortness of breath. Headaches, palpitations, and giddiness were assessed using a customized Visual Analog Scale (VAS) graded as "none," "mild," "moderate," and "severe". Fatigue was assessed on a binary scale as either absent or present, and dyspnea was assessed using the modified Medical Research Council (mMRC) scale for breathlessness. Both primary and secondary outcomes were assessed at baseline and each follow-up visit (2nd week, 4th week, and 6th week) until the completion of the trial. RESULTS: At the end of the trial, the mean differences for the primary outcomes were as follows:SBP:-1.8895%CI:-4.82,1.05,p=0.203,d=0.33, DBP: -2.8395%CI:-4.67,-0.10,p=0.003,d=0.8, hsCRP: -1.4095%CI:-2.80,-0.003,p=0.49,d=0.53, and IL6: -88.6795%CI:-148.90,-28.43,p=0.005,d=0.78. No statistically significant differences were observed between the two groups for any of the secondary outcomes. CONCLUSIONS: Based on the preliminary results, it can be inferred that the hydro-alcoholic extract of Evolvulus alsinoides L. exhibits significant antihypertensive potential, comparable to that of ramipril. Furthermore, it appears that Evolvulus alsinoides L. may be more effective than ramipril in reducing the biochemical markers of inflammation associated with primary hypertension. However, additional research is required to validate these findings.

Ramipril for the Treatment of COVID-19: RAMIC, a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

INTRODUCTION: Retrospective studies report that angiotensin-converting enzyme inhibitors (ACEIs) may reduce the severity of COVID-19, but prospective data on de novo treatment with ACEIs are limited. The RAMIC trial was a randomized, multicenter, placebo-controlled, double-blind, allocation-concealed clinical trial to examine the efficacy of de novo ramipril versus placebo for the treatment of COVID-19. METHODS: Eligible participants were aged 18 years and older with a confirmed diagnosis of SARS-CoV-2 infection, recruited from urgent care clinics, emergency departments, and hospital inpatient wards at eight sites in the USA. Participants were randomly assigned to daily ramipril 2.5 mg or placebo orally in a 2:1 ratio, using permuted block randomization. Analyses were conducted on an intention-to-treat basis. The primary outcome was a composite of mortality, intensive care unit (ICU) admission, or invasive mechanical ventilation by day 14. RESULTS: Between 27 May 2020 and 19 April 2021, a total of 114 participants (51% female) were randomized to ramipril (n = 79) or placebo (n = 35). The overall mean (± SD) age and BMI were 45 (± 15) years and 33 (± 8) kg/m2. Two participants in the ramipril group required ICU admission and one died, compared with none in the placebo group. There were no significant differences between ramipril and placebo in the primary endpoint (ICU admission, mechanical ventilation, or death) (3% versus 0%, p = 1.00) or adverse events (27% versus 29%, p = 0.82). The study was terminated early because of a low event rate and subsequent Emergency Use Authorization of therapies for COVID-19. CONCLUSION: De novo ramipril was not different compared with placebo in improving or worsening clinical outcomes from COVID-19 but appeared safe in non-critically ill patients with COVID-19. TRIAL REGISTRATION: Clinicaltrials.gov NCT04366050.

Finerenone Added to RAS/SGLT2 Blockade for CKD in Alport Syndrome. Results of a Randomized Controlled Trial with Col4a3-/- Mice.

SIGNIFICANCE STATEMENT: We hypothesized that triple therapy with inhibitors of the renin-angiotensin system (RAS), sodium-glucose transporter (SGLT)-2, and the mineralocorticoid receptor (MR) would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression in Col4a3 -deficient mice, a model of Alport syndrome. Late-onset ramipril monotherapy or dual ramipril/empagliflozin therapy attenuated CKD and prolonged overall survival by 2 weeks. Adding the nonsteroidal MR antagonist finerenone extended survival by 4 weeks. Pathomics and RNA sequencing revealed significant protective effects on the tubulointerstitium when adding finerenone to RAS/SGLT2 inhibition. Thus, triple RAS/SGLT2/MR blockade has synergistic effects and might attenuate CKD progression in patients with Alport syndrome and possibly other progressive chronic kidney disorders. BACKGROUND: Dual inhibition of the renin-angiotensin system (RAS) plus sodium-glucose transporter (SGLT)-2 or the mineralocorticoid receptor (MR) demonstrated additive renoprotective effects in large clinical trials. We hypothesized that triple therapy with RAS/SGLT2/MR inhibitors would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression. METHODS: We performed a preclinical randomized controlled trial (PCTE0000266) in Col4a3 -deficient mice with established Alport nephropathy. Treatment was initiated late (age 6 weeks) in mice with elevated serum creatinine and albuminuria and with glomerulosclerosis, interstitial fibrosis, and tubular atrophy. We block-randomized 40 male and 40 female mice to either nil (vehicle) or late-onset food admixes of ramipril monotherapy (10 mg/kg), ramipril plus empagliflozin (30 mg/kg), or ramipril plus empagliflozin plus finerenone (10 mg/kg). Primary end point was mean survival. RESULTS: Mean survival was 63.7±10.0 days (vehicle), 77.3±5.3 days (ramipril), 80.3±11.0 days (dual), and 103.1±20.3 days (triple). Sex did not affect outcome. Histopathology, pathomics, and RNA sequencing revealed that finerenone mainly suppressed the residual interstitial inflammation and fibrosis despite dual RAS/SGLT2 inhibition. CONCLUSION: Experiments in mice suggest that triple RAS/SGLT2/MR blockade may substantially improve renal outcomes in Alport syndrome and possibly other progressive CKDs because of synergistic effects on the glomerular and tubulointerstitial compartments.

Cost-effectiveness of the CNIC-Polypill versus separate monocomponents in cardiovascular secondary prevention in Spain.

INTRODUCTION AND OBJECTIVES: Despite advances in treatment, cardiovascular disease is the second leading cause of death in Spain. The objective of this study was to determine the cost-effectiveness of the CNIC-Polypill strategy (acetylsalicylic acid 100 mg, atorvastatin 20/40 mg, ramipril 2.5/5/10 mg) compared with the same separate monocomponents for the secondary prevention of recurrent cardiovascular events in adults in Spain. MATERIALS AND METHODS: A Markov cost-utility model was adapted considering 4 health states (stable, subsequent major adverse cardiovascular event, subsequent ischemic stroke and death) and the SMART risk equation over a lifetime horizon from the perspective of the Spanish National Healthcare System. The CNIC-Polypill strategy was compared with monocomponents in a hypothetical cohort of 1000 secondary prevention patients. Effectiveness, epidemiological, cost and utilities data were obtained from the NEPTUNO study, official databases and literature. Outcomes were costs (in 2021 euros) per life-year (LY) and quality-adjusted LY (QALY) gained. A 3% discount rate was applied. Deterministic one-way and probabilistic sensitivity analyses evaluated the robustness of the model. RESULTS: The CNIC-Polypill strategy in secondary prevention results in more LY (13.22) and QALY (11.64) gains at a lower cost than monocomponents. The CNIC-Polypill is dominant and saves є280.68 per patient compared with monocomponents. The probabilistic sensitivity analysis shows that 82.4% of the simulations are below the threshold of є25,000 per QALY gained. CONCLUSIONS: The CNIC-Polypill strategy in secondary cardiovascular prevention is cost-effective compared with the same separate monocomponents, resulting in a cost-saving strategy to the Spanish National Healthcare System.

Prognostic Importance of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) Following High-Risk Myocardial Infarction in the PARADISE-MI Trial.

BACKGROUND: NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a potent predictor of death and heart failure (HF) across multiple populations. We evaluated the prognostic importance of NT-proBNP in patients with acute myocardial infarction (MI) complicated by left ventricular systolic dysfunction, pulmonary congestion, or both and ≥1 of 8 risk-augmenting factors enrolled in the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction). METHODS: Patients were randomized to sacubitril/valsartan 200 mg or ramipril 5 mg twice daily within 0.5 to 7 days of a MI. Patients with prior HF were excluded. NT-proBNP and hs-cTnT (high-sensitivity troponin T) were collected at randomization in a prespecified substudy of 1129 patients. The primary end point of PARADISE-MI was a composite of cardiovascular death or incident HF (hospitalization or outpatient symptomatic HF), analyzed as time-to-first event; additional end points included all-cause death and the composite of fatal or nonfatal MI or stroke. RESULTS: Median NT-proBNP was 1757 ng/L (25th-75th percentiles, 896-3462 ng/L) at randomization (4.0±1.8 days after the index MI). Patients in the highest quartile of NT-proBNP were older, more commonly women and had more hypertension, atrial fibrillation, renal dysfunction, and pulmonary congestion on presentation (all P<0.001). NT-proBNP was strongly associated with the primary end point (adjusted hazard ratio, 1.45 per doubling of NT-proBNP; [95% CI, 1.23-1.70]), adjusted for clinical variables and baseline hs-cTnT. NT-proBNP was also independently associated with all-cause death (adjusted hazard ratio, 1.74 [95% CI, 1.38-2.21]) and fatal or nonfatal MI or stroke (adjusted hazard ratio, 1.24 [95% CI, 1.05-1.45]). NT-proBNP did not significantly modify the neutral treatment effect of sacubitril/valsartan relative to ramipril (P interaction=0.46). CONCLUSIONS: Within the first week of a high-risk MI NT-proBNP is associated with incident HF, death and atherosclerotic events. This prognostic information is independent of hs-cTnT. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02924727.

Firibastat Versus Ramipril After Acute Mechanical Reperfusion of Anterior Myocardial Infarction: A Phase 2 Study.

BACKGROUND: Preclinical data suggest that central renin-angiotensin system blockade by the brain aminopeptidase-A inhibitor firibastat can improve left ventricular ejection fraction (LVEF) after myocardial infarction (MI). OBJECTIVES: This study aimed to compare the effect of firibastat versus ramipril on post-MI LVEF. METHODS: In this phase 2, randomized, double-blind trial, patients selected within 24 h of first acute anterior MI treated by primary percutaneous coronary intervention were randomly assigned (1:1:1) to firibastat 100 mg, firibastat 500 mg or ramipril 5 mg, each twice daily for 12 weeks. The primary endpoint was change in LVEF on cardiac magnetic resonance imaging (cMRI) from baseline to day 84 in the modified intent-to-treat (mITT) population (at least one dose received and one follow-up cMRI available) for each treatment group. RESULTS: From June 4, 2019 to April 12, 2021, 294 patients were randomized and 229 were evaluable for the mITT analysis. After 12 weeks, mean ± standard deviation (SD) percent change in LVEF was 5.6 ± 1.2 with firibastat 100 mg, 5.3 ± 1.1 with firibastat 500 mg and 5.7 ± 1.1 with ramipril. The absolute ± SE adjusted difference in LVEF change from baseline between firibastat 500 mg and ramipril was - 0.36 ± 1.32% (p = 0.79). Occurrence of treatment-related adverse events was similar in the three groups. CONCLUSIONS: Firibastat was not superior to ramipril for prevention of left ventricular dysfunction after first acute anterior MI, and their safety profiles were similar. REGISTRATION: ClinicalTrials.gov identifier NCT03715998.

Projecting the potential cost-effectiveness of dapagliflozin for chronic kidney disease in Kuwait.

INTRODUCTION: In 2019, the prevalence of dialysis in Kuwait were 465 patient/million population, while the annual mortality rate among dialysis patients reached 12%. To improve resource allocation within the health care system, a cost-effectiveness model was conducted from a societal perspective to assess the cost-effectiveness of the use of dapagliflozin as an add-on-therapy against SoC (ramipril) among CKD patients with or without type-2 diabetes over their lifetime. METHODOLOGY: A Markov process model was utilized to assess the cost-effectiveness of dapagliflozin + ramipril versus ramipril alone on a cohort of patients with an eGFR of 25 to 75 mL/min/1.73, with or without type-2 diabetes and a urinary ACR of 200 to 5,000 over their lifetime. The model included nine health states: (i) the six stages of CKD representing stages 1, 2, 3a, 3b, 4 and 5; (ii)ESRD, which represents RRT as dialysis or kidney transplant and (iii) death. Most of the clinical data were captured from the DAPA-CKD study. We assumed that the mortality risk of our study was similar to DAPA-CKD. The utility data were captured from different studies. Direct medical and indirect costs were captured from local data sources. Sensitivity analyses were conducted. RESULTS: The difference in QALY between dapagliflozin + ramipril versus ramipril was 0.2. The difference in cost between the two arms was KWD -4,120 (-USD25750). Dapagliflozin + ramipril generate better QALYs and lower costs than ramipril in CKD patients. Dapagliflozin improved the outcomes and generated cost savings in CKD patients. CONCLUSION: Adoption of dapagliflozin + ramipril is considered to be a cost saving option in addition to the improvement in QALYs in CKD patients with or without type-2 diabetes due to its nephroprotective effect, regardless of the aetiology of CKD, which eventually leads to reduction of dialysis and the transplantation cost burden on the Kuwaiti health care system. This study was focussed only on DAPA-CKD cohort.

The membrane-associated protein 17 (MAP17) is up-regulated in response to empagliflozin on top of RAS blockade in experimental diabetic nephropathy.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have proven to delay diabetic kidney disease (DKD) progression on top of the standard of care with the renin-angiotensin system (RAS) blockade. The molecular mechanisms underlying the synergistic effect of SGLT2i and RAS blockers is poorly understood. We gave a SGLT2i (empagliflozin), an angiotensin-converting enzyme inhibitor (ramipril), or a combination of both drugs for 8 weeks to diabetic (db/db) mice. Vehicle-treated db/db and db/m mice were used as controls. At the end of the experiment, mice were killed, and the kidneys were saved to perform a differential high-throughput proteomic analysis by mass spectrometry using isobaric tandem mass tags (TMT labeling) that allow relative quantification of the identified proteins. The differential proteomic analysis revealed 203 proteins differentially expressed in one or more experimental groups (false discovery rate < 0.05 and Log2 fold change ≥ ±1). Fourteen were differentially expressed in the kidneys from the db/db mice treated with empagliflozin with ramipril. Among them, MAP17 was up-regulated. These findings were subsequently validated by Western blot. The combined therapy of empagliflozin and ramipril up-regulated MAP17 in the kidney of a diabetic mice model. MAP17 is a major scaffolding protein of the proximal tubular cells that places transporters together, namely SGLT2 and NHE3. Our results suggest that SGLT2i on top of RAS blockade may protect the kidney by boosting the inactivation of NHE3 via the up-regulation of key scaffolder proteins such as MAP17.

The Effects of Angiotensin Receptor-Neprilysin Inhibition on Major Coronary Events in Patients With Acute Myocardial Infarction: Insights From the PARADISE-MI Trial.

BACKGROUND: In patients who survive an acute myocardial infarction (AMI), angiotensin-converting enzyme inhibitors decrease the risk of subsequent major cardiovascular events. Whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan reduce major coronary events more effectively than angiotensin-converting enzyme inhibitors in high-risk patients with recent AMI remains unknown. We aimed to compare the effects of sacubitril/valsartan on coronary outcomes in patients with AMI. METHODS: We conducted a prespecified analysis of the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitors Trial to Determine Superiority in Reducing Heart Failure Events After MI), which compared sacubitril/valsartan (97/103 mg twice daily) with ramipril (5 mg twice daily) for reducing heart failure events after myocardial infarction in 5661 patients with AMI complicated by left ventricular systolic dysfunction, pulmonary congestion, or both. In the present analysis, the prespecified composite coronary outcome was the first occurrence of death from coronary heart disease, nonfatal myocardial infarction, hospitalization for angina, or postrandomization coronary revascularization. RESULTS: Patients were randomly assigned at a median of 4.4 [3.0-5.8] days after index AMI (ST-segment-elevation myocardial infarction 76%, non-ST-segment-elevation myocardial infarction 24%), by which time 89% of patients had undergone coronary reperfusion. Compared with ramipril, sacubitril/valsartan decreased the risk of coronary outcomes (hazard ratio, 0.86 [95% CI, 0.74-0.99], P=0.04) over a median follow-up of 22 months. Rates of the components of the composite outcomes were lower in patients on sacubitril/valsartan but were not individually significantly different. CONCLUSIONS: In survivors of an AMI with left ventricular systolic dysfunction and pulmonary congestion, sacubitril/valsartan-compared with ramipril-reduced the risk of a prespecified major coronary composite outcome. Dedicated studies are necessary to confirm this finding and elucidate its mechanism. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02924727.

Study of possible sex features of ramipril and candesartan treatment under experimental arterial hypertension in rats.

The article presents the results of a preclinical study of ramipril and candesartan in an experimental group of hypertensive rats of different sexes. Antihypertensive therapy was performed for 21 days. The drugs were administered daily in moderate therapeutic doses calculated for rats using the coefficient of species sensitivity. It was found that the course of experimental hypertension has gender differences, and in males, according to blood pressure, the level of NO metabolites is more pronounced. The use of ramipril from the group of ACE inhibitors and candesartan from the ARBs group in experimental hypertension in rats has gender differences. Ramipril is likely to be more effective in normalizing blood pressure and endothelial function in males than females. The use of candesartan did not show significant gender differences, but there was a tendency for females to be slightly more effective than males. Established gender differences in hypertension pharmacotherapy should be considered to optimize treatment.

Impact of Sacubitril/Valsartan Compared With Ramipril on Cardiac Structure and Function After Acute Myocardial Infarction: The PARADISE-MI Echocardiographic Substudy.

BACKGROUND: Angiotensin-converting enzyme inhibitors attenuate left ventricular (LV) enlargement after acute myocardial infarction (AMI). Preclinical data suggest similar benefits with combined angiotensin receptor neprilysin inhibition, but human data are conflicting. The PARADISE-MI Echo Study (Prospective ARNI Versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction) tested the effect of sacubitril/valsartan compared with ramipril on LV function and adverse remodeling after high risk-AMI. METHODS: In a prespecified substudy, 544 PARADISE-MI participants were enrolled in the Echo Study to undergo protocol echocardiography at randomization and after 8 months. Patients were randomized within 0.5 to 7 days of presentation with their index AMI to receive a target dose of sacubitril/valsartan 200 mg or ramipril 5 mg twice daily. Echocardiographic measures were performed at a core laboratory by investigators blinded to treatment assignment. The effect of treatment on change in echo measures was assessed with ANCOVA with adjustment for baseline value and enrollment region. The primary end points were change in LV ejection fraction (LVEF) and left atrial volume (LAV), and prespecified secondary end points included changes in LV end-diastolic and end-systolic volumes. RESULTS: Mean age was 64±12 years; 26% were women; mean LVEF was 42±12%; and LAV was 49±17 mL. Of 544 enrolled patients, 457 (84%) had a follow-up echo at 8 months (228 taking sacubitril/valsartan, 229 taking ramipril). There was no significant difference in change in LVEF (P=0.79) or LAV (P =0.62) by treatment group. Patients randomized to sacubitril/valsartan demonstrated less increase in LV end-diastolic volume (P=0.025) and greater decline in LV mass index (P=0.037), increase in tissue Doppler e'lat (P=0.005), decrease in E/e'lat (P=0.045), and decrease in tricuspid regurgitation peak velocity (P=0.024) than patients randomized to ramipril. These differences remained significant after adjustment for differences in baseline characteristics. Baseline LVEF, LV end-diastolic volume, LV end-systolic volume, LV mass index, LAV, and Doppler-based diastolic indices were associated with risk of cardiovascular death or incident heart failure. CONCLUSIONS: Treatment with sacubitril/valsartan compared with ramipril after AMI did not result in changes in LVEF or LAV at 8 months. Patients randomized to sacubitril/valsartan had less LV enlargement and greater improvement in filling pressure. Measures of LV size, systolic function, and diastolic properties were predictive of cardiovascular death and incident heart failure after AMI in this contemporary, well-treated cohort. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02924727.

Sacubitril/valsartan versus ramipril for patients with acute myocardial infarction: win-ratio analysis of the PARADISE-MI trial.

AIM: The win ratio can incorporate different types of outcomes and enhance statistical power, making it a useful method for analysing composite outcomes in cardiovascular trials. The application of this approach to the PARADISE-MI trial provides an additional perspective into understanding the effects of sacubitril/valsartan in patients with acute myocardial infarction. METHODS AND RESULTS: We conducted a post-hoc analysis of the PARADISE-MI trial, which randomly assigned patients with acute myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril/valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to guideline-recommended therapy. The principal composite outcome was analysed in the hierarchical order of death due to cardiovascular causes, first hospitalization for heart failure, and first outpatient episode of symptomatic heart failure. We included events confirmed by the clinical events classification (CEC) committee as well as events identified by investigators that did not meet study definitions. Results were analysed by the unmatched win-ratio method. A win ratio that exceeds 1.00 reflects a better outcome. A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril/valsartan and 2831 to receive ramipril. The hierarchical analysis of the principal composite outcome demonstrated a larger number of wins (1 265 767 [15.7%]) than losses (1 079 502 [13.4%]) in the sacubitril/valsartan group (win ratio of 1.17, 95% confidence interval [CI] 1.03-1.33; p = 0.015). Sensitivity analyses using alternative definitions of the composite outcome showed results similar to those of the principal analysis, except for analysis restricted to events that met CEC definitions (win ratio of 1.11, 95% CI 0.96-1.30; p = 0.16). CONCLUSION: In this post-hoc analysis of the PARADISE-MI trial using the win ratio and including investigator-identified events not having CEC confirmation, sacubitril/valsartan was superior to ramipril among high-risk survivors of acute myocardial infarction.

Polypill Strategy in Secondary Cardiovascular Prevention.

BACKGROUND: A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction. METHODS: In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke. RESULTS: A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups. CONCLUSIONS: Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).

INDICATORS OF ENDOTHELIAL DYSFUNCTION, MARKERS OF INFLAMMATION AND LIPID METABOLISM IN PATIENTS WITH HYPERTENSION WITH THE ADMINISTRATION OF QUERCETIN.

OBJECTIVE: The aim: To improve the effectiveness of treatment of patients with hypertension using metabolic therapy based on the evaluation of endothelial dysfunction indicators, markers of inflammation, and blood lipid spectrum. PATIENTS AND METHODS: Materials and methods: A clinical study was performed with 72 patients (34 male and 38 female) with stage 2 arterial hypertension of 2-3 degrees, admitted to the cardiology department of the municipal non-profit enterprise "Lviv Emergency Clinical Hospital". The mean age of patients was 44.8±8.5 years. Patients were divided into 2 groups: Group I was taking quercetin in addition to basic therapy (Ramipril/Amlodipine in individually adjusted dose); Group II - had basic therapy following the clinical protocol. The level of nitric oxide, IL-1, IL-6, TNF-a, CRP, seromucoid, blood lipid spectrum was determined. RESULTS: Results: There is a significant decrease in the NO and CRP levels. There is a decrease in the TNF-a level by 31.27±2.13 (p<0.01) after the treatment of patients with hypertension. The TNF-a level decreased by 22.2±1.13 (p<0.01) with the use of basic therapy. IL-1 decreased significantly in the two groups, but it was more pronounced in group I, by 40.68±1.67 (p<0.01) and 21.4±2.1 in group II (p<0.05). There is a positive change in the blood lipid spectrum, but the changes were more pronounced in the group of patients receiving metabolic therapy. CONCLUSION: Conclusions: The use of quercetin (Corvitin, Quertin) in combination therapy with the combined antihypertensive drug containing ramipril/amlodipine (Egis-Hungary) significantly reduces the levels of nitric oxide, CRP, IL-1, and blood lipid spectrum, which reduces the incidence of complications and progression of hypertension.