Receptor Blockers Research Articles

Sex-differences in prescription patterns of secondary prevention pharmacotherapy in patients with acute myocardial infarction: a 20-year perspective

Abstract Background Recent studies have demonstrated sex-related differences in secondary prevention pharmacotherapy in patients with acute myocardial infarction (AMI), although guidelines recommend the same preventive approach in both women and men. Purpose This study extends earlier work by examining temporal trends of prescribing practices of secondary prevention medications using contemporary data from a long-term period in Switzerland, with particular regard to sex inequalities. Methods For the purpose of this retrospective analysis of prospectively collected data in the Acute Myocardial Infarction in Switzerland (AMIS) Plus registry, optimal medical therapy (OMT) was defined as the combination of all five guideline-recommended medications in AMI at discharge: aspirin, P2Y12 inhibitors, lipid-lowering drugs, beta blockers, and angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Uni- and multivariable logistic regression analyses were performed. Results A total of 34'612 patients (men n=25’913, 75%) hospitalised with AMI between 2003 and 2022 were included in the analysis. The mean age was 66±13 years and women were on average 7 years older than men. Despite having more comorbidities, women benefited less frequently from OMT than men (51% vs. 60%) across all age groups (all p<0.001), with the greatest gap occurring in patients <50 years of age. Within the 20-year study period, significant increases over time were observed in the singular prescription of all OMT components, except for beta blockers (p=0.2). This translated into a marked increase in OMT prescription irrespective of age and sex (from 36% to 60%), mainly due to greater prescription of dual antiplatelet therapy (DAPT, from 71% to 91%) and lipid-lowering drugs (LLD, from 69% to 93%). The sex-related gap in OMT disfavoring women showed a uctuating trend over the years (getting reduced from 14% in 2003 to 0.7% in 2016 to widen again to 12% in 2022) whereas there was a continuous narrowing over time regarding the combination of DAPT plus LLD, from 18% to 10% at the beginning and the end of the observation, respectively (Figure 1). In multivariable analysis, age (OR 0.99, 95%CI 0.98-0.99, p<0.001) and female sex (OR 0.90, 95%CI 0.85-0.95, p<0.001) were independent predictors of deficient OMT prescription, while the performance of percutaneous coronary intervention was identified as the strongest positive predictor favoring it (OR 4.85, 95%CI 4.49-5.24, p<0.001). Conclusion Although there has been a gradual increase in the prescription of OMT over time among both women and men, concerning sex disparities disfavoring women, and particularly young women, remained. Targeted programs to reduce sex-related differences in secondary prevention care are warranted.

Elegibility for Sacubitril/Valsartan in italian clinical practice: insights from the OPTIMA-HF registry

Abstract Background/Introduction Guidelines strongly recommend patients with heart failure with reduced ejection fraction (HFrEF) be treated with multiple medications proven to improve clinical outcomes, as tolerated. Among them, angiotensin receptor blocker/neprylisin inhibitor (ARNi) are the foundation of neuro-hormonal blockade in patients with HFrEF, however the degree to which gaps in this medication use and dosing persist in outpatient practice is unclear. Purpose To assess the proportion of patients with HFrEF who are eligible for ARNi based on the PARADIGM-HF trial criteria and the association between eligibility and baseline characteristics. Methods The OPTIMA-HF (Optimization of Therapy in the Italian Management of Heart Failure) registry included outpatients in Italy with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB)/ARNI, beta-blocker, mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter II inhibitor (SGLT2i). Patient-level factors associated with medication use were examined. Results Outpatients with HFrEF from 29 ambulatory cardiology practices and university hospitals in the OPTIMA-HF registry recruited between January 2022 and September 2023 were included. Of 1291 patients, 1018 (79%) met the PARADIGM-HF criteria and 949 of them (93%) were on ARNi. Of the enrolled patients, 342 (27%) were not on ARNi, however only 129 (38%) did not met the PARADIGM-HF inclusion criteria for ARNi prescription. Reasons for not meeting PARADIGM-HF criteria were no beta-blocker background therapy (22%), hyperkalemia (4%), hypotension (15%), chronic kidney disease (65%) and hyperkalemia (79%). In a logistic regression model not being on ARNi was associated with older age, chronic kidney disease, not being on cardiac resynchronization therapy, lower systolic blood pressure, lower BMI, and higher PAPs (Figure), representing the picture of a more fragile patient net of compliance with the PARADIGM-HF criteria. Conclusions Among outpatients with HFrEF in the OPTIMA-HF Registry, 79% met the PARADIGM-HF criteria. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.

Heart failure burden among adults with congenital heart disease

Abstract Background Adult congenital heart disease (ACHD) is associated with high rates of healthcare utilization and mortality. Data on Heart failure (HF) burden among ACHD patients are limited. Purpose To study the association between HF and healthcare utilization and mortality among ACHD patients in the community. Methods The retrospective cohort study comprised 11,653≥ 18 year old ACHD patients insured by two large Israeli healthcare providers between January 2007 and December 2011. We used multivariable Cox proportional hazard and negative binomial models to study the associations of HF with mortality and healthcare utilization, respectively. Inverse treatment probability weighting accounted for drug indication. Results ACHD-HF patients (N=908; 7.8%) were older (median: 69 vs. 45 years), more likely men (53% vs. 45%), with complex congenital heart disease (14% vs. 4%), and higher comorbidity rates than ACHD patients without HF. HF was associated with higher healthcare utilization. Compared to patients without HF, ACHD-HF patients had higher adjusted relative rates (RR) of primary care (1.26, 95% confidence interval [CI]: 1.17-1.3), and cardiology clinic visits (1.9, 95% CI: 1.7-2.0), higher hospitalization rates (RR=2.0, 95% CI: 1.7-2.1), and higher risk of death (mortality hazard ratio [HR]: 1.9, 95% CI: 1.5-20.) over the study period. Among ACHD-HF patients, Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and diuretics were associated with a lower mortality risk (treated vs. untreated HR=0.56, 95% CI: 0.48-0.65; HR=0.7, 95% CI: 0.6-0.8; HR=0.84, 95% CI: 0.73-0.97; respectively). Conclusions HF presents a major burden on ACHD patients and health care systems. Drugs recommended to the general HF patient population are also associated with lower risk of hospitalization and mortality in ACHD patients. Clinical trials are needed to establish the benefit of HF pharmacotherapy in ACHD patients.Age adjusted ACHD patient survival by HF

Clinical characteristics and treatment patterns of new users of dapagliflozin for heart failure with reduced ejection fraction: an observational study programme across 12 countries (EVOLUTION HF)

Abstract Background Clinical trials have shown that dapagliflozin, a sodium–glucose cotransporter-2 inhibitor (SGLT-2i), reduces cardiovascular mortality and worsening heart failure (HF). Adoption of new therapies has historically been slow despite robust evidence. Furthermore, treatment profiles of patients in real-world settings are scarce. Purpose EVOLUTION HF is a multinational study programme that aims to describe clinical characteristics and treatment patterns among patients initiating dapagliflozin for HF with reduced ejection fraction (HFrEF) in routine clinical practice. Methods The EVOLUTION HF primary data study programme consists of prospective, observational, descriptive studies of new users of dapagliflozin for HFrEF in 12 countries (Italy, Portugal, UK and the Central and Eastern Europe and Baltic [CEEBA] region [Bulgaria, Croatia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania and Slovenia]). Patients with type 1 diabetes or prior SGLT-2i treatment were excluded. Clinical characteristics were obtained from electronic health records. A total of 2170/2555 (85%) patients were enrolled from November 2021 to November 2023; 1736 patient profiles were assessed using descriptive statistics in this interim analysis. Results In total, 256, 228, 125 and 1127 new dapagliflozin users were analysed from Italy, Portugal, the UK and the CEEBA region, respectively (Table 1). Across the 12 countries, mean patient age in the studies was 65–70 years. Patients were predominantly male (67–76%) and generally had HF with an ischaemic aetiology (35–56%) and New York Heart Association functional class II (52–85%). Mean left ventricular ejection fraction in the studies was 29–32% and estimated glomerular filtration rate was 61–77 mL/min/1.73m². Hypertension and atrial fibrillation were common comorbidities. Mean time between HF diagnosis and dapagliflozin initiation in the studies was 23–52 months. Background therapy included angiotensin receptor-neprilysin inhibitors (36–72%), angiotensin receptor blockers (4–12%) and angiotensin-converting enzyme inhibitors (9–33%). At 6 and 12 months after dapagliflozin initiation, respectively, treatment discontinuation rates across the CEEBA region were 5.22% (59/1131) and 4.66% (50/1072). Conclusions The EVOLUTION HF primary data study programme provides novel insights into clinical characteristics and treatment patterns in patients with HFrEF initiating dapagliflozin in real-world practice across a broad European population. At dapagliflozin initiation, a large proportion of patients were receiving other HF therapeutics, suggesting dapagliflozin is one of the later therapies to be initiated. Indeed, this study identified a substantial delay (23–52 months) in dapagliflozin initiation following HF diagnosis. Treatment discontinuation rates following dapagliflozin initiation were also low, reinforcing the findings of the EVOLUTION HF secondary data studies.

Association of ticagrelor vs clopidogrel with net adverse clinical events in patients with mild thrombocytopenia undergoing PCI

Abstract Backgrounds Current guidelines recommend aspirin plus ticagrelor as the preferred dual antiplatelet therapy (DAPT) for managing ST-elevation myocardial infarction (STEMI). However, there is a lack of consensus or guidelines to direct clinicians on managing patients with mild thrombocytopenia, defined as a platelet count of 100~150×109/L, undergoing percutaneous coronary intervention (PCI). Purpose This study aims to investigate the association between ticagrelor and clopidogrel with ischemic and hemorrhagic events for patients with mild thrombocytopenia undergoing PCI. Methods A retrospective cohort study of patients with mild thrombocytopenia undergoing PCI who received DAPT consisting of aspirin and a P2Y12 receptor antagonist (includinig clopidogrel or ticagrelor) was conducted using Health and Medical Big Data Super Platform from January 2010 to June 2023. All patients meeting the criteria were included in the analysis, with a follow-up of at least one year. Propensity Score Matching (PSM) was performed to equalize the effects of following characteristics: age, sex, hypertension, diabetes, dyslipidemia, stroke, atrial fibrillation, Killip class, percutaneous coronary intervention (PCI), beta-blockers, statins, calcium channel blockers (CCB), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI or ARB), angiotensin receptor-neprilysin inhibitor (ARNI), diuretic, organic nitrates, and oral anticoagulation. The primary endpoint was net adverse clinical events (NACE) at 1 year, composed of ischemic events (recurrent myocardial infarction or ischemic stroke), Bleeding Academic Research Consortium (BARC) classification ≥ 3, and cardiac death. Secondary outcomes included the components of NACE. Results A total of 3647 patients met the inclusion criteria, with 2684 receiving aspirin plus clopidogrel and 963 receiving aspirin plus ticagrelor, matched by a 1:3 ratio using the PSM method. Demographic characteristics were well balanced between the clopidogrel and ticagrelor groups. The 1-year risk of NACE did not significantly differ between ticagrelor and clopidogrel (11.1% vs. 8.4%, p=0.370). Similarly, there was no significant difference in the risk of cardiac death (7.3% vs. 4.2%, p=0.720), recurrent myocardial infarction (9.3% vs. 5.8%, p=0.550), ischemic stroke (8.8% vs. 6.7%, p=0.055), or BARC type ≥ 3 bleeding (7.9% vs. 4.5%, p=0.990). Conclusion In routine clinical practice, among patients with a platelet count of 100~150×109/L undergoing PCI, ticagrelor compared with clopidogrel was not associated with a significant difference in the risk of NACE at 1 year. Further research is warranted to assess whether ticagrelor is more effective than clopidogrel in this setting, considering potential unmeasured confounders.

Guideline-directed medical therapy implementation changes after acute coronary syndrome and their effect of prognosis: insights from Japanese real-world database using a storage system

Abstract Background The implementation of guideline-directed medical therapy (GDMT) after acute coronary syndrome (ACS) was reported to improve prognosis. However, there have been limited number of real-world studies clarifying the association between the status of GDMT implementation and clinical prognosis in ACS patients based on recent multicenter database. Purpose The purpose of this study was to survey the extent to which GDMT was performed over time in patients after percutaneous coronary intervention (PCI) for ACS, as well as to investigate the prognostic impact of GDMT. Methods This study is a retrospective, multicenter, observational study. We developed the Clinical Deep Data Accumulation System (CLIDAS), which consists of 6 university hospitals and the national cardiovascular center in Japan, directly obtains clinical data including patients background, laboratory data, echocardiogram, electrocardiogram, cardiac catheterization report, prescription, and long-term outcome from electronic medical records. 4107 patients who underwent PCI for ACS and were prescribed one or more antiplatelet drugs at baseline from April 2013 to March 2019 were analyzed, and divided into GDMT group (n = 2514) and non-GDMT group (n = 1593). GDMT was defined as all prescriptions for angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, beta-blocker, and statin at baseline. The primary outcome was the major adverse cerebrocardiovascular event (MACCE) defined as being the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Results The median follow-up duration was 2.36 years (interquartile range: 0.78-4.00 years). The study cohort consisted of 76% of men with a median age of 71 years. The incidence of MACCE was significantly lower in the GDMT group than in the non-GDMT group (8.8% vs. 13.0%, log rank P <0.001). Multivariable Cox regression analyses revealed that the GDMT group was a lower hazard ratio (HR) for MACCE after adjusting for confounding factors including the information about the first half and the second half (HR, 0.80; 95% confidence interval, 0.65-0.98; P = 0.035). The implementation rate of GDMT in the first half group (from April 2013 to March 2016) was lower than that in the second half group (from April 2016 to March 2019) (58.3% vs. 64.4%, P <0.001). Conclusion The real-world CLIDAS database revealed that GDMT was significantly associated with the reduction of MACCE in patients with ACS after PCI. In addition, an increase in the rate of GDMT implementation over time was observed.Kaplan-Meier curves for MACCE

ACE inhibitor and angiotensin receptor blocker use during pregnancy: data from the ESC Registry of pregnancy and cardiac disease (ROPAC)

Abstract Background and Aims Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are not recommended during the second and third trimester due to the significant risk of congenital anomalies associated with their use. However, data are scarce, especially regarding their use in the first trimester. Our study illustrates the profile of the women who used ACE-Is or ARBs during pregnancy and to evaluate the impact on perinatal outcomes. Methods The Registry of Pregnancy and Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with structural heart disease. Outcomes were compared between women who used ACE-Is or ARBs and those who did not. Multivariable regression analysis was performed to assess the effect of ACE-I or ARB use on the occurrence of congenital anomalies. In addition, the perinatal outcomes of patients who stopped ACE-Is and/or ARBs before pregnancy were assessed. Results ACE-I (n=35) and/or ARB (n=8) were used in 42 (0.7%) of the 5739 ROPAC pregnancies. Women who used ACE-Is or ARBs more often came from a low-or-middle-income country (57% vs 40%, p=0.021), had chronic hypertension (31% vs 6%, p<0.001), or a left ventricular ejection fraction <40% (33% vs 4%, p<0.001). No pregnancy terminations due to fetal anomaly were reported. ACE-I use during the first trimester was independently associated with an increased risk of congenital anomaly (OR 3.1; 95% CI 1.0-9.3). No adverse fetal or neonatal effects were seen when ACE-I and/or ARB were discontinued prior to pregnancy. Conclusions ACE-Is and ARBs are seldom used during pregnancy and based on our data, ACE-Is should also be avoided in the first trimester due to a higher risk of congenital anomalies. Preconception counseling is crucial to discuss the potential risks of these medications, and to evaluate the clinical condition and, if possible, the woman can be switched to an alternative medication.

Modern heart failure treatment is superior to conventional treatment across the left ventricular ejection spectrum: Real-life data from the Swedish Heart Failure Registry 2013-2020

Abstract Background Heart failure (HF) is a clinical syndrome characterized by high mortality and morbidity. In 2016, Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was recommended as a new treatment option for HF in patients with HFrEF. In the 2021 European Society of Cardiology guidelines for treatment of HFrEF patients Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were introduced because they demonstrated significantly reduced HF events or cardiovascular (CV) mortality. Since ARNI and SGLT2i were introduced to treat HF, its therapeutic regimen has modernized from previous treatment with beta-blocker (BB) and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) with mineralocorticoid receptor antagonist (MRA) as added-on in HF with reduced ejection fraction (HFrEF). Purpose This study is aimed to compare effectiveness of modern therapy including ARNI and SGLT2i with conventional heart failure treatment. Conventional HF treatment includes (BB, ACEi/ARB, with or without MRA) and modern heart failure treatment (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i) in real-world. Methods This observational study (2013-2020), using the Swedish HF Registry, involved 20,849 HF patients. Patients received either conventional (BB, ACEi/ARB, with/without MRA, n=20,140) or modern (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i, n=709) treatment at the index visit. The endpoints were all-cause and cardiovascular (CV) mortality. Results Modern HF therapy was associated with a significant 28% reduction in all-cause mortality compared to conventional HF treatment (adjusted HR [aHR]: 0.72 (95% CI 0.54 - 0.96), p=0.024), and had 33% reduced all-cause mortality (aHR: 0.67 (95% CI 0.48 - 0.94), p=0.019) within 2 years of index registration. Similarly, modern HF therapy was associated with a significant 62% reduction in CV mortality compared to conventional HF treatment (aHR: 0.38 (95% CI 0.21 - 0.68), p=0.0013). In addition, we found a 58% reduced CV mortality (aHR 0.42 (95% CI 0.22 - 0.79), p=0.0067) within 2 years of index registration. In the propensity score 1:1 matched cohort in which ARNI was included in the matching procedure, i.e., no ARNI was used in any of the two treatment groups and the effect of SGLT2i was the target assessment. The results were associated with a statistically significant risk reduction of 42% in all-cause mortality in the modern HF treatment group compared to the conventional treatment group (aHR: 0.58 (95% CI 0.36 - 0.94), p=0.028), and a 49% (aHR: 0.51 (95% CI 0.29 - 0.89), p=0.018) risk reduction within 2 years of index registration. Conclusion This study demonstrates that modern HF therapy in a real-world Swedish HF population is associated with a statistically significant risk reduction in all-cause and CV mortality, regardless of EF, sex, age, eGFR, and etiology of HF compared to conventional HF therapy.Central Illustration

Effect of renin-angiotensin system inhibitors in elderly patients with heart failure and reduced ejection fraction

Abstract Background More than half of the patients admitted for acute decompensated heart failure (ADHF) in Japan are over 80 years of age. Both Japanese and European heart failure guidelines recommend the use of renin-angiotensin system inhibitors (RASIs) in patients with heart failure with reduced ejection fraction (HFrEF). However, there is a paucity of data on the effect of RASIs in elderly patients with HFrEF, because elderly patients have been excluded from large clinical trials. Purpose The purpose of the current study was to clarify the effect of RASIs in elderly patients with HFrEF. Methods This was a post-hoc analysis of a prospective, observational, multicentre cohort study that enrolled consecutive patients admitted with ADHF to 19 secondary and tertiary hospitals in Japan between October 2014 and March 2016. Patients who were ≥ 80 years old, with left ventricular ejection fraction (LVEF) < 40% and discharged alive were included in the present study. RASIs were defined as either ACE inhibitors or angiotensin II receptor blockers. The primary endpoint was a composite of all-cause death and heart failure (HF) hospitalisation. Results Among 518 patients enrolled, 288 patients received RASIs at discharge and 230 patients did not. The median follow-up period was 335 days (interquartile range; 124 – 499 days). Patients receiving RASIs were younger (85.7 ± 4.4 vs. 86.5 ± 4.4 years of age, p=0.03), had a higher body mass index (BMI; 21.4 ± 3.3 vs. 20.6 ± 3.7 kg/m², p=0.01) and better renal function (eGFR; 45.4 ± 21.5 vs. 38.2 ± 19.2 ml/min/1.73m², p<0.001). Patients receiving RASIs had a higher LVEF (30.9 ± 6.3 vs. 28.5 ± 7.1%, p<0.001). The use of beta-blockers at discharge was more prevalent in patients receiving RASIs (77.8% vs. 60.4%, p<0.001), but the use of mineralocorticoid receptor antagonists was not (50.0% vs. 42.2%, p=0.08). The cumulative incidence of all-cause death or HF hospitalisation one year after discharge was significantly lower in patients receiving RASIs (40.1% vs. 59.5%, p<0.001). Even after adjusting for confounders, the risk of a composite of all-cause death and HF hospitalisation was significantly lower in patients receiving RASIs (adjusted hazard ratio 0.59, 95% confidence interval 0.45-0.77, p<0.001). There was no interaction between the effect of RASIs and subgroup factors such as age, BMI, dementia, malignancy, frailty, and renal function. Conclusion Use of RASIs at discharge was associated with lower incidence of all-cause death or HF hospitalisation in elderly patients with HFrEF.

Guideline-directed medical therapy titration for heart failure with ischaemic aetiology and its effect on cardiac remodelling and cardiovascular mortality-from a real world perspective

Abstract Background Contemporary Heart Failure (HF) pharmacological treatment has been reshaped by several landmark trials in recent years, and available evidence strongly encourages treatment up-titration to target doses. Recent literature regarding treatment sequencing demonstrated positive effects of up-titration on major outcomes regardless of HF aetiology. Purpose We investigated a contemporary Heart Failure with Reduced Ejection Fraction (HFrEF) patient cohort and ischaemic aetiology and sought to understand the effects both in terms of echocardiographic remodelling and upon mortality for cardiovascular (CV) causes of contemporary ESC guideline-directed medical therapy (GDMT) on a real-world level. Methods We retrospectively analysed data of consecutive patients with HFrEF and ischaemic genesis followed in our tertiary HF clinic between January 2019 and January 2022. Eligible patients were stratified into two groups: patients treated or not with full doses of ESC GDMT [including angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i)]. Results Overall, 203 patients (mean age 70.1±12.3 years, 165 males) were included into the analysis. Over a mean follow-up of 1223±221.2 days, 115 (56.6) patients achieved the full recommended doses of each drug. Patients with an unsuccessful up-titration had higher end-diastolic volume at transthoracic echocardiography (p for difference at first and second follow-up <0.001; figure 1, panel A), lower left ventricular ejection fraction (40.1±4.3% vs 44.3±7.8 and 38.7±4.9% vs 42.3±5.6% at the first and second follow-up, respectively) and higher CV mortality rates compared to those treated with the maximal doses (figure 1, panel B). Conclusions Up-titration of pharmacotherapy in our real-world cohort of patients with HFrEF and ischaemic aetiology demonstrated a positive effect both on pivotal echocardiographic parameters and on CV mortality. Our data suggest that timely identification and referral of patients with coronary artery disease who fail to achieve complete positive remodelling after an acute event (or during chronic disease course) for HF contemporary treatment implementation should be envisaged.Figure 1

Prognostic role of right ventricular-pulmonary artery coupling assessed by TAPSE/PASP ratio in patients with heart failure and mildly reduced ejection fraction

Abstract Background The development of right ventricular (RV)-pulmonary arterial (PA) coupling has resulted in a novel and comprehensive index for evaluating RV function in relation to the underlying RV afterload. In patients with heart failure (HF), it is acknowledged that RV-PA uncoupling are features that are associated with poor outcome. The RV-PA coupling index can be readily assessed non-invasively using the ratio of two standard echocardiographic measurements: tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP). However, few studies have defined the prognostic impact of the TAPSE/PASP ratio in patients with HF and mildly reduced EF (HFmrEF). Methods From the prospective cohort study of 1,410 hospitalized HF patients (age 68+/-15, men 62%) between August 2015 and September 2019, this study enrolled 191 HFmrEF (i.e., left ventricular ejection fraction (LVEF) 41–49%) patients whose TAPSE and PASP were measured during hospitalization and discharged alive. We studied the prognostic impact of TAPSE/PASP ratio on HFmrEF patients using by cut-off value obtained from receiver operating characteristic (ROC) analysis. The primary and secondary endpoints was defined as the all-cause death and HF re-hospitalization after discharge, respectively. Results During median follow-up of 38 [23–52] months, 48 patients (25%) died. The deceased patients had a significantly older (median 75 vs. 71 years, p<0.05), higher rate of ischemic heart disease (50% vs. 23%, p<0.05), elevated brain natriuretic peptide levels (325 vs. 159 pg/ml, p<0.05) and lower rate of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (65% vs. 80%, p<0.05) at discharge. In the ROC analysis, the cut-off value of TAPSE/PASP ratio for mortality was 0.46. Patients with TAPSE/PASP ≤0.46 had a significantly higher all-cause mortality (log-rank p<0.05) and had a tendency of higher rate of HF re-hospitalization than patients with TAPSE/PASP >0.46 (log-rank p=0.06) (Figure). Using multivariate analysis, the lower TAPSE/PASP ratio had an independent predictive value of prognosis in patients with HFmrEF (hazard ratio 2.16, 95% confidence interval; 1.08–3.92, p<0.05) (Table). Conclusion The TAPSE/PASP ratio has a significant prognostic value in patients with HFmrEF. The RV-PA uncoupling assessed by TAPSE/PASP ratio might be useful for risk assessment in patients with HFmrEF.

Pregnancy protection in women of child-bearing age prescribed ACE inhibitors, ARBs or statins - A nationwide cohort study

Abstract Background Cardiometabolic disorders, including hypertension, type-2 diabetes, and hyperlipidemia are increasingly prevalent among younger people. Consequently, women of child-bearing age may be prescribed renin-angiotensin system (RAS) inhibitors and statins. Both angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are known teratogens. Statins are considered possibly teratogenic. In Denmark, ACEIs and ARBs have a ‘Do not use’ recommendation in pregnancy while statins ‘Should not be used’ in pregnancy. Previous studies have reported widespread use of RAS inhibitors without concomitant contraception among women of child-bearing age. This study investigated the situation in Denmark. Purpose To examine prescribing patterns of RAS inhibitors and statins alongside use of concomitant contraception among women of child-bearing age in Denmark. Methods Using nationwide Danish registers, women aged 15–50 years initiating ACEIs, ARBs and statins during 1995–2021 were identified and use of concomitant contraception was evaluated. Contraception was categorized as oral pill, implant, intrauterine device (IUD), or non-use. The duration of protection was assumed to be 1 year for oral contraceptives, 2 years for implants and 4 years for IUDs. Where multiple types of contraceptives were retrieved by individual patients, they were categorized as taking the contraceptive retrieved most recently. Data on non-prescription contraceptives were unavailable, e.g., condoms. Women unable to conceive due to infertility were excluded. Results 79 547 women (median age: 44 years; [interquartile range (IQR): 39–47]) on ACEIs, 64 326 women (median age: 44 years [IQR: 38–48]) on ARBs, and 71 499 women (median age: 45 years [IQR: 40–48]) on statins were included (Figure 1). Correspondingly, 69.1%, 62.8%, and 73.5% were not on contraceptives when starting treatment. Among women prescribed contraception: 70.2%/56.2%/63.1% were on oral contraceptives, 25.3%/30.9%/26.6% had IUDs and 4.5%/12.9%/10.3% had implants, respectively (Figure 1). Younger patients aged 15–29 years were least likely to be unprotected with 41.8%/29.7%/33.4% being unprotected. Among women aged 25 to 35 years the percentage of unprotected women was 51.3%/41.1%/47.7%. Older patients were more likely to have IUDs. Conclusion Substantial numbers of women of child-bearing age were prescribed ACEIs, ARBs and statins from 1995–2021. Most were not prescribed contraceptives. The lack of prescribed pregnancy protection was prevalent even among the youngest women aged 15–29 years and women aged 25 to 35 years, who are the most likely to become pregnant—inferring a potential risk of teratogenic exposure during pregnancy (Figure 2). Subsequent studies should investigate the extent of exposure to ACEIs, ARBs, and statins during pregnancy and the impact of the exposure on pregnancy outcomes.Figure 1 Contraceptive useFigure 2 Study rationale

Guideline-directed medical therapy patterns in heart failure with reduced ejection fraction: the OPTIMA-HF registry

Abstract Background/Introduction European guidelines strongly recommend an optimized pharmacological treatment in patients with heart failure with reduced ejection fraction (HFrEF) with a fast introduction of the four-pillars. Purpose Aim of the Optimization of Therapy in the Italian Management of Heart Failure [OpTIMa-HF] Registry was to collect data on HF patients to describe the current Italian population of HF patients with a specific focus on HFrEF treatment adherence and prescription rates, according to the most recent European Guidelines. Methods OPTIMA-HF is an observational, cross-sectional, multicenter, real-life study conducted in two different clinical settings: HF outpatients’ clinics of Italian University Hospitals and territorial Italian Cardiology outpatients’ services, that enrolled patients with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter II inhibitor (SGLT2i). Patient-level factors associated with medication use were examined. Results Overall, 1390 patients from 29 ambulatory cardiology practices and university hospitals were included. Mean age was 69.5 ± 11.9 years, 24% were female, and median EF was 33 (28-37). Among enrolled patients, 72.2% were prescribed ARNI, 17.1% ACEI/ARB, 95% beta-blocker, 75.5% MRA and 63% SGLT2i therapy (Figure 1). Despite high prescription rates for each single class, a still not sufficient number of patients was on treatment with all four pillars, in particular 40.4% considering the presence ARNI and 6.2%. When medications were prescribed, few patients were receiving target doses of ACEI/ARB (31.7%), ARNI (16%), and beta-blocker (33.3%), whereas a higher proportion were receiving target doses of MRA therapy (38%), and all were receiving target dose for SGLT2i. Among patients eligible for all classes of medication, only 1.1% were simultaneously receiving target doses of ACE/ARB/ARNI, beta-blocker, MRA and SGLT2i. Prescription rates did not significantly differ between the type of center (University Hospital vs. territorial Cardiology outpatients’ services). As regards patients not on treatment with any of the four pillars, a small but still present amount of patients had no contraindications to these drugs (Figure 1). Conclusions In this contemporary outpatient HFrEF Italian registry, significant high prescription rates of the four-pillars were observed, however therapy combination rate is still not sufficient and drugs' titration need to be implemented to receive the greatest benefits from an optimized treatment. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.

Comparative Study of Olmesartan versus Telmisartan, in Patient with Stage I Hypertension

Background: Hypertension is one of the most common diseases in the world. It is defined as sustained increase in blood pressure ≥ 140/90 mmHg. The risk of both microvascular & microvascular complications including stroke, coronary artery disease, peripheral vascular disease, retinopathy, nephropathy & possibly neuropathy increases with hypertension. Olmesartan medoxomil is a non-peptide angiotensin II receptor antagonist. The drug acts by selectively blocking angiotensin II type 1 receptor. Telmisartan is angiotensin receptor blocker shows high affinity for the angiotensin II type 1 receptors. Objective of the study is to compare the efficacy of Olmesartan and Telmisartan in Patient with stage –I hypertension. Materials and methods: This was a randomized, open‑label, parallel‑group, comparative study conducted in 120 patients of Stage I hypertension carried out from January 2021to June 2022. Patients were recruited from the cardiology outpatient department (OPD) of Shaheed Suhrawardy Medical College hospital.Results: In olmesartan group there were 39 male and 21 female patients and in telmisartan group there were 36 male and 24 female patients. Both Olmesartan and Telmisartan are effective in lowering systolic & diastolic BP at different intervals of 2nd, 4th, 8th and 12th week. There was a statistically significant decrease in mean blood glucose level after 12 weeks of treatment in telmisartan group when compared to baseline. Serum total cholesterol, triglycerides, and low‑density lipoproteins decreased significantly after 12‑week treatment with olmesartan and telmisartan. Conclusion: Olmesartan and telmisartan are equally efficacious in reducing DBP. Olmesartan, when compared to telmisartan is more efficacious in reducing SBP. Whereas Telmisartan shows the most favorable effects on FBG and lipid profile. J Shaheed Suhrawardy Med Coll 2023; 15(1): 8-12

The Selective Endothelin Receptor Antagonist SC0062 in IgA Nephropathy: A Randomized Double-Blind Placebo-Controlled Clinical Trial.

Key Points Patients with IgA nephropathy and significant proteinuria are at high risk of progressive kidney function loss and kidney failure.We report the results of a clinical trial assessing the selective endothelin receptor antagonist SC0062 for the treatment of IgA nephropathy.SC0062 led to clinically meaningful improvements in proteinuria and did not increase risk of peripheral edema at higher doses. Background Endothelin receptor type A activation contributes to kidney injury in patients with IgA nephropathy. SC0062 is a novel selective endothelin receptor type A antagonist. We report the results of a phase 2 dose-finding trial to characterize the efficacy and safety of SC0062 in patients with IgA nephropathy. Methods We conducted a randomized, placebo-controlled, double-blind, clinical trial in adults with biopsy-proven IgA nephropathy and eGFR ≥30 ml/min per 1.73 m2 with urinary protein-creatinine ratio (UPCR) ≥0.75 g/g or proteinuria ≥1 g/24 hour despite using maximum tolerated doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were randomized 1:1:1:1 to 24-week treatment with SC0062 5, 10, and 20 mg or matching placebo once daily. The primary efficacy outcome was percent change from baseline in UPCR in 24-hour urine samples after 12 weeks of treatment. Secondary end points included changes in eGFR. Safety outcomes including treatment emerging adverse events and serious adverse events were recorded. Results Overall, 131 patients (mean age 42 years [SD, 11]; mean eGFR 72 ml/min per 1.73 m2 [SD 24] and median 24-hour UPCR 1.2 g/g [25th–75th percentile, 0.9–1.5 g/g]) were randomized to placebo (n=34) or SC0062 5 mg (n=33), 10 mg (n=32), or 20 mg (n=32). All SC0062 doses reduced UPCR versus placebo throughout treatment. At week 12, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UPCR with SC0062 5, 10, and 20 mg were−27.6% (−43.0 to −8.2), −20.5% (−37.4 to 1.0), and −38.1% (−51.4 to −21.0), respectively, and at week 24 they were−22.4% (−42.2 to 4.3), −30.9% (−48.6 to −7.0), and −51.6% (−64.2 to −34.6), respectively. No differences in eGFR were observed among treatment groups. The proportion of participants with treatment emerging adverse events or serious adverse events was balanced among treatment groups. Peripheral edema was reported by 2 (6%), 1 (3%), 1 (3%) participants in the 5, 10, and 20 mg SC0062-treated groups, respectively, compared with 5 (15%) in the placebo group. Conclusions In patients with IgA nephropathy, SC0062 reduced proteinuria and did not increase risk of peripheral edema. Clinical Trial registry name and registration number: A Study to Evaluate the Efficacy and Safety of SC0062 in the Treatment of CKD, NCT05687890.

ACE Inhibitors and Angiotensin Receptor Blockers for the Primary and Secondary Prevention of Cardiovascular Outcomes: Recommendations from the 2024 Egyptian Cardiology Expert Consensus in Collaboration with the CVREP Foundation.

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in regulating blood pressure (BP), with dysregulation of RAAS resulting in hypertension and potentially heart failure (HF), myocardial infarction (MI), cardio-renal syndrome, and stroke. RAAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs), have advantages beyond BP control. However, differences between these two drug classes need to be considered when choosing a therapy for preventing cardiovascular events. A panel of 36 Egyptian cardiologists developed consensus statements on RAAS inhibitors for primary and secondary prevention of cardiovascular outcomes and stroke, using a modified three-step Delphi process. The consensus statements highlight the importance of effective BP control and the role of RAAS blockade for prevention and management of various cardiovascular diseases. ACEis and ARBs differ in their mode of action and, thus, clinical effects. On the basis of available evidence, the consensus group recommended the following: ACEis should be considered as first choice (in preference to ARBs) to reduce the risk of MI, for primary prevention of HF, and for secondary prevention of stroke. ACEis and ARBs show equivalent efficacy for the primary prevention of stroke. Evidence also favors the preferential use of ACEis in patients with type 2 diabetes, for BP control, for the primary prevention of diabetic kidney disease, and to reduce the risk of major cardiovascular and renal outcomes. Treatment with an ACEi should be started within 24 h of ST segment elevation MI (and continued long term) in patients with HF, left ventricular systolic dysfunction, and/or diabetes. Angiotensin receptor/neprilysin inhibitors (ARNIs) are the first choice for patients with HF and reduced ejection fraction, with ACEis being the second choice in this group. ARBs are indicated as alternatives in patients who cannot tolerate ACEis. ACEis may be associated with cough development, but the incidence tends to be overestimated, and the risk can be reduced by use of a lipophilic ACEi or combining the ACEi with a calcium channel blocker. RAAS blockade is an essential component of hypertension therapy; however, the protective effects provided by ACEis are superior to those of ARBs. Therefore, an ACEi is indicated in almost all cases, unless not tolerated.

Renin–angiotensin system inhibition and mortality in patients undergoing dialysis with coronary artery disease: insights from a multi-center observational study

ABSTRACT Background While the survival benefits of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are firmly established in the general population, their efficacy within patient undergoing dialysis with coronary artery disease (CAD) remains controversial. Methods Between January 2015 and June 2021, 1168 patients undergoing dialysis with CAD were assessed from 30 tertiary medical centers. The primary outcome was all-cause death, and the secondary outcome was cardiovascular death. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for between-group differences. Results Overall, ACEI or ARB were prescribed to 518 patients (44.3%) upon discharge. After a median follow-up of 22.2 months, 361 (30.9%) patients died, including 243 cardiovascular deaths. The use of ACEI or ARB was associated with a significantly lower risk of all-cause (25.3% vs 35.4%, hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.52–0.82, p < 0.001) and cardiovascular death (17.0% vs 23.8%; HR 0.64, 95% CI 0.48–0.83, p = 0.001). These findings remained consistent across IPTW and PSM analyses. Sensitivity analyses for ACEI and ARB use separately yielded similar results. Conclusions Our findings suggested that among patients undergoing dialysis with CAD, ACEI or ARB use was associated with a lower risk of all-cause and cardiovascular death.

Evaluation effect of alginate hydrogel containing losartan on wound healing and gene expression.

Skin tissue engineering has become an increasingly popular alternative to conventional treatments for skin injuries. Hydrogels, owing to their advantages have become the ideal option for wound dressing, and they are extensively employed in a mixture of different drugs to accelerate wound healing. Sodium alginate is a readily available natural polymer with advantages such as bio-compatibility and a non-toxicological nature that is commonly used in hydrogel form for medical applications such as wound repair and drug delivery in skin regenerative medicine. Losartan is a medicine called angiotensin receptor blocker (ARB) that can prevent fibrosis by inhibiting AT1R (angiotensin II type 1 receptor). In this research, for the first time, three-dimensional scaffolds based on cross-linked alginate hydrogel with CaCl2 containing different concentrations of losartan for slow drug release and exudate absorption were prepared and characterized as wound dressing. Alginate hydrogel was mixed with 10, 1, 0.1, and 0.01mg/mL of losartan, and their properties such as morphology, chemical structure, water uptake properties, biodegradability, stability assay, rheology, blood compatibility, and cellular response were evaluated. In addition, the therapeutic efficiency of the developed hydrogels was then assessed in an in vitro wound healing model and with a gene expression. The results revealed that the hydrogel produced was very porous (porosity of 47.37 ± 3.76µm) with interconnected pores and biodegradable (weight loss percentage of 60.93 ± 4.51% over 14days). All hydrogel formulations have stability under various conditions. The use of CaCl2 as a cross-linker led to an increase in the viscosity of alginate hydrogels. An in vitro cell growth study revealed that no cytotoxicity was observed at the suggested dosage of the hydrogel. Increases in Losartan dosage, however, caused hemolysis. In vivo study in adult male rats with a full-thickness model showed greater than 80% improvement of the primary wound region after 2weeks of treatment with alginate hydrogel containing 0.1mg/mL Losartan. RT-PCR and immunohistochemistry analysis showed a decrease in expression level of TGF-β1 and VEGF in treatment groups. Histological analysis demonstrated that the alginate hydrogel containing Losartan can be effective in wound repair by decreasing the size of the scar and tissue remodeling, as evidenced by future in vivo studies.

Topical application of beta-blockers accelerates epithelialization to mesh skin grafted full-thickness burn in sheep

Aim : Beta-adrenergic receptor blockers are conventionally used for the treatment of hypertension, tachycardia, and glaucoma. Research has shown that beta-blockers can accelerate wound epithelialization. In this study, we tested the efficacy of the beta-blocker timolol in an ovine model of grafted full-thickness burn wound healing, which closely mimics clinical scenarios. Methods : Six full-thickness burn wounds were created on the sheep’s posterior surface. Twenty-four hours later, eschars were excised and meshed skin was grafted (Day0). The wounds in the treatment group received topical application of timolol. Blood flow was measured using a blood perfusion imager. Cardiovascular hemodynamics and blood glucose levels were recorded daily. The epithelialization rate on Day 14 was determined by planimetric assay and analyzed by paired t -test. The days that the epithelialization rate exceeded 85%, 90%, and 95% were analyzed by survival analysis. To assess the potential influence of TGFβ, epithelial-mesenchymal transition (EMT), or myofibroblast activation (MFA) on wound healing, the RNA abundance of gene products related to these pathways was measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). Results : The epithelialization rate on Day 14 was significantly higher in the treatment group. The days that the epithelialization rate exceeded 85%, 90%, and 95% were significantly shorter in the treatment group. There was no significant difference in wound blood flow or RNA abundance related to TGFβ, EMT, or MFA-related pathways among the groups at any time point. Conclusion : The results demonstrate that the beta-blocker timolol accelerates epithelialization of mesh skin grafted full-thickness burn wounds through a mechanism other than improving wound blood flow.

Analysis factors influencing left ventricular thrombus in patients with non-ischemic heart failure

Objective: To explore the influencing factors of left ventricular thrombus (LVT) in patients with non-ischemic heart failure (NIHF) and to construct a nomogram prediction model for NIHF patients with LVT. Methods: This study was a case-control study. A total of 2 592 patients with NIHF hospitalized in Beijing Anzhen Hospital affiliated to Capital Medical University from January 2018 to July 2022 were selected. Fifty-one patients with LVT identified by echocardiography and cardiac magnetic resonance were classified into LVT group. One hundred and sixty patients were selected as the non-LVT group using a 1∶3 propensity score matching based on age and gender. Multivariate logistic regression analysis was used to explore the influencing factors of LVT in patients with NIHF. A nomogram prediction model was constructed, and the area under (AUC) the receiver operating characteristic (ROC) curve was calculated to evaluate the predictive effect of the model. Results: A total of 211 patients were enrolled, with a median age of 40 years old and 160 males (76%). Compared with non-LVT group, LVT group had lower systolic blood pressure ((112±20) mmHg vs. (120±19) mmHg; 1 mmHg=0.133 kPa), lower left ventricular ejection fraction (LVEF; (27±12)% vs. (39±14)% ), lower proportion of patients with history of hypertension (28% (14/51) vs. 44% (70/160)) and atrial fibrillation (8% (4/51)vs.39% (62/160)), higher proportion of patients with New York Heart Association functional class Ⅲ to Ⅳ (class Ⅲ: 59% (30/51) vs. 41% (66/160); class Ⅳ: 28% (14/51) vs. 19% (31/160)), and larger left ventricular end-systolic diameter (LVESD; (56±14) mm vs. (50±15) mm). The levels of hemoglobin ((152±23) g/L vs. (142±30) g/L), D-dimer (508 (300, 1 105) μg/L vs. 158 (68, 379) μg/L), and N-terminal pro-brain natriuretic peptide (3 429 (2 462, 4 734) ng/L vs. 1 288 (422, 2 544) ng/L) were higher in LVT group than in non-LVT group (P all<0.05). LVT group had a higher proportion of patients using beta-blockers (92% (47/51) vs. 78% (124/160)), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers or angiotensin receptor neprilysin inhibitors (88% (45/51) vs. 72% (115/160)), and anticoagulant drugs (98% (50/51) vs. 32% (51/160)) than non-LVT group (all P <0.05). Multivariate logistic regression showed that reduced LVEF (OR=1.08, 95%CI 1.02-1.15, P=0.008), decreased LVESD (OR=1.07, 95%CI 1.01-1.12, P=0.013), and increased D-dimer levels (OR=5.40, 95%CI 1.98-14.74, P=0.001) were independent influencing factors for LVT in patients with NIHF. The ROC curve showed that the AUC of the nomogram for predicting LVT in patients with NIHF was 0.793 (95%CI 0.710-0.876, P<0.001). Conclusion: Reduced LVEF, decreased LVESD, and elevated D-dimer are associated with LVT in NIHF patients. The predictive model developed based on the above indicators has certain value in predicting LVT in NIHF patients.