Angiotensin System Inhibitors Research Articles

S-39-1: COVID-19 AND HYPERTENSION IN JAPAN, AND KANAGAWA RASI COVID-19 STUDY

Severe acute respiratory syndrome coronavirus 2 (SARSCoV2) caused a global coronavirus disease-2019 (COVID19) pandemic, as declared by the World Health Organization on March 11, 2020. COVID19 was confirmed for the first time in January 2020, and despite epidemic prevention efforts, the number of patients with COVID19 continued to increase, primarily in metropolitan areas. To prevent the further spread of COVID19, the Japanese government announced a state of emergency on 7 April 2020, similar to the lockdowns impleme nted in other countries. We showed a significant increase in office BP with the white coat phenomenon was observed during the state of emergency, as well as an increase in related stress, thereby indicating that we should pay more attention to BP management during stressful global events, including the COVID19 pandemic, to prevent cardiovascular events (Kobayashi K, et al. Hypertens Res 2022; Kobayashi K, et al. Ito S, et al. J Diabetes Investig Apr 18 Epub, 2022). In addition, since the onset of the COVID19 pandemic, the possible roles of renin angiotensin system (RAS) inhibitors in COVID19 have been debated as favorable, harmful, or neutral. ACE2 not only is the entry route of SARSCoV2 infection but also triggers a major mechanism of COVID19 aggravation by promoting tissue RAS dysregulation, which induces a hyperinflammatory state in several organs, leading to lung injury, hematological alterations, and immunological dysregulation. ACE inhibitors and ARBs inhibit the detrimental hyperactivation of the RAS by SARSCoV2 and increase the expression of ACE2, which is a counterregulator of the RAS. Several studies have investigated the beneficial profile of RAS inhibitors in COVID19; however, this finding remains unclear. Further prospective studies are warranted to confirm the role of RAS inhibitors in COVID19 (Matsuzawa Y, et al. Hypertens Res 2020; Matsuzawa Y, et al. Hypertens Res, 202; Sato R, et al. Clin Exp Nephrol 2022).

S-17-5: EFFECT OF MINERALOCORTICOID RECEPTOR BLOCKER, ESAXERENONE, ON HOME BLOOD PRESSURE AND ALBUMINURIA IN JAPANESE HYPERTENSIVE PATIENTS WITH DKD (EX-DKD STUDY)

Objective: To investigate the effect of esaxerenone on home blood pressure (BP) and albuminuria in Japanese hypertensive patients with diabetic kidney disease (DKD) who had an inadequate response to BP-lowering treatment with a renin angiotensin system (RAS) inhibitor or a RAS inhibitor plus a calcium channel blocker (CCB). Design and method: The EX-DKD study (jRCTs061190027) was a multicenter, open-label study conducted in Japan. The study enrolled hypertensive patients with DKD who had previously received a RAS inhibitor or a RAS inhibitor plus CCB for < 12 weeks, and had sitting office systolic BP (SBP) 130 to < 180 mmHg and/or diastolic BP (DBP) 80 to < 110 mmHg, UACR < 1000 mg/g creatinine, and eGFRcreat 30 to < 60 mL/min/1.73m2 at baseline. Based on baseline UACR, the patients were divided into 3 subcohorts: UACR < 30, 30 to < 300, and 300 to < 1000 mg/g creatinine. Esaxerenone was incrementally dosed for 12 weeks: 1.25, 2.5, and 5 mg/day at the start of treatment, Week4, and Week8, respectively, based on each patient's condition. The primary efficacy endpoint was change in morning home SBP/DBP from baseline to end of treatment (EOT). Secondary endpoints included the proportion of patients achieving target BP at Week12, change in UACR from baseline to EOT, and safety (including serum potassium level). Results: The baseline characteristics of the overall study population (n = 109) were mean age, 72.6 years; male, 54.1%; morning home SBP/DBP, 135.6/75.9 mmHg; UACR < 30, 30 to < 300, and 300 to < 1000 mg/g creatinine, 41.3%, 37.6%, and 21.1%, respectively; eGFRcreat, 49.4 mL/min/1.73m2; RAS inhibitor, 33.0%; RAS inhibitor plus CCB, 67.0%. Morning home SBP/DBP decreased significantly from baseline to EOT in the total population (-11.6/-5.2 mmHg, both p < 0.001) and all UACR subcohorts (all p < 0.001). Similar results were obtained for bedtime home and office BP. At Week12, 38.5% of the total population had achieved target morning home BP. UACR improved significantly from baseline to EOT in the total population and UACR subcohorts; the overall percentage change was -50.9% (p < 0.001). Incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 23.2% and 7.1%, respectively. The percentage of patients with serum potassium <5.5 mEq/L during the study period was 2.7%, and no patients had serum potassium < 6.0 mEq/L. Conclusions: Esaxerenone significantly reduced morning home BP as well as bedtime home and office BP and significantly halved albuminuria in Japanese hypertensive patients with DKD. The effects were consistent regardless of their UACR severity without clinically relevant serum potassium elevation.

PS-P15-8: EFFICACY AND SAFETY OF ESAXERENONE IN HYPERTENSIVE PATIENTS WITH TYPE 2 DIABETES AND RECEIVING SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS (EAGLE-DH STUDY)

Objective: Hypertensive patients with type 2 diabetes mellitus (T2DM) who respond inadequately to antihypertensive therapy are at high risk for cardiorenal events and require effective treatment options. Clinical trials have shown that esaxerenone, a non-steroidal mineralocorticoid receptor blocker, has favorable antihypertensive and renoprotective effects in hypertensive patients with various characteristics including T2DM and albuminuria. However, clinical evidence is lacking regarding the concomitant use of esaxerenone and sodium-glucose cotransporter 2 (SGLT2) inhibitors in hypertensive patients with T2DM. The study aimed to evaluate the efficacy and safety of esaxerenone and SGLT2 inhibitor combination therapy in Japanese hypertensive patients with T2DM who had an inadequate response to blood pressure (BP)-lowering treatment with renin angiotensin system (RAS) inhibitor or calcium channel blocker (CCB) monotherapy or combined therapy. Design and method: EAGLE-DH (jRCTs031200273) was a multicenter, open-label, interventional study in hypertensive patients (age, ≧ 20 years) with T2DM. Inclusion criteria were previous use of antihypertensive therapy (a RAS inhibitor, CCB, or RAS inhibitor plus CCB) and oral hypoglycemic drugs (a SGLT2 inhibitor with or without one or two other oral hypoglycemic drugs) for ≧ 12 weeks; morning home systolic BP (SBP) 125 to < 160 mmHg and/or diastolic BP (DBP) 75 to < 100 mmHg; and eGFRcreat ≧ 30 mL/min/1.73m2 at baseline. Over the 24-week study period, esaxerenone dose was started at 1.25 or 2.5 mg/day, and based on the individual patient's condition, the dose could be titrated at weeks 4 and 8 to a maximum of 5 mg/day. The primary endpoints were change in morning home BP from baseline to weeks 12 and 24. Secondary endpoints included change in bedtime home BP and office BP, proportion of patients achieving target SBP/DBP (home, < 125/75 mmHg; office, < 130/80 mmHg), change in urine albumin-to-creatinine ratio (UACR), and safety variables including adverse events, eGFR, and serum potassium. Results: The study population comprised 93 patients. Baseline characteristics were mean age, 66.3 years; male, 68.8%; mean morning home SBP/DBP, 136.4/82.3 mmHg; mean UACR 145.3 mg/g creatinine; one RAS inhibitor use, 33.3%; one CCB inhibitor use, 19.4%; RAS inhibitor plus CCB, 47.3%; mean HbA1c 6.8%; mean serum potassium, 4.2 mEq/L; and mean eGFRcreat 66.8 mL/min/1.73m2. Efficacy and safety results will be presented at the conference. Conclusions: EAGLE-DH will provide the first evidence from clinical practice for the efficacy of esaxerenone plus SGLT2 inhibitor in reducing morning/bedtime home and office BP with improving albuminuria as well as for its safety profile in Japanese hypertensive patients with T2DM.

Pharmacodynamic benefits of combined renin angiotensin system inhibition and alpha-1 adrenergic antagonism in the management of hypertension and cardiovascular disease in people with African ancestry

Abstract Genetic differences exist between Blacks and whites through sympathetic-vascular transduction signaling mechanisms. However, the lack of benefit of alpha-1 blockers in whites may not be applicable in Africans. The angiotensin II (Ang II) and alpha-1 receptor pathways are critical for vasoconstriction in Blacks. This article reviewed the consequence of the dual blockade among Nigerians, those with and without cardiovascular disease. Both receptors exhibited crosstalk and mutual regulations. Synergistic inhibition of Forearm vasoconstriction and hypotensive response to enalapril + prazosin (alpha-1 blocker [A1B]) occurred (P < 0.05). High efficacy of dual blockade by angiotensin converting enzyme inhibitor (ACEI) + A1B was reported in hypertensive urgency, hypertensive crises, and heart failure (HF) with reduced ejection fraction congestive HF compared to ACEI (P < 0.05). The high efficacy of dual blockade by ACEI + A1B + diuretics is beneficial for widespread use in Nigerians with cardiovascular disease.

699 HYPERKALIEMIA, USE OF DRUGS TARGETING THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM AND MORTALITY IN PATIENTS FOLLOWED AT A TERTIARY CENTER

Abstract Background Hyperkalemia (HK) has been related to increased mortality in patients with heart failure (HF), at least in part because it leads to down-titration or interruption of renin angiotensin system inhibitors (RASi) and mineralocorticoid receptor antagonists (MRA). Methods We reviewed the records of the HF outpatients with ≥2 visits at our clinic between 2014 and 2021 and complete data on therapy, and identified those who had HK at any time after the first visit. The characteristics between these subjects and those without HK were compared by chi-square test, T-test, or Mann-Whitney test. The use of RASi, MRA and beta-blockers at multiple time points was examined by chi-square or Fisher exact test, and the mean dose for each drug class, expressed as percentage of the guideline-recommended dose, by Wilcoxon rank sum test. The trend of RASi dose over time in HK vs no-HK was assessed by two-way ordinal regression analysis, and the association of HK with all-cause death by Kaplan-Meier method and Cox regression analysis. Results 110 of 690 patients (15.9%) had HK, with the mean potassium concentration being 5.6 mEq/L. Subjects with HK were older [73 (66-79) vs 68 (58-78) years, p<0.001], had more often diabetes (42% vs 27%, p=0.002) and LVEF <40% (77% vs 67%, p=0.03), and had higher creatinine [1.3 (1-1.8) vs 1.1 (0.9-1.3) mg/dL, p<0.001], potassium [4.6 (4.2-5.2) vs 4.2 (3.9-4.5) mEq/L, p<0.001], and NT-proBNP levels [6,480 (2,110-11,000) vs 2,900 (1,115-6,070)], p=0.003] than those without HK. The distribution of RASi, MRA, and beta-blocker was comparable between the two groups at baseline and during follow-up, with the exception of a transient reduction in an early phase (panel A). The mean dose of RASi did not vary significantly between groups and over time (group/timepoint interaction p=0.27; panel B). HK was not associated with all-cause death (panel C; hazard ratio 1.05, 95% confidence interval 0.72–1.52). A sensitivity analysis limited to patients with LVEF <40% yielded similar results (not shown). Conclusions The negative impact of HK on RASi and MRA prescription and on prognosis may be mitigated in tertiary centers with expertise in HF treatment.

The use of angiotensin system inhibitors correlates with longer survival in resected pancreatic adenocarcinoma patients

BackgroundActivities and inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) may affect the survival of resected pancreatic ductal adenocarcinoma (PDAC) patients MethodA single-institution retrospective analysis of resected PDAC patients between 2010 and 2019. To estimate the effect of angiotensin system inhibitors (ASIs) on patient survival, we performed Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse probability weighting (IPW) analysis. Results742 patients were included in the analysis. The average age was 67.0 years, with a median follow-up of 24.1 months. The use of ASI was associated with significantly longer overall survival in univariate (p = 0.004) and multivariable (HR = 0.70 [0.56–0.88],p = 0.003) adjusted analysis. In a propensity score-matched cohort of 400 patients, ASI use was again associated with longer overall survival (p = 0.039). Lastly, inverse probability weighting (IPW) analysis suggested that the use of ASI was associated with an average treatment effect on the treated (ATT) of HR = 0.68 [0.53–0.86],p = 0.002) for overall survival. ConclusionIn this single-institution retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival in multiple statistical models. Prospective clinical trials are needed before routine clinical implementation of ASI as an adjuvant to existing therapy can be recommended.

The Association Between Beta-blocker and Renin–Angiotensin System Inhibitor Use After Heart Failure With Reduced Ejection Fraction Hospitalization and Outcomes in Older Patients

IntroductionBeta-blockers (BB) and renin–angiotensin system inhibitors (RASi) are foundational for the treatment of heart failure with reduced ejection fraction (HFrEF). However, given the increased risk of side effects in older patients, uncertainty remains as to whether, on net, older patients benefit as much as the younger patients studied in trials. Methods and ResultsUsing the Get With The Guidelines–Heart Failure registry linked with Medicare data, overlap propensity weighted Cox proportional hazard models were used to examine the association between BB and RASi use at hospital discharge and 30-day and 1-year outcomes among patients with HFrEF. Among the 48,711 patients (aged ≥65 years) hospitalized with HFrEF, there were significant associations between BB and/or RASi use at discharge and lower rates of 30-day and 1-year mortality, including those over age 85 (30-day hazard ratio 0.56, 95% confidence interval 0.45–0.70; 1-year hazard ratio 0.69, 95% confidence interval 0.61–0.78). In addition, the magnitude of benefit associated with BB and/or RASi use after discharge did not decrease with advancing age. Even among the oldest patients, those over age 85, with hypotension, renal insufficiency or frailty, BB and/or RASi use at discharge was still associated with lower 1-year mortality or readmission. ConclusionsAmong older patients hospitalized with HFrEF, BB and/or RASi use at discharge is associated with lower rates of 30-day and 1-year mortality across all age groups and the magnitude of this benefit does not seem to decrease with advancing age. These data suggest that, absent a clinical contraindication, BB and RASi should be considered in all patients hospitalized with HFrEF before or at hospital discharge, regardless of age.

Renin–Angiotensin System Inhibition in Advanced Chronic Kidney Disease

BackgroundRenin–angiotensin system (RAS) inhibitors — including angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) — slow the progression of mild or moderate chronic kidney disease. However, the results of some studies have suggested that the discontinuation of RAS inhibitors in patients with advanced chronic kidney disease may increase the estimated glomerular filtration rate (eGFR) or slow its decline.MethodsIn this multicenter, open-label trial, we randomly assigned patients with advanced and progressive chronic kidney disease (eGFR, <30 ml per minute per 1.73 m2 of body-surface area) either to discontinue or to continue therapy with RAS inhibitors. The primary outcome was the eGFR at 3 years; eGFR values that were obtained after the initiation of renal-replacement therapy were excluded. Secondary outcomes included the development of end-stage kidney disease (ESKD); a composite of a decrease of more than 50% in the eGFR or the initiation of renal-replacement therapy, including ESKD; hospitalization; blood pressure; exercise capacity; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria.ResultsAt 3 years, among the 411 patients who were enrolled, the least-squares mean (±SE) eGFR was 12.6±0.7 ml per minute per 1.73 m2 in the discontinuation group and 13.3±0.6 ml per minute per 1.73 m2 in the continuation group (difference, −0.7; 95% confidence interval [CI], −2.5 to 1.0; P=0.42), with a negative value favoring the outcome in the continuation group. No heterogeneity in outcome according to the prespecified subgroups was observed. ESKD or the initiation of renal-replacement therapy occurred in 128 patients (62%) in the discontinuation group and in 115 patients (56%) in the continuation group (hazard ratio, 1.28; 95% CI, 0.99 to 1.65). Adverse events were similar in the discontinuation group and continuation group with respect to cardiovascular events (108 vs. 88) and deaths (20 vs. 22).ConclusionsAmong patients with advanced and progressive chronic kidney disease, the discontinuation of RAS inhibitors was not associated with a significant between-group difference in the long-term rate of decrease in the eGFR. (Funded by the National Institute for Health Research and the Medical Research Council; STOP ACEi EudraCT number, 2013-003798-82; ISRCTN number, 62869767.)

Effect of renin–angiotensin system inhibitors in patients with cancer treated with anti-VEGF therapy

BackgroundCancer treatment with vascular endothelial growth factor signalling pathway (VSP) inhibitors frequently causes hypertension. Although previous reports suggested that the antihypertensive drug renin–angiotensin system inhibitor (RASI) may have a positive...

Endothelin receptor antagonists in kidney protection for diabetic kidney disease and beyond?

The burden of chronic kidney disease is increasing worldwide, largely due to the increasing global prevalence of diabetes mellitus and hypertension. While renin angiotensin system inhibitors and sodium-glucose cotransporter two inhibitors are the management cornerstone for reducing kidney and cardiovascular complications in patients with diabetic and non-diabetic kidney disease (DKD), they are partially effective and further treatments are needed to prevent the progression to kidney failure. Endothelin receptor antagonism represent a potential additional therapeutic option due to its beneficial effect on pathophysiological processes involved in progressive kidney disease including proteinuria, which are independently associated with progression of kidney disease. This review discusses the biological mechanisms of endothelin receptor antagonists (ERA) in kidney protection, the efficacy and safety of ERA in randomised controlled trials reporting on kidney outcomes, and its potential future use in both diabetic and non-DKDs.

Care Gaps in Sodium-Glucose Cotransporter-2 Inhibitor and Renin Angiotensin System Inhibitor Prescriptions for Patients with Diabetic Kidney Disease

BackgroundRenin and angiotensin system inhibitors (RAASi) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) are recommended for patients with diabetic kidney disease (DKD) to reduce the progression to end-stage kidney disease; however, they are under-prescribed.ObjectiveTo evaluate the frequency of care gaps in RAASi and SGLT2i prescription by patient demographic, health system, and clinical factors in patients with DKD.DesignRetrospective cohort study.ParticipantsAdult primary care patients with DKD at an integrated health system in Bronx, NY, with 23 primary care sites in 2021.Main MeasuresThe odds of having a care gap for (1) SGLT2i or (2) RAASi prescription. Multivariate logistic regression models were performed for each outcome measure to evaluate associations with patient demographic, health system, and clinical factors.Key ResultsOf 7199 patients with DKD, 80.3% had a care gap in SGLT2i prescription and 42.0% had a care gap in RAASi prescription. For SGLT2i, patients with A1C at goal (aOR 2.32, 95% CI 1.96–2.73), Black non-Hispanic race/ethnicity (aOR 1.46, 95% CI 1.15–1.87), and Hispanic race/ethnicity (aOR 1.46, 95% CI 1.11–1.92) were more likely to experience a care gap. For RAASi, patients with blood pressure at goal (aOR 1.34, 95% CI 1.21–1.49) were more likely to experience a care gap.ConclusionsThe care gaps for SGLT2i and RAASi for patients with DKD with well-controlled diabetes and blood pressure suggest failure to recognize DKD as an independent indication for these medications. Racial/ethnic disparities for SGLT2i, but not for RAASi, suggest systemic racism exacerbates care gaps for novel medications. These factors can be targets for interventions to improve patient care.

Combined Neuro-Humoral Modulation and Outcomes in Patients with Chronic Heart Failure and Mildly Reduced or Preserved Ejection Fraction.

Pharmacotherapy of chronic heart failure with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF) remains challenging. We aimed to assess whether combined neuro-humoral modulation (NHM) (renin-angiotensin system inhibitors, betablockers, mineralocorticoid receptor antagonists) was differentially associated with outcome according to phenotype and age groups. Between 1999 and 2018 we recruited in a nationwide cardiology registry 4707 patients (HFmrEF n = 2298, HFpEF n = 2409) from three age groups: &lt;65, 65-79 and 80+ years old. We analyzed clinical characteristics and 1 year all-cause mortality/cardiovascular hospitalization according to none/single, any double, or triple NHM. Prescription rates of no/single and triple NHM were 25.1% and 26.7% for HFmrEF; 36.5% and 17.9% for HFpEF patients, respectively. Older age was associated with higher prescription of no/single NHM in HFmrEF (ptrend = 0.001); the reverse was observed among HFpEF (ptrend = 0.005). Triple NHM increased over time in both phenotypes (all p for trend &lt; 0.0001). Compared to no/single NHM, triple, but not double, NHM was associated with better outcomes in both HFmrEF (HR 0.700, 95%CI 0.505-0.969, p = 0.032) and HFpEF (HR 0.700, 95%CI 0.499-0.983, p = 0.039), with no interaction between NHM treatment and age groups (p = 0.58, p = 0.80, respectively). In a cardiology setting, among HF outpatients with EF &gt; 40%, triple NHM treatment increased over time and was associated with better patient outcomes.

Abstract 9825: Trajectories of Pharmacotherapy After Acute Cardiac Decompensation - Impact of Heart Failure Phenotype

Background &amp; Aim: Longitudinal data on prescription rates (PR) of guideline-directed medical therapy (GDMT) in patients with acute heart failure (HF) are scarce. We investigated GDMT patterns in patients with reduced (HFrEF), mildly reduced (HFmrEF), and preserved (HFpEF) ejection fraction (EF) and determined mortality risk. Patients &amp; Methods: 943 acute HF patients, consecutively recruited between 2015 and 2019, with EF measured while in hospital. PR of betablockers (BB), renin angiotensin system inhibitors (RASi), mineralocorticoid receptor antagonists (MRA), and diuretics were recorded on admission, at discharge, and 6-month follow-up. Results: Little more than one third of patients had HFrEF ( Table ). Patients with HFpEF were older and more often female. Irrespective of EF, comorbidity burden was high ( Table ). Mortality at 12 months was similar across HF phenotypes. The Figure shows that PR of all disease-modifying drug classes increased from admission to discharge irrespective of HF phenotype. PR of MRA were highest in HFrEF. After 6-months, in HFrEF patients, PR of BB (-9%), RASi (-8%), and diuretics (-10%) had decreased again to admission levels. Similar patterns were apparent in HFmrEF and HFpEF including PR of diuretics ( Figure ). Treatment discontinuation of one or more disease modifying drug classes after discharge was frequent (38% in HFrEF, 29% in HFmrEF, 39% in HFpEF). Post-discharge discontinuation was associated with an age-adjusted increase of 12-month mortality risk (OR 10.9, 95%CI 7.6–15.7): for BB 24.5 (16.0–37.5); for RASi 17.6 (11.1–28.0); for MRA 12.3 (6.9–22.1); for diuretics 27.7 (18.3–42.1), with comparable impact across HF phenotypes. Conclusion: In this cohort of patients with AHF, prescription patterns of GDMT were often changed along the HF trajectory, yet similar across HF phenotypes and time. Irrespective of HF phenotype, stopping GDMT was associated with a consistently increased mortality risk.

Implementation, not hesitation, for SGLT2 inhibition as foundational therapy for chronic kidney disease.

Despite the increasing burden of ill health attributable to chronic kidney disease, appropriate pharmacotherapy has been inadequate. Based on trials in the 1990s and 2000s,1 guidelines recommend renin angiotensin system (RAS) inhibition to reduce progression of chronic kidney disease and its associated cardiovascular risk. However, the global burden of chronic kidney disease continues to increase.1 Furthermore, data from the US CURE-CKD registry highlights that uptake of chronic kidney disease management strategies is low, with only around 21% of patients prescribed RAS inhibitors between 2006 and 2017.

In-hospital major bleeding in patients with acute coronary syndrome medically treated with dual anti-platelet therapy: Associated factors and impact on mortality.

Major bleeding is associated with poor hospital prognosis in patients with acute coronary syndrome (ACS). Despite its clinical importance, there are limited studies on the incidence and risk factors for major bleeding in ACS patients with dual anti-platelet therapy (DAPT) without access to revascularization. We analyzed data from 19,186 patients on DAPT after ACS with no access to revascularization from Clinical Pathway for Acute Coronary Syndrome in China Phase 3 (CPACS-3) cohort, which was conducted from 2011 to 2014. Major bleeding included intracranial hemorrhage, clinically significant bleeding, or bleeding requiring blood transfusion. Factors associated with in-hospital major bleeding were assessed using Poisson regressions with generalized estimating equations to account for the clustering effect. A total of 75 (0.39%) patients experienced major bleeding during hospitalization. Among subtypes of ACS, 0.65% of patients with STEMI, 0.33% with NSTEMI, and 0.13% with unstable angina had in-hospital major bleeding (p < 0.001). The patients who experienced major bleeding had a longer length of stay (median 12 vs. 9 days, p = 0.011) and a higher all-cause in-hospital death rate (22.7 vs. 3.7%, p < 0.001). Multivariable analysis showed advancing age (RR = 1.52 for every 10 years increase, 95% CI: 1.13, 2.05), impaired renal function (RR = 1.79, 95% CI: 1.10, 2.92), use of fibrinolytic drugs (RR = 2.93, 95% CI: 1.55, 5.56), and severe diseases other than cardiovascular and renal diseases (RR = 5.56, 95% CI: 1.10, 28.07) were associated with increased risk of major bleeding, whereas using renin-angiotensin system inhibitors (RR = 0.54, 95% CI: 0.36, 0.81) was associated with decreased risk of major bleeding. These independent factors together showed good predictive accuracy with an AUC of 0.788 (95% CI: 0.734, 0.841). Among ACS patients on DAPT, advancing age, impaired renal function, thrombolytic treatment, and severe comorbidities were independently associated with a higher risk of in-hospital major bleeding.

Does the Naked Emperor Parable Apply to Current Perceptions of the Contribution of Renin Angiotensin System Inhibition in Hypertension?

To address contemporary hypertension challenges, a critical reexamination of therapeutic accomplishments using angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, anda greater appreciation of evidence-based shortcomings from randomized clinical trials are fundamental in accelerating future progress. Medications targeting angiotensin II mechanism of action are essential for managing primary hypertension, type 2 diabetes, heart failure, and chronic kidney disease. While the ability of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers to control blood pressure is undisputed, practitioners, hypertension specialists, and researchers hold low awareness of these drugs' limitations in preventing or reducing the risk of cardiovascular events. Biases in interpreting gained knowledge from data obtained in randomized clinical trials include a pervasive emphasis on using relative risk reduction over absolute risk reduction. Furthermore, recommendations for clinical practice in international hypertension guidelines fail to address the significance of a residual risk several orders of magnitude greater than the benefits. We analyze the limitations of the clinical trials that have led to current recommended treatment guidelines. We define and quantify the magnitude of the residual risk in published hypertension trials and explore how activation of alternate compensatory bioprocessing components within the renin angiotensin system bypass the ability of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers to achieve a significant reduction in total and cardiovascular deaths. We complete this presentation by outlining the current incipient but promising potential of immunotherapy to block angiotensin II pathology alone or possibly in combination with other antihypertensive drugs. A full appreciation of the magnitude of the residual risk associated with current renin angiotensin system-based therapies constitutes a vital underpinning for seeking new molecular approaches to halt or even reverse the cardiovascular complications of primary hypertension and encourage investigating a new generation of ACE inhibitors and ARBs with increased capacity to reach the intracellular compartments at which Ang II can be generated.

Healthcare resource utilization and costs among patients with heart failure with preserved, mildly reduced, and reduced ejection fraction in Spain

AimsTo describe healthcare resource utilization (HCRU) of patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF) in Spain. MethodsAdults with ≥ 1 HF diagnosis and ≥ 1 year of continuous enrolment before the corresponding index date (1/January/2016) were identified through the BIG-PAC database. Rate per 100 person-years of all-cause and HF-related HCRU during the year after the index date were estimated using bootstrapping with replacement.ResultsTwenty-one thousand two hundred ninety-seven patients were included, of whom 48.5% had HFrEF, 38.6% HFpEF and 4.2% HFmrEF, with the rest being of unknown EF. Mean age was 78.8 ± 11.8 years, 53.0% were men and 83.0% were in NYHA functional class II/III. At index, 67.3% of patients were taking renin angiotensin system inhibitors, 61.2% beta blockers, 23.4% aldosterone antagonists and 5.2% SGLT2 inhibitors. Rates of HF-related outpatient visits and hospitalization were 968.8 and 51.6 per 100 person-years, respectively. Overall, 31.23% of patients were hospitalized, mainly because of HF (87.88% of total hospitalizations); HF hospitalization length 21.06 ± 17.49 days (median 16; 25th, 75th percentile 9–27). HF hospitalizations were the main cost component: inpatient 73.64%, pharmacy 9.67%, outpatient 9.43%, and indirect cost 7.25%. Rates of all-cause and HF-related HCRU and healthcare cost were substantial across all HF subgroups, being higher among HFrEF compared to HFmrEF and HFpEF patients.ConclusionsHCRU and cost associated with HF are high in Spain, HF hospitalizations being the main determinant. Medication cost represented only a small proportion of total costs, suggesting that an optimization of HF therapy may reduce HF burden.

Effects of guideline directed medical therapy on secondary mitral regurgitation

Abstract Background Guideline directed medical therapy (GDMT) is the recommended initial treatment for secondary mitral regurgitation (SMR), however supported by only little comprehensive evidence. This study therefore sought to assess the effect of GDMT titration on SMR and to identify specific substance combinations able to reduce SMR severity. Methods We included 261 patients who completed two visits with an echocardiographic exam available within one month at each visit. After comprehensively defining GDMT titration as well as SMR reduction, logistic regression analysis was applied in order to assess the effects of overall GDMT titration and specific substance combinations on SMR severity. Results SMR severity improved by at least one degree in 39.3% of patients with subsequent titration of GDMT and was accompanied by reverse remodelling and clinical improvement. The effects of GDMT titration were significantly associated with SMR reduction (adj. OR 0.31, 95% CI 0.13–0.71, P=0.006). Moreover, ARNI as well as the combined dosage effects of (i) renin angiotensin system inhibitors (RASi) and mineralocorticoid-receptor antagonists (MRA), (ii) betablockers (BB) and MRA, as well as (iii) RASi, BB, and MRA were all significantly associated with SMR improvement (P&amp;lt;0.001 for all). Conclusions The present study provides comprehensive evidence for the effectiveness of contemporary GDMT to specifically improve SMR. Our data indicates that GDMT titration conveys a threefold increased chance of reducing SMR severity. Moreover, the dosage effects of ARNI, as well as the combination of RASi and MRA, BB and MRA, and all three substances in aggregate are able to significantly improve SMR. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): FWF - Austrian Science Fund

Comprehensive Review of Hepatocellular Carcinoma in India: Current Challenges and Future Directions.

There is not much information on hepatocellular carcinoma (HCC) in India. Here, we review the existing data, available treatment choices, and future directions in HCC management. An extensive search was conducted through PubMed and MEDLINE for studies published between January 2000 and June 2022 on the epidemiology of HCC in India using the following key words: atezolizumab, BCLC staging, hepatocellular carcinoma, immune checkpoint inhibitors, immunotherapy, and programmed cell death ligand-1, with the filters humans and English language. The most frequent risk factors for the development of HCC in India include nonalcoholic fatty liver disease, hepatitis B virus and hepatitis C virus infection, liver cirrhosis, and alcohol intake. On the basis of new findings, the Barcelona Clinic Liver Cancer (BCLC) Staging Criteria need to be revised. As most cases in India are discovered at a later stage, curative treatments such as surgical resection, ablation, or liver transplantation may not be an option. Clinical trials are underway for a number of immune checkpoint drugs that target cytotoxic T-cell lymphocyte-4 and programmed cell death-1/programmed cell death-ligand 1. In India, phase III trials of atezolizumab in combination with other drugs are underway for the treatment of various malignancies. Renin angiotensin system inhibitors, antivirals, primary hepatocyte transplantation, and bioartificial liver devices are among the future options for the management of HCC. In developing countries like India, HCC is often diagnosed at an advanced stage because of a delay in routine testing or screening. Therefore, developing effective treatment regimens for such stages is critical. Immunotherapy is a promising treatment option that has the potential to increase overall response and survival rate.

Does Dapagliflozin influence arterial stiffness and levels of circulating anti-aging hormone soluble Klotho in people with type 2 diabetes and kidney disease? Results of a randomized parallel group clinical trial.

ObjectiveThe mechanisms that explain the cardio-renal benefits of sodium glucose co-transporter 2 (SGLT-2) inhibitors are unknown. The effect of SGLT-2 inhibitors on arterial aging, measured by Aortic Pulse Wave Velocity (Ao-PWV) and Soluble Klotho (s-Klotho), a circulating anti-aging biomarker of arterial health are also unclear.Design/SettingA 24-week single center randomized controlled trial (registry number/ EudraCT Number: 2013-004042-42) comparing Dapagliflozin and Ramipril (D+R) versus Ramipril (R) on the primary endpoint of urine albumin excretion rate (AER) and pre-specified secondary endpoints of Ao-PWV and biomarkers of arterial aging [s-Klotho and Fibroblast Growth Factor 23 (FGF-23)]. People with type 2 diabetes who had estimated glomerular filtration rate (eGFR) > 60 ml/min and residual microalbuminuria on maximum tolerated renin angiotensin system (RAS) inhibition were included in this study.ResultsIn total, 33 participants (male 73%) were randomized to either D+R (n = 17) or R (n = 16) arms. After 24 weeks of treatment, Ao-PWV (mean ± SD) did not change significantly from baseline D +R [9.06 ± 1.91 m/s to 9.13 ± 2.03 m/s], and R [9.88 ± 2.12 m/s to 10.0 ± 1.84 m/s]. AER fell significantly by 43.5% (95% CI: −57.36%, −29.56%; p < 0.01) in people in the D+ R arm only. We do not observe any significant changes in FGF-23 or s-Klotho. HbA1c and Angiotensin 1–7 fell significantly only in D + R arm.ConclusionsThe combination of Dapagliflozin and Ramipril had no effects on Ao-PWV and s-Klotho which are biomarkers of arterial aging and cardio-renal risk. Our data suggest that the early cardio-renal benefits observed with SGLT-2 inhibitors are unlikely to be related to an improvement in arterial aging.