Use Of Angiotensin II Receptor Blockers Research Articles

Advancing Community Care and Access to Follow-Up after Acute Kidney Injury Hospitalization: A Randomized Clinical Trial.

Key Points A risk-guided intervention improved adherence to processes of care for AKI survivors.Further supports are necessary to improve uptake of processes of care for AKI survivors in primary care. Background AKI is associated with development and progression of CKD. Gaps in recommended care for CKD are common after AKI. Methods In this randomized controlled trial conducted in Alberta, Canada, we allocated adults hospitalized with Kidney Disease Improving Global Outcomes (KDIGO) stage 2 or greater AKI to a risk-guided, transition of care intervention versus usual practices at the time of hospital discharge. For people in the intervention group, we used a validated risk index to predict risk of severe CKD after AKI. People at low risk (<1%) received patient education alone. People at medium risk received additional clinical guidance, provided to their primary care physician. People at high risk (>10%) were referred to nephrology. The primary outcome was the proportion of patients who received treatment with an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB), statin, and nephrology specialist follow-up within 90 days of discharge. Results One hundred fifty-five patients were recruited; the mean (SD) age was 60 (15) years, 91 (60%) were male, and 96 (62%) had eGFR <60 ml/min per 1.73 m2 or urine albumin-creatinine ratio >30 mg/g at discharge. The proportion of participants who received ACE-I/ARB, statin treatment, and nephrologist follow-up was 28% in the intervention group versus 3% in the usual care group (absolute risk difference [RD], 25%; 95% confidence interval [CI], 15% to 36%). The use of ACE-I or ARB in participants with urine albumin-creatinine ratio >300 mg/g or diabetes was greater in the high-risk group with the intervention versus usual care (RD, 37%; 95% CI, 6% to 67%), as was statin use among those with CKD (RD, 30%; 95% CI, 5% to 56%) and nephrologist follow-up for those with sustained eGFR <30 ml/min per 1.73 m2 at discharge (RD, 78%; 95% CI, 56% to 100%). Hyperkalemia was more frequent in the intervention group (RD, 10%; 95% CI, 9% to 19%). Conclusions A risk-guided intervention for patients hospitalized with AKI increased recommended processes of care for CKD for high-risk patients after hospital discharge. Clinical Trial registry name and registration number: Improving Post Discharge Care after Acute Kidney Injury (AFTER AKI), NCT02915575.

Characteristics and outcomes of heart failure in Japan: A hospital-based administrative database analysis.

Epidemiological and outcome studies on patients in Japan with heart failure (HF) categorized by left ventricular ejection fraction (LVEF) are currently limited. The aim of this non-interventional database study was to provide further information on these patients. Administrative claims data and electronic medical records from hospitals participating in the Voluntary Hospitals in Japan (VHJ) organization were used. Patients hospitalized with a primary diagnosis of HF between 1 April 2017 and 30 March 2020 were categorized by baseline LVEF on echocardiogram: HF with reduced EF (HFrEF, LVEF <40%); HF with preserved EF (HFpEF, LVEF ≥50%); and HF with mildly reduced EF (HFmrEF, 40% to <50% LVEF). Patients were evaluated for baseline characteristics, pre-admission diagnosis, prescription drugs, length of hospitalization, HF treatment cost, overall cost of hospitalization, and in-hospital prescription. An exploratory analysis compared post-hospitalization mortality and re-hospitalization rates. In total, 10646 hospitalized patients from 17 VHJ hospitals were enrolled. Of these, 7212 were included in the analysis set and categorized into HFpEF (3183, 44.1%), HFmrEF (1280, 17.7%), and HFrEF (2749, 38.1%) groups based on baseline LVEF. Beta-blocker use increased during hospitalization, with a mean (95% confidence interval [CI]) of 23.3% (22.3-24.3) of patients receiving these agents before admission versus 69.4% (68.3-70.5) at discharge. Administration of diuretics, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) showed a similar trend. Differences in treatments were observed between HF categories at discharge, with a higher proportion (95% CI) of ACE inhibitor use in the HFrEF group (40.6% [38.7-42.4]) versus HFmrEF (27.5% [25.1-30.0]) and HFpEF (20.6% [19.2-22.1]) groups (P<0.0001), and more ARB use in the HFmrEF and HFpEF groups (32.5% [29.9-35.1] and 31.2% [29.6-32.9], respectively) versus HFrEF (25.1% [23.5-26.8]; P<0.0001). Mean (standard deviation [SD]) length of hospitalization was 22.2 (23.3) days, and the median (interquartile range) was 17 (11-25) days. Estimated average cost of HF treatment per patient during index hospitalization was 300090 yen with HFrEF treatment costing the most. Average total healthcare expenditure during hospitalization was 1225650 yen per index hospitalization per patient, with HFrEF also the most expensive. During a mean (SD) observation period of 324 (304) days, ~21% of patients in each group required re-hospitalization for HF, and 625 patients (8.7%) died. The proportion of patients in each HF category was largely consistent with existing data. Discharge medications indicated high prescription of guideline-directed therapy. This study provides real-world data on patients with HF in Japan that can help inform future clinical decision-making.

Renin-angiotensin system inhibitors and risk of hepatocellular carcinoma among patients with hepatitis B virus infection.

Hepatitis B virus (HBV) infection is a common cause of liver-related morbidity and mortality. Evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) decrease liver fibrosis, an intermediate step between liver injury and hepatocellular carcinoma (HCC). Our aim was to investigate the association between the use of ACEIs and ARBs on incident HCC and liver-related mortality among patients with HBV infection. We conducted a population-based study on a new-user cohort of patients seen at 24 hospitals across China. We included adult patients with HBV infection who started ACEIs or ARBs (ACEIs/ARBs), or calcium channel blockers or thiazide diuretics (CCBs/THZs) from January 2012 to December 2022. The primary outcome was incident HCC; secondary outcomes were liver-related mortality and new-onset cirrhosis. We used propensity score matching and Cox proportional hazards regression to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of study outcomes. Among 32 692 eligible patients (median age 58 [interquartile range (IQR) 48-68] yr, and 18 804 male [57.5%]), we matched 9946 pairs of patients starting ACEIs/ARBs or CCBs/THZs. During a mean follow-up of 2.3 years, the incidence rate of HCC per 1000 person-years was 4.11 and 5.94 among patients who started ACEIs/ARBs and CCBs/THZs, respectively, in the matched cohort. Use of ACEIs/ARBs was associated with lower risks of incident HCC (HR 0.66, 95% CI 0.50-0.86), liver-related mortality (HR 0.77, 95% CI 0.64-0.93), and new-onset cirrhosis (HR 0.81, 95% CI 0.70-0.94). In this cohort of patients with HBV infection, new users of ACEIs/ARBs had a lower risk of incident HCC, liver-related mortality, and new-onset cirrhosis than new users of CCBs/THZs.

Risk of pneumonia-related hospitalization after initiating angiotensin-converting enzyme inhibitors compared with angiotensin II receptor blockers: a retrospective cohort study using LIFE Study data.

There is insufficient evidence that angiotensin-converting enzyme inhibitors (ACEIs) can reduce pneumonia by inducing a dry cough that confers a protective effect on the airway. To increase the evidence base on the clinical use of ACEIs for pneumonia prevention, this retrospective cohort study aimed to comparatively examine the risk of pneumonia-related hospitalization between ACEI initiators and angiotensin II receptor blocker (ARB) initiators using claims data from two Japanese municipalities. We identified persons who were newly prescribed any ACEI or ARB as their first antihypertensive agent between April 2016 and March 2020. The Fine-Gray method was applied to a Cox proportional hazards model to estimate the subdistribution hazard ratio (HR) of ACEI use (reference: ARB use) for pneumonia-related hospitalization, with death treated as a competing risk. Sex, age, comorbidities, medications, and pneumococcal immunization were included as covariates. The analysis was conducted on 1421 ACEI initiators and 9040 ARB initiators, and the adjusted subdistribution HR of ACEI use was estimated to be 1.21 (95% confidence interval: 0.89-1.65; P = 0.22). ACEI initiation did not demonstrate any significant preventive effect against pneumonia-related hospitalization relative to ARB initiation. There remains a lack of strong evidence on the protective effects of ACEIs, and further research is needed to ascertain the benefits of their use in preventing pneumonia. We conducted a large-scale retrospective cohort study using real-world healthcare data from a Japanese population. In this study, ACEI initiation did not indicate a significant preventive effect against pneumonia-related hospitalization.

Relationship of angiotensin II receptor blocker (ARB) to the effectiveness of immune checkpoint blockade (ICB) in non-small-cell lung cancer (NSCLC) and inhibition of angiotensin II/AGTR1 signaling in fibroblasts to reduce collagen deposition in the tumor microenvironment (TME).

e14618 Background: Immune checkpoint blockade (ICB) has achieved remarkable success. However, not all patients with advanced tumors respond to ICB. Remodeling of the tumor microenvironment (TME) has emerged as a strategy to facilitate the development of cancer therapies. As the most notable features of TME, immune cells and collagens play a significant role in influencing anti-tumor immunity, with collagen deposition is the most significant physical barrier that hinders immune cell infiltration. Cancer patients are often prescribed multiple medications to address pre-existing comorbidities or side effects from anti-tumor therapy. Given the high prevalence of concurrent medications and the potential for interactions between them and ICB, we identified that the angiotensin II receptor 1 (AGTR1) was positively expressed in CAFs and AGTR1 inhibitor angiotensin receptor blocker (ARB) suppressed the expression of type I collagen and promote immune infiltration. Methods: Retrospective clinical study: An in-house cohort was a multi-center cohort and included 270 patients with non-small-cell lung cancer (NSCLC) receiving ICB therapy from 2020 to 2021 from The Affiliated Wuxi People's Hospital of Nanjing Medical University and The First Affiliated Hospital of Nanjing Medical University. Meta-analysis: 4 studies involving 1,268 participants in total and an in-house cohort with 270 participants were included. We performed an additional meta-analysis on the association between the use of ARBs in cancer patients receiving ICB therapy. Animal models: Xenograft tumor models were randomly divided into two groups, including control and Losartan-treated groups, and mouse cancer models were randomly divided into three groups at the first round and four groups at the second round. Three groups included control, Losartan-treated, and Losartan-treated &amp; CD8-deleted groups, and four groups included control, Losartan-treated, anti-PD-1-treated, and Losartan &amp; anti-PD-1-treated groups. Results: Patients with NSCLC who received ARBs showed improved overall survival and response to immunotherapy compared to those who did not receive ARBs. Losartan, a representative drug of the ARB class, significantly increased collagen deposition in mice tumors, elevated levels of immune cell infiltration, and sensitized anti-PD-1 therapy. Conclusions: We reported that Losartan shaped an inflamed TME by inhibiting collagen I expression of CAFs and enhanced anti-PD-1 immunotherapy in the mouse tumor model. We recommend that ARB should be selected as much as possible for patients receiving ICB therapy and requiring antihypertensive treatment.

RAAS inhibitors in patients undergoing transcatheter aortic valve implantation: insights from the EffecTAVI registry

Abstract Background Aortic Stenosis (AS) is the most common heart disease in western countries, with a prevalence that is increasing in tandem with life expectancy. Renin-angiotensin-aldosterone system (RAAS) activation participates to myocardial fibrosis and worse clinical consequences. Purpose The association between baseline treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and cardiovascular (CV) mortality was evaluated in hypertensive patients with severe AS undergoing transcatheter aortic valve implantation (TAVI). Methods We retrospectively examined hypertensive patients with AS who had undergone TAVI at 2-year follow-up. Univariable and multivariable Cox regression models were built according to baseline RAAS inhibitors (RAASi) therapy status and a second analysis was undertaken by categorizing patients in ARBs (n= 110), ACEi (n= 112) and other antihypertensive meds (n= 105). As a sensitivity analysis, survival-time data were converted to case-control data in order to conduct a case–control study nested in the observational study. Results The present analysis included 327 hypertensive patients with severe AS undergoing TAVI. During the 2-year follow-up 43 patients died for CV death. In univariable Cox regression, the rate of the 2-year CV mortality was significantly lower in patients taking RAASi at baseline (HR=0.44, 95% CI 0.23-0.81 p=0.009), however after multivariable adjustment for significant confounders baseline treatment with RAASi was no more significant. Patients were then grouped based on ARBs/ACEIs/other antihypertensive therapy (Figure 1). In the univariate regression analysis ARBs therapy was associated with 65% reduction in CV mortality (HR=0.35, 95% CI 0.15-0.78 p=0.011) significantly lower than other anti-hypertensive meds (figure 1). The results were confirmed in multivariate analysis adjusted for significant confounders (HR=0.34, 95% CI 0.14-0.85 p=0.021). To reduce the risk of bias and better evaluate the stability of the results, a case–control study nested in the observational study was performed. Based on preliminary analysis, patients exposed to ARBs were selected as the case group, those not exposed as the control group, matching controls and cases in a 1:1 manner and balancing for sex, chronic kidney disease, atrial fibrillation and type 2 diabetes mellitus. Multivariable logistic regression analyses were conducted to determine the possible risk factors for CV mortality. After adjusting for the effect of significant confounders, the use of ARBs was found to be associated with a significant reduced risk of CV mortality (OR 0.30, 95% CI 0.11 – 0.82, p=0.019) (Figure 2). Conclusion In patients with severe AS undergoing TAVI, baseline treatment with ARBs was associated with reduced risk of CV mortality over 2 years of follow-up compared to the use of other antihypertensive drugs. The results were also confirmed by the nested, balanced, case-control analysis.KM curves grouped for ACEI/ARBs/otherAdjusted odds-ratio in the nested case-c

Abstract 13617: Spironolactone Use is Associated With Better Survival in Heart Failure Patients With Preserved Ejection Fraction With Concomitant Angiotensin Receptor Blocker Treatment

Introduction: The guidelines recommend using renin-angiotensin-aldosterone system inhibitors, including spironolactone and angiotensin II receptor blocker (ARB), and spironolactone rather than angiotensin-converting enzyme inhibitors (ACEI) for treating heart failure with preserved ejection fraction (HFpEF). However, it is unclear whether there is an additive effect of spironolactone when combined with ACEI/ARB on HFpEF. Hypothesis: Spironolactone combined with ACEI or ARB may provide additional benefits in patients with HFpEF. Methods: We conducted a post hoc analysis of the TOPCAT (Heart Failure Trial with Aldosterone Antagonist for Preservation of Heart Function) trial using Cox proportional hazards models to evaluate the effect of spironolactone on the clinical prognosis of HFpEF patients, with or without ACEI or ARB. Our primary outcomes were defined as death from cardiovascular causes, aborted cardiac arrest, and hospitalization for heart failure. Results: A total of 1767 HFpEF patients from the Americas were included (49.9% women, median age 71.5 years). During a median follow-up of 2.98 years, 522 (29.5%) primary outcomes occurred. Compared with placebo, spironolactone use was associated with a lower incidence of primary outcomes (hazard ratio [HR]: 0.69, P=0.02), cardiovascular mortality (HR: 0.45, P=0.004) and all-cause mortality (HR: 0.58, P=0.01) after adjustments in HFpEF patients who were concomitantly taking ARB at baseline but not in those without ARB use. Significant interactions were found between spironolactone use and baseline ARB use for cardiovascular and all-cause death (P=0.01). In contrast, spironolactone use was associated with lower cardiovascular death (HR: 0.59, P=0.01) in patients without ACEI baseline use but not in those with ACEI use. There was no significant interaction observed between spironolactone use and baseline ACEI for adverse outcomes. Conclusions: Among HFpEF patients enrolled in TOPCAT-Americas, the survival benefit of spironolactone was enhanced by ARB use but not ACEI use. Further prospective studies are necessary to validate these findings.

Prior Use of Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Blockers and Clinical Outcomes of Sepsis and Septic Shock: A Systematic Review and Meta-analysis.

Sepsis and septic shock are life-threatening conditions that are associated with high mortality and considerable health care costs. The association between prior angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) use and outcomes after sepsis is elusive. The aim of this study was to evaluate the role of the prior use of ACEi or ARBs and outcomes after sepsis and septic shock. A relevant literature review was performed in 4 databases from inception until July 2022. Independent reviewers first screened the title, abstract, and full text, and then, data extraction and analysis were performed. One post hoc analysis of a trial and 6 retrospective cohort studies were included in this review. There were 22% lower odds of in-hospital/30-day mortality among patients who have used ACEi/ARBs in the past [23.83% vs. 37.20%; odds ratio (OR), 0.78, 95% confidence interval (CI), 0.64-0.96], and reduced 90-day mortality (OR, 0.80, 95% CI, 0.69-0.92). ACEi/ARBs users were found to have 31% lesser odds of developing acute kidney injury as compared with nonusers (OR, 0.69, 95% CI, 0.63-0.76). There was no significant difference in the length of hospital stay (MD 1.26, 95% CI, ‒7.89 to 10.42), need for renal replacement therapy (OR, 0.71, 95% CI, 0.13-3.92), mechanical ventilation (OR, 1.10, 95% CI, 0.88-1.37) or use of vasopressors (OR, 1.21, 95% CI, 0.91-1.61). Based on this analysis, prior use of ACEi/ARBs lowers the risk of mortality and adverse renal events in patients with sepsis and septic shock.

The association between angiotensin receptor blockers and lung, bladder, and colon cancer development: A 10-year multicentric retrospective Lebanese study.

Cardiovascular diseases (CVD) are the leading cause of death globally, followed by cancer. Angiotensin II contributes greatly to CVD pathogenesis, and Angiotensin II receptor blockers (ARBs) constitute a mainstay in hypertension and CVD management. However, the relationship between ARBs and cancer initiation is controversial, with no clear data in Lebanon. Therefore, our study aimed to determine the association between ARBs intake and lung, bladder, and colorectal cancers development in the Lebanese population. A retrospective study was conducted on 709 subjects divided into 2 main groups: Control (subjects without cancer; n = 177), and Cases (patients with cancer (n = 532): lung, bladder, or colorectal), taking ARBs (n = 236, (n = 121 in control and n = 115 in cases)) or not (n = 473). Collected information included the patients demographics, comorbidities, cancer's risk factors, and ARBs dose and duration intake. Bivariate, multivariate, and binary logistic analyses were enrolled. ARBs use was significantly protective (P value = 0.000) against overall cancer development (odds ratio [OR] = 0.127) and against each, lung (OR < 1), bladder (OR < 1), and colorectal cancers (OR < 1). A duration-response relationship was established. This protective effect and the time-dependent relationship remained unchanged after omitting the most relevant risk factors. In summary, a significant overall protective effect of ARBs against lung, bladder and colorectal cancers was found. This beneficial response was time-dependent. These results can guide patients on treatment options and clinicians for informed decision-making.

Effect of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers on need for operative intervention for idiopathic adhesive capsulitis

The exact pathogenesis of idiopathic adhesive capsulitis (IAC) is not fully understood, but an inflammatory profibrotic cascade, largely mediated by transforming growth factor-beta 1 (TGF- β1) has been implicated. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) both decrease the activity of TGF-β1. The aim of this study was to determine the impact of ACE-Is or ARBs use on the need for operative intervention in IAC. This was a retrospective cohort study of patients from a single institutional database with IAC, divided into two cohorts, with and without ACE-I and/or ARB use as the primary exposure and a minimum 2-year follow-up. The primary outcome measured was the incidence of operative intervention including manipulation under anesthesia (MUA) and arthroscopic capsular release (ACR). Additional multivariable logistic regression analysis was performed to evaluate associations between ACE-I/ARB use and likelihood of undergoing an operative procedure. A total of 17,645 patients met inclusion criteria, with 5424 patients in the ACE-I/ARB cohort and 12,221 in the non-ACE-I/ARB cohort. Overall, 422 (2.4%) patients underwent surgical treatment, 378 (2.1%) ACR, and 74 (0.4%) MUA. There was no significant difference between cohorts in the frequency of surgical procedures or time to procedure since diagnosis. There were no significant differences between individual ACE-Is or ARBs, although Losartan was found to have a trend of decreased rate of intervention (31.7% vs. 36.8%, P=.209) when compared to patients not on losartan that did not reach statistical significance. Patient factors predictive of undergoing MUA/ACR were diabetes (P=.013), obesity (P<.001), and male sex (P<.001). Increasing patient age reduces the likelihood of undergoing operative intervention, with patients aged 50-70 years (P=.022) and age >70 years (P<.001) demonstrating reduced odds as compared to patients aged <30 years. Patients with IAC have an overall low (2.4%) rate of requiring surgical intervention. While the antifibrotic mechanism of ACE inhibitors and ARBs did not significantly affect the rate of requiring surgical intervention, male gender, obesity, younger age, and diabetes, all increased the risk for operative intervention. Losartan, specifically, may have a disease modifying effect on IAC that should be investigated with larger controlled trials.

Neuroprotective effect of angiotensin II receptor blockers on the risk of incident Alzheimer's disease: A nationwide population-based cohort study.

Recent studies on renin-angiotensin system (RAS) inhibitors have reported a reduced risk of Alzheimer's disease (AD). Nevertheless, the effect of RAS inhibitor type and blood-brain barrier (BBB) permeability on the risk of AD is still unknown. To assess the effects of RAS inhibitors on the risk of AD based on the type and BBB permeability and investigate the cumulative duration-response relationship. This was a population-based retrospective cohort study using the Korean Health Insurance Review and Assessment database records from 2008 to 2019. The data of patients diagnosed with ischemic heart disease between January 2009 and June 2009 were identified for inclusion in the analyses. Propensity score matching was used to balance RAS inhibitor users with non-users. The association between the use of RAS inhibitors and incident AD was evaluated using a multivariate Cox proportional hazard regression model. The results are presented in adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Among the 57,420 matched individuals, 7,303 developed AD within the follow-up period. While the use of angiotensin-converting enzyme inhibitors (ACEIs) was not significantly associated with AD risk, the use of angiotensin II receptor blockers (ARBs) showed a significant association with reduced risk of incident AD (aHR = 0.94; 95% CI = 0.90-0.99). Furthermore, the use of BBB-crossing ARBs was associated with a lower risk of AD (aHR = 0.83; 95% CI = 0.78-0.88) with a cumulative duration-response relationship. A higher cumulative dose or duration of BBB-crossing ARBs was associated with a gradual decrease in AD risk (P for trend < 0.001). No significant association between the use of ACEIs and the risk of AD was observed regardless of BBB permeability. Long-term use of BBB-crossing ARBs significantly reduced the risk of AD development. The finding may provide valuable insight into disease-modifying drug options for preventing AD in patients with cardiovascular diseases.

Association between prognosis and the use of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blocker in frail patients with heart failure with preserved ejection fraction

Abstract Background The effectiveness of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) has not been demonstrated in patients with heart failure with preserved ejection fraction (HFpEF). We recently reported significant interaction between the use of ACE-I and/or ARB (ACE-I/ARB) and frailty on prognosis in patients with HFpEF. Purpose In the present study, we examined the association between ACE-I/ARB and prognosis in patients with HFpEF stratified by the presence or absence of frailty. Methods We examined the association between the use of ACE-I/ARB and prognosis according to the presence (Clinical Frailty Scale (CFS) ≥5) or absence (CFS ≤4) of frailty in patients with HFpEF in a post-hoc analysis of registry data. Primary endpoint was the composite of all-cause mortality and heart failure admission. Secondary endpoints were all-cause mortality and heart failure admission. Results Of 1059 patients, median age was 83 years and 45% were male. Kaplan-Meier analysis showed that the risk of composite endpoint (log-rank P=0.001) and all-cause death (log-rank P=0.005) in patients with ACE-I/ARB was lower in those with CFS ≥5, but similar between patients with and without ACE-I/ARB in patients with CFS ≤4 (composite endpoint: log-rank P=0.830; all-cause death: log-rank P=0.192). In a multivariable Cox proportional hazards model, use of ACE-I/ARB was significantly associated with lower risk of the composite endpoint (hazard ratio = 0.52, 95% CI: 0.33–0.83, P=0.005) and heart failure admission (hazard ratio = 0.45, 95% CI: 0.25–0.83, P=0.010) in patients with CFS ≥5, but not in patients with CFS ≤4 (composite endpoint: hazard ratio = 1.41, 95% CI: 0.99–2.02, P=0.059; heart failure admission: hazard ratio = 1.43, 95% CI: 0.94–2.18, P=0.091). The association between ACE-I or ARB and prognosis did not significantly differ by CFS (CFS ≤4: log-rank P=0.562; CFS ≥5: log-rank P=0.100, for with ACE-I vs. ARB, respectively). Adjusted HRs for CFS 1–4 were higher than 1.0, but were less than 1.0 at CFS 5. Conclusions In patients with HFpEF, use of ACE-I/ARB was associated with better prognosis in patients with frailty as assessed with the CFS, but not in those without frailty. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Roche

Fracture Risk and Use of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers

Medications used to treat hypertension may affect fracture risk. This study investigated fracture risk for users of angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). Participants (899 men, median age 70.3 yr (59.9–79.1), range 50.0–96.6 yr; 574 women, median age 65.5 yr (58.1–75.4), range 50.1–94.6 yr) were from the Geelong Osteoporosis Study. Medication use was self-reported and incident fractures were ascertained using radiological reports. Bone mineral density (BMD) was measured at the femoral neck. Participants were divided into four groups: (1) non-users without hypertension, (2) non-users with hypertension, (3) ACEI users and (4) ARB users. Dosage was calculated using the defined daily dose (DDD) criteria. Participants were followed from date of visit to first fracture, death or 31 December 2016, whichever occurred first. Cox proportional hazards models were used for analyses. At least one incident fracture was sustained by 156 men and 135 women over a median(IQR) of 11.5(6.2–13.2) and 10.9(6.3–11.6) years of follow-up, respectively. In unadjusted analyses, compared to non-users without hypertension, men in all three other groups had a higher risk of fracture (Hazard Ratio (HR, 95%CI) 1.54, 1.00–2.37; 1.90, 1.18–3.05; 2.15, 1.26–3.66), for non-users with hypertension, ACEI and ARB users, respectively). Following adjustment for age, prior fracture and BMD, these associations became non-significant. A dose effect for ARB use was observed; men using lower doses had a higher risk of fracture than non-users without hypertension, in both unadjusted (2.66, 1.34–5.29) and adjusted (2.03, 1.01–4.08) analyses, but this association was not observed at higher doses. For women, unadjusted analyses showed a higher risk for ACEI users compared to non-users without hypertension (1.74, 1.07–2.83). This was explained after adjustment for age, alcohol consumption, prior fracture and BMD (1.28, 0.74–2.22). No other differences were observed. In men, lower dose (0 < DDD ≤ 1) ARB use was associated with an increased risk of fracture. ACEI or ARB use was not associated with increased risk of incident fracture in women. These findings may be important for antihypertensive treatment decisions in individuals with a high risk of fracture.

Effects of Renin-Angiotensin System Inhibitors on Mortality and Disease Severity of COVID-19 Patients: A Meta-analysis of Randomized Controlled Trials.

There is controversy over the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on the prognosis in patients with coronavirus disease 2019 (COVID-19), therefore, we aim to further explore the effect of renin-angiotensin-aldosterone system inhibitors on COVID-19-associated disease severity and mortality. We systematically searched PubMed, Embase, Cochrane Library databases, medRxiv, and bioRxiv from inception to 6 September 2021. The primary outcome was all-cause mortality. Secondary outcome was severe disease which was defined as admission to the intensive care unit, the use of noninvasive or invasive mechanical ventilation, or death. A total of 7 randomized controlled trials involving 1,321 COVID-19 patients were included. Fixed-effects meta-analysis demonstrated that the use of ACEI/ARB was not associated with higher risk of mortality (risk ratio [RR] = 0.84, 95% confidence interval [CI] 0.57-1.22, P = 0.10, I2 = 43%) and disease severity (RR = 0.86, 95% CI 0.71-1.05, P = 0.11, I2 = 47%). However, the subgroup analysis showed that compared with no ACEI/ARB use, the use of ARB was associated with a significant reduction of mortality (RR = 0.23, CI 0.09-0.60, P = 0.55, I2 = 0%) and disease severity (RR = 0.38, CI 0.19-0.77, P = 0.007). In conclusion, based on the available data, ACEI/ARB is not associated with the risk of mortality and disease severity in COVID-19 patients. And ACEI/ARB medications, especially ARB, should not be discontinued for patients with COVID-19.

Price and Quality in the Generic Pharmaceutical Market.

Price and Quality in the Generic Pharmaceutical Market.

Association between prognosis and the use of angiotensin‐converting enzyme inhibitors and/or angiotensin II receptor blockers in frail patients with heart failure with preserved ejection fraction

AimsThe effectiveness of angiotensin‐converting enzyme inhibitors (ACE‐I) and angiotensin II receptor blockers (ARB) has not been demonstrated in patients with heart failure with preserved ejection fraction (HFpEF). We recently reported significant interaction between the use of ACE‐I and/or ARB (ACE‐I/ARB) and frailty on prognosis in patients with HFpEF. In the present study, we examined the association between ACE‐I/ARB and prognosis in patients with HFpEF stratified by the presence or absence of frailty.Methods and resultsWe examined the association between the use of ACE‐I/ARB and prognosis according to the presence [Clinical Frailty Scale (CFS) ≥ 5] or absence (CFS ≤ 4) of frailty in patients with HFpEF in a post hoc analysis of registry data. Primary endpoint was the composite of all‐cause mortality and heart failure admission. Secondary endpoints were all‐cause mortality and heart failure admission. Of 1059 patients, median age was 83 years and 45% were male. Kaplan–Meier analysis showed that the risk of composite endpoint (log‐rank P = 0.001) and all‐cause death (log‐rank P = 0.005) in patients with ACE‐I/ARB was lower in those with CFS ≥ 5, but similar between patients with and without ACE‐I/ARB in patients with CFS ≤ 4 (composite endpoint: log‐rank P = 0.830; all‐cause death: log‐rank P = 0.192). In a multivariable Cox proportional hazards model, use of ACE‐I/ARB was significantly associated with lower risk of the composite endpoint [hazard ratio (HR) = 0.52, 95% confidence interval (CI) = 0.33–0.83, P = 0.005] and heart failure admission (HR = 0.45, 95% CI = 0.25–0.83, P = 0.010) in patients with CFS ≥ 5, but not in patients with CFS ≤ 4 (composite endpoint: HR = 1.41, 95% CI = 0.99–2.02, P = 0.059; heart failure admission: HR = 1.43, 95% CI = 0.94–2.18, P = 0.091). The association between ACE‐I or ARB and prognosis did not significantly differ by CFS (CFS ≤ 4: log‐rank P = 0.562; CFS ≥ 5: log‐rank P = 0.100, for with ACE‐I vs. ARB, respectively). Adjusted HRs for CFS 1–4 were higher than 1.0 but were <1.0 at CFS 5.ConclusionsIn patients with HFpEF, use of ACE‐I/ARB was associated with better prognosis in patients with frailty as assessed with the CFS, but not in those without frailty.

Anti-hypertensive medications and risk of colorectal cancer: a systematic review and meta-analysis.

Antihypertensive medications may impact colorectal cancer risk. We conducted a systematic review and meta-analysis of associations, with colorectal cancer risk, of five classes of antihypertensive medications: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and diuretics. A systematic search was conducted in MEDLINE, Embase, Web of Science, and the Cochrane library to identify relevant studies evaluating associations of ACEIs, ARBs, BBs, CCBs, and diuretics with colorectal cancer risk. Meta-analytic risk ratios (RRs) and corresponding 95% confidence intervals (95% CIs) were calculated using the inverse variance method. No overall significant associations with colorectal cancer risk were observed; ACEIs (5 studies) RR 1.05, 95% CI 0.91-1.23, ARBs (5 studies) RR 0.94, 95% CI 0.80-1.11, BBs (4 studies) RR 1.00, 95% CI 0.92-1.08, CCBs (4 studies) RR 1.02, 95% CI 0.88-1.18, and diuretics (6 studies) RR 1.02, 95% CI 0.90-1.17. There was considerable heterogeneity across studies, partly explained by differences in study design and location. When stratified by study location, there was significantly reduced colorectal cancer risk for ARB use in Asian populations (2 studies, RR 0.69, 95% CI 0.58-0.83). No significant colorectal cancer risk with ACEIs, BBs, CCBs, or diuretics was observed. ARB use may be associated with decreased risk of colorectal cancer in Asian populations, although additional studies in diverse populations are needed to confirm associations and help understand possible reasons for geographical differences.

Protective Effect of Renin-Angiotensin System Inhibitors on Parkinson’s Disease: A Nationwide Cohort Study

Background: Renin-angiotensin system (RAS) inhibitors have been suggested as protective agents in Parkinson’s disease (PD). However, epidemiological evidence on the association between RAS inhibitors and the development of PD is inconsistent. Objectives: To investigate the effect of RAS inhibitors on PD risk in patients with ischemic heart disease (IHD) by type and cumulative duration of RAS inhibitors and their degree of blood-brain barrier (BBB) penetration ability. Methods: This was a propensity score-matched retrospective cohort study using 2008–2019 healthcare claims data from the Korean Health Insurance Review and Assessment database. The association between RAS inhibitor use and PD in patients with IHD was evaluated using multivariate Cox proportional hazard regression analysis. The risks are presented as adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Results: Over a 10-year follow-up, 1,086 of 62,228 IHD patients developed PD. The Cox regression model showed that the use of RAS inhibitors was significantly associated with a lower risk of PD (aHR = 0.75; 95% CI 0.66–0.85) than the non-use of RAS inhibitors. Specifically, this reduced risk of PD only remained with the use of BBB-crossing angiotensin II receptor blockers (ARBs) (aHR = 0.62; 95% CI = 0.53–0.74), and this association was more definite with an increasing cumulative duration. A significantly reduced risk of PD was not observed with the use of BBB-crossing angiotensin-converting enzyme inhibitors. Conclusions: The use of ARBs with BBB-penetrating properties and a high cumulative duration significantly reduces the risk of PD in IHD patients. This protective effect could provide insight into disease-modifying drug candidates for PD.

The use of angiotensin II receptor blocker is associated with greater recovery of cardiac function than angiotensin-converting enzyme inhibitor in dilated cardiomyopathy.

AimsAngiotensin‐converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) have been shown to be associated with recovery of cardiac function in patients with dilated cardiomyopathy (DCM). The aim of this study was to assess comparative effectiveness of ACEis vs. ARBs on recovery of left ventricular ejection fraction (LVEF) among patients with DCM.Methods and resultsWe analysed the clinical personal records of DCM, a national database of the Japanese Ministry of Health, Labour and Welfare, from 2003 to 2014. Patients with LVEF < 40% and on either ACEis or ARBs were included. Eligible patients were divided into two groups according to the use of ACEis or ARBs. A one‐to‐one propensity case‐matched analysis was used. The primary outcome was defined as LVEF ≥ 40% at 3 years of follow‐up. Out of 4618 eligible patients, 2238 patients received ACEis and 2380 patients received ARBs. Propensity score matching yielded 1341 pairs. Mean age was 56.0 years, 2041 (76.1%) were male, median duration of heart failure was 1 year, and mean LVEF was 27.6%. The primary outcome was observed more frequently in ARB group than in ACEi group (59.8% vs. 54.1%; odds ratio 1.26; 95% confidence interval 1.08–1.47; P = 0.003). The per‐protocol analysis showed similar results (62.0% vs. 54.0%; odds ratio 1.39; 95% confidence interval 1.17–1.66; P < 0.001). The change in LVEF from baseline to 3 years of follow‐up was greater in ARB group than in ACEi group (15.8 ± 0.4% vs. 14.0 ± 0.4%, P = 0.003). The subgroup analysis showed that this effect was observed independently of systolic blood pressure, heart rate, LVEF, chronic kidney disease, and concomitant use of beta‐blockers and mineralocorticoid receptor antagonists.ConclusionsThe use of ARBs was associated with LVEF recovery more frequently than ACEis among patients with DCM and reduced LVEF.

Angiotensin-Converting Enzyme (ACE) Inhibitors May Moderate COVID-19 Hyperinflammatory Response: An Observational Study with Deep Immunophenotyping.

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARB), the most commonly prescribed antihypertensive medications, counter renin-angiotensin-aldosterone system (RAAS) activation via induction of angiotensin-converting enzyme 2 (ACE2) expression. Considering that ACE2 is the functional receptor for SARS-CoV-2 entry into host cells, the association of ACEi and ARB with COVID-19 outcomes needs thorough evaluation. We conducted retrospective analyses using both unmatched and propensity score (PS)-matched cohorts on electronic health records (EHRs) to assess the impact of RAAS inhibitors on the risk of receiving invasive mechanical ventilation (IMV) and 30-day mortality among hospitalized COVID-19 patients. Additionally, we investigated the immune cell gene expression profiles of hospitalized COVID-19 patients with prior use of antihypertensive treatments from an observational prospective cohort. The retrospective analysis revealed that there was no increased risk associated with either ACEi or ARB use. In fact, the use of ACEi showed decreased risk for mortality. Survival analyses using PS-matched cohorts suggested no significant relationship between RAAS inhibitors with a hospital stay and in-hospital mortality compared to non-RAAS medications and patients not on antihypertensive medications. From the analysis of gene expression profiles, we observed a noticeable up-regulation in the expression of 1L1R2 (an anti-inflammatory receptor) and RETN (an immunosuppressive marker) genes in monocytes among prior users of ACE inhibitors. Overall, the findings do not support the discontinuation of ACEi or ARB treatment and suggest that ACEi may moderate the COVID-19 hyperinflammatory response.