Angiotensin-converting Enzyme Inhibitors Users Research Articles

Association between chronic ACE inhibitor exposure and decreased odds of severe disease in patients with COVID-19.

Objective:Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Renin-angiotensin-aldosterone-system (RAAS) inhibitors may increase the expression of angiotensin-converting enzyme 2, which is the receptor for SARS-CoV-2 Spike protein. The consequences of using angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) during the COVID-19 pandemic are unknown.Methods:A retrospective cohort study aiming to identify the odds of severe disease (defined as either hospitalization of ≥14 days, admission to the intensive care unit, or death) associated with exposure to ACEi or ARB was conducted. Adult patients (age ≥18 years) with COVID-19 admitted to the İstanbul Faculty of Medicine Corona Center between March 9 and May 11, 2020, were included. Chronic users of ACEi, ARB, or other antihypertensive drugs were matched according to age, sex, sick days before hospitalization, comorbidities, smoking, number of antihypertensive regimens, doxazosin use, furosemide use, and serum creatinine level. Odds ratios (OR) of having severe disease were calculated.Results:In total, 611 patients were admitted with COVID-19, confirmed by either reverse-transcriptase polymerase chain reaction or computed tomography (CT). There were 363 males, and the age ranged from 18 to 98 years, with an average age of 57±15 years. Of these, 165 participants had severe disease (53 deaths, case fatality rate: 8.7%). Among those with hypertension (n=249), ARB exposure was compatible with decreased odds (OR=0.60, 95% CI: 0.27–1.36, p=0.31) of severe disease though not statistically significant, while ACEi exposure significantly reduced the risk of severe disease (OR=0.37, 95% CI: 0.15–0.87, p=0.03). ACEi exposure was associated with milder infiltrations seen on baseline CT, lower C-reactive protein and ferritin, higher monocytes, shorter hospitalization, and less requirement for specific empirical treatments (favipiravir and meropenem).Conclusion:Our data suggest that exposure to ACEi drugs may have favorable effects in the context of COVID-19 pneumonia.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Might Be Associated with Lung Adenocarcinoma Risk: A Nationwide Population-Based Nested Case–Control Study

Objectives: To analyze the association of the use of different doses of angiotensin II receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI) independently with lung cancer risk and to evaluate the lung cancer type that may be related to ARB or ACEI use. Patients and Methods: A nationwide population-based nested case–control study was conducted using Taiwan National Health Insurance Research Database linked to the Taiwan Cancer Registry database between January 1, 2000, and December 31, 2016. The cumulative defined daily dose (DDD) was estimated. We divided all users of ACEI or ARB into three categories based on the DDD of ACEI or ARB: low dose, middle dose, and high dose. Results: We identified 16,091 patients with newly diagnosed lung cancer, and 80,455 controls with hypertension were selected. Univariate and multivariate conditional logistic regressions showed that the independent risk factor for lung cancer was high-dose (≥1095 DDD) ARB use (adjusted odds ratio [OR]: 1.069, 95% confidence interval [CI]: 1.02–1.12, P = 0.003). An increase in lung adenocarcinoma (ADC) risk was associated with middle-dose (adjusted OR: 1.073, 95% CI: 1.01–1.14, P = 0.025) to high-dose (adjusted OR: 1.106, 95% CI: 1.05–1.17, P < 0.001) ARB use and high-dose ACEI use (adjusted OR: 1.095, 95% CI: 1.01–1.19, P = 0.033). No association was observed between different ARB or ACEI dose levels and the risk of lung squamous cell carcinoma and small-cell lung carcinoma. Conclusions: Our results suggest that the use of both ACEI and ARB at a high cumulative dose is associated with the risk of lung ADC. Funding Statement: Taipei Medical University and Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital (Funding Number 10908 & 10909). Declaration of Interests: The authors have no potential conflicts of interest to declare. Ethics Approval Statement: Our protocols were reviewed and approved by the Institutional Review Board of Taipei Medical University (TMU-JIRB No. 201712019).

Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Short-Term Mortality After Sepsis: A Population-Based Cohort Study.

Antagonists of the renin-angiotensin-aldosterone system (RAAS), including ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers), may prevent organ failure. We, therefore, investigated whether specific RAAS inhibitors are associated with reduced mortality in patients with sepsis.We conducted a population-based retrospective cohort study using multivariable propensity score-based regression to control for differences among patients using different RAAS inhibitors. A multivariable-adjusted Cox proportional-hazards regression model was used to determine the association between RAAS inhibitors and sepsis outcomes. To directly compare ACEI users, ARB users, and nonusers, a 3-way propensity score matching approach was performed. Results were pooled with previous evidence via a random-effects meta-analysis. A total of 52 727 patients were hospitalized with sepsis, of whom 7642 were prescribed an ACEI and 4237 were prescribed an ARB. Using propensity score-matched analyses, prior ACEI use was associated with decreased 30-day mortality (hazard ratio, 0.84 [95% CI, 0.75-0.94]) and 90-day mortality (hazard ratio, 0.83 [95% CI, 0.75-0.92]) compared with nonuse. Prior ARB use was associated with an improved 90-day survival (hazard ratio, 0.88 [95% CI, 0.83-0.94]). These results persisted in sensitivity analyses focusing on patients without cancer and patients with hypertension. By contrast, no beneficial effect was found for antecedent β-blockers exposure (hazard ratio, 0.99 [95% CI, 0.94-1.05]). The pooled estimates obtained from the meta-analysis was 0.71 (95% CI, 0.58-0.87) for prior use of ACEI/ARB.The short-term mortality after sepsis was substantially lower among those who were already established on RAAS inhibitor treatment when sepsis occurred.

Acute Respiratory Failure Secondary to ACE Inhibitor–Induced Angioedema after Five Years of Lisinopril Therapy

Angiotensin-converting enzyme (ACE) inhibitors are amongst the commonest prescribed medications in the United States and considered to be the leading causes of drug induced angioedema. High bradykinin levels stimulate vasodilation and increased vascular permeability of the post-capillary venules and allow for plasma extravasation into the submucosal tissue, leading to angioedema. Usually, the angioedema occurs within the first week of exposure to therapy, but cases occurring after years of stable ACE inhibitor usage are not uncommon. Here, we present a 43-year-old Caucasian female who developed acute respiratory failure requiring mechanical ventilation secondary to ACEi–induced angioedema after five years of Lisinopril usage. This case will help to increase physicians’ awareness that this potentially fatal complication can still occur after years of ACE inhibitor usage.

Transcatheter closure of atrial septal communication: Impact on quality of life in mid-term follow-up.

Atrial septal defect (ASD) and patent foramen ovale (PFO) are specific types of atrial septal communications (ASC). We aimed to assess quality of life (QoL) in patients before and after percutaneous closure of ASC and determine the factors influencing QoL in this group of patients. We performed a clinical assessment and conducted an SF-36 questionnaire, electrocardiography and echocardiography studies in patients before and 6 months after percutaneous ASC closure. Patients with ASD (n = 56) had a lower SF-36 total score than those with PFO (n = 73), before and after percutaneous ASC occlusion (both p < 0.001). After the procedure, the improvement of SF-36 total score in patients with ASD or atrial fibrillation was greater (p < 0.001 and p = 0.005, respectively). We observed correlations between improvement of QoL and baseline supraventricular extrasystolic beats (rs = 0.28; p = 0.002), but not ventricular extrasystolic beats (rs = 0.03; p = 0.76). Quality of life improvement was predicted in patients with ASD by higher baseline tricuspid annular plane systolic excursion (TAPSE) and right ventricular longitudinal dimension R2 = 0.38; p < 0.001. However, in patients with PFO, this was predicted by TAPSE, lack of arterial hypertension and usage of angiotensin-converting enzyme inhibitors, R2 = 0.30; p < 0.001. Patients with ASD have lower QoL than those with PFO before and after percutaneous ASC occlusion. Six months after the procedure, the improvement of QoL in patients with ASD was higher than in those with PFO. The change in QoL self-assessed by patients after the procedure was associated with episodes of arrhythmia and was predicted with echocardiographic and clinical parameters.

Angiotensin converting enzyme inhibitors use and development of lung cancer: A systematic review and meta-analysis.

e13093 Background: Angiotensin-converting enzyme inhibitors (ACEIs) are commonly prescribed medications for hypertension and heart failure. Generally, ACEIs are well-tolerated medications with reasonable safety profile making them a favorable choice by many clinicians. However, several studies with conflicting results have signaled an association between ACEIs use and the development of lung cancer. We sought to systematically review the literature and perform the first meta-analysis to study the risk of lung cancer among ACEI users. Methods: We performed a literature review by searching multiple databases. A random effect meta-analysis approach was used to pool the data and relative risk was used to calculate the overall effect estimate. Results: A total of 423 articles were identified but only 6 observational studies were included with a total of 872,220 patients (634,672. ACEIs users). The relative risk of lung cancer development among ACEIs users was 1.02 (CI 0.89-1.16) compared to non-ACEIs users. Conclusions: Current systematic review and meta-analysis show no significant association between ACEIs use and the development of lung cancer. The result of our meta-analysis provides further assurance to the health care providers regarding ACEIs use.

Angiotensin II receptor blockers are safe in patients with prior angioedema related to angiotensin-converting enzyme inhibitors - a nationwide registry-based cohort study.

It has long been suggested that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (AT2s) have some degree of 'cross-reactivity' in causing angioedema. Therefore, caution has been advised when switching patients with ACEi-related angioedema to an AT2. To clarify whether AT2s can be used safely in patients with a history of angioedema during ACEi treatment and to estimate the incidence rate of angioedema in patients subsequently treated with other antihypertensive drugs (beta-adrenergic blockers, calcium channel blockers, thiazides and analogues) or no antihypertensives. This is a nationwide retrospective registry-based cohort study of the Danish population during the period 1994 to 2016, and it uses Danish health registries. Propensity score adjusted and conventional proportional hazards regression models have been employed. A total of 1106024 ACEi users were identified. In total, 5507 (0.5%) of these patients had experienced angioedema during ACEi treatment and were included in the study. The highest risk of angioedema recurrence was associated with continued ACEi use at an adjusted hazard ratio of 1.45 (95% CI, 1.19 to 1.78). An inverse association was found between AT2s and angioedema (adjusted hazard ratio, 0.39; 95% CI, 0.30 to 0.51) compared with other antihypertensives (adjusted hazard ratios, 0.77 to 0.97). Compared with other antihypertensive drugs, AT2s do not increase the incidence of angioedema in patients with previous ACEi-related angioedema.

Antihypertensive drugs and prostate cancer survival after radical prostatectomy in Finland-A nationwide cohort study.

Antihypertensive (anti-HT) drugs targeting renin-angiotensin-aldosterone (RAA)- system have been associated with improved prostate cancer (PCa)-specific survival. Challenge is that often multiple drugs are used simultaneously. We evaluated the association between use of anti-HT drugs and PCa survival among 14,422 surgically treated Finnish PCa patients. Information on drug purchases was obtained from a national prescription database. We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for risk of PCa death and initiation of androgen deprivation therapy (ADT) with adjustment for age, tumor extent, use of statins and for Charlson Comorbidity Index. Angiotensin-converting enzyme (ACE)- inhibitors, angiotensin- receptor (ATR)-blockers, diuretics, calcium-channel blockers, beta-blockers and other anti-HT drugs were analyzed as separate time-dependent variables to model simultaneous use. Overall anti-HT drugs were associated with an increased risk of PCa death. Conversely use of ATR-blockers was associated with decreased risk of PCa death (HR: 0.43, 95% CI: 0.26-0.72 and HR: 0.60, 95% CI 0.37-0.97 for pre- and post-diagnostic use). Similar risk decrease was not observed in other drug groups. Anti-HT drugs were also associated with an increased risk of starting ADT, with the exception of ATR-blockers (HR: 0.81 CI:0.71-0.92). ATR- blockers differ from other anti-HT drugs as the survival is better in users of this drug group. The result partly supports the role of RAA system in PCa progression. Nevertheless, the risk decrease was not observed in ACE-inhibitor users. Further research is needed to elucidate the molecular mechanism for the potential anticancer effect of ATR- blockers.

The association of multiple anti-hypertensive medication classes with Alzheimer's disease incidence across sex, race, and ethnicity.

BackgroundAntihypertensive treatments have been shown to reduce the risk of Alzheimer’s disease (AD). The renin-angiotensin system (RAS) has been implicated in AD, and thus RAS-acting AHTs (angiotensin converting enzyme inhibitors (ACEIs), and angiotensin-II receptor blockers (ARBs)) may offer differential and additional protective benefits against AD compared with other AHTs, in addition to hypertension management.MethodsIn a retrospective cohort design, we examined the medical and pharmacy claims of a 20% sample of Medicare beneficiaries from 2007 to 2013, and compared rates of AD diagnosis for 1,343,334 users of six different AHT drug treatments, 65 years of age or older (4,215,338 person-years). We compared AD risk between RAS and non-RAS AHT drug users, and between ACEI users and ARB users, by sex and race/ethnicity. Models adjusted for age, socioeconomic status, underlying health, and comorbidities.FindingsRAS-acting AHTs were slightly more protective against onset of AD than non-RAS-acting AHTs for males, (male OR = 0.931 (CI: 0.895–0.969)), but not so for females (female OR = 0.985 (CI: 0.963–1.007)). Relative to other AHTs, ARBs were superior to ACEIs for both men (male ARB OR = 0.834 (CI: 0.788–0.884); male ACEI OR = 0.978 (CI: 0.939–1.019)) and women (female ARB OR = 0.941 (CI: 0.913–0.969); female ACEI OR = 1.022 (CI: 0.997–1.048)), but only in white men and white and black women. No association was shown for Hispanic men and women.ConclusionHypertension management treatments that include RAS-acting ARBs may, in addition to lowering blood pressure, reduce AD risk, particularly for white and black women and white men. Additional studies and clinical trials that include men and women from different racial and ethnic groups are needed to confirm these findings. Understanding the potentially beneficial effects of certain RAS-acting AHTs in high-risk populations is of great importance.

Renin-angiotensin system inhibition is associated with reduced risk of left atrial appendage thrombosis formation in patients with atrial fibrillation.

Inhibition of the renin-angiotensin axis can reduce the likelihood of atrial fibrillation (AF). However, the effects of angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on thrombogenicity in AF remain incompletely elucidated. Thisretrospective case-control study was conducted to evaluate whether the use of ACEI or ARB could reduce the incidence of left atrial appendage thrombus (LAAT) and spontaneous echocardiographic contrast (SEC) in patients with AF. A total of 199 AF patients who received both transesophageal echocardiogram (TEE) and transthoracic echocardiogram (TTE) successively on the same day from 2012 to 2016 were enrolled. Left atrial dimension, maximal left atrial volume (LAVmax), left ventricular end-diastolic dimension, left ventricular ejection fraction, and the ratio of the early transmitral flow velocity and the early mitral annular velocity (E/e') were determined. Longitudinal LA strain was evaluated using two-dimensional speckle tracking imaging at each LA segment. Peak systolic strain was calculated by averaging total segments. LAAT, LAA emptying flow velocity (LAAeV) and SEC were evaluated by TEE. Risk factors for LAAT and usage of ACEIs or ARBs were recorded. The incidence of LAAT was 27.6%. Among the patients with renin-angiotensin system (RAS) inhibitors, 20.5% were demonstrated to have LAAT, compared with 33.3% in the nonuser group (p = 0.044). LA peak systolic strain and LAAeV were significantly increased in patients with RAS inhibitors compared to the nonuser group (p = 0.002, p = 0.047, respectively). Patients with LAAT had higher CHA2DS2-VASc scores and evident SEC compared with those without LAAT (p = 0.000, p = 0.000, respectively). Usage of ACEIs/ARBs and antiplatelet drugs were frequent in patients with LAAT than in those without LAAT (p = 0.044, p = 0.000, respectively). Even after controlling for LAAT-related risk factors (age, body mass index, AF type, hypertension, diabetes mellitus, prior stroke or transient ischemic attack, drinking history and usage of antiplatelet drugs and LAVmax), use of RAS inhibitors remained significantly associated with a lower risk of LAAT (OR = 0.222; 95% CI 0.084-0.585, p = 0.002). This study shows that RAS inhibitors may be effective in reducing the risk of LAAT in patients with AF through atrial reverse remodeling.

High Incidence of Cough among Users of Angiotensin-Converting Enzyme Inhibitors

High Incidence of Cough among Users of Angiotensin-Converting Enzyme Inhibitors

Decreased Risk of Radiation Pneumonitis With Coincident Concurrent Use of Angiotensin-converting Enzyme Inhibitors in Patients Receiving Lung Stereotactic Body Radiation Therapy.

Angiotensin-converting enzyme inhibitors (ACEi) have demonstrated decreased rates of radiation-induced lung injury in animal models and clinical reports have demonstrated decreased pneumonitis in the setting of conventionally fractionated radiation to the lung. We tested the role of ACEi in diminishing rates of symptomatic (grade ≥2) pneumonitis in the setting of lung stereotactic body radiation therapy (SBRT). We analyzed patients treated with thoracic SBRT to 48 to 60 Gy in 4 to 5 fractions from 2006 to 2014. We reviewed pretreatment and posttreatment medication profiles to document use of ACEi, angiotensin receptor blockers, bronchodilators, aspirin, PDE-5 inhibitors, nitrates, and endothelin receptor antagonists. Pneumonitis was graded posttreatment based on Common Terminology Criteria for Adverse Events Version 4.0. Univariate and multivariate analysis was performed and time to development of pneumonitis was evaluated by the Kaplan-Meier method. A total of 189 patients were evaluated with a median follow-up of 24.8 months. The overall 1-year rate of symptomatic pneumonitis was 13.2%. The 1-year rate of symptomatic pneumonitis was 4.2% for ACEi users versus 16.3% in nonusers (P=0.03). On univariate analysis, the odds of developing grade 2 or greater pneumonitis were significantly lower for patients on ACEi (P=0.03). On multivariate analysis, after controlling for clinicopathologic characteristics and dosimetric endpoints, there was a significant association between ACEi use and decreased risk of clinical pneumonitis (P=0.04). Angiotensin receptor blockers or other bronchoactive medications did not show significant associations with development of pneumonitis. Incidental concurrent use of ACEi demonstrated efficacy in diminishing rates of symptomatic pneumonitis in the setting of lung SBRT.

PND17 - Differences in Alzheimer’s Disease Protectiveness Among Renin-Angiotensin System Acting Anti-Hypertensive Prescription Drugs

Hypertension management with antihypertensive (AHT) prescription drugs has been shown to reduce risk of Alzheimer’s disease (AD). The renin-angiotensin system (RAS) has been implicated in AD and may induce differences in protectiveness within RAS-acting AHTs (angiotensin converting enzyme inhibitors (ACEIs), and angiotensin-II receptor blockers (ARBs)) and between RAS-acting and other AHTs (beta blockers, calcium channel blockers, loop diuretics, and thiazide diuretics). We identify the association between AD risk and AHT use, across class, sex, and race/ethnicity. We examined the medical and pharmacy claims of a 20% sample of Medicare beneficiaries from 2007 to 2013, and compared rates of AD diagnosis for 1,347,356 AHT users 65 years of age or older (4,229,259 person-years). We compare RAS-acting AHT users to other AHT users, and ACEI users to ARB users, for black, Hispanic, and non-Hispanic white men and women. RAS-acting AHTs are slightly more protective against onset of AD than non-RAS-acting AHTs for males, but insignificantly different for females (male HR = 0.933 (CI: 0.897-0.971), female HR = 0.983 (CI: 0.961-1.005)). Relative to other AHTs, ARBs are more protective than ACEIs for both sexes (male ACEI HR = 0.982 (CI: 0.943-1.022), female ACEI HR = 1.021 (CI: 0.997-1.047). Male ARB HR = 0.829 (CI: 0.783-0.877), female ARB HR = 0.939 (CI: 0.911-0.967)). The magnitudes of the associations consistently showed better protection for ARBs than ACEIs across race/ethnicity, except for Hispanic females (ACEI HR = 1.010 (CI: 0.924-1.103), ARB HR = 0.995 (CI: 0.899-1.102)). The reduction in AD risk is higher for users of ARBs than other AHTs for most subpopulations, with stronger protection for males than females. Clinical trials that include racial and ethnic groups need to confirm these findings. Physicians should consider potential benefits of some AHTs for reducing AD risk when making prescribing decisions.

The Role of Angiotensin-Converting Enzyme Inhibitors in Patients with Chronic Subdural Hematoma: A Scandinavian Population-Based Multicenter Study.

To investigate the role of angiotensin converting enzyme (ACE) inhibitors in the recurrence of chronic subdural hematoma (cSDH) after burr hole surgery. A retrospective review was conducted of a Scandinavian multicenter, population-based cohort of 1252 adults with cSDH who underwent with burr hole surgery between January 1, 2005, and December 31, 2010. The risk of cSDH recurrence was assessed in users of ACE inhibitors, users of angiotensin II receptor blockers (ARBs), and those without ACE inhibitor treatment (no ACE inhibitor group) using univariable and multivariable regression analyses. The cohort included 98 (7.8%) ACE inhibitor users and 63 (5%) ARB-only users. The recurrence rate was 16.3% (n= 16) in the ACE inhibitor group, compared with 13.3% (n= 153) in the no ACE inhibitor group (P= 0.39) and 14.3% (n= 9) in the ARB group (P= 0.73). When comparing groups, age (P= 0.01), Charlson Comorbidity Index (P= 0.01), use of platelet inhibitors (P= 0.001) and use of anticoagulants (P= 0.01) differed between the ACE inhibitor and no ACE inhibitor groups. Only age differed significantly between the ACE inhibitor and ARB groups (P= 0.03). In the analyses adjusted for differences in baseline characteristics, ACE inhibitor treatment did not influence the risk of recurrence (odds ratio, 1.2; 95% confidence interval, 0.7-2.2; P= 0.46). In this population-based study, the use of ACE inhibitors was not associated with the risk of recurrence following burr hole surgery for cSDH.

Angiotensin receptor blockers are associated with lower mortality than ACE inhibitors in predialytic stage 5 chronic kidney disease: A nationwide study of therapy with renin-angiotensin system blockade.

Dual renin angiotensin system (RAS) blockade using angiotensin-receptor blockers (ARBs) in combination with angiotensin converting enzyme inhibitors (ACEIs) is reported to improve proteinuria in both diabetic and non-diabetic patients. However, its renoprotective effect and safety remain uncertain in patients with advanced chronic kidney disease (CKD). From January 1, 2000 through June 30, 2009, we enrolled 14,117 pre-dialytic stage 5 CKD patients with serum creatinine >6mg/dL and hematocrit <28% under the treatment with erythropoiesis stimulating agents and RAS blockade. We used Cox proportional hazards regression models to estimate the hazard ratios (HRs) against the commencement of long-term dialysis and all-cause mortality for ACEI/ARB users. Over a median follow-up of 7 months, 9,867 patients (69.9%) required long-term dialysis and 2,805 (19.9%) died before progression to end-stage renal disease requiring dialysis. In comparison with the ARB-only users, dual blockade with ACEIs and ARBs was associated with a significantly higher risk of (1) death in all CKD patients (HR = 1.49, [95%CI, 1.30–1.71]; P = 0.02) and in diabetic subgroup (HR = 1.58, [95%CI, 1.34–1.86]; P = 0.02); (2) composite endpoint of long-term dialysis or death in diabetic subgroup (HR = 1.10, [95%CI, 1.01–1.20]; P = 0.04); (3) hyperkalemia-associated hospitalization in non-diabetic subgroup (HR, 2.74, [95%CI, 1.05–7.15]; P = 0.04). However, ACEIs users were associated with higher mortality than ARBs users in all CKD patients (HR = 1.17, [95%CI, 1.07–1.27]; P = 0.03) and in diabetic subgroup (HR = 1.32, [95%CI, 1.18–1.48]; P = 0.03). Monotherapy of RAS blockade, especially ARB, is more effective and safer than dual RAS blockade in pre-dialytic stage 5 CKD patients.

Renin-angiotensin system inhibitors and risk of fractures: a prospective cohort study and meta-analysis of published observational cohort studies

The renin-angiotensin system (RAS) represents an important target of antihypertensive medications. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), which are widely-used RAS inhibiting drugs, have been suggested to have beneficial effects on bone tissue. We aimed to assess the associations of use of ACEIs and/or ARBs with the risk of fractures using a population-based prospective cohort and a meta-analysis of published prospective cohort studies. Information on antihypertensive medication use (including both ACEIs and ARBs) were assessed in 1743 men and women of the Kuopio Ischemic Heart Disease prospective cohort study. Hazard ratios (HRs) [95% confidence intervals (CI)] of ACEIs or ARBs use with incident fractures were calculated. A total of 203 composite (hip, humeral, and wrist) fractures occurred during a median follow-up of 14.8 years. In multivariate adjusted analysis, the HR for composite fractures comparing users of ACEIs or ARBs with non-users was 1.00 (0.59–1.69). The corresponding adjusted HR for hip fractures comparing users versus non-users of ACEIs or ARBs was 0.89 (0.32–2.47). Including the current study, a total of 11 observational cohort studies involving 3526,319 participants and >323,355 fractures were included in a meta-analysis. Comparing ACEI users with non-users and ARB users with non-users, the HRs for composite fractures were 1.09 (0.89–1.33) and 0.87 (0.76–1.01) respectively. The corresponding HRs for hip fractures were 0.91 (0.86–0.95) and 0.80 (0.75–0.85) respectively. Use of RAS inhibitors was not associated with long-term risk of composite fractures in both primary and pooled analyses. Pooled evidence however suggests a beneficial effect of RAS blockers on hip fracture risk.

Effect of dual compared to no or single renin-angiotensin system blockade on risk of renal replacement therapy or death in predialysis patients: PREPARE-2 study

Current guidelines on hypertension treatment in chronic kidney disease (CKD) patients discourage combined angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II receptor blocker (ARB) use due to the risk of an increased kidney function decline. However, dual compared to single renin-angiotensin system (RAS) blockade may have more efficacy with regard to hypertension and proteinuria. Among incident predialysis patients (CKD 4-5), we compared dual with no or single RAS blockade regarding kidney function decline and risk of renal replacement therapy (RRT) or death. In a multicenter cohort study, 495 incident predialysis patients (>18 years) were included between 2004 and 2011 and followed until RRT, death, or October 2016. At baseline, patients were divided into four categories: nonuser, single or dual user of ACEi and/or ARB. Cox models were used to estimate the hazard ratio for the combined end point RRT or death. Differences in decline of kidney function among the four drug groups were compared with a linear mixed model. A total of 119 patients were nonusers, 164 ACEi users, 133 ARB users, and 79 dual RAS users. Compared to nonusers, the multivariable adjusted hazard ratio (95% confidence interval) for the combined end point was 0.75 (0.65 to 0.86) for ACEi users, 0.87 (0.76 to 1.00) for ARB users, and 0.79 (0.67 to 0.94) for dual RAS users. The average annual decline in kidney function did not differ among the four groups. We observed in predialysis patients that compared to no RAS blockade, both dual RAS blockade and single ACEi use were associated with about 20%-25% lower risk of RRT or death, without difference in kidney function decline.

Memory is preserved in older adults taking AT1 receptor blockers

BackgroundPrior work suggests that some but not all antihypertensive treatments may benefit cognition and risk for Alzheimer’s disease, independent of stroke. Angiotensin II receptor blockers (ARBs) have been highlighted as one antihypertensive drug class that may confer greatest benefit.MethodsThe participants comprised 1626 nondemented adults, aged 55–91 years, recruited from Alzheimer’s Disease Neuroimaging Initiative sites. Three groups were compared: ARB users (HTN-ARBs), other antihypertensive drug users (HTN-Other), and normotensives. In post hoc analyses, we also examined (1) users of ARBs and angiotensin-converting enzyme inhibitors (ACEIs), (2) users of blood-brain barrier (BBB)-crossing ARBs and users of non-BBB-crossing ARBs, and (3) users of BBB-crossing ARBs and ACEIs (BBB crossers) and users of non-BBB-crossing ARBs and ACEIs (BBB noncrossers). Groups were compared regarding cognition and magnetic resonance imaging measures of brain volume and white matter hyperintensities (WMH), using analysis of covariance and multilevel models.ResultsAt baseline, the HTN-Other group performed worse than normotensives on Rey Auditory Verbal Learning Test (RAVLT) Immediate Recall (p = 0.002), Delayed Recall (p < 0.001), Recognition Memory (p = 0.001), and Trails A (p < 0.001) and B (p = 0.01). ARB users performed better than the HTN-Other group on Recognition Memory (p = 0.04) and worse than normotensives on Trails A (p = 0.04). The HTN-Other group performed worse than normotensives on Logical Memory Immediate (p = 0.02) and Delayed Recall over the 3-year follow-up (p = 0.007). Over the follow-up period, those taking BBB-crossing ARBs performed better than the HTN-Other group on AVLT Delayed Recall (p = 0.04), Logical Memory Immediate (p = 0.02), and Delayed Recall (p = 0.05). They also had fewer WMH than the HTN-Other group (p = 0.008) and those taking non-BBB-crossing ARBs (p = 0.05). There were no group differences in brain volume. Users of BBB-crossing medications (ARBs or ACEIs) showed better performance on AVLT Delayed Recall over time than all other groups, including normotensives (all p < 0.01), and had less WMH volume over time than the BBB noncrossers group (p = 0.03), although they had more WMH volume than normotensives (p = 0.01). The BBB noncrossers group performed worse than normotensives on Logical Memory Delayed Recall over time (p = 0.01), but the BBB crossers group was not significantly different (p = 0.13).ConclusionsHypertensive participants demonstrated worse baseline memory and executive function, as well as greater memory decline, over the 3-year follow-up than normotensives, unless they were ARB users, who showed preserved memory compared with those taking other antihypertensive drugs. Users of BBB-crossing ARBs showed superior memory performance over time compared with other antihypertensive drug users and had less WMH volume. Users of BBB-crossing medications (ARBs or ACEIs) showed better list-learning memory performance over time than all other groups, including normotensives, and had less WMH volume over time than users of non-BBB-crossing medications. These findings demonstrate that ARBs, especially those of the BBB-crossing variety, are associated with greater memory preservation and less WMH volume than other antihypertensive medications.

Angiotensin II receptor blockers and risk of acute pancreatitis - a population based case\u2013control study in Sweden

BackgroundAcute pancreatitis is a potentially lethal disease, with a rising incidence in the Western world. Yet, no pharmacological prevention or specific treatment for acute pancreatitis exists. Also, the connection with severity of acute pancreatitis is unknown. Experimental and epidemiological research suggests a protective effect of angiotensin II receptor blockers.MethodsDuring 2006 to 2008, we performed a nationwide case–control study on Swedish residents aged 40–84 years. First-time cases with acute pancreatitis were identified in the National Patient Register and data on dispensed prescriptions was retrieved from the Prescribed Drug Register. Controls were randomly selected from the general population in Sweden frequency-matched on sex, age, and calendar year. To estimate relative risk of acute pancreatitis, by degree of severity, among users of angiotensin II receptor blockers, as compared to non-users, we used multivariable logistic regression analysis to calculate odds ratios (OR) with 95% confidence interval (CI).ResultsAmong 6,161 cases of acute pancreatitis and 61,637 controls, current use of angiotensin II receptor blockers was followed by a decreased risk of acute pancreatitis, compared to non-users, adjusted OR 0 · 77 (95% CI 0 · 69–0 · 86). No protective association, but an increased risk was found for users of angiotensin-converting enzyme inhibitors (adjusted OR 1 · 11, 95% CI: 1 · 01–1 · 21), analysed for comparison reasons. There was a significant decreased risk associated with both severe acute pancreatitis, (OR 0 · 71 (0 · 59–0 · 85), and mild acute pancreatitis; adjusted OR 0 · 81 (0 · 70–0 · 94).ConclusionThis population-based case–control study indicates that use of angiotensin II receptor blockers might be associated with a lesser risk of acute pancreatitis, and that the protective association was significant among cases of both severe and mild acute pancreatitis.

Recurrent pneumonia among Japanese adults: disease burden and risk factors

BackgroundIn Japan and other societies with rapidly aging populations, recurrent pneumonia (RP) is a major clinical problem yet only limited information exists regarding the burden of this disease.MethodsA prospective study of adult pneumonia was conducted to investigate the incidence of RP and potential risk factors. From February 1, 2012 to January 31, 2013, patients aged ≥ 15 years who were diagnosed with pneumonia were prospectively enrolled in a representative community hospital located in central Japan. Patients were followed for one-year to evaluate the recurrence of pneumonia and characteristics associated with RP. Cox proportional hazards models were constructed to compute adjusted hazard ratios (aHR) and ascertain risk factors significantly associated with RP.ResultsIn total, 841 patients with a median age of 73 years (range 15–101 years) were enrolled totaling 1,048 person-years of observation with a median follow-up time of 475 days. A total of 137 patients had at least one recurrent episode with an incidence rate of 13.1 per 100 person-years (95% confidence interval: 11.1–15.5). In multivariate analysis, a past history of pneumonia (aHR 1.95, 95% CI: 1.35–2.8), chronic pulmonary disease (aHR 1.86, 1.24–2.78) and inhaled corticosteroid usage (aHR 1.78, 1.12–2.84) and hypnotic/sedative medication usage (aHR 2.06, 1.28–3.31) were identified as independent risk factors for recurrent pneumonia, whereas angiotensin converting enzyme-inhibitors usage was associated with a reduction of the risk of RP (aHR 0.22, 0.05–0.91). The detection of P. aeruginosa was significantly associated with RP even after adjusting for chronic pulmonary diseases (aHR = 2.37).ConclusionsRecurrent pneumonia constitutes a considerable proportion of the pneumonia burden in Japan. A past history of pneumonia, chronic pulmonary disease, inhaled corticosteroid and hypnotic/sedative medication usage and detection of P. aeruginosa were identified as independent risk factors for recurrent pneumonia and special attention regarding the use of medications in this vulnerable population is needed to reduce the impact of this disease in aging populations.