Angiotensin-converting Enzyme Inhibitors Exposure Research Articles

Impact of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on the mortality in sepsis: A meta-analysis.

The effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on the mortality of patients with sepsis is not well characterized. To elucidate the association between prior ACEI or ARB exposure and mortality in sepsis. The PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched for all studies of premorbid ACEI or ARB use and sepsis mortality until November 30 2019. Two reviewers independently assessed, selected, and abstracted data from studies reporting ACEIs or ARBs, sepsis, and mortality. The primary extracted data consisted of premorbid ACEI or ARB exposure, mortality, and general patient data. Two reviewers independently assessed the risk of bias and quality of evidence. A total of six studies comprising 281238 patients with sepsis, including 49799 cases with premorbid ACEI or ARB exposure were eligible for analysis. Premorbid ACEIs or ARBs exposure decreased the 30-d mortality in patients with sepsis. Moreover, the use of ACEIs or ARBs was associated with approximately a 6% decreased risk of 30-d mortality. The results of this systematic review suggest that ACEI or ARB exposure prior to sepsis may be associated with reduced mortality. Further high-quality cohort studies and molecular mechanism experiments are required to confirm our results.

Relationship between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prescribing and delirium in the ICU-A secondary analysis.

Studies suggest Angiotensin-Converting Enzyme inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) may slow the decline of memory function in individuals with mild to moderate Alzheimer's disease by regulating migroglial activation and oxidative stress within the brain's reticular activating system. Therefore, we evaluated the relationship between delirium prevalence and being prescribed ACEI and ARB in participants admitted to the intensive care units (ICU). A secondary analysis of data from two parallel pragmatic randomized controlled trials was performed. ACEI and ARB exposure was defined as being prescribed an ACEI or an ARB within six months prior to the ICU admission. The primary endpoint was the first positive delirium assessment based on Confusion Assessment Method for the ICU (CAM-ICU) for up to thirty days. A total of 4791 patients admitted to the medical, surgical, and progressive ICU and screened for eligibility for the parent studies between February 2009 and January 2015 from two level 1 trauma and one safety net hospital in a large urban academic health system were included. Delirium rates in the ICU were not significantly different among participants with no exposure to ACEI/ARB (12.6%), or exposure to ACEI (14.4%), ARB (11.8%), or ACEI and ARB in combination (15.4%) in six months prior to the ICU admission. Exposure to ACEI (OR=0.97[0.77, 1.22]), ARB (OR=0.70 [0.47, 1.05]), or both (OR=0.97 [0.33, 2.89]) in six months prior to ICU admission was not significantly associated with odds of delirium during the ICU admission after adjusting for age, gender, race, co-morbidities, and insurance status. While the impact of ACEI and ARB exposure prior to the ICU admission was not associated with the prevalence of delirium in this study, further research is needed to fully understand the impact of antihypertensive medications on delirium.

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and COVID-19-related outcomes: A patient-level analysis of the PCORnet blood pressure control lab

SARS-CoV-2 accesses host cells via angiotensin-converting enzyme-2, which is also affected by commonly used angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), raising concerns that ACEI or ARB exposure may portend differential COVID-19 outcomes. In parallel cohort studies of outpatient and inpatient COVID-19-diagnosed adults with hypertension, we assessed associations between antihypertensive exposure (ACEI/ARB vs. non-ACEI/ARB antihypertensives, as well as between ACEI- vs. ARB) at the time of COVID-19 diagnosis, using electronic health record data from PCORnet health systems. The primary outcomes were all-cause hospitalization or death (outpatient cohort) or all-cause death (inpatient), analyzed via Cox regression weighted by inverse probability of treatment weights. From February 2020 through December 9, 2020, 11,246 patients (3477 person-years) and 2200 patients (777 person-years) were included from 17 health systems in outpatient and inpatient cohorts, respectively. There were 1015 all-cause hospitalization or deaths in the outpatient cohort (incidence, 29.2 events per 100 person-years), with no significant difference by ACEI/ARB use (adjusted HR 1.01; 95% CI 0.88, 1.15). In the inpatient cohort, there were 218 all-cause deaths (incidence, 28.1 per 100 person-years) and ACEI/ARB exposure was associated with reduced death (adjusted HR, 0.76; 95% CI, 0.57, 0.99). ACEI, versus ARB exposure, was associated with higher risk of hospitalization in the outpatient cohort, but no difference in all-cause death in either cohort. There was no evidence of effect modification across pre-specified baseline characteristics. Our results suggest ACEI and ARB exposure have no detrimental effect on hospitalizations and may reduce death among hypertensive patients diagnosed with COVID-19.

An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo.

Angiotensin-converting enzyme inhibitors (ACEIs) are used by millions of patients to treat hypertension, diabetic kidney disease, and heart failure. However, these patients are often at increased risk of infection. To evaluate the impact of ACEIs on immune responses to infection, we compared the effect of an ACEI versus an angiotensin receptor blocker (ARB) on neutrophil antibacterial activity. ACEI exposure reduced the ability of murine neutrophils to kill methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae in vitro. In vivo, ACEI-treated mice infected with MRSA had increased bacteremia and tissue bacteria counts compared to mice treated with an ARB or with no drug. Similarly, ACEIs, but not ARBs, increased the incidence of MRSA-induced infective endocarditis in mice with aortic valve injury. Neutrophils from ACE knockout (KO) mice or mice treated with an ACEI produced less leukotriene B4 (LTB4) upon stimulation with MRSA or lipopolysaccharide, whereas neutrophils overexpressing ACE produced more LTB4 compared to wild-type neutrophils. As a result of reduced LTB4 production, ACE KO neutrophils showed decreased survival signaling and increased apoptosis. In contrast, neutrophils overexpressing ACE had an enhanced survival phenotype. Last, in a cohort of human volunteers receiving the ACEI ramipril for 1 week, ACEI administration reduced neutrophil superoxide and reactive oxygen species production and neutrophils isolated from volunteers during ramipril treatment had reduced bactericidal activity. Together, these data demonstrate that ACEI treatment, but not ARB treatment, can reduce the bacterial killing ability of neutrophils.

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

Background:We performed a meta-analysis to determine whether a consistent relationship exists between the use of angiotensin converting enzyme inhibitors (ACEIs) and the risk of lung cancer. Accordingly, we summarized and reviewed previously published quantitative studies.Methods:Eligible studies with reference lists published before June 1st, 2019 were obtained from searching several databases. Random effects’ models were used to summarize the overall estimate of the multivariate adjusted odds ratios (ORs) with 95% confidence intervals (CIs)Results:Thirteen observational studies involving 458,686 ACEI users were included in the analysis, Overall, pooled risk ratios indicate that ACEIs use was not a risk factor for lung cancer (RR 0.982, 95% C.I. 0.873 – 1.104; P = .76). There was significant heterogeneity between the studies (Q = 52.54; P < .001; I2 = 86.07). There was no significant association between ACEIs use and lung cancer in studies with over five years of ACEIs exposure (RR 0.95, 95% C.I. 0.75 – 1.20; P = .70); and ≤ 5years of exposure to ACEIs (RR 0.98, 95% C.I. 0.83 – 1.15; P = .77). There were no statistically significant differences in the pooled risk ratio obtained according to the study design (Q = 0.65; P = .723) and the comparator regimen (Q = 3.37; P = .19).Conclusions:The use of ACEIs was not associated with an increased risk of lung cancer. Nevertheless, well-designed observational studies with different ethnic populations are still needed to evaluate the long-term (over 10 years) association between ACEIs use and lung cancer.

Hypertension Treatment Modality and Suicide Risk Among Veterans in Veterans Health Administration Care From 2015 to 2017

The Veterans Health Administration (VHA) serves a population of veterans with a high prevalence of comorbid health conditions and increased risk for suicide. To replicate the findings of a previous study and assess whether exposure to angiotensin receptor blockers (ARBs) is associated with differential suicide risk compared with angiotensin-converting enzyme inhibitors (ACEIs) among veterans receiving VHA care. This nested case-control design included all suicide decedents from 2015 to 2017 with a VHA inpatient or outpatient encounter in the prior year and with either an active ACEI or ARB prescription in the 100 days prior to death. Using a 4:1 ratio, controls were matched to cases by age, sex, and hypertension and diabetes diagnoses. Controls were alive at the time of the death of the matched case, had a VHA encounter within the previous year, and had either an active ACEI or ARB medication fill within 100 days before the death of the matched case. An active ACEI or ARB prescription within 100 days before the death of the case. Cases were suicide decedents from 2015 to 2017 per National Death Index search results included in the Veteran Affairs/Department of Defense Mortality Data Repository. Among 1309 cases, the median (interquartile range [IQR]) age was 68 (60-76) years and among 5217 controls, the median (IQR) age was 67 (60-76) years, and 1.9% of veterans in both groups were female. ARBs were received by 20.2% of controls and 19.6% of cases; ACEIs were received by 79.8% of controls and 80.4% of cases. The crude suicide odds ratio for ARBs vs ACEIs was 0.966 (95% CI, 0.828-1.127). Controlling for covariates, the adjusted odds ratio for ARBs was 0.985 (95% CI, 0.834-1.164). Sensitivity analyses using only those covariates that differed significantly between groups, restricting to veterans ages 65 and older, dropping matching criteria, and adjusting for the quantity and temporal proximity of ACEI and ARB exposure in the 100 days prior to the index date, had consistent findings. This case-control study did not identify differences in suicide risk by receipt of ARBs vs ACEIs in analyses specific to veterans receiving VHA care in contrast with findings from the referent study.

Re: Association of Inpatient Use of Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients with Hypertension Hospitalized with COVID-19.

To the Editor: We read with interest the study by Zhang et al.,1 examining the association between inpatient use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) and mortality in patients hospitalized with coronavirus disease 2019 (COVID-19), published in Circulation Research. The use of ACEIs or ARBs was associated with an important 58% risk reduction in all-cause mortality (hazard ratio, 0.42; 95% confidence interval, 0.19, 0.92). The association was even stronger with the use of propensity score models, resulting in a risk reduction of almost 70%. We believe that these remarkable effects are mainly driven by immortal time bias. In this study, patients were deemed exposed to ACEIs or ARBs if they had received a prescription at any time during the hospitalization period. In contrast, patients who did not receive these drugs during the hospitalization period were categorized as nonusers. This method of identifying users and nonusers can introduce immortal time bias.2 Indeed, by design, ACEI or ARB users had to survive from the date of admission to the date of an ACEI or ARB prescription to be categorized as a user. This time period was both misclassified as exposed (instead of unexposed) and immortal, as it was impossible for patients to die during this time span. In contrast, it was possible for nonusers to die at any point during the hospitalization period. This is particularly evident in Zhang et al.’s1 Figures 2A and 2B, where there were no deaths in the first 7 days of follow-up for the ACEIs/ARBs group, whereas deaths occurred as early as the second day after admission in the non-user group. Given the maximum 28-day follow-up, even a small amount of misclassified exposed person–time could lead to important bias, as was shown previously with β-blockers for patients hospitalized for chronic obstructive pulmonary disease.3 The authors also compared the risk of death among users of ACEIs/ARBs versus users of other antihypertensive drugs. In this analysis, the authors first identified ACEI/ARB users and then users of other antihypertensive drugs. This hierarchical exposure definition introduced immortal time bias,4 as the time between hospital admission and first ACEI/ARB prescription was misclassified as exposed and immortal because no events could have occurred during that period. In summary, although residual confounding is always a concern in observational studies, immortal time bias can introduce severely skewed results, though it can be avoided using proper methods of analysis.2–4 It would be informative to repeat the analyses by modeling ACEI or ARB exposure using time-dependent methods.

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.

The effect of angiotensin-converting enzyme inhibitor exposure on coronary artery bypass grafting.

This study evaluated the impact of preoperative angiotensin-converting enzyme inhibitor (ACEi) exposure on outcomes of coronary artery bypass grafting (CABG). Isolated CABGs from January 2010 to January 2018 at a single institution were included. Primary stratification was based on exposure to an ACEi within 48-hours of CABG. Propensity-matching with a 1:1 ratio was performed to generate cohorts with comparable baseline characteristics. Primary outcomes included operative mortality and morbidity rates as well as prolonged intensive care unit (ICU) stay. Secondary outcomes included hospital readmission. Five-thousand two hundred seventy propensity-matched patients underwent isolated CABG. Baseline characteristics were comparable between those exposed and unexposed to ACEi, with a Society of Thoracic Surgeons predicted risk of mortality of 2.4% in each group (P = .98). Rates of postoperative renal failure (5.0% vs 8.2%; P = .002), new-onset dialysis (1.2% vs 2.2%; P = .004), and prolonged ventilation (7.0% vs 13.4%; P < .0001) were higher in patients without ACEi exposure. The rates of prolonged ICU stay were similar (25.8% vs 27.7%; P = .127). ACEi exposed patients had lower unadjusted (1.7% vs 2.8%; P = .009) and risk-adjusted hazards for mortality at 30-days (hazard ratio, 0.59; 95% confidence interval, 0.40, 0.88; P = .01). Overall readmission rates were similar. Similar findings persisted when limiting the analysis to CABGs performed with the use of cardiopulmonary bypass. This study of 5270 propensity-matched patients suggests that ACEi can safely be continued until the time of CABG without an adverse impact on clinical outcomes, and in fact, may confer an early survival advantage and reduced postoperative renal failure rates.

Risk for Anaphylactic Reaction from Cardiac Catheterization in Patients Receiving β-Adrenergic Blockers or Angiotensin-Converting Enzyme-Inhibitors

β-Adrenergic blockers (BBs) have been associated with increased risk for severe anaphylactic reaction (AR) from contrast media; however, this was shown with intravenous contrast media, before widespread use of low osmolar contrast media, angiotensin-converting enzyme-inhibitors (ACE-Is), and cardioselective BBs. To assess the risk for AR during cardiac catheterization (CC) associated with BB or ACE-I exposure. Patients who experienced adverse reactions during CC from January 2004 to December 2013 were identified; 1 to 2 matched controls were assigned for each case. We analyzed AR rates in association with demographic variables, medication exposures (BBs, ACE-Is, angiotensin-receptor blockers, aspirin), and comorbidities: cardiovascular disorders, asthma, and atopy. We analyzed 71,782 CCs. Of these, severe 70 reactors were identified-46 (0.06%) fulfilled AR criteria. There were 35 cases of mild to moderate AR and 11 cases of severe AR (0.015%). There were no significant differences in age (61.3% vs 61.5%), sex (63% vs 64% males), cardiovascular disorder rate (78% vs 93%), and exposure to BBs (46% vs 51%; cardioselective: 77% vs 80%) and ACE-Is (37.0% vs 37.2%) in cases versus controls. Via multivariate logistic regression, BB exposure was not associated with greater AR frequency (P= .35) or severity (P= .40). Neither cardioselective BBs (P= 0.2) nor noncardioselective BBs (P= .5) influenced AR severity. ACE-Is had no effect on AR frequency (P= .35) or severity (P= .14). Lower AR frequency was associated with cardiovascular disorder (P= .01). In this case-control study, severe AR was rarely observed. Exposure to BBs or ACE-Is did not significantly influence AR frequency or severity; however, most BBs were cardioselective. Our findings imply that cardioselective BB or ACE-I suspension is not warranted in association with CC.

Association Between Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Blockers, and Suicide

The renin-angiotensin system has been implicated in mood disorders. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are among the most commonly used medications, yet their effects on mental health outcomes, particularly suicide, are poorly understood. This study examined the association between suicide and exposure to ACEIs and ARBs. Because of differences in their mode of action, it was speculated that ARBs would be associated with a higher risk of suicide than ACEIs. To examine the association between suicide and exposure to ARBs compared with ACEIs. This population-based nested case-control study of individuals aged 66 years and older used administrative claims databases in Ontario, Canada, from January 1, 1995, to December 31, 2015. Data analysis was performed from January to April 2019. Cases were individuals who died by suicide within 100 days of receiving an ACEI or ARB. The date of death served as the index date. For each case, 4 controls were identified and matched by age (within 1 year), sex, and presence of hypertension and diabetes. All individuals received an ACEI or ARB within 100 days before the index date. Use of an ACEI or ARB. Conditional logistic regression was used to estimate odds ratios for the association between suicide and exposure to ARBs compared with ACEIs. Nine hundred sixty-four cases were matched to 3856 controls. The median (interquartile range) age of cases and controls was 76 (70-82) years. Most cases (768 [79.7%]) and controls (3068 [79.6%]) were men. Among cases, 260 (26.0%) were exposed to ARBs, and 704 (18.4%) were exposed to ACEIs. Among controls, 741 (74.0%) were exposed to ARBs, and 3115 (81.6%) were exposed to ACEIs. Compared with ACEI exposure, ARB exposure was associated with higher risk of death by suicide (adjusted odds ratio, 1.63; 95% CI, 1.33-2.00). The findings were consistent in a sensitivity analysis excluding individuals with a history of self-harm (odds ratio, 1.60; 95% CI, 1.29-1.98). The use of ARBs may be associated with an increased risk of suicide compared with ACEIs. Preferential use of ACEIs over ARBs should be considered whenever possible, particularly in patients with severe mental health illness.

Psoriasis After Exposure to Angiotensin-Converting Enzyme Inhibitors: French Pharmacovigilance Data and Review of the Literature.

Angiotensin-converting enzyme inhibitors (ACEIs) can induce or aggravate psoriasis. This risk is not specified in the Summary of Product Characteristics (SmPC) of some drugs of this class, such as captopril or enalapril. We aimed to investigate the association between psoriasis and ACEI exposure. We analyzed spontaneous reports recorded in the French national Pharmacovigilance Database (FPVD) from 1985 to 31 December 2018. The association between psoriasis and ACEI exposure was assessed using the case/non-case method. We also reviewed literature reports. One hundred reports of psoriasis after ACEI exposure were registered in the FPVD. The reporting odds ratio (ROR) was 2.40 (95% CI 1.96-2.95). Time to onset was < 1year in 67% of reports. Outcome was favorable in 73% of reports after ACEI discontinuation. Almost all ACEIs were concerned. In the literature, we found 21 published reports of psoriasis with ACEIs. Time to onset ranged from 1week to 4months. Outcome was also favorable after ACEI discontinuation in over half of the literature reports. We found a statistically significant association between psoriasis and ACEI, which constitutes a potential safety signal. The risk of psoriasis is a class effect, time to onset is less than1year, and outcome is favorable after ACEI discontinuation. Psoriasis should be mentioned in the SmPCs of all ACEIs, and healthcare professionals should be informed about this risk.

Chasing the ongoing consequences of the cascade of intervention during labour and birth

Previous research reported greater risk of adverse perinatal outcomes associated with first trimester exposure to angiotensin converting enzyme inhibitors (ACEIs) in comparison to unexposed pregnancies among non-hypertensive women. We examined the relationship between first trimester exposure to ACEIs and angiotensin receptor blockers (ARBs), and maternal and perinatal outcomes, whilst controlling for the underlying hypertension.We performed a population-based cohort study among 130,061 pregnancies resulting in birth in NSW, Australia between 2005 and 2012. Birth data were linked to hospital discharge and pharmaceutical dispensing records. After restricting to women with chronic hypertension, 67 and 73 pregnancies exposed to ACEIs and ARBs respectively during the first trimester were compared with 316 pregnancies exposed to methyldopa.Preterm delivery, caesarean section, low birth weight, small for gestational age and Apgar score <7.Compared to pregnancies exposed to methyldopa, the adjusted odds ratio (aOR) for ACEI exposure was 0.5 (95% CI: 0.2–1.1) for preterm delivery, 1.6 (0.8–3.1) for caesarean section, 0.6 (0.2–1.3) for LBW and 0.8 (0.4–1.9) for SGA. The corresponding aORs and confidence intervals for ARB exposure were 0.7 (0.3–1.5), 1.2 (0.6–2.6), 1.3 (0.7–2.6), and 1.2 (0.6–2.4).No association between early pregnancy exposure to ACEIs and ARBs and perinatal outcomes was observed, however, the possibility of an association cannot be ruled out due to limited power. Nonetheless, this study suggests that the magnitude of risk is smaller than that reported previously.

Increased rate of birth defects after first trimester use of angiotensin converting enzyme inhibitors - Treatment or hypertension related? An observational cohort study.

To analyze the risk of spontaneous abortions and major birth defects in pregnancies of women treated with angiotensin converting enzyme inhibitors (ACEIs) during the first trimester. Observational cohort study of prospectively ascertained pregnancies from the German Embryotox pharmacovigilance institute. Pregnancy outcomes after maternal exposure to ACEIs during the first trimester were compared with pregnancies without antihypertensive treatment. In a sensitivity analysis, ACEI exposed hypertensive women were compared with hypertensive women on methyldopa. The risk of spontaneous abortion among 329 ACEI exposed women was not increased compared to 654 women without antihypertensive treatment (adjusted hazard ratio 1.20, 95% confidence interval (CI) 0.74-1.92), whereas the risk for major birth defects (14/255; 5.5% vs. 19/567; 3.4%) was significantly increased (adjusted odds ratio 2.41, 95% CI 1.07-5.43). In contrast, birth defect rates were not significantly different between hypertensive women on ACEIs and hypertensive women on methyldopa. In addition, we did not observe a distinct pattern of birth defects among retrospectively ascertained pregnancies after ACEI exposure during the first trimester. Women with hypertension treated with ACEIs in early pregnancy are at higher risk for major birth defects, which may be explained by other factors associated with maternal hypertension. Women (inadvertently) exposed during early pregnancy may be reassured and treatment switched to antihypertensive drugs recommended for pregnancy.

Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chemoprevention of hepatocellular carcinoma: a nationwide high-risk cohort study

BackgroundResearch has revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may prevent cancers such as hepatocellular carcinoma (HCC). The comparative chemopreventive effects of ACEIs and ARBs in high-risk populations with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection have yet to be investigated.MethodsFrom 2005 to 2014, high-risk HBV and HCV cohorts of hypertensive patients without HCC history were recruited from three linked national databases of Taiwan, and were classified into two groups based on the ACEI or ARB exposure within the initial six months after initiating antiviral agent. Intergroup differences in clinical characteristics and duration of drug exposure within study period were evaluated. HCC-free survival was compared using the log-rank test. Multivariate Cox regression including time-dependent variables for the use of ACEIs or ARBs and other medications was applied to adjust for confounders.ResultsAmong the 7724 patients with HBV and 7873 with HCV, 46.3% and 42.5%, respectively, had an initial exposure to ACEIs or ARBs. The median durations of exposure were 36.4 and 38.9 months for the HBV and HCV cohorts, respectively. The median durations of ACEI or ARB use during study period between initial exposure and nonexposure groups were 41.8 vs. 18.3 months and 46.4 vs. 22.7 months for the HBV and HCV cohorts, respectively. No significant difference was observed in HCC risk within 7 years between the initial exposure and non-exposure groups. After adjustment for comorbidities, namely liver cirrhosis, diabetes mellitus (DM), and hyperlipidemia, and medications, namely aspirin, metformin, and statins, the hazard ratios (HRs) for ACEI or ARB exposure for HCC risk were 0.97 (95% confidence interval [CI]: 0.81–1.16) and 0.96 (0.80–1.16) in the HBV and HCV cohorts, respectively. In the HCV cohort, the increased HCC risk was associated with ACEI or ARB use in patients without cirrhosis, DM, and hyperlipidemia (HR: 4.53, 95% CI: 1.46–14.1).ConclusionCompared with other significant risk and protective factors for HCC, ACEI or ARB use in the HBV and HCV cohorts was not associated with adequate protective effectiveness under standard dosages and may not be completely safe.

Melanoma and Non-Melanoma Skin Cancer Associated with Angiotensin-Converting-Enzyme Inhibitors, Angiotensin-Receptor Blockers and Thiazides: A Matched Cohort Study.

Controversy exists about an association between angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), and thiazides (TZs) and the risk of malignant melanoma (MM), and non-melanoma skin cancer-basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The aim of this study was to determine if an association exists for ACEI, ARB, or TZ exposure and skin cancers. This was a matched cohort study using a large electronic medical records repository, the Northwestern Medicine Enterprise Data Warehouse (NMEDW). The exposed population consisted of patients with a documented order for an ACEI, ARB, or TZ with no prior history of skin cancer. The control population consisted of matched patients without documented exposure to ACEI, ARB, or TZ and no previous skin cancer. Incident MM, BCC, or SCC diagnosis by ICD-9 codes was recorded. Odds ratios (ORs) were obtained by using logistic regression analyses. Among the 27,134 patients exposed to an ACEI, 87 MM, 533 BCC, and 182 SCC were detected. Among the 13,818 patients exposed to an ARB, 96 MM, 283 BCC, and 106 SCC were detected. Among the 15,166 patients exposed to a TZ, 99 MM, 262 BCC, and 130 SCC were detected. Significant associations using ORs from logistic regression were found for MM and TZs (OR 1.82; 95% confidence interval [CI] 1.01-3.82); BCC and ARBs (OR 2.86; 95% CI 2.13-3.83), ACEIs (OR 2.23; 95% CI 1.78-2.81) and TZs (OR 2.11; 95% CI 1.60-2.79); SCC and ARBs (OR 2.22; 95% CI 1.37-3.61), ACEIs (OR 1.94; 95% CI 1.37-2.76), and TZs (OR 4.11; 95% CI 2.66-6.35). A safety signal for ACEIs, ARBs, and TZs and BCC and SCC, as well as for TZs and MM, was detected. An increased awareness and education, especially for those who are at high risk for skin cancer, are warranted for patients and healthcare providers. Further exploration of such associations for these commonly used drug classes is warranted.

The use of angiotensin II in distributive shock.

The interest in the use of non-catecholamine vasopressors for the treatment of hypotension and shock has increased in recent years. The use of vasopressin as an adjunctive vasopressor in shock was reinvigorated by Landry and colleagues [1] and then carefully assessed in the Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock (VASST) trial [2]. In a large, international, multi-center trial, vasopressin demonstrated a satisfactory safety profile, but did not show an improvement in survival compared to norepinephrine [2]. In addition to vasopressin, angiotensin II (ATII) has been proposed as a useful vasopressor for the management of shock [3, 4]. The original studies that assessed ATII for the management of shock were conducted decades ago [3, 5]. In those trials, ATII was assessed primarily in head-to-head studies compared to catecholamine vasopressors, and was shown to have comparable vasopressor effect to norepinephrine [5]. Multiple case reports demonstrated the ability of ATII to work effectively as a vasopressor and also showed that ATII could be used in combination with catecholamines. However, ATII has not been subjected to a randomized controlled trial (RCT) and ATII has not been available at the bedside for at least 15 years. ATII has been used extensively in physiology, hypertension, cancer, and pregnancy studies in humans and has a good safety profile. Recently, we published in Critical Care the first RCT of ATII in patients with distributive shock, and showed that a dose of ATII of 5–40 ng/kg/min was associated with improved blood pressure that resulted in significant catecholamine sparing [6]. In that modest-sized study, we noted that 2 of the 10 patients treated with ATII were exquisitely sensitive to ATII. In these two cases, the subjects receiving physiologic doses of ATII were hypertensive despite the discontinuation of their norepinephrine. When ATII was stopped in these two patients, re-initiation of a high dose of norepinephrine (i.e., 0.3 μg/kg/min) was immediately required in order to maintain mean arterial pressure goals. We speculated that the reason for this sensitivity was likely due to premorbid exposure to angiotensin-converting enzyme (ACE) inhibitors prior to the development of shock. Our theory was that if the subjects were previously treated with ACE inhibitors, their ATII Type I receptors would be upregulated, thus making the patient more sensitive to exogenous ATII infusion. However, after a thorough chart review and re-review, we could not document an ACE inhibitor exposure. While it is possible that the ACE inhibitor exposure was present and not documented, there is an alternative explanation which is related to the nature and distribution of ACE. Angiotensin I (ATI) is converted efficiently to ATII almost exclusively in the lung [7]. ACE is an ectoenzyme which is distributed primarily on the pulmonary capillary endothelium [8, 9]. As a consequence, diseases that affect the pulmonary capillary endothelium can disrupt ACE functionality. Acute respiratory distress syndrome (ARDS) is often associated with significant pulmonary endothelial injury [10]. Patients with more severe ARDS have less capacity to convert angiotensin ATI to ATII, and this disturbance is inversely correlated to the severity of ARDS [11]. Upon re-review, we found that the two patients in our study who were exquisitely ATII sensitive had severe ARDS. Our revised hypothesis is that patients with severe ARDS may have significant pulmonary endothelial injury, which results in either an absolute or relative insufficiency of ATII due to loss of pulmonary ACE. Pre-clinical and human case reports demonstrate that when ATII production is inhibited by ACE inhibition, patients become catecholamine resistant [12]. Thus, patients with ARDS may be at particular risk for ATII insufficiency, which would likely exacerbate existing hypotension. In addition, ATII insufficiency can lead to acute kidney injury due to decreased intra-glomerular pressure. We hypothesize that some patients with shock and ARDS may be at particular risk for a deleterious cascade of events related to ATII insufficiency (Fig. 1). Fig. 1 Proposed cascade of events leading to angiotensin II insufficiency. The figure outlines a cascade of events that could occur amongst patients with inflammation and/or lung injury. When acute lung injury is significantly complicated by pulmonary endothelial ... We would anticipate that, for those patients with ATII insufficiency, increased levels of ATI and reduced ATII may be indicative of this pathophysiology, and that ATI and ATII levels, as well as the ratio of ATI/ATII, may be useful as biomarkers of early ARDS or ARDS severity prior to the development of severe hypoxemia. Moreover, we would anticipate these patients to be ATII-sensitive. We believe that further research to test this hypothesis is warranted. Currently, ATII is being studied in a multi-center international RCT (NCT02338843) wherein some of these parameters will be assessed and may shed further light on this proposed hypothesis.

Angiotensin II Blockade Is Associated With Worse Clinical Outcomes in IBD Patients

Introduction: Preclinical data support the notion that activation of the renin-angiotensin system (RAS) contributes to the pathogenesis of inflammatory bowel disease (IBD), and inhibition of RAS by angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) protects against colitis in animal models. Less is known regarding clinical outcomes with use of these medications in IBD patients. In order to test the hypothesis that blockade of RAS improves intestinal inflammation, we compared clinical outcomes in ACEI or ARB treated individuals to matched untreated patients in a cohort of IBD patients from a single tertiary care center. Methods: We performed a retrospective cohort study using the IBD registry at the University of Chicago. ACEI or ARB users were compared to non-users matched 1:4 on the basis of sex, age +/- 5 years, diagnosis, and disease location. Data on clinical outcomes including rates of hospitalizations, operations, and corticosteroid use were collected in addition to comorbidities and medication use. Results: Sixty-five ACEI- or ARB-treated patients with a minimum of six months of follow up were included, 41 patients with Crohn's disease (CD) and 24 with ulcerative colitis (UC) with mean follow up of 2.3 years. The control group was comprised of 260 matched IBD patients with no history of ACEI or ARB exposure with mean follow up of 2.9 years. Mean age was 53 years in the ACEI/ARB group and 52 years in the control group. Thiopurine, anti-TNFα, and 5-ASA medications were similar between the two groups. Compared to control patients, CD patients taking ACEI or ARB had higher rates of hospitalizations per year (0.45 v. 0.21), similar numbers of operations per year (0.17 v. 0.16), and more corticosteroid prescriptions per year (0.70 v. 0.61). UC patients taking ACEI or ARB had more hospitalizations per year (0.35 v. 0.11), more operations per year (0.16 v. 0.08), and more corticosteroid prescriptions per year (1.22 v. 0.34) compared to control patients. ACEI use was also associated with increased hospitalization rates and operations compared to ARB use among IBD patients (0.45 v. 0.34 and 0.19 v. 0.14, respectively), but a lower number of corticosteroid prescriptions per year (0.68 v. 1.30). Conclusion: ACEI or ARB use in IBD patients was associated with more hospitalizations, operations, and corticosteroid use in our tertiary referral population. Prospective studies are needed to assess the causal role of RAS inhibition on disease activity.

Risk of acute myocardial infarction, stroke, or death in patients initiating olmesartan or other angiotensin receptor blockers — a cohort study using the Clinical Practice Research Datalink

Results of two randomized trials (ROADMAP and ORIENT) suggest that high-dose (40 mg/day) olmesartan (Olm) is associated with increased cardiovascular mortality compared to placebo in diabetic patients. We evaluated the risks of acute myocardial infarction (AMI) and death in patients initiating Olm compared with an active comparator group, other angiotensin receptor blockers (ARBs), with a focus on high-dose and diabetic subgroups. We conducted a cohort study with patients who initiated Olm or another ARB between 2003 and 2011, using the UK Clinical Practice Research Datalink GOLD. We included patients who had no prior ARB or angiotensin converting enzyme inhibitor exposure during the preceding 6 months. Hazard ratios (HRs) were estimated using Cox regression models with both multivariable adjustment and propensity score matching. There were 3964 Olm and 54 653 other-ARB initiators, respectively. Adjusted HRs comparing Olm and other-ARBs were 1.04 (95% CI: 0.75-1.42) for AMI and 1.16 (0.95-1.42) for death, using multivariable adjustment. Comparing patients initiated with a high-dose Olm and a high-dose other-ARB, HRs were 3.09 (0.94-10.13) for AMI and 2.03 (0.74-5.61) for death, using multivariable adjustment; and 4.38 (0.97-19.66) and 1.99 (0.63-6.32) for AMI and death, using propensity score matching. Overall, no differences in risk were observed in the main cohort analyses comparing Olm initiators with patients initiating therapy with other ARBs; however, HRs were marginally increased for all study endpoints which compared high-dose subgroups, suggesting potential increased risk may be associated with high-dose Olm. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Patterns of outpatient antihypertensive medication use during pregnancy in a Medicaid population.

Hypertensive disorders occur in approximately 6% to 8% of all pregnancies and are a significant source of maternal and fetal morbidity. Little is known about the range of agents routinely used in practice. We used Medicaid claims from 2000 to 2007 to identify completed pregnancies. We included women who were Medicaid beneficiaries from at least 3 months prior to last menstrual period to 1 month postdelivery, and were successfully linked to infant records. Maternal exposure to antihypertensive medications was derived from Medicaid pharmacy claim files, and duration of exposure was assigned based on the days' supply dispensed. We identified 1,106,757 Medicaid patients in our cohort, of whom 48,453 (4.4%) were exposed to antihypertensive medications during pregnancy. The prevalence of antihypertensive use increased from 3.5% to 4.9% during the study period. Antihypertensive medication users were older than nonusers, more likely to be white or black, and more likely to have comorbid diabetes mellitus and renal disease. Overall, 1.9% of pregnant women were exposed during the first trimester, 1.7% during the second trimester, and 3.2% during the third trimester. The range of antihypertensive medications to which patients were exposed was highly heterogeneous and frequently included agents other than methyldopa or labetalol. Angiotensin-converting enzyme inhibitor exposure, which is contraindicated in late pregnancy, occurred in 928 (4.9%) antihypertensive medication users in the second trimester and 383 (1.1%) in the third trimester. Antihypertensive use during pregnancy is relatively common and increasing. The wide range of agents used during pregnancy includes medications considered contraindicated during pregnancy.