Angiotensin Receptor Blockers 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.

Retrospective analysis of the effect of angiotensin receptor blockers and angiotensin converting enzyme inhibitors on the efficacy of anti-PD-1/PD-L1 immunotherapy in patients with advanced cancer.

2605 Background: Components of the renin angiotensin system (RAS) are expressed in tumors with activation leading to tumor and stromal cell release of immunomodulatory cytokines promoting an immunosuppressive microenvironment and increased infiltration of tumor associated macrophages. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are anti-hypertensives that inhibit the RAS. It is unknown if ACEi and ARB treatment modulates the efficacy of anti-PD-1/PD-L1 immunotherapy. Methods: A retrospective chart review was conducted to identify patients with unresectable malignancies initiating treatment with a PD-1 or PD-L1 inhibitor based regimen between 1/1/13 and 6/1/19 at Valley Hospital in New Jersey. IRB approval was obtained. Efficacy of treatment was measured by medical oncologist documentation of clinical benefit (CB = stable disease / treatment response) versus disease progression. Chi-square tests were performed to assess relationship between ACEi or ARB exposure and immunotherapy benefit. To assess for a broader anti-hypertensive effect, the relationship in patients on a beta-blocker but not ACEi/ARB was assessed. Results: 197 patients were identified of which 190 had documentation of clinical outcome. The mean age was 72.8 years with 54% female and 46% male. 56 patients were exposed to ACEi (N = 28) or ARB (N = 28) and 141 patients to neither. 37 patients were exposed to beta blocker but not ACEi or ARB. 60 patients had nonsquamous NSCLC (16 on ACEi or ARB), 26 squamous NSCLC (7 on ACEi or ARB) and 24 melanoma (10 on ACEi or ARB). 71% of ACEi/ARB exposed patients had CB by clinician assessment as opposed to 47% in those not on ACEi or ARB (p = 0.003). In ACEi exposed patients, 71% had CB versus 51% in unexposed patients (p = 0.048). In ARB exposed patients, 70% had CB versus 51% in unexposed patients (p = 0.069). By contrast, 51% of beta-blocker treated patients had CB versus 55% in untreated patients (p = 0.72). 36% of ACEi/ARB exposed patients remained on treatment at 12 months versus 22% of ACEi/ARB unexposed patients. Subset analyses were performed on the 3 largest patient populations: squamous NSCLC, nonsquamous NSCLC and melanoma. ACEi/ARB exposed melanoma patients had CB rate of 70% versus 43% in those unexposed. ACEi/ARB exposed squamous NSCLC patients had CB rate of 86% versus 47% in unexposed patients. By contrast, ACEi/ARB exposed nonsquamous NSCLC patients had a 56% CB rate versus 48% in unexposed patients. Conclusions: Based on retrospective analysis, advanced cancer patients treated with anti-PD-1/PD-L1 regimens had a statistically significant increase in clinical benefit if administered in the context of renin angiotensin system blockade. Prospective disease specific trials can further validate these findings and define the degree of clinical benefit.

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.

Abstract 10482: Renin-Angiotensin-Aldosterone System Inhibition is Associated with Reduced In-Hospital Mortality in Critically Ill Covid-19 Patients with Pre-Existing Hypertension

Background: The virus responsible for COVID-19 enters human cells by binding angiotensin-converting enzyme 2. The influence of renin-angiotensin-aldosterone system (RAAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), remains uncertain. Aim: To examine the role of ACEi / ARB exposure on outcomes in COVID-19 patients with pre-existing hypertension (HTN) admitted to intensive care units (ICU). Methods: The COVID-19 Critical Care Consortium is a prospective, observational cohort study of patients requiring ICU admission for active COVID-19 spanning 354 participating sites in 54 countries. Patients >18 years old with pre-existing HTN requiring antihypertensive therapy were analysed. Length of stay and in-hospital mortality to 90 days post ICU admission were analysed as time-to-event outcomes by multistate survival analysis, and the influence of ACEi / ARB use on the hazards of death and discharge by multi-state Cox proportional hazard modelling and sensitivity analysis. Results: From December 1, 2019 through December 30, 2020, 663 eligible patients were registered. Of these, 480 patients had received ACEi and / or ARB therapy (median age 65 years, 67% male) in the 2 weeks before ICU admission, while 183 had not (66 years, 61% male). Average lengths of ICU and general ward stays were longer in the ACEi / ARB than non-ACEi / ARB group (20.8 days and 6.5 days vs. 15.5 and 6.0 days, respectively). ACEi / ARB use was associated with a decreased hazard of death (HR, 0.69, 95% CI, 0.54 — 0.88) that persisted after adjusting for propensity scores (0.67, 0.53 — 0.86). Cumulative probabilities (unadjusted for baseline characteristics) for death and discharge post ICU admission are depicted in the figure for ACEi/ARB (red) and non-ACEi / ARB (blue) patients. Conclusions: In 663 critically ill COVID-19 patients with pre-existing HTN, RAAS inhibition pre-ICU admission was linked to reduced in-hospital mortality.

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.

Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: Systematic review and meta-analysis.

ObjectiveAnimal studies suggested that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) facilitate the inoculation of potentially leading to a higher risk of infection and/or disease severity. We aimed to systematically evaluate the risk of COVID-19 infection and the risk of severe COVID-19 disease associated with previous exposure to (ACEi) and/or ARB).MethodsMEDLINE, CENTRAL, PsycINFO, Web of Science Core Collection were searched in June 2020 for controlled studies. Eligible studies were included and random-effects meta-analyses were performed. The estimates were expressed as odds ratios (OR) and 95% confidence intervals (95%CI). Heterogeneity was assessed with I2 test. The confidence in the pooled evidence was appraised using the GRADE framework.ResultsTwenty-seven studies were included in the review. ACEi/ARB exposure did not increase the risk of having a positive test for COVID-19 infection (OR 0.99, 95%CI 0.89–1.11; I2 = 36%; 5 studies, GRADE confidence moderate). The exposure to ACEi/ARB did not increase the risk of all-cause mortality among patients with COVID-19 (OR 0.91, 95%CI 0.74–1.11; I2 = 20%; 17 studies; GRADE confidence low) nor severe/critical COVID-19 disease (OR 0.90, 95%CI 0.74–1.11; I2 = 55%; 17 studies; GRADE confidence very low). Exploratory analyses in studies enrolling hypertensive patients showed a association of ACEi/ARB with a significant decrease of mortality risk.ConclusionsACEi/ARB exposure does not seem to increase the risk of having the SARS-CoV-2 infection or developing severe stages of the disease including mortality. The potential benefits observed in mortality of hypertensive patients reassure safety, but robust studies are required to increase the confidence in the results.

Angiotensin Receptor Blockers and the Risk of Cancer: Insights from Clinical Trials and Recent Drug Recalls.

The purpose of this review is to familiarize readers with issues surrounding angiotensin receptor blockers (ARBs) and the risk of cancer, both from the perspective of clinical trial data and the more recent concerns about impurities in certain ARB products. Approximately 45.6% of adults in the USA have hypertension. ARB-containing medications are widely used in the USA, with tens of millions of prescriptions written yearly. Whether exposure to certain ARB drug products contributes to the development of cancer has been the topic of a series of publications. Nonetheless, ARBs' link to cancer, if any, remains inconclusive. Any mechanistic link between ARBs and cancer is poorly understood, with a variety of basic science studies suggesting that ARBs should exert a protective effect. Due to the presence of potentially carcinogenic nitrosamine impurities in certain ARB products, a series of large recalls in the USA and in countries around the world has occurred since 2018. These recalls have occurred in the context of two recent trends affecting antihypertensive drugs: nearly ubiquitous reliance on generic drugs and increased use of manufacturing facilities in China and India to supply the USA. Despite substantial efforts directed toward understanding whether ARBs have the potential to cause cancer, the available studies do not provide a consistent answer, and a causal link remains speculative. The principal conclusion must be that there is not a definitive signal for cancer associated with ARB exposure, although the possibility has not been fully excluded. The problem of nitrosamine impurities in certain ARB products (and some other drug products) is in need of further investigation, so that the risks can be mitigated by eliminating these impurities from the drug supply chain.

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.

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.

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.

Psoriasis during angiotensin receptor blocker exposure: an underestimated adverse drug reaction

ABSTRACTBackground: Angiotensin receptor blockers (ARBs) can induce or exacerbate psoriasis. Psoriasis is unlisted in the Summary of Product Characteristics (SmPC) of ARBs. We aimed to investigate the association between psoriasis and ARB exposure.Methods: We reviewed spontaneous reports recorded in the French national Pharmacovigilance Database (FPVD). The association between psoriasis and ARB exposure was assessed using the case/non-case method. We also analyzed literature reports.Results: We identified 89 reports of psoriasis during ARB exposure in the FPVD. Time to onset was most often less than 1 year. Outcome was favorable in 67% of reports after ARB discontinuation. Almost all ARBs were concerned. The reporting odds ratio (ROR) for psoriasis with this therapeutic class was 4.86 (95%CI 3.92–6.03). In the literature, we found 14 published reports of psoriasis with ARB exposure. Time to onset ranged from 6 weeks to 9 months. Outcome was also favorable after ARB discontinuation in the literature.Conclusions: This underestimated adverse drug reaction is a class effect, time to onset is most often less than 1 year and outcome seems favorable after ARB discontinuation. The case/non-case approach highlights a potential safety signal. The SmPC of ARBs should be updated, increased awareness among healthcare professionals is warranted.

Effect of angiotensin 2 receptor blockers on chronic obstructive lung disease mortality: A retrospective cohort study

IntroductionChronic Obstructive Pulmonary Disease (COPD) is the fifth cause of mortality worldwide. Systemic inflammation is a crucial element in its physiopathology. As Renin-Angiotensin System is one of the main components of this inflammatory neurohumoral cascade, Angiotensin Receptor Blockers (ARBs) might have an effect on mortality in COPD patients. GoalTo evaluate the association between ARBs treatment and mortality in COPD patients. MethodsRetrospective cohort of patients with diagnosis of COPD from 2003 to 2013. COPD cases were detected according to the diagnosis by treating physicians in any field of the electronic clinical health records by controlled vocabulary in patients older than 18 years affiliated to the Hospital Italiano de Buenos Aires (HIBA) Health Plan. Patients were classified in two groups depending on their use of ARBs according to the hospital pharmacy records. The mortality registry of the HIBA was used to obtain the event of death. The 8 year survival experience was described using Kaplan Meier estimator and survival curve comparisons were calculated with the Cox Mantel test. Hazard Ratios (HR) were estimated using a Cox proportional risk model. A propensity score (PS) was developed for the use of ARBs. Results1140 deaths were detected, 1063 in the no exposure group and 77 in the ARBs exposure group. The 8 year survival was 71% (CI 95% 69–72%). The survival in the non exposed group was 71% (CI 95% 69–73%) and 76% (CI 95% 0,69-0,81) in the ARBs exposed group. The unadjusted HR for mortality was 0.85 (CI 95% 0.67–1.07, p = 0.17) and the adjusted HR by PS was 0.63 (CI 95% 0.50–0.80, p < 0.001). DiscussionARBs use seems to be associated to a lower mortality in patients with COPD. Additional studies are needed to corroborate this finding.

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.

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.

Use of Angiotensin Receptor Blockers and the Risk of Cancer

A recent meta-analysis of randomized trials suggested that use of angiotensin receptor blockers (ARBs) may be associated with a modestly increased risk of incident cancer, particularly lung cancer. We linked individual-level data from Danish registries on filled drug prescriptions, diagnostic information, and covariates. In a nationwide cohort of new users of ARBs and angiotensin-converting enzyme inhibitors ≥35 years of age during 1998 to 2006, we compared incidence rates of all cancer, cancer subgroups by anatomic site, and cancer mortality. Among 107 466 ARB users, 3954 cases of cancer were detected during 312 753 person-years of follow-up compared with 6214 cases during 435 207 person-years of follow-up in 209 692 angiotensin-converting enzyme inhibitor users (adjusted rate ratio, 0.99; 95% confidence interval, 0.95 to 1.03). Cancer risk did not increase with increasing duration of ARB exposure (increase in rate ratio per year, 0.99; 95% confidence interval, 0.99 to 1.00,) and was similar across individual ARBs. In subgroup analyses, there was a significant association between ARB use and cancer of male genital organs (rate ratio, 1.15; 95% confidence interval, 1.02 to 1.28), but no significantly increased risk of any of the other 15 cancer subgroups, including lung cancer (rate ratio, 0.92; 95% confidence interval, 0.82 to 1.02). For cancer mortality, the rate ratio was 0.77 (95% confidence interval, 0.72 to 0.82). In this large nationwide cohort, use of ARBs was not significantly associated with increased risk of incident cancer overall or of lung cancer.

Melanoma incidence and exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

A reduced incidence of nonmelanoma skin cancer among users of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARb) has been reported. A similar effect is suggested for cutaneous melanoma. We aimed to investigate the possible association between use of ACEi and ARb and the risk of cutaneous melanoma. A general population-based case control study with the PHARMO database, containing drug-dispensing records from community pharmacies and the national pathology database (PALGA) was conducted. Cases were patients with a primary cutaneous melanoma between January 1st 1991 and December 14th 2004, aged ≥18 years and having ≥3 years of follow-up prior to diagnosis. Finally, 1272 cases and 6520 matched controls were included. Multivariable conditional logistic regression showed no statistically significant associations between the incidence of melanoma and the use of ACEi (adjusted OR = 1.0, 95%CI: 0.8–1.3) or ARb (adjusted OR = 1.0, 95%CI: 0.7–1.5). Thus, in this study, the use of ACEi or ARb does not seem to protect against the development of cutaneous melanoma. However, we cannot exclude an association between ACEi and ARb exposure and an increased or decreased incidence of cutaneous melanoma.