Association Of Angiotensin-converting Enzyme Inhibitors Research Articles

Influence of cardiometabolic medications on abdominal aortic aneurysm growth in the UK Aneurysm Growth Study: metformin and angiotensin-converting enzyme inhibitors associated with slower aneurysm growth.

There is a clinical need for treatments that can slow or prevent the growth of an abdominal aortic aneurysm, not only to reduce the need for surgery, but to provide a means to treat those who cannot undergo surgery. Analysis of the UK Aneurysm Growth Study (UKAGS) prospective cohort was conducted to test for an association between cardiometabolic medications and the growth of an abdominal aortic aneurysm above 30 mm in diameter, using linear mixed-effect models. A total of 3670 male participants with data available on abdominal aortic aneurysm growth, smoking status, co-morbidities, and medication history were included. The mean age at recruitment was 69.5 years, the median number of surveillance scans was 6, and the mean(s.e.) unadjusted abdominal aortic aneurysm growth rate was 1.75(0.03) mm/year. In a multivariate linear mixed-effect model, smoking (mean(s.e.) +0.305(0.07) mm/year, P = 0.00003) and antiplatelet use (mean(s.e.) +0.235(0.06) mm/year, P = 0.00018) were found to be associated with more rapid abdominal aortic aneurysm growth, whilst metformin was strongly associated with slower abdominal aortic aneurysm growth (mean(s.e.) -0.38(0.1) mm/year, P = 0.00019), as were angiotensin-converting enzyme inhibitors (mean(s.e.) -0.243(0.07) mm/year, P = 0.0004), angiotensin II receptor antagonists (mean(s.e.) -0.253(0.08) mm/year, P = 0.00255), and thiazides/related diuretics (mean(s.e.) -0.307(0.09) mm/year, P = 0.00078). The strong association of metformin with slower abdominal aortic aneurysm growth highlights the importance of the ongoing clinical trials assessing the effectiveness of metformin with regard to the prevention of abdominal aortic aneurysm growth and/or rupture. The association of angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and diuretics with slower abdominal aortic aneurysm growth points to the possibility that optimization of cardiovascular risk management as part of abdominal aortic aneurysm surveillance may have the secondary benefit of also reducing abdominal aortic aneurysm growth rates.

The association of angiotensin-converting enzyme inhibitors and angiotensin 2 receptor blockers with renal protection in patients with SARS-CoV-2

Abstract Background Kidney dysfunction is a prevalent disease that leads to many complications over time, such as hypertension, heart disease, and death. ACEI/ARBs are known to be renoprotective. However, few studies describe the association between ACEI/ARB use and kidney dysfunction in patients with SARS-CoV-2 infection. Purpose To explore the association between patients with SARS-CoV-2 and kidney dysfunction in patients taking an ACEI/ARB. We hypothesize a negative association between patients with SARS-CoV-2 taking an ACEI/ARB and kidney dysfunction. Methods A retrospective query between March 2020 and April 2021 was performed in patients 18 years and older who tested positive for SARS-CoV-2 using a polymerase chain reaction test. Patients were divided into two groups: kidney dysfunction and no kidney dysfunction. Kidney dysfunction was defined as any diagnosis of chronic kidney disease or acute kidney injury. Primary outcomes were all-cause mortality and hospitalization rate. Secondary outcomes included myocardial infarction (MI), hypotension, intubation, vasopressor use, ventricular tachycardia, and ventricular fibrillation. We used multivariate logistic regression to adjust for baseline characteristics. Results We identified 996 patients with kidney dysfunction and 22,106 without kidney dysfunction who tested positive for SARS-CoV-2. The incidence was 258 (25.9%) for ACEI/ARB use in patients with kidney dysfunction. Adjusted odds ratio (OR) for patients with kidney dysfunction was 5.705 (95% Confidence Interval [CI]: 4.554–7.146; p<0.001) for hospitalization, 0.895 (95% CI: 0.707–1.135; p<0.361) for patients taking ACEI/ARB, and 0.529 (95% CI: 0.333–0.838; <0.007) for mortality in patients with kidney dysfunction who took ACEI/ARB. All secondary outcomes had significantly greater adjusted OR (p<0.001), except for MI (p<0.339), ventricular tachycardia (p<0.697), and ventricular fibrillation (p<0.060). Conclusion To date, the benefits of ACEI/ARB in SARS-CoV-2 patients have been controversial. While ACEI/ARB is known to have renoprotective properties, we did not find a significant association between ACEI/ARB and kidney dysfunction in patients with SARS-CoV-2. However, we found the use of ACEI/ARB in patients with kidney dysfunction to be associated with lower mortality. Therefore, clinicians should continue using this medication for its mortality benefits in patients with kidney dysfunction and its cardioprotective effects. Funding Acknowledgement Type of funding sources: None.

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

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

Association of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists use with risk of atrial fibrillation after pacemaker implantation among very old patients

It remains unknown whether and to what extend the angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) can play a role in the development of atrial fibrillation (AF) after pacemaker implantation in very old patients. Therefore, we aimed to investigate the association between oral ACEIs or ARBs and the risk of developing AF in very old patients after pacemaker implantation. Patients above 80 years old with pacemaker implantation and without baseline history of AF were included and their real-world information about ACEIs or ARBs use was extracted from electronic medical records. New AF cases were confirmed via the records of outpatient visits. The multivariable Cox proportional-hazards model was used to evaluate the associations between oral ACEIs or ARBs and risk of AF after pacemaker implantation. Among a total of 388 identified patients aged 80 to 98 years, 118 used ACEIs, 174 had ARBs therapy, and 115 AF were identified after pacemaker implantation during a median follow-up time of 3.1 years. After adjustment for potential confounders, patients with daily use of ARBs had a relatively lower risk of AF after pacemaker implantation (HR: 0.627, 95% CI: 0.425, 0.926; P = 0.019) compared with those non-users, whereas ACEIs therapy didn't show a significant relation with AF risk (HR: 1.335, 95% CI: 0.894, 1.995; P = 0.157). In conclusion, for very old patients with a permanent pacemaker, daily use of oral ARBs was associated with a relative lower risk of AF after pacemaker implantation, however, daily use of ACEIs was not related with AF risk.

Association of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers with risk of mortality, severity or SARS-CoV-2 test positivity in COVID-19 patients: meta-analysis

The effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in the treatment of COVID-19 are highly debated. This study was aimed to assess aggregated risk by investigating the association of ACEIs/ARBs users against non-users of ACEIs/ARBs with the risk of mortality or severe clinical manifestations or magnitude of SARS-CoV-2 test positivity in COVID-19 patients. Systematic literature search was carried out in different databases for eligible studies. The pooled relative risks (RRs) were measured using RevMan software where P<0.05 was set as statistical significance. In total, 10 studies were included in this analysis. After pooled estimation, it was demonstrated that SARS-CoV-2 positive patients taking ACEIs/ARBs were not associated with an increased risk of mortality compared to those not taking ACEIs/ARBs (RR 0.89; 95% CI 0.64–1.23; P=0.48). Furthermore, the risk of composite severe clinical manifestations was not significantly different between the positive patients with or without ACEIs/ARBs users (RR 1.29; 95% CI 0.81–2.04; P=0.28). There was no risk difference for SARS-CoV-2 test positivity in patients with or without ACEIs/ARBs users (RR 1.00; 95% CI 0.95–1.05; P=0.91). These findings may augment current professional society guidelines for not discontinuing ACEIs/ARBs in treating COVID-19 patients where it is clinically indicated.

Angiotensin receptor blockers use and changes in frailty, muscle mass, and function indexes: Singapore Longitudinal Ageing Study

AbstractBackgroundPre‐clinical studies suggest that renin–angiotensin system blockade may improve muscle function. Clinical reports of the effect of angiotensin converting enzyme inhibitors (ACEIs) on physical functioning are inconsistent. There are no reports of the effect of angiotensin receptor blockers (ARBs) treatment in older adults.MethodsWe analysed data of 1268 participants in the Singapore Longitudinal Ageing Study (SLAS‐2) who provided information on the use of ACEI, ARB, and other antihypertensive drugs at baseline and follow‐up (mean 4.5 years later). Baseline and follow‐up outcome measures were cumulated deficits frailty index (CD‐FI), physical phenotype frailty index (PP‐FI), calf circumference (CC), knee extension strength, composite muscle mass and strength (MMS) z‐score, and gait speed (GS). In primary analyses, we compared the use and non‐use of an anti‐hypertensive drug class among participants with hypertensive and cardiac disease, and secondarily with participants having other chronic diseases, and those who reported no chronic diseases. Multi‐variable analyses adjusted for socioeconomic status, body mass index ≥30, ≥5 comorbidities, ≥5 drugs use, other non‐ARB or non‐ACEI drugs (calcium channel blockers, beta blockers, or hydrochlorothiazide), MMSE &lt;23, Geriatric Depression Scale score, Nutrition Screening Initiative nutritional risk, physical activities, baseline frailty, and physical performance.ResultsAmong study participants, 7.8% (N = 99) were ARB users (62% used losartan), 11.7% (N = 148) were ACEI users (53% used enalapril), and 34.2% (N = 434) were users of other anti‐hypertensive drug classes. The cohort participants overall showed increases in the mean levels and changes in CD‐FI and PP‐FI and decreases in knee extension strength, GS, CC, and MMS. However, among groups, ARB users showed decreasing trends in CD‐FI and increasing trends of CC and MMS. Among participants with hypertensive and cardiovascular disease, there were significant differences in CD‐FI and PP‐FI changes, adjusted for confounding variables: ARB users compared with non‐users showed lesser declines in CD‐FI (0.013 vs. 0.028, P = 0.018) and PP‐FI (0.924 vs. 1.170, P = 0.017). ARB users also showed statistically significantly greater gains in MMS z‐scores: 0.329 vs. 0.076, P = 0.022. There was no association of ACEI or other anti‐hypertensive class use with changes in frailty, MMS, or GS.ConclusionsThe use of ARBs is associated with a reduction in frailty and age‐related loss of muscle mass and strength.

Associations of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use with Colorectal Cancer Risk in the Women's Health Initiative.

Use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) has been postulated to reduce cancer risk by inhibition of tumor progression, vascularization, and metastasis. The renin-angiotensin system is upregulated in colorectal cancers; however, the association of ACEi and ARB use with colorectal cancer risk is not well understood. The study population was 142,812 Women's Health Initiative participants free of colorectal cancer who reported on ACEi and ARB use at baseline; 2,216 incident colorectal cancers were diagnosed during 10 years of follow-up. Cox regression models estimated adjusted HRs and 95% confidence intervals for associations relative to nonuse among normotensive women, untreated hypertensive women, and hypertensive women treated with other antihypertensive medications. HRs among women who used any ACEi or ARB compared with nonuse in the three referent groups ranged between 0.97 and 1.01. Findings were similar for increased ACEi/ARB duration and for medications examined as separate classes or individually. In this large prospective study of women, no associations of ACEi or ARB use with colorectal cancer risk were observed. Choice of drug in the large population of aging women who will be prescribed ACEi and ARB should be made without factoring in any benefit on colorectal cancer risk.

Impact of renin-angiotensin system inhibitors use on mortality in severe COVID-19 patients with hypertension: a retrospective observational study.

ObjectiveAssociation of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) use with coronavirus disease 2019 (COVID-19) remains controversial. We aimed to investigate the impact of ACEI/ARB use on all-cause mortality in severe COVID-19 patients with hypertension.MethodsWe enrolled 650 COVID-19 patients from Changsha and Wuhan city between 17 January 2020 and 8 March 2020. Demographic, clinical characteristics, and outcomes were collected. Multivariable analysis and propensity-score matching were performed to assess the impact of ACEI/ARB therapy on mortality.ResultsAmong the 650 patients, 126 who had severe COVID-19 concomitant with hypertension were analyzed. The average age was 66 years and 56 (44.4%) were men. There were 37 ACEI/ARB users and 21 in-hospital deaths (mortality rate, 16.7%). Male sex (odds ratio [OR], 5.13; 95% confidence interval [CI], 1.75 to 17.8), but not ACEI/ARB use (OR, 1.09; 95%CI, 0.31 to 3.43), was an independent risk factor for mortality in severe COVID-19 patients with hypertension. After propensity-score matching, 60 severe COVID-19 patients were included and no significant correlation between use of ACEI/ARB and mortality was observed.ConclusionsThere was no significant association of ACEI/ARB use with mortality in severe COVID-19 patients with hypertension. These findings support the continuation of ACEI/ARB therapy for such patients.

Angiotensin II and COVID-19. Secrets of interactions

The article describes current data on the relationship of renin-angiotensin system and related drugs with the risk of COVID-19 infection and its outcomes. Analysis of the latest publications did not reveal association of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with any risk of an unfavorable outcomes, and there was no data for withdrawal of these drugs.

Beneficial association of angiotensin-converting enzyme inhibitors and statins on the occurrence of possible Alzheimer\u2019s disease after traumatic brain injury

BackgroundPathological analysis of brain tissue from animals and humans with a history of traumatic brain injury (TBI) suggests that TBI could be one of the risk factors facilitating onset of dementia with possible Alzheimer’s disease (AD), but medications to prevent or delay AD onset are not yet available.MethodsThis study explores four medication classes (angiotensin-converting enzyme inhibitors (ACEI), beta blockers, metformin, and statins) approved by the Food and Drug Administration (FDA) for other indications and evaluates their influence when used in combination on the risk of possible AD development for patients with a history of TBI. We identified patients with history of TBI from an existing Department of Veterans Affairs (VA) national database. Among 1,660,151 veterans who used VA services between the ages of 50 to 89 years old, we analyzed 733,920 patients, including 15,450 patients with a history of TBI and 718,470 non-TBI patients. The TBI patients were followed for up to 18.5 years, with an average of 7.7 ± 4.7 years, and onset of dementia with possible AD was recorded based on International Statistical Classification of Diseases (ICD) 9 or 10 codes. The effect of TBI on possible AD development was evaluated by multivariable logistic regression models adjusted by age, gender, race, and other comorbidities. The association of ACEI, beta blockers, metformin, statins, and combinations of these agents over time from the first occurrence of TBI to possible AD onset was assessed using Cox proportional hazard models adjusted for demographics and comorbidities.ResultsVeterans with at least two TBI occurrences by claims data were 25% (odds ratio (OR) = 1.25, 95% confidence intervals (CI) (1.13, 1.37)) more likely to develop dementia with possible AD, compared to those with no record of TBI. In multivariable logistic regression models (propensity score weighted or adjusted), veterans taking a combination of ACEI and statins had reduced risk in developing possible AD after suffering TBI, and use of this medication class combination was associated with a longer period between TBI occurring and dementia with possible AD onset, compared to patients who took statins alone or did not take any of the four target drugs after TBI.ConclusionsThe combination of ACEI and statins significantly lowered the risk of development of dementia with possible AD in a national cohort of people with a history of TBI, thus supporting a clinical approach to lowering the risk of dementia with possible AD.

Association of Angiotensin-Converting Enzyme Inhibitors with Increased Mortality Among Patients with Isolated Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is associated with one-third of all deaths from trauma. Preinjury exposure to cardiovascular drugs may affect TBI outcomes. Angiotensin-converting enzyme inhibitors (ACEIs) exacerbate brain cell damage and worsen functional outcomes in the laboratory setting. β-blockers (BBs), however, appear to be associated with reduced mortality among patients with isolated TBI. Examine the association between preinjury ACEI and BB use and clinical outcome among patients with isolated TBI. A retrospective cohort study of patients age ≥40years admitted to an academic level 1 trauma center with isolated TBI between January 2010 and December 2014 was performed. Isolated TBI was defined as a head Abbreviated Injury Scale (AIS) score ≥ 3, with chest, abdomen, and extremity AIS scores ≤ 2. Preinjury medication use was determined through chart review. All patients with concurrent BB use were initially excluded. In-hospital mortality was the primary measured outcome. Over the 5-year study period, 600 patients were identified with isolated TBI who were naive to BB use. There was significantly higher mortality (P = .04) among patients who received ACEI before injury (10 of 96; 10%) than among those who did not (25 of 504; 5%). A multivariate stepwise logistic regression analysis revealed a threefold increased risk of mortality in the ACEI cohort (P < .001), which was even greater than the twofold increased risk of mortality associated with an Injury Severity Score ≥ 16. A second analysis that included patients who received preinjury BBs (n = 98) demonstrated slightly reduced mortality in the ACEI cohort with only a twofold increased risk in multivariate analysis (P = .05). Preinjury exposure to ACEIs is associated with an increase in mortality among patients with isolated TBI. This effect is ameliorated in patients who receive BBs, which provides evidence that this class of medications may provide a protective benefit.

Prescription of LCZ696 in 1442 patients with Heart Failure with reduced Ejection Fraction included in the Multicenter French Survey OFICSEL

In paradigm-HF study, LCZ696 was superior to angiotensin converting enzyme inhibitors (ACEI) and reduced mortality in heart failure with reduced ejection fraction (HFrEF) patients. LCZ696 is now recommended in symptomatic patients with HFrEF despite optimal treatment with beta-blockers, ACEI and mineralocorticoid receptor antagonists (MRA). To evaluate LCZ696 prescription in real-life in and outpatients. Prospective enrolment during 6 months in 2017. Data collection included demographic, burden, clinical, biological, echocardiography and treatment characteristics. A total of 1442 patients with left-ventricular ejection fraction (LVEF) < 40% were included of whom 31% were outpatients. Their mean age was 65 ± 14 years and 77% were men. Eighty-three percent were in NYHA II or III class and the mean LVEF was 28.2 ± 6.3%. Ischemic cardiopathy affected 49.8% of the patients. Heart failure was recently diagnosed (< 3 months) in 19% of the patients. A total of 343 patients were treated with LCZ696 (24%), in association with beta-blocker (91%) and, or MRA (67%). One hundred and nine patients were outpatients (37.1%). Seventeen patients (5%) were treated by LCZ696 and ACEI. As compared with ACEI or angiotensin receptor blockers (ARB) or neither of them, patients treated with LCZ696 were younger ( P < 0.0001) and more likely to be men ( P = 0.016). NYHA status was better ( P < 0.0001), NTpro-BNP was lower ( P < 0.0001) and Minnesota physical score was lower ( P = 0.003) in LCZ696 patients. Patients treated by LCZ696 were more likely to be outpatients ( P < 0.001). Almost one in four patients with LVEF < 40% was treated with LCZ696. Symptoms, cardiac biomarkers and quality of life were improved compared to ACEI, ARB or no treatment. LCZ696 treatment was less prescribed in older patients and women although there is no specific contraindication in this population. The association of ACEI and LCZ696 has to be avoided due to an increased risk of angioedema.

Angiotensin‐converting enzyme inhibitors and bacterial pneumonia in patients with Parkinson disease

To evaluate the association of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with pneumonia development in patients with Parkinson's disease (PD). The study cohort consisted of patients aged 50 years or older who were initially diagnosed with PD and had hypertension. We assessed the patients' exposure statuses and accumulated doses of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. We then evaluated the risk of pneumonia development in the patients who were exposed to these drugs and those who were not. We examined 2,310 patients. During the observation period, 608 patients developed pneumonia. Angiotensin-converting enzyme inhibitors were associated with a lower risk of pneumonia. This association was dose-dependent. Angiotensin-converting enzyme inhibitor use was associated with a dose-dependent reduction in the risk of pneumonia in patients with PD and hypertension.

Metabolomics approach reveals effects of antihypertensives and lipid-lowering drugs on the human metabolism.

The mechanism of antihypertensive and lipid-lowering drugs on the human organism is still not fully understood. New insights on the drugs’ action can be provided by a metabolomics-driven approach, which offers a detailed view of the physiological state of an organism. Here, we report a metabolome-wide association study with 295 metabolites in human serum from 1,762 participants of the KORA F4 (Cooperative Health Research in the Region of Augsburg) study population. Our intent was to find variations of metabolite concentrations related to the intake of various drug classes and—based on the associations found—to generate new hypotheses about on-target as well as off-target effects of these drugs. In total, we found 41 significant associations for the drug classes investigated: For beta-blockers (11 associations), angiotensin-converting enzyme (ACE) inhibitors (four assoc.), diuretics (seven assoc.), statins (ten assoc.), and fibrates (nine assoc.) the top hits were pyroglutamine, phenylalanylphenylalanine, pseudouridine, 1-arachidonoylglycerophosphocholine, and 2-hydroxyisobutyrate, respectively. For beta-blockers we observed significant associations with metabolite concentrations that are indicative of drug side-effects, such as increased serotonin and decreased free fatty acid levels. Intake of ACE inhibitors and statins associated with metabolites that provide insight into the action of the drug itself on its target, such as an association of ACE inhibitors with des-Arg(9)-bradykinin and aspartylphenylalanine, a substrate and a product of the drug-inhibited ACE. The intake of statins which reduce blood cholesterol levels, resulted in changes in the concentration of metabolites of the biosynthesis as well as of the degradation of cholesterol. Fibrates showed the strongest association with 2-hydroxyisobutyrate which might be a breakdown product of fenofibrate and, thus, a possible marker for the degradation of this drug in the human organism. The analysis of diuretics showed a heterogeneous picture that is difficult to interpret. Taken together, our results provide a basis for a deeper functional understanding of the action and side-effects of antihypertensive and lipid-lowering drugs in the general population.Electronic supplementary materialThe online version of this article (doi:10.1007/s10654-014-9910-7) contains supplementary material, which is available to authorized users.

Association of ACE Inhibitors and Angiotensin Receptor Blockers with Keratinocyte Cancer Prevention in the Randomized VATTC Trial

The observation that angiotensin II is a potent angiogenic and growth factor raises the possibility that blocking its effects could reduce the incidence of cancer. We evaluated associations between use of angiotensin-converting enzyme (ACE) inhibitors and of angiotensin receptor blockers (ARBs) and keratinocyte cancer incidence in a population at high risk of the disease. A cohort study design was conducted using data on 1051 participants in the randomized Department of Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial, all of whom were at increased risk of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). We followed participants from enrollment (November 1998 through January 2003) until first BCC or SCC. Study participants were examined every 6 months by a study dermatologist; biopsies were taken on all suspicious lesions and centrally reviewed. Use of ACE inhibitors and ARBs was ascertained from VA pharmacy records. Cox proportional hazards models were used to estimate adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of BCC and SCC with use of ACE inhibitors or ARBs. During a median follow-up of 3.4 years, 472 incident BCCs, 309 SCCs, and 200 deaths from any cause were observed. Compared with nonusers, users of ACE inhibitors or ARBs had statistically significantly reduced risks of BCC (IRR(BCC) = 0.61, 95% CI = 0.50 to 0.76) and SCC (IRR(SCC) = 0.67, 95% CI = 0.52 to 0.87). The combined absolute incidence rates of BCC and SCC were 237 per 1000 person-years among users of ACE inhibitors or ARBs and 374 per 1000 person-years among nonusers. The greatest reduction in keratinocyte cancer was seen among people who initiated use of ACE inhibitors or ARBs during the study period (IRR(BCC) = 0.45 [95% CI = 0.34 to 0.59]; IRR(SCC) = 0.48 [95% CI = 0.35 to 0.67]). Among a high-risk group of veterans, users of ACE inhibitors or ARBs had a lower incidence of keratinocyte cancers than nonusers. The more pronounced reduction among those who initiated use during the study may indicate an immediate effect.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with congestive heart failure and chronic kidney disease

Patients with coexistent heart failure and chronic kidney disease (CKD) have a poor prognosis, possibly related to the underuse of standard medical therapies--angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB). We performed a retrospective analysis of the Minnesota Heart Survey, identifying patients hospitalized in 2000 in the Minneapolis-St Paul metropolitan area with heart failure. The main outcome measure was the association of ACE-I and ARB use on 30-day and 1-year mortality, stratified by glomerular filtration rate (GFR). Compared to patients with heart failure with preserved renal function (GFR > or = 90 mL/min), patients with severely impaired renal function (GFR <15 mL/min) were far less likely to receive ACE-I or ARB during hospitalization (52.0% vs 69.5%, P < .0001) or at discharge (50.5% vs 65.1%, P < .0001). Worsening renal function was associated with increased mortality, both at 30 days and at 1 year. The inhospital use of either an ACE-I or ARB was associated with significantly reduced 30-day mortality (OR 0.45, 95% CI 0.28-0.59) after adjusting for multiple risk factors. Similarly, the discharge prescription of either an ACE-I or ARB was associated with a significant reduction in adjusted 1-year mortality (OR 0.72, 95% CI 0.58-0.91). However, among patients on dialysis, there was no benefit of ACE-I or ARB on either 30-day or 1-year mortality. Angiotensin-converting enzyme inhibitors and ARB are underused in patients with heart failure with chronic kidney disease. Given the reduction in 30-day and 1-year mortality, these medications should be considered in most patients with heart failure, independent of underlying renal function. Among patients on hemodialysis, further investigation is warranted.

Use of ACE inhibitors is associated with elevated levels of IGFBP-3 among hypertensive older adults: results from the IlSIRENTE study

Several studies in vitro or in rodent models have suggested a potential relationship between angiotensin-converting enzyme (ACE) inhibition and the insulin-like growth factor 1 (IGF-1) axis. However, this relationship has only rarely been investigated in humans. The aim of the present cross-sectional study was to assess the association of ACE inhibitors with free IGF-1 and IGFBP-3 in the blood of older hypertensive adults. Data are from the baseline evaluation of the IlSIRENTE study, which enrolled 364 subjects aged 80 or older. For the present study we selected a subpopulation of 264 hypertensive participants without congestive heart failure. Free IGF-1 and IGFBP-3 in the blood were measured by a radioimmunoassay method. Analyses of covariance were performed to evaluate the differences in free IGF-1 and IGFBP-3 levels according to the use of ACE inhibitors. The mean age of participants was 85.7 years (SD: 4.9), 170 (64%) were women and 123 (47%) were using an ACE inhibitor. Following adjustment for potential confounders, the concentration of free IGF-1 was slightly, but not significantly higher among ACE inhibitor users than among non-users (0.74 vs. 0.65 ng/mL; p=0.20). In contrast, ACE inhibitor users had a significantly higher IGFBP-3 serum levels than non-users (4821 vs. 4330 ng/mL; p=0.005). In addition, the concentration of IGFBP-3 was significantly higher among ACE inhibitors users than among non-users of antihypertensive drugs (p=0.02) and users of other antihypertensive drugs (p=0.01). Among hypertensive older adults, ACE inhibitors use is associated with higher IGFBP-3 levels.

Dual Blockade of the Renin-Angiotensin System in the Progression of Renal Disease

There is clear evidence that pharmacologic blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) reduces proteinuria and slows the progression of renal disease in diabetic and nondiabetic nephropathies, a beneficial effect that is not related to BP control. Some patients exhibit a significant beneficial response, whereas others do not. The absence of response may be explained by the incomplete blockade of the RAS obtained with ACEI. In the search of new alternatives that could improve the antiproteinuric and nephroprotective effects of RAS blockers, the association of ACEI and ARB might prove useful. ARB produces a complete blockade of the RAS. Several studies have shown a more marked antiproteinuric effect of the dual blockade of the RAS versus ACEI or ARB alone. A recent study also demonstrated that this more marked antiproteinuric effect is associated with less progression of renal disease in primary nondiabetic nephropathies despite a similar effect on BP. Until now, there has not been any reference to a beneficial effect on progression of the dual blockade in type 2 diabetic nephropathy, which is the most frequent cause of ESRD. A multicenter, prospective, open, active-controlled, and parallel-group trial was designed to compare the effects of an ACE inhibitor versus an ARB or its combination on renal disease progression, proteinuria, and cardiovascular events in type 2 diabetic nephropathy.

The Reno-Protective Effect of the Dual Blockade of the Renin Angiotensin System (RAS)

Hypertension and proteinuria are risk factors for renal disease progression. There is clear evidence that pharmacological blockade of the RAS with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) reduces proteinuria and slows down the progression of renal disease in diabetic and non diabetic nephropathies, a beneficial effect not related to blood pressure control. However, not all patients respond similarly to these treatments. Some patients exhibit a significant beneficial response while others do not. The absence of response may be explained by the incomplete blockade of the RAS obtained with ACEI, which are unable to block completely the formation of AII, some generation of AII is produced via other non ACE pathways. In the search of new alternatives that could improve the antiproteinuric and nephroprotective effects of RAS blockers, the association of ACEI and ARB might prove to be useful. ARB produces a complete blockade of the RAS and stimulates the vasodilating and non-proliferative actions of AII via the AT-2 receptor. Furthermore, ACE inhibitors but not ARB; inhibit the metabolism of kinins, which increases the level of bradykinin, a potent vasodilator. Recently, several authors have shown a more marked antiproteinuric effect of the dual blockade of the RAS versus ACEI or ARB alone in spite of a similar effect on blood pressure. A recent study also has demonstrated that this more marked antiproteinuric effect is associated with a less progression of renal disease in primary, non diabetic nephropathies. Furthermore, at least two studies have shown that, treatment with ARB postpones end-stage renal disease and reduces the rate of decline in renal function in patients with type 2 diabetes and nephropathy, but until now, there is not any clear evidence of a superior beneficial effect of dual blockade versus maximal recommended dose of ARB regarding renal progression in type 2 diabetic nephropathy, which is the most frequent cause of end stage renal disease. Long-term clinical trials are needed and encouraged to further establish the significant role of dual blockade in renal protection particularly in diabetic nephropathy.

Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non-case study in the French pharmacovigilance system database.

To test the existence of an association between reports of hypoglycaemia and angiotensin converting enzyme inhibitors, in a spontaneous reports database. The French Pharmacovigilance database was examined for an association between adverse drug reaction reports mentioning hypoglycaemia, and angiotensin converting enzyme inhibitors (ACEI) using the case/non-case methodology, with reports of hypoglycaemia as cases and all other reports as comparators. The association between ACEI or other chosen drugs and hypoglycaemia was also tested in the subgroups of patients taking or not antidiabetic agents (ADA). 428 of 93,338 reports mentioned hypoglycaemia (202/2227 with ADA (OR 40, 95% CI 33-48)). 46/5717 reports mentioned ACEI (OR 1.8 (1.25-2.54)). Other study drugs associated with hypoglycaemia were cibenzoline (OR 80 (57-112)), disopyramide (OR 32 (22-46)), nifedipine (OR 2.16 (1.32-3.51)), diltiazem (OR 1.76 (1.01-3.06)) nitrates (nitroglycerin, molsidomine) (OR 1.91 (1.16-3.16)) and frusemide (OR 1.89 (1.31-1.76)), but not nicardipine, amlodipine, felodipine or nitrendipine, diazepam, atenolol or combination thiazide diuretics. However, ACEI and other drugs were associated with ADA, so that in the subgroups of patients taking or not ADA, the association of ACEI with hypoglycaemia disappeared (OR 0.9 (0.5-1.4) and 1.2 (0.7-2.2), respectively). The same was found for other drugs except cibenzoline. The association between reporting of hypoglycaemia and ACE inhibitors was related to concomitant use of antidiabetic agents. This was true also for other drugs used in arterial disease or renal failure, such as calcium channel blockers, nitrates, and frusemide.