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Introduction: Angiotensin receptor blockers are widely used antihypertensive drugs in South Korea. In 2021, the Korea Ministry of Food and Drug Safety acknowledged the need for national compensation for a drug-induced liver injury (DILI) after azilsartan use. However, little is known regarding the association between angiotensin receptor blockers and DILI., Objective: We conducted a retrospective cohort study in incident users of angiotensin receptor blockers from a common data model database (1 January, 2017-31 December, 2021) to compare the risk of DILI among specific angiotensin receptor blockers against valsartan., Methods: Patients were assigned to treatment groups at cohort entry based on prescribed angiotensin receptor blockers. Drug-induced liver injury was operationally defined using the International DILI Expert Working Group criteria. Cox regression analyses were conducted to derive hazard ratios and the inverse probability of treatment weighting method was applied. All analyses were performed using R., Results: In total, 229,881 angiotensin receptor blocker users from 20 university hospitals were included. Crude DILI incidence ranged from 15.6 to 82.8 per 1000 person-years in treatment groups, most were cholestatic and of mild severity. Overall, the risk of DILI was significantly lower in olmesartan users than in valsartan users (hazard ratio: 0.73 [95% confidence interval 0.55-0.96]). In monotherapy patients, the risk was significantly higher in azilsartan users than in valsartan users (hazard ratio: 6.55 [95% confidence interval 5.28-8.12])., Conclusions: We found a significantly higher risk of suspected DILI in patients receiving azilsartan monotherapy compared with valsartan monotherapy. Our findings emphasize the utility of real-world evidence in advancing our understanding of adverse drug reactions in clinical practice., (© 2024. The Author(s).)

Heart failure is a prevalent syndrome among older adults, with a major impact on morbidity and mortality. Higher age is correlated with underuse of guideline-directed medical therapies which, in turn, has been linked to worse clinical outcomes. Importantly, most evidence so far has been collected in adults who were younger, less multi-morbid and polymedicated compared with those who are commonly treated in daily clinical practice. Hence, we aimed to assess and describe the evidence base for pharmacotherapy in older adults with heart failure with a reduced ejection. First, a narrative review was undertaken using Medline, from inception to January 2023. Four foundational therapies were selected based on the latest European Society of Cardiology clinical practice guideline: angiotensin-converting enzyme inhibitors/angiotensin receptor neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists and sodium-glucose cotransporter-2 inhibitors. Post hoc analyses from landmark heart failure drug trials were searched and included if they contained data on the impact of age on efficacy, safety and/or timeliness of therapies in the management of heart failure with a reduced ejection fraction. Second, a proposal was developed to support and promote the use of evidence-based heart failure pharmacotherapy in complex, older adults. In total, 11 articles were selected: 4 meta-analyses, 6 post hoc analyses and 1 review paper. No attenuation of efficacy for any of the foundational agents was found in older adults. Regarding safety, dedicated analyses showed that beta blockers, mineraloid receptor antagonists, sacubitril-valsartan, dapagliflozin and empagliflozin retained their overall benefit-risk profile regardless of age. Time to benefit was short and occurred generally within 1 month. Consensus was achieved on a five-step proposal to manage complex medication regimens in older adults suffering from heart failure. In conclusion, older adults suffering from heart failure with a reduced ejection fraction should not be denied treatment based on their age., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Since sacubitril/valsartan (LCZ696) has neprilysin inhibition and angiotensin receptor-blocking properties, it is anticipated to have strong antihypertensive effects. However, there is not enough evidence to compare the safety and efficacy of sacubitril/valsartan to those of olmesartan in patients with hypertension., Aim: To compare the efficacy and safety of sacubitril/valsartan versus olmesartan in patients with hypertension., Methods: This study follows the guidelines of the Cochrane Handbook. We searched MEDLINE, Cochrane Central, Scopus, and Web of Science databases for relevant clinical trials. We extracted outcome endpoints regarding mean ambulatory systolic/diastolic blood pressure (maSBP/maDBP), mean sitting systolic/diastolic blood pressure (msSBP/msDBP), mean ambulatory/mean sitting pulse pressure (maPP/msPP), the proportion of patients achieving blood pressure control (< 140/90 mmHg), and adverse events. We used Review Manager Software for the conduction of the analysis of this study. The effect estimates of the studies were pooled as Mean difference or risk ratio and 95% confidence interval. We also conducted a subgroup analysis based on the dose of sacubitril/valsartan., Results: A total of six clinical trials were included. The studies showed an overall low risk of bias. The pooled effect estimate revealed that sacubitril/valsartan significantly reduces maSBP, maDBP, maPP, msSBP, and msDBP measurements compared with olmesartan (p < 0.001). A significantly higher portion of patients achieved blood pressure control in the sacubitril/valsartan group (p < 0.001). The test of subgroup difference showed that 400 mg dose is significantly more effective than 200 mg dose in reducing maSBP. Regarding the safety profile, olmesartan was associated with more side effects due to drug discontinuation and more serious side effects., Conclusion: Sacubitril/valsartan or LCZ696 is more effective and safer than olmesartan for controlling blood pressure in patients with hypertension., (© 2023. Italian Society of Hypertension.)

Introduction: COVID-19 related mortality is about 2%, and it increases with comorbidities, like hypertension. Regarding management, there is debatable evidence about the benefits of continuation vs. discontinuation of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARB)., Aim: We performed a systematic review to assess the effects and safety of in-hospital discontinuation compared to continuation of ACEI/ARB in COVID-19 patients., Methods: We systematically searched on PubMed, Scopus, and EMBASE from inception to June 19, 2021. We included observational studies and trials that compared the effects and safety of continuing ACEI/ARB compared to discontinuing it in COVID-19 patients. Effects sizes for dichotomous variables were expressed as risk ratios (RR) and 95% confidence intervals. For continuous variables, effects were expressed as mean difference (MD). We used random effect models with the inverse variance method. We assessed certainty of evidence using the GRADE approach., Results: We included three open-label randomized controlled trials and five cohort studies. We found that the continuation group had lower risk of death compared with the discontinuation group only in the cohort group (RR: 0.46, 95% CI: 0.24-0.90), but not in the RCT group (RR: 1.22, 95% CI: 0.75-2.00). The ICU admission rate was significantly lower in the continuation group (RR: 0.46, 95% CI: 0.31-0.68) in the cohort group, but not in RCT group (RR: 1.03, 95% CI: 0.67-1.59). We did not find significant differences between groups regarding hospitalization length, hypotension, AKI needing renal replacement therapy, mechanical ventilation, new or worsening heart failure, myocarditis, renal replacement therapy, arrhythmias, thromboembolic events and SOFA AUC. The GRADE approach revealed that the certainty ranged from moderate to high level., Conclusions: There is no significant difference in mortality and other outcomes between continuation and discontinuation groups., (© 2023. Italian Society of Hypertension.)

Background: Sacubitril/valsartan (S/V) improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Data about the immediate, short-, and intermediate-term hemodynamic effects of S/V are limited., Methods: In this prospective observational study, 37 outpatients with chronic HFrEF were treated with S/V according to current guideline recommendations. Next to clinical, laboratory and echocardiographic parameters, haemodynamic variables were assessed non-invasively by use of inert gas rebreathing and bioimpedance cardiography at baseline and at 2-week, 3-month and 6-month follow-up. The course of variables throughout the study and the relationship between variables were analysed using fractional polynomials., Results: S/V treatment resulted in short- and intermediate-term improvements in NYHA functional class (2.3 ± 0.6 at baseline vs. 1.9 ± 0.5 at 6-month follow-up, p = 0.14), 6-min walk test (453 ± 110 vs. 528 ± 98 m, p = 0.02), ejection fraction (31 ± 9 vs. 36 ± 12%, p = 0.13), pulmonary artery pressure (39 ± 10 vs. 31 ± 10 mmHg, p = 0.02), and NT-proBNP values (1702 (782-2897 vs. 1004 (599-1627) ng/L, p = 0.03). In addition, S/V caused immediate decreases in systemic vascular resistance index (SVRI) and systolic blood pressure (SBP), which were associated with a simultaneous drop in stroke volume (SV) and cardiac index (CI). However, while SVRI and SBP remained at low levels during further treatment, SV and CI restored rapidly and increased to slightly higher levels thereafter., Conclusion: The vasodilative effects of S/V result in immediate reductions in SVRI, SBP, SV and CI. However, S/V induces reverse cardiac remodelling, which is apparent shortly after treatment initiation and leads to improvements of clinical, functional, echocardiographic, laboratory and haemodynamic variables., (© 2022. The Author(s).)

Introduction: There are conflicting reports on the effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) on acute pancreatitis incidence., Objective: The aim was to determine whether use of ACE inhibitors and ARBs is associated with the incidence of acute pancreatitis, compared with use of dihydropyridine calcium channel blockers (dCCBs)., Methods: We assembled two population-based, new-user, active comparator cohorts using the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics repository and Office for National Statistics from 1998 to 2018, with follow-up until 2019. The first cohort included 304,083 ACE inhibitor initiators and 194,431 dCCB initiators. The second cohort included 29,160 ARB initiators and 203,610 dCCB initiators. Cox proportional hazards models were fit to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of acute pancreatitis, comparing ACE inhibitors and ARBs, separately, with dCCBs. Models were weighted using standardized mortality ratio weights generated from calendar time-specific propensity scores., Results: ACE inhibitors were associated with an increased risk of acute pancreatitis, compared with dCCBs (64.3 vs 45.2 per 100,000 person-years, respectively; HR 1.45, 95% CI 1.15-1.83). The number needed to harm after 2 and 5 years of use was 2438 and 1019, respectively. In contrast, ARBs were not associated with an increased risk of acute pancreatitis, compared with dCCBs (40.1 vs 47.6 per 100,000 person-years, respectively; HR 0.88, 95% CI 0.60-1.31)., Conclusions: ACE inhibitors were associated with a modest increased risk of acute pancreatitis compared with dCCBs. This association should be balanced with the known clinical benefits of ACE inhibitors in hypertension management. In contrast, no association was observed with ARBs., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Hyperkalemia is an elevated level of serum potassium (K + ) and does represent a life-threatening condition. In clinical practice, hyperkalemia mainly derives from an impaired renal K + excretion which, in turn, is usually caused by either acute or chronic renal failure. In concordance with this, hyperkalemia is very common in several chronic conditions, such as kidney disease, diabetes mellitus, heart failure, hypertension, and coronary heart disease. In all of these conditions the use of Renin-Angiotensin-Aldosterone System inhibitors (RAASIs), such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonist is widely recommended and further increases the risk of hyperkalemia. As hypertension is concerned, clinical trials suggest that the risk of hyperkalemia associated with RAASIs ranges from 2 to 10%. This often leads to a reduction or complete cessation of RAASIs, leaving patients without protective medications. Patiromer, a new oral potassium-binding agent, has been approved for clinical use in several countries, including Europe and US. Clinical studies have demonstrated that patiromer is effective in inducing a rapid and sustained K + reduction in various patient settings, including those where RAASIs are a fundamental component of cardiorenal protection. Patiromer is generally well tolerated and characterised by a good safety profile. Most importantly, patiromer use might allow the continuation of ACEIs and ARBs in hypertensive patients developing hyperkalemia during treatment and thereby favour a more effective and long-lasting cardiorenal protection., (© 2021. Italian Society of Hypertension.)

Introduction: The safety of renin-angiotensin-aldosterone system inhibitors (RAASi) among COVID-19 patients has been controversial since the onset of the pandemic., Methods: Digital databases were queried to study the safety of RAASi in COVID-19. The primary outcome of interest was mortality. The secondary outcome was seropositivity improvement/viral clearance, clinical manifestation progression, and progression to intensive care units. A random-effect model was used to compute an unadjusted odds ratio (OR)., Results: A total of 49 observational studies were included in the analysis consisting of 83,269 COVID-19 patients (RAASi n = 34,691; non-RAASi n = 48,578). The mean age of the sample was 64, and 56% were males. We found that RAASi was associated with similar mortality outcomes as compared to non-RAASi groups (OR 1.07; 95% CI 0.99-1.15; p > 0.05). RAASi was associated with seropositivity improvement including negative RT-PCR or antibodies, (OR 0.96; 95% CI 0.93-0.99; p < 0.05). There was no association between RAASi versus control with progression to ICU admission (OR 0.99; 95% CI 0.79-1.23; p > 0.05) or higher odds of worsening of clinical manifestations (OR 1.04; 95% CI 0.97-1.11; p > 0.05). Metaregression analysis did not change our outcomes for effect modifiers including age, sex, comorbidities, RAASi type, or study type on outcomes., Conclusions: COVID-19 is not a contraindication to hold or discontinue RAASi as they are not associated with higher mortality or worsening symptoms. Continuation of RAASi might be associated with favorable outcomes in COVID-19, including seropositivity/viral clearance.

Ever since its outbreak, Corona Virus Disease 2019(COVID-19) caused by SARS-CoV-2 has affected more than 26 million individuals in more than 200 countries. Although the mortality rate of COVID-19 is low, but several clinical studies showed, patients with diabetes mellitus (DM) or other major complication at high risk of COVID-19 and reported more severe disease and increased fatality. The angiotensin-converting-enzyme 2 (ACE2), a component of renin-angiotensin-system (RAS); acts on ACE/Ang-II/AT1recptor axis, and regulates pathological processes like hypertension, cardiac dysfunction, Acute Respiratory Distress Syndrome (ARDS) etc. The progression of T2DM and hypertension show decreased expression and activity of ACE2. There are several treatment strategies for controlling diabetes, hypertension, etc; like ACE2 gene therapies, endogenous ACE2 activators, human recombinant ACE2 (hrACE2), Angiotensin-II receptor blockers (ARBs) and ACE inhibitors (ACEi) medications. ACE2, the receptors for SARS-CoV2, facilitates virus entry inside host cell. Clinicians are using two classes of medications for the treatment of COVID-19; one targets the SARS-CoV-2-ACE2 interaction, while other targets human immune system. The aim of this review is to discuss the role of ACE2 in diabetes and in COVID-19 and to provide an analysis of data proposing harm and benefit of RAS inhibitor treatment in COVID-19 infection as well as showing no association whatsoever. This review also highlights some candidate vaccines which are undergoing clinical trials.

Background: Evidence regarding differences in outcomes between angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) among older nursing home (NH) residents after acute myocardial infarction (AMI) is limited., Objectives: The purpose of our study was to estimate the post-AMI effects of ARBs versus ACEIs on mortality, rehospitalization, and functional decline outcomes in this important population., Methods: This retrospective cohort study used national Medicare claims linked to Minimum Data Set assessments. The study population included individuals aged ≥ 65 years who resided in a US NH ≥ 30 days, were hospitalized for AMI between May 2007 and March 2010, and returned to the NH. We compared 90-day mortality, rehospitalization, and functional decline outcomes between ARB and ACEI users with inverse-probability-of-treatment-weighted binomial and multinomial logistic regression models., Results: Of the 2765 NH residents, 270 (9.8%) used ARBs and 2495 (90.2%) used ACEIs. The mean age of ARB versus ACEI users was 82.3 versus 82.7 years, respectively. No marked differences existed between ARB and ACEI users for mortality [odds ratio (OR) 1.18; 95% confidence interval (CI) 0.78-1.79], rehospitalization (OR 1.22; 95% CI 0.90-1.65), or functional decline (OR 1.23; 95% CI 0.88-1.74). In subgroup analyses, ARBs were associated with increased mortality and rehospitalization in individuals with moderate to severe cognitive impairment and with increased rehospitalization in those aged < 85 years., Conclusions: Our findings align with prior data and suggest that clinicians can prescribe either ARBs or ACEIs post-AMI for secondary prevention in NH residents, although the subgroup findings merit further scrutiny and replication. Providers should consider factors such as patient preferences, class-specific adverse events, and costs when prescribing.

Cardiovascular diseases, in particular hypertension, as well as the cardiovascular treatment with Renin-Angiotensin System inhibitors such as Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs), are claimed once again as mechanisms of Severe Acute Respiratory Syndrome (SARS) during the COVID-19 outbreak due to Cov-2 epidemics. In vitro studies are available to support the eventual role of ACE inhibitors and ARBs in both the promotion and antagonism of the disease. The available literature, indeed, presents contrasting results, all concentrated in experimental models. Evidence in humans is lacking that those mechanisms are actually occurring in the present COVID-19 outbreak. Here we present the reasoned statement of the Italian Society of Hypertension to maintain ongoing antihypertensive treatments. Furthermore, the Italian Society of Hypertension presents its own initiative to investigate the issue using an online questionnaire to collect relevant data in human disease.

Background: Although angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been recommended for patients with heart failure, their clinical and prognostic impact in the very acute phase of acute heart failure (AHF) is unclear, mainly because data on their safety and efficacy are lacking., Methods: This study was a post hoc analysis of the REALITY-AHF trial. Patients with AHF who did not take an ACEI or ARB at admission were enrolled. Patients who received these medications within 48 h of admission were categorized as the ACEI/ARB group, and all other patients were categorized as the no ACEI/ARB group. The primary endpoint was a composite of all-cause death and heart failure readmission within 1 year of admission., Results: Of the 1682 patients in the REALITY-AHF cohort, 900 were enrolled in this study, and 288 (32%) were included in the ACEI/ARB group. After propensity score matching, 152 pairs were evaluated, and no significant difference was found for in-hospital mortality, worsening renal function, or length of hospital stay. The ACEI/ARB group had significantly higher event-free survival (hazard ratio 0.51; 95% confidence interval 0.32-0.82; p = 0.006)., Conclusions: Early initiation of ACEIs/ARBs within 48 h of admission for hospitalized patients with AHF was not associated with adverse events and correlated with improved outcomes at 1 year from admission.

Introduction: The goal of this study was to determine the association between the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) and follow-up heart failure (HF) according to left ventricular ejection fraction (LVEF) in patients with acute myocardial infarction (AMI)., Methods: This cohort study used a retrospective registry of 8169 consecutive patients discharged with a diagnosis of AMI from two university hospitals in Spain between 2010 and 2016. We used a multivariable competing risk analysis, survival-time inverse probability weighting (IPW) propensity score adjusting, and propensity score matching (PSM) to investigate the association between ACEI/ARB treatment and follow-up HF., Results: During the follow-up (3.3 ± 2.2 years), 1296 patients were admitted for HF (5.2 per 100 person-years). ACEI/ARB use was not associated with fewer follow-up HF admissions in patients with LVEF > 40% (univariate analysis: sub-hazard ratio [sHR] 1.10; 95% confidence interval [CI] 0.95-1.27; p = 0.197; IPW adjusting analysis: sHR 1.11; 95% CI 0.95-1.29; p = 0.192; PSM analysis: sHR 1.12; 95% CI 0.92-1.36; p = 0.248). However, ACEI/ARB use was associated with a significant reduction in HF admission rates in patients with LVEF ≤ 40% (univariate analysis: HR 0.70; 95% CI 0.56-0.88; p = 0.003; IPW adjusting analysis: HR 0.64; 95% CI 0.50-0.83; p = 0.001; PSM analysis: HR 0.65; 95% CI 0.46-0.92; p = 0.014)., Conclusion: Among hospitalized survivors of AMI, the use of ACEIs/ARBs was associated with a lower risk of follow-up HF in patients with LVEF ≤ 40% but not in those with LVEF > 40%. Further prospective studies are needed to confirm our results.

Background: The use of renin-angiotensin-aldosterone system inhibitors has increased over the past few years. There are conflicting data as to their relationship with acute kidney injury following surgery., Objectives: The objective of the article was to evaluate the risk of acute kidney injury in diabetic older patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and their medical outcomes following fragility hip fracture surgery., Methods: Consecutive diabetic patients presenting with fragility hip fractures to our primary trauma center between January 2012 and June 2016 were included. Demographic and clinical data, including co-morbidities, medication use, and laboratory results, were collected from the electronic medical records. The primary outcome was the incidence of acute kidney injury; the secondary outcome was 1-year mortality., Results: Two hundred and seventeen patients were included; 125 were receiving treatment with medications targeting the renin-angiotensin-aldosterone system. Demographic and clinical characteristics were similar between groups. No association was found between the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and the risk of acute kidney injury, which occurred in 25% of the cohort. Univariate analysis revealed that diuretic use, particularly furosemide, increased the risk of acute kidney injury during hospitalization (p = 0.003). However, in a multivariate analysis, only age and estimated glomerular filtration rates were associated with an increased risk of acute kidney injury. Patients with acute kidney injury were found to have increased mortality during the first post-operative year (p < 0.001)., Conclusions: Acute kidney injury is a frequent complication after hip fracture surgery in elderly diabetic patients and is associated with increased 1-year mortality; however, it was not found to be associated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker pre-fracture treatment.

Introduction: Current guidelines recommend renin-angiotensin-aldosterone system (RAAS) inhibitors in the treatment of diabetic kidney disease (DKD). However, evidence suggests that the combined use of RAAS blockers may be associated with increased rates of adverse events., Objectives: Our objective was to examine the efficacy and safety of dual blockade of the RAAS in patients with DKD., Methods: This was a systematic review and meta-analysis of randomized controlled trials (RCTs) published between January 1990 and January 2018 sourced via the PubMed, EMBASE, and Cochrane Library databases. RCTs were included if they investigated the efficacy and safety of dual blockade therapy compared with monotherapy in patients with DKD. Random effects models were used in meta-analysis to account for heterogeneities in effect sizes across the reviewed studies. Analyses were stratified by blood pressure and albuminuria. We further conducted subgroup analyses by considering various combinations of RAAS inhibitors., Results: Based on 42 RCTs with 14,576 patients, dual RAAS blockade therapy was associated with significant decreases in blood pressure, albuminuria, and proteinuria. However, dual therapy was not superior to monotherapy in terms of reductions in all-cause mortality, cardiovascular mortality, or progression to end-stage renal disease (ESRD). Significant increases in serum potassium and rates of hyperkalemia and hypotension were more common in patients treated with dual therapy. However, glomerular filtration rates (GFR) did not decrease significantly with dual therapy. In subgroup analysis, an angiotensin-converting enzyme inhibitor (ACEI) plus an angiotensin-receptor blocker (ARB) or a direct renin inhibitor (DRI) plus an ACEI/ARB did not significantly increase the risk of hyperkalemia, hypotension, and adverse events, and the risk of hypotension increased significantly within the normotensive subgroup but not within the hypertensive subgroup. The risk of hyperkalemia increased significantly in patients with DKD with macroalbuminuria but not in those with microalbuminuria., Conclusion: Dual inhibition therapy is superior to monotherapy for blood pressure control and urine protein reduction, though such superiority does not translate into improvements in longer-term outcomes, such as reduced progression to ESRD, all-cause mortality, and cardiovascular mortality. An ACEI plus an ARB or a DRI plus an ACEI/ARB may be a safe and effective therapy for patients with DKD, and combination therapy may be suitable for patients with DKD and hypertension and microalbuminuria.

The clinical syndrome of heart failure (HF) can be described as the reduced capacity of the heart to deliver blood throughout the body. To compensate for inadequate tissue perfusion, the renin-angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS) become activated, resulting in increased blood pressure, heart rate, and blood volume. Consequent activation of the natriuretic peptide system (NPS) typically balances these effects; however, the NPS is unable to sustain compensation for excessive neurohormonal activation over time. Until recently, mortality benefits have been provided to patients with HF only by therapies that target the RAAS and SNS, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, and beta-blockers. Sacubitril/valsartan, the first-in-class angiotensin receptor/neprilysin inhibitor (ARNI), targets both the NPS and RAAS to further improve clinical outcomes. This review discusses the focused management of patients with HF with reduced ejection fraction (HFrEF) and suggests changes to current management paradigms. From this assessment, the evidence supports favoring sacubitril/valsartan over ACEIs or ARBs, and this therapy should be used in conjunction with beta-blockers to further decrease morbidity and mortality in patients with HFrEF.

Objective: The objective of this research was to describe the use of pharmacist-managed sacubitril/valsartan therapy in a multi-center, outpatient cardiac group., Background: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNi), is a novel agent for the treatment of heart failure. An ARNi is recommended by national guidelines to be used in place of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy for patients who remain symptomatic., Methods: A retrospective chart review was performed to identify patients initiated and fully titrated on sacubitril/valsartan therapy from July 7, 2015 to March 7, 2017., Results: Fifty-two of the 72 symptomatic heart failure with reduced ejection fraction (HFrEF) patients prescribed sacubitril/valsartan during the 21-month period were included in this analysis. The average ejection fraction was 26%. The average age was 69 years. At baseline, 26.9% of patients were not on ACEi/ARB therapy and 13.5% were on target-dose therapy. After completing the uptitration process, the maximally tolerated dose of sacubitril/valsartan was 5.8% low-dose, 7.7% mid-dose, and 86.5% target-dose. Loop and thiazide diuretic use decreased significantly. There was a significant mean reduction in systolic blood pressure of 6 mmHg with no significant changes in serum creatinine, blood urea nitrogen, or potassium levels., Conclusions: With close monitoring and follow-up, ARNi therapy was a safe alternative to ACEi/ARB therapy for chronic symptomatic HFrEF when initiated within a pharmacist clinic.

Introduction: Several antihypertensive drugs are photosensitizing and may promote the development of malignant melanoma (MM), but evidence remains inconsistent. We sought to quantify the association between use of antihypertensive drugs and MM risk., Methods: We systematically searched PubMed, Embase, and CENTRAL from inception to August 17, 2017 to identify observational studies that reported the MM risk associated with the use of antihypertensive drugs. A random-effects meta-analysis was used to estimate the odds ratio (OR) with 95% confidence interval (CI)., Results: Overall, we included eight observational studies (two cohort studies and six case-control studies). Compared with non-use, use of diuretics (OR 1.10; 95% CI 1.03-1.17) or β-adrenergic blocking agents (OR 1.19; 95% CI 1.04-1.37) was significantly associated with increased risk of MM. The use of angiotensin-converting enzyme inhibitors (OR 1.08; 95% CI 0.95-1.23), angiotensin II receptor blockers (OR 1.12; 95% CI 0.95-1.31), and calcium channel blockers (OR 1.12; 95% CI 0.72-1.74) was not significantly associated with increased risk of MM., Conclusions: Current evidence from observational studies suggests that use of diuretics or β-adrenergic blocking agents may be associated with increased risk of MM. Further large well-conducted prospective studies are required to confirm our findings.

Introduction: Although improved during the past few years, blood pressure control remains sub optimal., Aim: The impact of follow-up assessment on blood pressure control was evaluated in a group of patients of the HYT (HYperTension survey), treated with a combination of different dihydropyridine calcium-channel blockers (CCBs regimen) and inhibitors of renin-angiotensin-aldosterone system (RAAS) and with uncontrolled blood pressure. This was obtained assessing (a) the rate of blood pressure control at 3 and 6 months of follow-up in the whole group of patients, (b) the rate of blood pressure control and the average blood pressure values in subjects treated with different DHP-CCBs regimen., Methods: From the 4993 patients with uncontrolled blood pressure, (BP ≥ 140/90 or ≥140/85 in patients with diabetes), 3729 (mean age 61.2 ± 11.5 years), maintained CCBs regimen combined wih RAAS blockers and were evaluated at 3 and 6 months follow-up. At each visit BP (semiautomatic device, Omron-M6, 3 measurements), heart rate, adverse events and treatment persistence were collected., Results: At 1st and 2nd follow-up the rate of controlled BP was 63.5 and 72.8% respectively (p < 0.05 vs 35.3% at baseline), whereas in diabetes was 32.5 and 37.9% respectively (p < 0.05 vs 20% at baseline). No differences in heart rate were observed. No differences in control rate were observed between the different CCBs regimen. The incidence of drugs related adverse events was 3.6%., Conclusions: These findings provide evidence that: (a) the follow-up of hypertensive patients under therapy increase the rate of blood pressure control; (b) there is no significant difference in the antihypertensive effect between different CCBs regimen;, ((c) lipophilic CCBs induce less ankle edema.)

Introduction: Previous studies of antihypertensive treatment of older patients have focused on blood pressure control, cardiovascular risk or adherence, whereas data on inappropriate antihypertensive prescriptions to older patients are scarce., Objectives: The aim of the study was to assess inappropriate antihypertensive prescriptions to older patients., Methods: An observational, prospective multicentric study was conducted to assess potentially inappropriate prescription of antihypertensive drugs, in patients aged 75 years and older with arterial hypertension (HTN), in the month prior to hospital admission, using four instruments: Beers, Screening Tool of Older Person's Prescriptions (STOPP), Screening Tool to Alert Doctors to the Right Treatment (START) and Assessing Care of Vulnerable Elders 3 (ACOVE-3). Primary care and hospital electronic records were reviewed for HTN diagnoses, antihypertensive treatment and blood pressure readings., Results: Of 672 patients, 532 (median age 85 years, 56% female) had HTN. 21.6% received antihypertensive monotherapy, 4.7% received no hypertensive treatment, and the remainder received a combination of antihypertensive therapies. The most frequently prescribed antihypertensive drugs were diuretics (53.5%), angiotensin-converting enzyme inhibitors (ACEIs) (41%), calcium antagonists (32.2%), angiotensin receptor blockers (29.7%) and beta-blockers (29.7%). Potentially inappropriate prescription was observed in 51.3% of patients (27.8% overprescription and 35% underprescription). The most frequent inappropriately prescribed drugs were calcium antagonists (overprescribed), ACEIs and beta-blockers (underprescribed). ACEI and beta-blocker underprescriptions were independently associated with heart failure admissions [beta-blockers odds ratio (OR) 0.53, 95% confidence interval (CI) 0.39-0.71, p < 0.001; ACEIs OR 0.50, 95% CI 0.36-0.70, p < 0.001]., Conclusion: Potentially inappropriate prescription was detected in more than half of patients receiving antihypertensive treatment. Underprescription was more frequent than overprescription. ACEIs and beta-blockers were frequently underprescribed and were associated with heart failure admissions.

Introduction: 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)., Objective: The aim of this study was to determine if an association exists for ACEI, ARB, or TZ exposure and skin cancers., Methods: 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., Results: 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)., Conclusions: 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.

Background: Heart failure with reduced ejection fraction (HFrEF) is a disease of older people, but the target doses of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are unknown., Objective: To evaluate the association of ACEI/ARB dose level with long-term survival in stable older patients (aged >70 years) and octogenarian outpatients with HFrEF., Population and Methods: A total of 138 outpatients aged >70 years (35.5 % > 80 years), with an LVEF <40 % and who were clinically stable on optimal therapy were followed up for 3 years. The ACEI/ARB doses were categorized as: none (0), low (1-50 % target dose), and high (50-100 % target dose). The Cox regression survival model was adjusted for age, ischemic etiology, and renal function., Results: ACEIs/ARBs were prescribed to 91.3 % of patients, and 52.9 % received the high dose. Survival improved with increasing ACEI/ARB dose level in the total population (Hazard Ratio [HR] = 0.67; 95 % confidence interval [CI] 0.55-0.82; p < 0.001), older patients aged >70 years (HR = 0.65; 95 % CI 0.51-0.83; p < 0.001), and octogenarians (HR = 0.71; 95 % CI 0.51-0.99; p = 0.045). The low (HR = 0.35; 95 % CI 0.16-0.76; p = 0.008) and high doses (HR = 0.13; 95 % CI 0.06-0.32; p < 0.001) improved survival compared with not receiving ACEIs/ARBs. The high dose was associated with a better survival than the low dose in the total population (HR = 0.35; 95 % CI 0.19-0.67; p = 0.001) and in a propensity score-matched cohort (HR = 0.41; 95 % CI 0.16-1.02; p = 0.056). In octogenarians, all dose levels were associated with improved survival compared with not receiving ACEIs/ARBs, but there was no difference between ACEI/ARB doses., Conclusion: The achieved optimal dose of ACEIs/ARBs in ambulatory older people with HFrEF is associated with long-term survival.

Sacubitril/valsartan (Entresto™; LCZ696) is an orally administered supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, which was recently approved in the US and the EU for the treatment of chronic heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF). In the large, randomized, double-blind, PARADIGM-HF trial, sacubitril/valsartan reduced the incidence of death from cardiovascular causes or first hospitalization for worsening heart failure (composite primary endpoint) significantly more than the angiotensin converting enzyme (ACE) inhibitor enalapril. Sacubitril/valsartan was also superior to enalapril in reducing death from any cause and in limiting the progression of heart failure. Sacubitril/valsartan was generally well tolerated, with no increase in life-threatening adverse events. Symptomatic hypotension was significantly more common with sacubitril/valsartan than with enalapril; the incidence of angio-oedema was low. Therefore, sacubitril/valsartan is a more effective replacement for an ACE inhibitor or an ARB in the treatment of HFrEF, and is likely to influence the basic approach to treatment.

Background: There are few data on the comparative effectiveness of angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) in a broad spectrum of patients with acute myocardial infarction (AMI), undergoing percutaneous coronary intervention (PCI)., Methods: A total of 8574 patients were selected from the prospective AMI registry, the Korean Working Group in Myocardial Infarction (KorMI) Registry, and divided into two groups on the basis of discharge prescription: ARB (n = 2281) or ACEI (n = 6293). The study was also designed using propensity-score matching (1171 patients in the ARB vs. 2752 patients in the ACEI group). The primary outcome was a composite of cardiac death or myocardial infarction (MI) during 1-year follow-up., Results: The Cox model showed both the ARB and ACEI groups had similar risk of cardiac death or MI [adjusted hazard ratio (HR) for ARB 0.69, 95% confidence interval (CI) 0.38-1.25, p = 0.22]. This result was consistent across various risk subgroups, including patients with preserved left ventricular systolic function, or according to the Global Registry of Acute Coronary Events (GRACE) risk scoring system. After propensity-score matching, there was no significant difference in the incidence of cardiac death or MI between the groups (1.3% in the ARB group vs. 1.7% in the ACEI group, adjusted HR for ARB 0.68, 95% CI 0.38-1.23, p = 0.21). The risks of all-cause death, cardiac death, or MI were also similar between groups., Conclusions: In a broad spectrum of AMI patients with interventional and pharmacologic treatments, the short-term risk of cardiac death or MI was similar between ARB and ACEI groups.

Background: Angiotensin II receptor blockers (ARBs) are widely used to treat hypertension and heart failure. Photosensitivity reactions are cutaneous adverse events due to exposure to a drug and either ultraviolet or visible radiation. Among the ARB class, this type of adverse drug reaction is labeled only for losartan., Objective: The aim of this study was to provide a descriptive evaluation of photosensitivity reports with ARBs in the World Health Organization Global Individual Case Safety Report database, VigiBase(®)., Methods: All reports of photosensitivity reported with ARBs were identified from VigiBase(®). All variables contained in the reports were analyzed. Information component (IC) and its lower limit of a 95% credibility interval (IC025) values were considered as measures of disproportionality for the assessment of photosensitivity cases reported with ARBs. VigiGrade completeness score (C) was used as a measure of quality of each report. Well-documented reports (C > 0.8) were fully described and analyzed., Results: Up to December 2014, a total of 203 reports on photosensitivity reported with ARBs and submitted by 25 different countries had been recorded in VigiBase(®). Among them, 25.1% involved losartan, 23.1% involved irbesartan, and 21.7% involved valsartan. In 126 cases, the ARB was the only suspected drug and in 10% of them the reaction was serious. IC and IC025 values indicated a possible positive correlation between photosensitivity and both irbersartan and losartan. A focus on well-documented reports, after excluding those with a co-prescription of other drugs known to cause photosensitivity, showed that out of 18 cases, six were related to losartan, four to olmesartan, three to irbesartan, two to valsartan and to candesartan, and one to telmisartan. Causality assessment was 'probable' in ten cases and 'possible' in eight cases. Moreover, positive dechallenge was reported in ten cases and positive rechallenge in one case., Conclusions: Photosensitivity reactions have been reported with almost all ARBs in VigiBase(®) with a positive disproportionality for irbesartan and losartan. Considering that ARBs share the same chemical structure, which may have the same response to sunlight, it is plausible to consider photosensitivity as a possible class effect. Physicians and patients should be aware of potentially serious photosensitivity reactions related to treatment with ARBs.

Apparent treatment-resistant hypertension (aTRH) is defined as blood pressure (BP) >140/90 mmHg despite three different antihypertensive drugs including a diuretic. aTRH is associated with an increased risk of cardiovascular events, including stroke, chronic renal failure, myocardial infarction, congestive heart failure, aortic aneurysm, atrial fibrillation, and sudden death. Preliminary studies of renal nerve ablation as a therapy to control aTRH were encouraging. However, these results were not confirmed by the Symplicity 3 trial. Therefore, attention has refocused on drug therapy. Secondary forms of hypertension and associated conditions such as obesity, sleep apnea, and primary aldosteronism are common in patients with aTRH. The pivotal role of aldosterone in the pathogenesis of aTRH in many cases is well recognized. For patients with aTRH, the Joint National Committee-8, the European Society of Hypertension, and a recent consensus conference recommend that a diuretic, ACE inhibitor, or angiotensin receptor blocker and calcium channel blocker combination be used to maximally tolerated doses before starting a 'fourth-line' drug such as a mineralocorticoid receptor (MR) antagonist. Although the best fourth-line drug for aTRH has not been extensively investigated, a number of studies summarized here show that an MR antagonist is effective in reducing BP when added to the standard multi-drug regimen.

All national guidelines for the management of hypertension recommend angiotensin receptor blockers (ARBs) as an initial or add-on antihypertensive therapy. The eight available ARBs have variable clinical efficacy when used for control of hypertension. Additive blood pressure-lowering effects have been demonstrated when ARBs are combined with thiazide diuretics or dihydropyridine calcium channel blockers, augmenting hypertension control. Furthermore, therapeutic use of ARBs goes beyond their antihypertensive effects, with evidence-based benefits in heart failure and diabetic renal disease particularly among angiotensin-converting enzyme inhibitor-intolerant patients. On the other hand, combining renin-angiotensin system blocking agents, a formerly common practice among medical subspecialists focusing on the management of hypertension, has ceased, as there is not only no evidence of cardiovascular benefit but also modest evidence of harm, particularly with regard to renal dysfunction. ARBs are very well tolerated as monotherapy, as well as in combination with other antihypertensive medications, which improve adherence to therapy and have become a mainstay in the treatment of stage 1 and stage 2 hypertension.

Background: Angiotensin II receptor blockers (ARBs) play a key role in hypertension therapy. Recently, fimasartan, the ninth ARB, was developed, but its safety and efficacy have not been well established., Objective: The objective of this study was to determine whether age, sex, concomitant disease, and current antihypertensive medications affect the safety and efficacy of fimasartan in patients with arterial hypertension., Methods: This was a large-scale, open-label observational study to determine the safety and efficacy of fimasartan in patients with hypertension. Patients who were treated for more than 2 months with fimasartan (60 or 120 mg, once daily) were recruited, and the data were systematically collected using electronic case report forms. Written informed consent forms were obtained from all patients., Results: A total of 14,151 patients (50.7 % males; mean age 59 ± 12 years) were evaluated, of whom 37.9 % were never treated with fimasartan, 53.5 % were switched to fimasartan, and 8.5 % had fimasartan added to their treatment. Overall, fimasartan reduced systolic blood pressure (SBP) from 145.4 ± 18.1 to 126.8 ± 12.6 mmHg and diastolic blood pressure (DBP) from 88.7 ± 11.8 to 79.0 ± 8.7 mmHg (all p < 0.001). The pulse rate decreased from 74.4 ± 10.3 to 71.9 ± 9.2 beats/min in comparison with before treatment (p < 0.001). The reductions were similar between sexes, age groups, and patients with and without co-morbidities, and were not dependent on prior or concomitant treatment with other antihypertensive drugs. Adverse events were reported in 3.31 % (treatment-emergent) and 2.35 % (drug-related) of patients; there were no dose differences for adverse events. The most frequent adverse events were dizziness (1.55 %) and headache (0.52 %); other adverse events were rare. The responder rate (DBP to <90 mmHg or a reduction of ≥10 mmHg) and the goal rate (combined SBP/DBP <140/90 mmHg) were 85.0 and 75.6 %, respectively. Global drug compliance was rated as excellent, very good, good, and poor in 68.1, 26.9, 3.4, and 1.7 % of patients, respectively., Conclusion: The safety, efficacy, and compliance of fimasartan were found to be excellent in a large patient population that included patients potentially at higher risk for adverse events.

Background: Between 5% and 20% of patients treated with angiotensin-converting enzyme inhibitors (ACE inhibitors) develop intolerance. Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) can be used as an alternative treatment., Objective: In this study we aimed to evaluate the tolerability of ARBs in patients with intolerance to ACE inhibitors., Data Sources: The electronic databases PubMed, MEDLINE/EMBASE via Dialog, CENTRAL, and ISI Web of Knowledge were searched., Study Selection: Randomized controlled trials (RCTs) evaluating ARBs in patients with intolerance to ACE inhibitors were selected., Data Synthesis: Risk ratio (RR) and 95% confidence intervals (CIs) were estimated assuming the random effects method. We found 11 RCTs comparing ARBs with ACE inhibitors, diuretics, or placebo, and one RCT comparing high-dose versus low-dose ARB., Results: ARBs had fewer cough events versus ACE inhibitors (RR 0.37; 95% CI 0.28, 0.48). ARBs had drug discontinuation (RR 0.99; 95% CI 0.84, 1.17) and cough risk (RR 1.01; 95% CI 0.74, 1.39) rates similar to placebo. Angioedema risk with ARBs was also similar to placebo (RR 1.62; 95% CI 0.17, 15.79). Compared with placebo, hypotension (RR 2.63; 95% CI 1.77, 3.92), renal dysfunction (RR 2.07; 95% CI 1.45, 2.95) and hyperkalemia (RR 3.37; 95% CI 1.60, 7.11) were more frequent with ARBs., Conclusions: ACE inhibitor rechallenge should be discouraged in patients with previous intolerance to ACE inhibitors due to a higher risk of cough. ARBs had cough and angioedema incidences similar to placebo. Despite a significantly higher incidence of hypotension, renal dysfunction and hyperkalemia, discontinuation of ARBs was similar to placebo.

Background and Aim: Clinical use of angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) is associated with hyperkalemia as an adverse drug reaction. Although it has significant clinical implications, the incidence and relative risks of hyperkalemia with various ARBs have not yet been fully evaluated. The purpose of this study was to determine the risk of hyperkalemic events in hospitalized patients treated with different ARBs and to compare the risk among them., Methods: We constructed a retrospective cohort composed of hospitalized adult patients who took ARBs in a single tertiary teaching hospital between April 2004 and March 2010. We estimated the incidence of hyperkalemia (serum potassium level >5.5 mEq/L) with various ARBs, and then compared the risk between them using a multivariate Cox proportional hazard model based on age, sex, Charlson co-morbidity score, baseline serum potassium, underlying diseases, and concomitant drugs., Results: We identified 6992 evaluable intervals from 5449 patients treated with one of the seven ARBs during hospitalization over the 71-month study period with 2521.6 patient-months. We found 381 hyperkalemic events (5.4%) during the study period and an overall event rate of 15.1/100 patient-months. Moderate to fatal hyperkalemia was relatively rare (>6.0 mEq/L, 2.1% [moderate]; >6.5 mEq/L, 0.9% [severe]; >7.0 mEq/L, 0.3% [fatal]). After adjustment for covariates, telmisartan showed a lower risk of hyperkalemia (hazard ratio 0.67; 95% confidence interval 0.51, 0.89) compared with all other ARBs., Conclusion: The risk of hyperkalemic events in hospitalized patients treated with different ARBs was defined. Telmisartan showed a relatively lower hyperkalemic risk profile in hospitalized patients compared with other ARBs.

Background: Renin angiotensin system inhibitors (RASIs) are frequently involved in serious adverse events. These events principally occur in high-risk patients and often arise within the first days after treatment initiation; therefore, guidelines recommend biochemical monitoring within 3 weeks after the start of therapy with RASIs., Objective: The purpose of this study was to examine the level of biochemical monitoring directly after treatment initiation with RASIs in patients with different risk profiles and to study the attitudes of the physicians involved towards biochemical monitoring., Methods: We carried out a retrospective analysis of 202 patients who started RASI therapy in 2006 in Groesbeek, the Netherlands. We determined the rate of serum creatinine and potassium monitoring within 3 weeks after the start of therapy. In addition, we studied the intentions and attitudes towards biochemical monitoring during RASI therapy among 68 general practitioners and medical specialists by way of a brief questionnaire., Results: Serum creatinine and potassium monitoring after treatment initiation was performed in 34% and 28% of patients, respectively. Of all the patients, 29% had two or more additional risk factors for renal function deterioration. In these high-risk patients, creatinine was significantly less often monitored compared with low-risk patients (22% vs 39%). In contrast to these findings, the prescribing physicians claimed to check serum creatinine within 2 weeks after treatment initiation in 85% of their patients. Most of the prescribing physicians (88%) rated this monitoring as (very) important., Conclusions: We demonstrated that, despite positive intentions of physicians, the biochemical monitoring recommendation in patients treated with RASIs is poorly met. In addition, serum creatinine monitoring was significantly less often performed in high-risk patients compared with low-risk patients.

Antihypertensive therapy has been demonstrated to significantly reduce cardiovascular and non-cardiovascular mortality in randomized controlled clinical trials. In the past, however, doubts have been raised on the safety of one class of blood pressure lowering drugs, namely the angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), in terms of increased risk of myocardial infarction. Several comprehensive meta-analyses have definitely demonstrated no significant increased risk of myocardial infarction in patients treated with ARBs compared with placebo or any other active treatments. More recently, a partial meta-analysis has suggested a potential link between the use of this drug class and an increased risk of cancer. Although a further comprehensive network meta-analysis demonstrated the lack of any increased risk of cancer development or cancer mortality in patients treated with different antihypertensive drug classes, including ARBs, compared with placebo, this report has generated claims and uncertainties in the medical community and produced a vast echo in the lay press. The biological plausibility, the potential pathophysiological mechanisms, and the clinical evidence that rule out such hypotheses are discussed here. The present article, which represents a position paper of the Italian Society of Hypertension (SIIA), states that the benefits derived from the use of ARBs outweigh the potential risks, and that the use of these drugs should be maintained according to present indications.