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Concept: ACE inhibitor


 To investigate the cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs) and estimate the risk of hospital admission for heart failure with use of individual NSAIDs.

Concepts: Hypertension, Glucocorticoid, Non-steroidal anti-inflammatory drug, Anti-inflammatory, Paracetamol, ACE inhibitor


Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.

Concepts: Chronic kidney disease, Myocardial infarction, Hypertension, Stroke, Blood pressure, Renin-angiotensin system, Angiotensin II receptor antagonist, ACE inhibitor


Angioedema is the end result of deep dermal, subcutaneous and/or mucosal swelling, and is potentially a life-threatening condition in cases where the pharynx or larynx is involved. Drug-induced angioedema has been reported to occur in response to a wide range of drugs and vaccines. Drug-induced angioedema, like other cutaneous drug reactions, has been reported to be most frequently elicited by beta-lactam antibiotics and non-steroidal anti-inflammatory drugs, although reliable data from epidemiologic studies are scarce. Recent reports suggested an increasing role of angiotensin-converting enzyme inhibitors (ACEIs) in the causation of life-threatening angioedema. ACEI-related angioedema is never accompanied by urticaria and occurs via a kinin-dependent mechanism. ACEI-related angioedema not only can start years after beginning the treatment, but it can then recur irregularly while under that treatment. Furthermore, allergy tests are unreliable for the diagnosis of ACEI-related angioedema, and so the relationship between angioedema and ACEIs is often missed and consequently quite underestimated. Accordingly, better understanding of the kinin-dependent mechanism, which is particular to angioedema, is necessary for the appropriate management of drug-induced angioedema.

Concepts: Pharmacology, Drug, Non-steroidal anti-inflammatory drug, Anti-inflammatory, Drug addiction, Penicillin, Angioedema, ACE inhibitor


Background We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. Methods In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. Results The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. Conclusions LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF number, NCT01035255 .).

Concepts: Blood, Myocardial infarction, Hypertension, Cardiology, Heart failure, Ejection fraction, Risk, ACE inhibitor


Objective To examine long term cardiorenal outcomes associated with increased concentrations of creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment.Design Population based cohort study using electronic health records from the Clinical Practice Research Datalink and Hospital Episode Statistics.Setting UK primary care, 1997-2014.Participants Patients starting treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers (n=122 363).Main outcome measures Poisson regression was used to compare rates of end stage renal disease, myocardial infarction, heart failure, and death among patients with creatinine increases of 30% or more after starting treatment against those without such increases, and for each 10% increase in creatinine. Analyses were adjusted for age, sex, calendar period, socioeconomic status, lifestyle factors, chronic kidney disease, diabetes, cardiovascular comorbidities, and use of other antihypertensive drugs and non-steroidal anti-inflammatory drugs.Results Among the 2078 (1.7%) patients with creatinine increases of 30% or more, a higher proportion were female, were elderly, had cardiorenal comorbidity, and used non-steroidal anti-inflammatory drugs, loop diuretics, or potassium sparing diuretics. Creatinine increases of 30% or more were associated with an increased adjusted incidence rate ratio for all outcomes, compared with increases of less than 30%: 3.43 (95% confidence interval 2.40 to 4.91) for end stage renal disease, 1.46 (1.16 to 1.84) for myocardial infarction, 1.37 (1.14 to 1.65) for heart failure, and 1.84 (1.65 to 2.05) for death. The detailed categorisation of increases in creatinine concentrations (<10%, 10-19%, 20-29%, 30-39%, and ≥40%) showed a graduated relation for all outcomes (all P values for trends <0.001). Notably, creatinine increases of less than 30% were also associated with increased incidence rate ratios for all outcomes, including death (1.15 (1.09 to 1.22) for increases of 10-19% and 1.35 (1.23 to 1.49) for increases of 20-29%, using <10% as reference). Results were consistent across calendar periods, across subgroups of patients, and among continuing users.Conclusions Increases in creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment were associated with adverse cardiorenal outcomes in a graduated relation, even below the guideline recommended threshold of a 30% increase for stopping treatment.

Concepts: Kidney, Myocardial infarction, Hypertension, Blood pressure, Angiotensin, Renin-angiotensin system, Angiotensin II receptor antagonist, ACE inhibitor


ACE Inhibitors (ACE-I) and Angiotensin-Receptor Antagonists (ARAs) are commonly prescribed but can cause acute kidney injury (AKI) during intercurrent illness. Rates of hospitalization with AKI are increasing. We aimed to determine whether hospital AKI admission rates are associated with increased ACE-I/ARA prescribing.

Concepts: Surgery, Diabetic nephropathy, Angiotensin-converting enzyme, Angiotensin II receptor antagonist, ACE inhibitor, Bradykinin, Hyperkalemia, Captopril


We aimed to characterize different cellular effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin 1 (AT1) receptor blockers (ARBs) as mono- or combination therapy in cardiac pressure overload. Methods and

Concepts: Hypertension, Enzyme inhibitor, Angiotensin-converting enzyme, Angiotensin II receptor antagonist, ACE inhibitor, Differential, Ramipril


QUESTION In patients with left ventricular (LV) dysfunction, what is the relative efficacy of eplerenone and other aldosterone antagonists (AAs)? REVIEW SCOPE Included studies compared eplerenone or other AAs with control (placebo, angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, or β-blocker) in patients > 18 years of age with symptomatic or asymptomatic LV dysfunction, had ≥ 8 weeks of follow-up, and reported ≥ 1 outcome of interest. Studies comparing AAs with each other were excluded. Outcomes were all-cause mortality, cardiovascular (CV) mortality, gynecomastia {per trial definition in individual studies}*, and hyperkalemia {serum potassium > 5.5 mEq/L}*. REVIEW METHODS MEDLINE, EMBASE/Excerpta Medica, CINAHL, and Cochrane Central Register of Controlled Trials (all to Jul 2011); reference lists; and reviews were searched for randomized controlled trials (RCTs). 16 RCTs (n = 12 505, mean age 55 to 69 y, 54% to 87% men) met selection criteria. 4 RCTs included patients after acute myocardial infarction LV dysfunction, and 12 included patients with heart failure. Study drugs were spironolactone (10 RCTs), canrenone (3 RCTs), and eplerenone (3 RCTs). Risk for bias (Cochrane criteria) was low for 8 RCTs, intermediate for 7, and high for 1. MAIN RESULTS Eplerenone and other AAs reduced all-cause mortality and CV mortality compared with no AA (Table). Eplerenone increased risk for hyperkalemia, and other AAs increased risk for gynecomastia, compared with no AA (Table). Based on an indirect comparison, other AAs reduced mortality more than eplerenone (P = 0.009). CONCLUSION Based on an indirect comparison, eplerenone is not more effective at reducing mortality for adults with left ventricular dysfunction than other aldosterone antagonists.Eplerenone or other AAs vs control in patients with left ventricular dysfunction†OutcomesNumber of trials (n)Weighted event ratesAt 2 to 24 moEplerenoneControl‡RRR (95% CI)NNT (CI)All-cause mortality2 (9369)14%16%15% (7 to 23)41 (27 to 88)CV mortality2 (9369)12%14%17% (8 to 25)42 (29 to 88)Gynecomastia2 (9361)0.49%0.66%26% (-27 to 57)NSRRI (CI)NNH (CI)Hyperkalemia3 (9489)6.1%3.8%72% (19 to 147)37 (19 to 140)Other AA§Control‡RRR (95% CI)NNT (CI)All-cause mortality12 (3569)19%25%26% (17 to 34)16 (12 to 24)CV mortality4 (2553)26%34%25% (16 to 33)12 (9 to 19)RRI (CI)NNH (CI)Gynecomastia6 (2279)5.4%0.86%526% (238 to 1057)23 (11 to 49)Hyperkalemia10 (3342)8.1%4.5%80% (-17 to 291)NS†AA = aldosterone antagonist; CV = cardiovascular; NS = not significant; other abbreviations defined in Glossary. Weighted event rates, RRR, RRI, NNT, NNH, and CI calculated from control event rates and risk ratios in article using a random-effects model.‡Placebo, angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, or β-blocker.§Other AAs were spironolactone or canrenone.

Concepts: Myocardial infarction, Hypertension, Heart failure, Spironolactone, Aldosterone antagonist, Eplerenone, ACE inhibitor, Hyperkalemia


Introduction: There are few clinical trials that provide evidence to support the hypothesis that combined therapies offer a favorable risk-benefit ratio in the reduction of cardiovascular mortality and morbidity. Combined therapies containing an angiotensin-converting enzyme inhibitor (ACEI) with a calcium channel blocker (CCB) is one of the recommended combinations in the reappraisal of the European Society of Hypertension. Areas covered: The authors have performed a systematic review of the available clinical evidence on the use of combined therapies containing an ACEI with a CCB versus other combinations in the management of arterial hypertension (HT) and in the reduction of cardiovascular morbidity/mortality, according to recommendations of The Cochrane Handbook for Systematic Reviews of Interventions. They identified 122 potentially relevant studies. Of these, 38 included combined therapies in one or both treatment arms. Overall, a total of 12 publications were retrieved from the search and provided data on the effects of the combined therapy with an ACEI and a CCB on cardiovascular mortality/morbidity in patients with HT. Clinical evidence corresponds to three double-blind clinical trials: ASCOT-BPLA, ACCOMPLISH and Syst-EUR. Expert opinion: The analysis demonstrates the superiority of the combined therapy with ACEI/CCB not only in the overall population included in the studies but also in subsets of patients with a high cardiovascular risk such as diabetes and chronic kidney disease.

Concepts: Chronic kidney disease, Medicine, Myocardial infarction, Hypertension, The Canon of Medicine, Evidence-based medicine, Calcium channel blocker, ACE inhibitor


Introduction: Bradykinin-mediated angioedema is characterized by subcutaneous and/or submucosal edema formation without wheals and pruritus. It is linked to bradykinin-enhanced vascular permeability and, therefore, it does not respond to conventional measures, but requires specific therapy. Areas covered: This summary briefly reviews the different types of bradykinin-mediated angioedema and its remedies. Therapy focuses on relieving edema, as well as on decreasing its incidence and severity. The modes of the actions of attenuated androgens and antifibrinolytics are not precisely known - these agents have been introduced on an empirical basis. Contemporary treatments, by contrast, have been purposely developed to inhibit bradykinin. Most experience pertains to angioedema resulting from C1-inhibitor deficiency, and the controlled studies have focused on the hereditary form of this disease type (HAE). The pathomechanisms of HAE with normal C1-inhibitor activity, as well as of angiotensin-converting enzyme inhibitor-releated, and of non-histaminergic idiopathic sporadic angioedemas are largely unknown. Appropriate laboratory methods for the diagnosis, or specific interventions for the therapy of these conditions are not available or only available off-label. Expert opinion: In this case, diagnosis and management are challenging. The range of targeted therapeutic options has increased in recent years and includes measures to handle emergencies, prevent edematous episodes and manage additional types of bradykinin-mediated angioedema.

Concepts: Allergy, Therapy, Pharmacotherapy, Classification of Pharmaco-Therapeutic Referrals, Angioedema, ACE inhibitor, Edema, Bradykinin