Angioedema Triggered by Medication Blocking the Renin/Angiotensin System: Retrospective Study Using the French National Pharmacovigilance Database.

INTRODUCTION: Bradykinin-mediated angioedema (AE) is a rare side effect of some medications, including angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). In France, side-effects to treatments are reported to the national pharmacovigilance database. METHODS: The national MedDRA database was searched using the term "angioedema". Patients were included if they met the clinical criteria corresponding to bradykinin-mediated AE, if their C1-inhibitor levels were normal, and if they were treated with an ACEi or an ARB. RESULTS: 7998 cases of AE were reported between 1994 and 2013. Among these, 112 met the criteria for bradykinin-mediated AE with normal C1-inhibitor levels. On the 112 drug-AE, patients were treated with an ARB in 21% of cases (24 patients), or an ACEi in 77% of cases (88 patients), in combination with another treatment in 17 cases (mTORi for 3 patients, iDPP-4 for 1 patient, hormonal treatment for 7 patients). ENT involvement was reported in 90% of cases (tongue: 48.2%, larynx: 23.2%). The median duration of treatment before the first attack was 720 days, and the mean duration of attacks was 36.6 h. Forty-one percent (19/46) of patients relapsed after discontinuing treatment. CONCLUSION: Angioedema triggered by medication blocking the renin/angiotensin system is rare but potentially severe, with a high risk of recurrence despite cessation of the causative drug.

Urine Albumin-Creatinine Ratio Versus Albumin Excretion for Albuminuria Staging: A Prospective Longitudinal Cohort Study.

BACKGROUND: New guidelines advocate the use of albumin-creatinine ratio (ACR) in a urine sample instead of 24-hour urinary albumin excretion (UAE) for staging albuminuria. Concern has been expressed that this may result in misclassification for reasons including interindividual differences in urinary creatinine excretion. STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: We examined 7,623 participants of the PREVEND and RENAAL studies for reclassified when using ACR instead of 24-hour UAE, the characteristics of reclassified participants, and their outcomes. Albuminuria was categorized into 3 ACR and UAE categories: <30, 30 to 300, and >300mg/g or mg/24 h, respectively. PREDICTORS: Baseline ACR and 24-hour UAE. OUTCOMES: Cardiovascular (CV) morbidity and mortality and all-cause mortality. RESULTS: When using ACR in the early morning void instead of 24-hour UAE, 88% of participants were classified in corresponding albuminuria categories. 307 (4.0%) participants were reclassified to a higher, and 603 (7.9%), to a lower category. Participants who were reclassified to a higher ACR category in general had a worse CV risk profile compared with nonreclassified participants, whereas the reverse was true for participants reclassified to a lower ACR category. Similarly, Cox proportional hazards regression analyses showed that reclassification to a higher ACR category was associated with a tendency for increased risk for CV morbidity and mortality and all-cause mortality, whereas reclassification to a lower ACR category was associated with a tendency for lower risk. Net reclassification improvement, adjusted for age, sex, and duration of follow-up, was 0.107 (P=0.002) for CV events and 0.089 (P<0.001) for all-cause mortality. LIMITATIONS: Early morning void urine collection instead of spot urine collection. CONCLUSIONS: Our results indicate that there is high agreement between early morning void ACR and 24-hour UAE categories. Reclassification is therefore limited, but when present, is generally indicative of the presence of CV risk factors and prognosis.

Effect of formulation variables on design, in vitro evaluation of valsartan SNEDDS and estimation of its antioxidant effect in adrenaline-induced acute myocardial infarction in rats.

Valsartan is a specific angiotensin II antagonist used for the treatment of hypertension. It suffers from low aqueous solubility and high variability in its absorption after oral administration. The aim of this study was to improve the dissolution and thereby the bioavailability of Valsartan through the development of self nano-emulsifying drug delivery systems. Four ternary phase diagrams were constructed to identify the self-emulsification region of Capmul® MCM, Labrafil® M1944, Capryol™ 90 and Labrafac® PG together with Cremophore® RH 40 and Transcutol™ HP as oil, surfactant and co-surfactant, respectively. The effect of oil type, oil and surfactant concentration on droplet size and in vitro Valsartan dissolution were studied. The protective effect of the optimum formula F5 in adrenaline-induced oxidative stress in rats during myocardial infarction was determined. Formula F5 exhibited globule size of (13.95 nm) with 76.07% ± 1.10 of Valsartan dissolved after five minutes compared to Disartan 80 mg capsules (13.43%). Results revealed a significant reduction (p < 0.05) in serum aspartate transaminase, creatine kinase myocardial band and malondialdehyde levels, while a significant increase (p < 0.05) in serum glutathione in F5. Therefore, self nano-emulsifying drug delivery systems could be considered as a promising approach to improve the dissolution and thereby the bioavailability of Valsartan.

Visit-to-visit variability in blood pressure and kidney and cardiovascular outcomes in patients with type 2 diabetes and nephropathy: a post hoc analysis from the RENAAL study and the Irbesartan Diabetic Nephropathy Trial.

BACKGROUND: Increased systolic blood pressure variability between outpatient visits is associated with increased incidence of cardiovascular end points. However, few studies have examined the association of visit-to-visit variability in systolic blood pressure with clinically relevant kidney disease outcomes. We analyzed the association of systolic blood pressure visit-to-visit variability with renal and cardiovascular morbidity and mortality among individuals with diabetes and nephropathy. STUDY DESIGN: Observational analysis of IDNT (Irbesartan Diabetic Nephropathy Trial) and the RENAAL (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan) Study. SETTING & PARTICIPANTS: 2,739 participants with type 2 diabetes and nephropathy with at least 1 year of blood pressure measurements available. PREDICTORS: Systolic blood pressure visit-to-visit variability was calculated from the SD of the systolic blood pressure from 4 visits occurring 3-12 months postrandomization. OUTCOMES: The kidney disease outcome was defined as time to confirmed doubling of serum creatinine level, end-stage renal disease, or death; the cardiovascular outcome was defined as time to cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, or revascularization. RESULTS: Mean visit-to-visit variability in systolic blood pressure from 3 to 12 months postrandomization was 12.0±6.8(SD)mmHg. Following this ascertainment period, there were 954 kidney disease and 542 cardiovascular events. Greater systolic blood pressure visit-to-visit variability was associated independently with increased risk of the composite kidney disease end point (HR per 1-SD increment, 1.08 [95%CI, 1.01-1.16]; P=0.02) and end-stage renal disease, but not with the cardiovascular outcome. LIMITATIONS: Observational study with the potential for confounding. CONCLUSIONS: In diabetic individuals with nephropathy, systolic blood pressure visit-to-visit variability is associated independently with hard kidney disease outcomes.

Modulation of Angiotensin-II and Angiotensin 1-7 Levels Influences Cardiac Function in Myocardial Ischemia-reperfusion Injury.

The angiotensin-converting enzyme-2 (ACE-2) alters the pathophysiology of various fatal cardiovascular diseases, including ischemic heart disease, whereas angiotensin 1-7 (Ang 1-7) exerts a wide range of actions. The effects of ischemia-reperfusion (IR) injury include damage to myocardial tissue that initiates protease action, causing cardiac cell death. Angiotensin- II (Ang-II) contributes through the renin-angiotensin system (RAS) to the IR injury, whereas Ang 1-7 paradoxically exerts a protective effect through the same. Thus, the myocardial ischemic reperfusion injury (MIRI) may be altered by the RAS of the heart. This review paper focuses on ACE-2, angiotensin-converting enzyme (ACE), and Ang 1-7 regulation in the RAS of the heart in the pathophysiology of MIRI. The treatment in such conditions using ACE-2 activator, ACE inhibitor, and Ang-II antagonists may promote vascular functions as well as cardio- protection.

Effects of angiotensin II type 1 receptor antagonist and temperature on prolonged cardioplegic arrest in neonatal rat myocytes.

Cardioplegic arrest is a model of ischemia/reperfusion injury and results in the death of irreplaceable cardiac myocytes by a programmed cell death or apoptosis. Signal transducers and activators of transcription (STAT) signaling pathways play an important role in the modulation of apoptosis after ischemia and reperfusion. Angiotensin II type 1 (AT1) receptor antagonist added to cardioplegia could represent an additional modality for enhancing myocardial protection during cardioplegic arrest. To test that hypothesis, we studied the effect of AT1 receptor antagonism and cardioplegia temperature perfusion on STATs modulation during cardioplegic arrest in neonatal rat hearts. Isolated, nonworking hearts (n = 4 per group) from neonatal rats were perfused aerobically in the Langendorff mode according to the following scheme: Dulbecco's Modified Eagle's Medium solution (Group 1); cold (4°C) modified St. Thomas' Hospital no. 2 (MSTH2) cardioplegic solution (Group 2); cold (4°C) MSTH2 cardioplegic solution plus AT1 antagonist (Valsartan) (Group 3); and warm (34°C) MSTH2 cardioplegic solution (Group 4). Thus, myocytes were isolated by enzymatic digestion, and STAT1, STAT2, STAT3, and STAT5 were investigated in Western blot studies. Times to arrest after cardioplegia were 6-10 s for all groups with the exception of Group 1 (spontaneous arrest after 12-16 s). Total cardioplegia delivery volume was about 300 mL in 15 min. Perfusion with cold MSTH2 supplemented with AT1 receptor antagonist (Group 3) induced a significant reduction in STAT1, STAT2, and STAT5 tyrosine phosphorylation versus other groups (P < 0.05). The decreased activation of STAT1, STAT2, and STAT5 observed in Group 3 was accompanied by reduction of interleukin-1ß (P < 0.05). On the other hand, STAT3 activation was significantly reduced in Groups 1 and 4 (P < 0.05). Only perfusion with AT1 receptor antagonist supplemented with cold MSTH2 significantly decreases the inflammatory response of the neonatal rat cardiomyocytes without affecting antiapoptotic influence provided by activation of STAT3. Therefore, AT1 receptor antagonist could play a pivotal role in cytoprotective effect and cardiac recovery in neonates and infants.

Mineralcorticoid Receptor Antagonist Withdrawal for Hyperkalemia and Mortality in Patients with Heart Failure.

BACKGROUND: Hyperkalemia is one of the most frequent side effects related to renin-angiotensin-aldosterone system (RAAS) inhibition, and can influence optimization of heart failure (HF) therapy. AIM: To evaluate the occurrence of hyperkalemia in a series of outpatients with chronic HF and its relationship with RAAS inhibitor therapy. METHOD: We evaluated consecutive outpatients with HF and a reduced left ventricular ejection fraction. The incidence of hyperkalemia and consequent changes in RAAS inhibitor therapy were evaluated for each patient. RESULTS: A history of hyperkalemia or at least 1 episode of hyperkalemia during follow-up was observed in 104 of 351 patients. Hyperkalemia mainly influenced mineralocorticoid receptor antagonist (MRA) therapy and, among patients with hyperkalemia, not taking MRA was associated with a greater risk of death on univariate analysis (HR = 6.39; 95% CI 2.76-14.79, p < 0.001) and multivariate analysis (HR = 5.24; 95% CI 1.87-14.72, p = 0.002) after correction for age, ischemic cardiomyopathy, diabetes, systolic arterial pressure, New York Heart Association class 3, left ventricular ejection fraction, presence of hyponatremia, glomerular filtration rate calculated by the EPI formula, and presence of N-terminal pro-B-type natriuretic peptide >1,000 pg/mL. CONCLUSION: The occurrence of hyperkalemia is common among outpatients with HF and it is the main cause of MRA withdrawal, which is associated with a worse prognosis. In this setting, the possibility of managing hyperkalemia using new classes of drugs could allow continuation of MRA therapy.

Role of cardiac renin angiotensin system in ischemia reperfusion injury and preconditioning of heart.

Cardio-vascular diseases are the leading cause of morbidity and mortality. Ischemia is a state of oxygen deprivation in tissues, whereas reperfusion is restoration of blood flow in ischemic tissues. Myocardial damage of tissue during reperfusion after ischemic insult is known as myocardial ischemia-reperfusion (I/R) injury. It induces damage to cardiac muscle via increasing expression of oxygen, sodium and calcium ions which are responsible in the activation of proteases and cell death. Heart renin angiotensin system (RAS) plays an important role in the myocardial ischemia and reperfusion injury. Angiotensin (1-7) is responsible for vasodilation and angiotensin II for vasoconstriction. Here-in we reviewed how myocardial I/R injury sets in by up-regulation of angiotensin II that leads to increased infarct size, which can be reduced by the use of ACE inhibitors, ACE2 activators and angiotensin II antagonist.

Blood pressure control and weight loss in overweight or obese patients with previously treated or untreated mild to moderate hypertension given valsartan: An open-label study comparing pretreatment and posttreatment values.

BACKGROUND: Hypertension is associated with obesity. Recent studies have indicated that therapy with an angiotensin II antagonist, in addition to having an antihypertensive effect, may cause a reduction in body weight. OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of valsartan in the treatment of overweight or obese patients with mild to moderate essential hypertension. METHODS: Overweight or obese outpatients aged 18 to <70 years with previously treated or untreated mild to moderate essential hypertension were eligible for this open-label study conducted at the Department of Internal Medicine and Aging, Clinica Medica II, Policlinico S. Orsola-Malpighi (Bologna, Italy). After a 1-week pharmacologic washout period, patients were treated with valsartan capsules at a fixed dosage of 80 mg once daily for 8 weeks. The dosage was increased to 160 mg once daily if, at 8 weeks, diastolic blood pressure (DBP) was not normalized; otherwise, the 80-mg/d dosage was maintained. Treatment was continued for an additional 16 weeks. Patients' heart rate, systolic blood pressure (SBP) and DBP, body mass index (BMI), and waist-hip ratio (WHR) were measured/calculated at baseline (week 0) and 8, 16, and 24 weeks. Patients were asked to maintain a 1600-kcal/d diet throughout the study. RESULTS: Forty-eight patients (28 men, 20 women; mean [SD] age, 57 [9] years) were included in the study. In the 45 patients (93.8%) who completed the study, mean SBP, DBP, and BMI were significantly decreased compared with baseline (all P < 0.001), but WHR was significantly increased (P < 0.05). After 24 weeks of treatment, 71.1 % of patients had SBP/DBP ≤ 140/≤90 mm Hg. Three patients (6.3%) withdrew from the study due to treatment-related adverse events. CONCLUSION: In this population of overweight or obese patients with mild to moderate hypertension, valsartan was well tolerated, and could be effective in controlling blood pressure and achieving weight loss in such patients.

Peripheral artery disease and outcomes after myocardial infarction: an individual-patient meta-analysis of 28,771 patients in CAPRICORN, EPEHESUS, OPTIMAAL and VALIANT.

OBJECTIVES: To examine the prevalence of peripheral artery disease (PAD) and the relationship between PAD and cardiovascular (CV) outcomes in subjects with left ventricular systolic dysfunction, heart failure or both after acute myocardial infarction (MI). BACKGROUND: PAD is associated with poorer prognosis in patients with stable and unstable coronary heart disease but whether PAD is associated with worse outcomes following substantial acute MI is unknown. METHODS: Univariate and multivariate Cox proportional hazards modelling was used to compare clinical outcomes in an individual-patient meta-analysis of 4 trials (CAPRICORN, EPHESUS, OPTIMAAL and VALIANT). RESULTS: Of the 28,771 patients randomized, 2357 (8.2%) had PAD. These patients were older and had more co-morbidity and were less likely to be prescribed aspirin or a beta-blocker compared to patients without PAD. Over a mean follow-up of 2.7 years, 5121 (17.8%) patients died and 15,055 (52.3%) experienced CV death or hospitalization. PAD was an independent predictor of all individual and composite CV outcomes examined (including heart failure), with the exception of stroke. In patients with PAD (compared to those without PAD), the adjusted hazard ratio (HR) for all-cause mortality was 1.25 (95% CI 1.15-1.37; p<0.001) and the HR for CV death, non-fatal MI, non-fatal stroke or heart failure hospitalization was 1.24 (1.16-1.33; p<0.001). CONCLUSIONS: PAD is common and is an independent predictor of worse outcomes in patients already at high risk after MI because of left ventricular systolic dysfunction, heart failure or both. These patients represent an important group for intensive application of secondary preventive therapies.