Overcoming Cough and Angioedema: Advocating for the Use of ARBs Over ACE Inhibitors.

Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors have comparable efficacy, but ARBs have a preferential safety profile with particular regard to cough and angioedema. Although guidelines have historically advocated for ACE inhibitor use before ARBs simply because of earlier market entry, data accumulation, and generic availability, updated verbiage advises an "ACE inhibitor or ARB" recommendation, as opposed to the classic "ACE inhibitor then ARB" approach. Despite these updates, clinical inertia in favor of ACE inhibitor use before ARBs overwhelmingly remains. Prescribers and educators should consider an "ARBs only" mentality, especially in high angioedema-risk groups such as black patients.

Angiotensin-converting enzyme inhibitor-induced angioedema: epidemiology, pathogenesis and management.

Angiotensin-converting enzyme-induced angioedema occurs in 0.1-0.7 % of recipients. Swelling often affects head and neck and makes it an extremely dangerous adverse effect. Bradykinin is considered to be the main mediator of edema in these cases. There is currently no specific treatment for angioedema of this etiology. Drugs used for treatment of attacks in hereditary angioedema with C1 inhibitor deficiency are tried also in this indication, but there are currently no clinical studies available supporting their effectiveness. Patients using angiotensin-converting enzyme inhibitors with angioedemas of unknown etiology must discontinue using this drug. Swelling episodes may appear even after this arrangement. Key words: angioedema - angiotensin-converting enzyme inhibitors - bradykinin.

Early health technology assessments in pharmacogenomics: a case example in cardiovascular drugs.

AIM: To assess the required characteristics (cost, sensitivity and specificity) of a pharmacogenomic test for being a cost-effective prevention of angiotensin-converting enzyme inhibitors induced angioedema. Furthermore, we assessed the influence of only testing high-risk populations. MATERIALS & METHODS: A decision tree was used. RESULTS: With a willingness-to-pay threshold of €20,000 and €80,000 per quality adjusted life year, a 100% sensitive and specific test may have a maximum cost of €1.30 and €1.95, respectively. When only genotyping high-risk populations, the maximum test price would be €5.03 and €7.55, respectively. CONCLUSION: This theoretical pharmacogenomic test is only cost-effective at high specificity, high sensitivity and a low price. Only testing high-risk populations yields more realistic maximum test prices for cost-effectiveness of the intervention.

Neprilysin Inhibitors: Emerging Therapy for Heart Failure.

Biologically active natriuretic peptides (NPs) are an integral part of cardiac homeostasis as they help to maintain sodium and fluid balance. When homeostasis is perturbed by neurohormonal activation in heart failure, levels of NPs rise in response. Neprilysin (NEP) is a naturally occuring enzyme that breaks down NPs. Scientists have recently discovered a novel pharmacologic agent that combines a NEP inhibitor and an angiotensin receptor blocker. In a large clinical trial, this new drug was found to reduce hospitalization and mortality in systolic heart failure. The challenges of implementing this therapy include patient selection, cost, and risk of side effects including angioedema and Alzheimer's disease.

Cost-Effectiveness of Sacubitril-Valsartan in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Sacubitril-valsartan therapy reduces cardiovascular mortality compared with enalapril therapy in patients with heart failure with reduced ejection fraction. OBJECTIVE: To evaluate the cost-effectiveness of sacubitril-valsartan versus angiotensin-converting enzyme inhibitor therapy in patients with chronic heart failure. DESIGN: Markov decision model. DATA SOURCES: Clinical trials, observational analyses, reimbursement data from the Centers for Medicare & Medicaid Services, drug pricing databases, and Centers for Disease Control and Prevention life tables. TARGET POPULATION: Patients at an average age of 64 years, New York Heart Association (NYHA) class II to IV heart failure, and left ventricular ejection fraction of 0.40 or less. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Treatment with sacubitril-valsartan or lisinopril. OUTCOME MEASURES: Life-years, quality-adjusted life-years (QALYs), costs, heart failure hospitalizations, and incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: The sacubitril-valsartan group experienced 0.08 fewer heart failure hospitalization, 0.69 additional life-year, 0.62 additional QALY, and $29 203 in incremental costs, equating to a cost per QALY gained of $47 053. The cost per QALY gained was $44 531 in patients with NYHA class II heart failure and $58 194 in those with class III or IV heart failure. RESULTS OF SENSITIVITY ANALYSIS: Sacubitril-valsartan treatment was most sensitive to the duration of improved outcomes, with a cost per QALY gained of $120 623 if the duration was limited to the length of the trial (median, 27 months). No variations in other parameters caused the cost to exceed $100 000 per QALY gained. LIMITATION: The benefit of sacubitril-valsartan is based on a single clinical trial. CONCLUSION: Treatment with sacubitril-valsartan provides reasonable value in reducing cardiovascular mortality and morbidity in patients with NYHA class II to IV heart failure. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs and Institute for Clinical and Economic Review.

Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.

Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.

[Assessment of the utilization of angiotensin receptor blockers in hypertension]. / Evaluación de la utilización de los antagonistas de los receptores de la angiotensina II en hipertensión arterial.

OBJECTIVE: To assess the degree in which the utilization of angiotensin receptor blockers (ARBs) in our Healthcare Area fits the criteria proposed by the Autonomous Community of Madrid (CAM) before setting «Plan de Actuación de ARA-II¼ («Action Plan ARA-II¼). To study the indications for which are prescribed and to identify those factors that can show influence in prescription. METHODS: Drug utilization study of the type indication-prescription, descriptive and transversal, for which ARBs-treated and hypertensive patients admitted to a University General Hospital for a study period of 3 months were selected. Based on the clinical situations summarized in the CAM Document «Criterios para establecer el lugar en la terapéutica de los antagonistas de los receptores de la angiotensina II¼ («Criteria for the place of angiotensin receptor blockers in the therapeutic¼), a percentage of patients with «appropriate prescription¼ and «inadequate prescription« of ARBs was calculated and analyzed in order to determine if the age and the sex were related to the type of prescription or the main indications for which they had been prescribed. RESULTS: Out of the 153 patients included in the study, 67.3% had a «inadequate prescription«, 47.6% of them due to an ARBs prescription as the first drug inhibitor of the reninangiotensin- aldosterone system and 34.0% owing to a poor control of blood pressure with angiotensin-converting enzyme inhibitors (ACEi). There were no statistically significant differences found either by age or sex in the type of prescription or in the main indications for which they were prescribed. CONCLUSIONS: The adequacy of the criteria for the utilisation of ARBs Document occurred in 32.7% of cases. In addition, factors such as age and sex did not seem to affect the type of prescription. Misconceptions of superiority of ARBs versus ACEi were evidenced as well.

Objetivo: Evaluar en nuestra área de Salud el grado en que la utilización de antagonistas de los receptores de la angiotensina II (ARA-II) se ajusta a los criterios propuestos por la Comunidad Autónoma de Madrid (CAM) antes de la instauración del «Plan de Actuación de ARA-II¼. Estudiar las indicaciones para las que se prescriben e identificar aquellos factores que han podido influir en su prescripción. Métodos: Estudio de utilización de medicamentos del tipo indicación- prescripción, descriptivo y transversal, en el que se seleccionaron pacientes con hipertensión arterial y en tratamiento con ARA-II ingresados en un Hospital General Universitario durante un periodo de estudio de 3 meses. De acuerdo con las situaciones clínicas recogidas en el Documento de la CAM «Criterios para establecer el lugar en la terapéutica de los antagonistas de los receptores de la angiotensina II¼, se calculó el porcentaje de pacientes con «prescripción adecuada¼ y «prescripción no adecuada¼ de ARA-II y se analizó si la edad y el sexo tenían influencia en el tipo de prescripción o en las principales indicaciones para las que se prescribieron. Resultados: De los 153 pacientes que se incluyeron en el estudio, el 67,3% tuvieron una «prescripción no adecuada¼, el 47,6% de ellos por prescripción de ARA-II como primer fármaco antagonista del sistema renina angiotensina aldosterona y el 34,0% por mal control de la tensión arterial con inhibidores de la enzima convertidora de angiotensina (IECA). No se encontraron diferencias estadísticamente significativas por edad o sexo en cuanto al tipo de prescripción o en las principales indicaciones para las que se prescribieron. Conclusiones: La adecuación a los criterios de uso del Documento de ARA-II se produjo en el 32,7% de los casos. Además, no se observó que factores como la edad y el sexo influyeran en el tipo de prescripción. Asimismo, se evidenciaron percep-

Determining safe alternatives for multidrug hypersensitive patients with the alternative triple antibiotic-analgesic test.

BACKGROUND: Drug provocation tests (DPTs) need technical equipment, staff and time. There are very few allergy centres performing DPTs in Turkey. Therefore many patients are referred to these centres. One day triple-double antibiotic or non-steroidal anti-inflammatory drug (NSAID) oral DPT for determining safe alternatives is safe, cost-effective and time saving compared to conventional one day one drug oral DPT. Our aim was to investigate the safety of antibiotic-NSAID oral DPT performed on the same day to find safe alternatives in multidrug hypersensitive patients. METHODS: Forty-two patients who had been diagnosed as having both antibiotic and NSAID hypersensitivity were enrolled to the study between 15 November and 15 July 2010. The reactions were urticaria and/or angio-oedema not including laryngeal oedema for all patients. Two antibiotics-one NSAID or two NSAIDs-one antibiotic triple test have been performed on the same day to study patients (n=22), while the control group (n=20) had taken drugs on three separate days. RESULTS: Only two patients had positive reactions during triple test and two patients had adverse reactions; one had gastric pain, one had nausea. Three patients in the control group had positive reactions. There were no significant differences between the two groups in frequency of adverse and allergic drug reactions (p>0.05). Sixty days were spent for the tests of the control group with only 28 days for the study population. CONCLUSION: Triple test performed with antibiotic and NSAID on the same day for determining safe alternatives for multidrug hypersensitive patients reporting non-life-threatening allergic reactions seems to be safe and time-saving.

ACE inhibitor-induced angioedema of the intestine: Case report, incidence, pathophysiology, diagnosis and management.

A case report of fosinopril-induced angioedema of the intestine with a chronic course accompanied by multiple acute exacerbations is described. Angiotensin-converting enzyme (ACE) inhibitor-induced angioedema of the intestine (AIAI) occurs in a minority of patients taking an ACE inhibitor. The clinical presentation encompasses acute abdominal symptoms, pronounced bowel edema and ascites with occasional facial and/or oropharyngeal swelling. AIAI is diagnosed based on the temporal relationship between the symptomatic presentation and drug use, absence of alternative diagnoses including other causes of angioedema, and the prompt resolution of symptoms upon discontinuation of the ACE inhibitor. Prompt radiological investigation (abdominal computerized tomography and/or ultrasound) is critical in making an early diagnosis and in preventing unnecessary surgical intervention. There is a female predominance of AIAI, which may reflect the interaction of estradiol with the various pathways involved in the pathophysiology of AIAI. Management of AIAI consists mainly of conservative measures and discontinuation of the ACE inhibitor. Angiotensin II receptor antagonists should not be considered as appropriate alternatives. Awareness and knowledge of AIAI are important because of the increasing use of ACE inhibitors, current delays in making the diagnosis, obvious management strategies once the diagnosis is made and the dysutility of alternative diagnoses, which may lead to considerable morbidity. AIAI must be considered in patients taking ACE inhibitors who develop gastrointestinal complaints irrespective of the duration of the therapy.

ACE inhibitor-induced angioedema. Incidence, prevention and management.

Available information from 1980 to 1997 on angiotensin converting enzyme (ACE) inhibitor-induced angioedema and its underlying mechanisms are summarised and discussed. The incidence of angioedema is low (0.1 to 0.2%) but can be considered as a potentially life-threatening adverse effect of ACE inhibitor therapy. This adverse effect of ACE inhibitors, irrespective of the chemical structure, can occur early in treatment as well as after prolonged exposure for up to several years. The estimate incidence is quite underestimated. The actual incidence can be far higher because of poorly recognised presentation of angioedema as a consequence of its late onset in combination with usually long term therapy. Also, a spontaneous reporting bias can contribute to an actual higher incidence of this phenomenon. The incidence can be even higher (up to 3-fold) in certain risk groups, for instance Black Americans. Treatment includes immediate withdrawal of the ACE inhibitor and acute symptomatic supportive therapy followed by immediate (and long term) alternative therapy with other classes of drugs to manage hypertension and/or heart failure. Preclinical and clinical studies for the elucidation of the underlying mechanism(s) of ACE inhibitor-associated angioedema have not generated definite conclusions. It is suggested that immunological processes and several mediator systems (bradykinin, histamine, substance P and prostaglandins) are involved in the pathogenesis of angioedema. A great part of all reviewed reports suggest a relationship between ACE inhibitor-induced angioedema and increased levels of (tissue) bradykinin. However, no conclusive evidence of the role of bradykinin in angioedema has been found and an exclusive role of bradykinin seems unlikely. So far, no clear-cut evidence for an immune-mediated pathogenesis has been found. In addition, ACE gene polymorphism and some enzyme deficiencies are proposed to be involved in ACE inhibitor-induced angioedema. Progress in pharmacogenetic and molecular biological research should throw more light on a possible genetic component in the pathogenesis of ACE inhibitor-associated angioedema.

Drug-induced severe skin reactions. Incidence, management and prevention.

Severe skin adverse drug reactions can result in death, but the rate of such events is fortunately low. The incidences of Stevens-Johnson syndrome and toxic epidermal necrolysis range from 1.2 to 6 per million per year and 0.4 to 1.2 per million per year, respectively. Stevens-Johnson syndrome is fatal in about 5% and toxic epidermal necrolysis in 30% of cases. Drugs implicated in these diseases are the sulphonamides, anticonvulsants, allopurinol, pyrazolone derivatives, oxicams and chlormezanone. The principles of symptomatic treatment are the same as for burns, and patients with extensive skin detachment should be transferred to an intensive care unit or a burn centre. Hypersensitivity syndrome is characterised by mucocutaneous eruption and fever with frequent lymphadenopathy, hepatitis and eosinophilia. Drugs implicated are mainly anticonvulsants and sulphonamides. The mortality rate of such a reaction has been estimated to be about 8%. Corticosteroid therapy has been widely used in hypersensitivity syndrome, despite the lack of controlled studies. Drug-induced vasculitis and serum sickness may also be life-threatening when the kidney, liver, gastrointestinal tract or nervous system are involved. In angioedema, congestion may involve mucous membranes and therefore impair swallowing and ventilation. Drugs associated with angioedema include penicillins, radiographic contrast agents and ACE inhibitors. Severe forms of angioedema necessitate epinephrine (adrenaline) subcutaneous injection and possibly resuscitative efforts. Corticosteroids and/or antihistamines are used to block or reduce prolonged or late phase reactions. Prompt recognition and withdrawal of the suspected drug is essential in severe drug-induced skin reactions.

Frequency and recognition of angiotensin-converting enzyme inhibitor-associated angioneurotic edema.

OBJECTIVE: To evaluate the frequency of association of angiotensin-converting enzyme (ACE) inhibitor therapy with angioneurotic edema and the frequency of correct diagnosis by treating physicians. DESIGN: Retrospective population-based chart review. SETTING: Medicare patients identified with 1991 and 1992 MEDPRO data set. RESULTS: 51 patients were identified from the MEDPRO data sets. Twenty-four patients (47%) had ACE inhibitor-associated angioneurotic edema of whom 17 (71% of the subgroup) had the medication stopped. Twenty-nine percent of the affected patients were discharged still taking an ACE inhibitor. Twenty-six patients (51% of the total population) had non-ACE inhibitor-associated angioneurotic edema and one patient had an uncertain history. CONCLUSION: ACE inhibitor therapy is the number one cause of angioneurotic edema in our hospitalized patient population. Recognition of the association of this drug with the condition was not recognized in 29% of cases and the offending agent was continued upon discharge from the hospital.