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Heart failure induced by itraconazole
Med Clin (Barc). 2017;148(2):69–70
www.elsevier.es/medicinaclinica
Clinical report
Heart failure induced by itraconazole夽 Ana Rodrigo-Troyano a,∗ , Marta M. Mediavilla b , Noé Garin b , Rosa Güell a a b
Servicio de Neumología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Servicio de Farmacia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 3 August 2016 Accepted 22 September 2016 Available online 21 February 2017 Keywords: Heart failure Itraconazole Drug-related adverse reactions
a b s t r a c t Introduction and objective: Itraconazole is an antifungal imidazole used for the treatment of aspergillosis. Evidence supporting the association between itraconazole and the onset of congestive heart failure (CHF) is limited and is based on cases reported after drug market release. Case report: We report the case of a 76-year-old man with hypertension and COPD GOLD D who experienced heart failure after receiving a new line of treatment with itraconazole. The patient’s symptoms resolved completely after the drug’s withdrawal and initiation of treatment with diuretic therapy. Using validated algorithms, we concluded that there was a probable association between itraconazole and the onset of CHF. Conclusions: The association between the administration of itraconazole and the onset of CHF is difficult to prove. Further observational studies are needed to assess this association. However, based on the available evidence, we should consider this possible adverse effect and even contraindicate this treatment in patients with a structural heart disease. ˜ S.L.U. All rights reserved. © 2016 Elsevier Espana,
Insuficiencia cardíaca secundaria a tratamiento con itraconazol r e s u m e n Palabras clave: Insuficiencia cardíaca Itraconazol Reacciones adversas a medicamentos
Introducción y objetivo: Itraconazol es un antifúngico imidazólico para el tratamiento de la aspergilosis. La evidencia que respalda la asociación entre itraconazol y el desarrollo de insuficiencia cardíaca congestiva (ICC) es limitada y se basa en los casos notificados poscomercialización del fármaco. ˜ Caso clínico: Presentamos el caso de un varón de 76 anos, hipertenso, con EPOC GOLD D, que presenta un inicio de insuficiencia cardíaca tras la introducción de tratamiento con itraconazol. Tras la retirada del fármaco y tratamiento diurético muestra resolución completa del cuadro clínico. Tras utilizar varios algoritmos validados sobre causalidad de efectos adversos se concluyó como probable la asociación entre itraconazol y el desarrollo de ICC en este caso. Conclusiones: La asociación entre la administración de itraconazol y el desarrollo de ICC es una relación causal difícil de demostrar. Son necesarios estudios observacionales dirigidos a evaluar tal asociación. No obstante, con la evidencia disponible debemos considerar la posibilidad de dicho efecto adverso e incluso valorar la contraindicación en pacientes con antecedentes de cardiopatía estructural. ˜ S.L.U. Todos los derechos reservados. © 2016 Elsevier Espana,
Introduction
report the case of a patient who developed symptoms of congestive heart failure (CHF) in the context of treatment with this drug.
Itraconazole is an antifungal imidazole used for treating onychomycosis and aspergillosis and other fungal conditions. We Clinical case 夽 Please cite this article as: Rodrigo-Troyano A, Mediavilla MM, Garin N, Güell R. Insuficiencia cardíaca secundaria a tratamiento con itraconazol. Med Clin (Barc). 2017;148:69–70. ∗ Corresponding author. E-mail address: [email protected] (A. Rodrigo-Troyano). ˜ S.L.U. All rights reserved. 2387-0206/© 2016 Elsevier Espana,
We report the case of a 76-year-old man with a history of hypertension and COPD GOLD D associated with bronchiectasis, with home oxygen therapy (forced expiratory volume in one second [FEV1 ]: 600 ml, 24%; forced vital capacity [FVC]: 1720 ml, 49%; FEV1 /FVC: 34). He consulted for cough with purulent expectoration
70
A. Rodrigo-Troyano et al. / Med Clin (Barc). 2017;148(2):69–70
in December 2015. Lab tests results showed a mild neutrophilia and a normal pro-BNP (273 ng/l). Chest X-ray showed signs of emphysema predominantly in LII, with no evidence of changes from previous studies. 2 lots of empiric antibiotic treatment were administered, without clinical improvement (levofloxacin 500 mg every 24 h for 7 days and cefditoren 400 mg every 12 h for 7 days). The collected sputum culture was positive for Aspergillus fumigatus, so it was decided to start treatment with itraconazole (200 mg every 12 h orally) and expand antibiotic coverage to ceftazidime (1 g every 8 h, intravenously). Subsequently, quinolone-resistant Pseudomonas aeruginosa was isolated from a new sputum culture, so it was decided to keep both treatments. A progressive clinical improvement was observed after the start of the treatment, with resolution of respiratory infectious symptoms (absence of cough and purulent expectoration). Symptoms of increased dyspnoea and orthopnoea started to occur 14 days after treatment initiation. Jugular venous distension, hepatojugular reflux, hepatomegaly and pitting oedema in the lower limbs were observed on physical examination. Right costophrenic angle blunting was appreciated on chest radiography. Lab test results highlighted a pro-BNP of 2638 ng/l, with the rest of the values being normal. The echocardiography showed a left ventricle with a mild septal hypertrophy, ejection fraction of 62%, slightly dilated left atrium, right ventricular dilation and moderate pulmonary arterial hypertension (45–50 mmHg). The diagnostic approach was CHF-compatible (according to the Framingham criteria1 : 2 major and 3 minor), which was attributed to respiratory infection and treatment with itraconazole. The said drug was withdrawn, diuretics were added and treatment with ceftazidime remained until completing 21 days. The patient had a rapid clinical improvement during hospitalization, with disappearance of heart failure clinical signs, normalization of pro-BNP levels at discharge (332 ng/l) and resolution of right costophrenic angle blunting in chest radiology.
effects. The scale proposed by Naranjo et al. was applied.,5 which resulted in a probable causal relationship (second strongest association category). The following factors were taken into account: existence of reported cases, temporality, clear clinical improvement after drug withdrawal and the presence of clinical and laboratory parameters consistent with CHF. Additionally, the combined causality/severity assessment scale proposed by Koh et al.6 was applied, of greater sensitivity, whereby the probable association was confirmed (second strongest association category) and, as it was necessary to withdraw the drug and treat CHF after hospital admission, a severity level of 3 was established (ascending severity level from 1 to 6). Furthermore, the involvement of other drugs was excluded from the clinical condition after reviewing other pharmacotherapy options. Conclusions This case reflects the association between administration of itraconazole and development of CHF. This causal relationship is difficult to prove and the limited scientific evidence on the subject is based on case reports and case series.2–4 Therefore, it is necessary to continue with pharmacovigilance and carry out observational studies targeting the assessment of this association. However, we believe that, with the available evidence, this adverse effect should be considered in clinical practice and even assess its contraindication in patients with a history of heart failure or left ventricular dysfunction. In these cases, voriconazole would be a reasonable alternative, since it is effective on Aspergillus sp. and has not been linked to the development of heart failure as an adverse effect. Conflict of interests The authors declare no conflict of interest.
Discussion The evidence supporting the association between itraconazole and development of CHF is limited and is based on cases reported after having marketed the drug.2–4 The mechanism by which itraconazole exerts its negative inotropic effect, which is not observed with other azoles, is unknown.3 This is a first episode of CHF in a patient with no evidence of significant structural heart disease upon echocardiographic examination, which led to the suspicion that itraconazole could be the cause of the heart condition. In addition, it is noteworthy that the patient has not had any new episodes of CHF to date (until the preparation of this work), with a total follow-up of 8 months. To eliminate subjective elements that could affect this analysis we decided to use algorithms validated on causality of adverse
References 1. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971;285:1441–6. 2. Vollenbroich R, Maeder MT, Weilenmann D. Congestive heart failure related to antifungal therapy with itraconazole. Int J Cardiol. 2014;172:170–1. 3. Ahmad SR, Singer SJ, Leissa BG. Congestive heart failure associated with itraconazole. Lancet. 2001;357:1766–7. 4. Fung SL, Chau CH, Yew WW. Cardiovascular adverse effects during itraconazole therapy. Eur Respir J. 2008;32:240. 5. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45. 6. Koh Y, Yap CW, Li SC. Development of a combined system for identification and classification of adverse drug reactions: Alerts Based on ADR Causality and Severity (ABACUS). J Am Med Inform Assoc. 2010;17:720–2.
www.elsevier.es/medicinaclinica
Clinical report
Heart failure induced by itraconazole夽 Ana Rodrigo-Troyano a,∗ , Marta M. Mediavilla b , Noé Garin b , Rosa Güell a a b
Servicio de Neumología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Servicio de Farmacia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 3 August 2016 Accepted 22 September 2016 Available online 21 February 2017 Keywords: Heart failure Itraconazole Drug-related adverse reactions
a b s t r a c t Introduction and objective: Itraconazole is an antifungal imidazole used for the treatment of aspergillosis. Evidence supporting the association between itraconazole and the onset of congestive heart failure (CHF) is limited and is based on cases reported after drug market release. Case report: We report the case of a 76-year-old man with hypertension and COPD GOLD D who experienced heart failure after receiving a new line of treatment with itraconazole. The patient’s symptoms resolved completely after the drug’s withdrawal and initiation of treatment with diuretic therapy. Using validated algorithms, we concluded that there was a probable association between itraconazole and the onset of CHF. Conclusions: The association between the administration of itraconazole and the onset of CHF is difficult to prove. Further observational studies are needed to assess this association. However, based on the available evidence, we should consider this possible adverse effect and even contraindicate this treatment in patients with a structural heart disease. ˜ S.L.U. All rights reserved. © 2016 Elsevier Espana,
Insuficiencia cardíaca secundaria a tratamiento con itraconazol r e s u m e n Palabras clave: Insuficiencia cardíaca Itraconazol Reacciones adversas a medicamentos
Introducción y objetivo: Itraconazol es un antifúngico imidazólico para el tratamiento de la aspergilosis. La evidencia que respalda la asociación entre itraconazol y el desarrollo de insuficiencia cardíaca congestiva (ICC) es limitada y se basa en los casos notificados poscomercialización del fármaco. ˜ Caso clínico: Presentamos el caso de un varón de 76 anos, hipertenso, con EPOC GOLD D, que presenta un inicio de insuficiencia cardíaca tras la introducción de tratamiento con itraconazol. Tras la retirada del fármaco y tratamiento diurético muestra resolución completa del cuadro clínico. Tras utilizar varios algoritmos validados sobre causalidad de efectos adversos se concluyó como probable la asociación entre itraconazol y el desarrollo de ICC en este caso. Conclusiones: La asociación entre la administración de itraconazol y el desarrollo de ICC es una relación causal difícil de demostrar. Son necesarios estudios observacionales dirigidos a evaluar tal asociación. No obstante, con la evidencia disponible debemos considerar la posibilidad de dicho efecto adverso e incluso valorar la contraindicación en pacientes con antecedentes de cardiopatía estructural. ˜ S.L.U. Todos los derechos reservados. © 2016 Elsevier Espana,
Introduction
report the case of a patient who developed symptoms of congestive heart failure (CHF) in the context of treatment with this drug.
Itraconazole is an antifungal imidazole used for treating onychomycosis and aspergillosis and other fungal conditions. We Clinical case 夽 Please cite this article as: Rodrigo-Troyano A, Mediavilla MM, Garin N, Güell R. Insuficiencia cardíaca secundaria a tratamiento con itraconazol. Med Clin (Barc). 2017;148:69–70. ∗ Corresponding author. E-mail address: [email protected] (A. Rodrigo-Troyano). ˜ S.L.U. All rights reserved. 2387-0206/© 2016 Elsevier Espana,
We report the case of a 76-year-old man with a history of hypertension and COPD GOLD D associated with bronchiectasis, with home oxygen therapy (forced expiratory volume in one second [FEV1 ]: 600 ml, 24%; forced vital capacity [FVC]: 1720 ml, 49%; FEV1 /FVC: 34). He consulted for cough with purulent expectoration
70
A. Rodrigo-Troyano et al. / Med Clin (Barc). 2017;148(2):69–70
in December 2015. Lab tests results showed a mild neutrophilia and a normal pro-BNP (273 ng/l). Chest X-ray showed signs of emphysema predominantly in LII, with no evidence of changes from previous studies. 2 lots of empiric antibiotic treatment were administered, without clinical improvement (levofloxacin 500 mg every 24 h for 7 days and cefditoren 400 mg every 12 h for 7 days). The collected sputum culture was positive for Aspergillus fumigatus, so it was decided to start treatment with itraconazole (200 mg every 12 h orally) and expand antibiotic coverage to ceftazidime (1 g every 8 h, intravenously). Subsequently, quinolone-resistant Pseudomonas aeruginosa was isolated from a new sputum culture, so it was decided to keep both treatments. A progressive clinical improvement was observed after the start of the treatment, with resolution of respiratory infectious symptoms (absence of cough and purulent expectoration). Symptoms of increased dyspnoea and orthopnoea started to occur 14 days after treatment initiation. Jugular venous distension, hepatojugular reflux, hepatomegaly and pitting oedema in the lower limbs were observed on physical examination. Right costophrenic angle blunting was appreciated on chest radiography. Lab test results highlighted a pro-BNP of 2638 ng/l, with the rest of the values being normal. The echocardiography showed a left ventricle with a mild septal hypertrophy, ejection fraction of 62%, slightly dilated left atrium, right ventricular dilation and moderate pulmonary arterial hypertension (45–50 mmHg). The diagnostic approach was CHF-compatible (according to the Framingham criteria1 : 2 major and 3 minor), which was attributed to respiratory infection and treatment with itraconazole. The said drug was withdrawn, diuretics were added and treatment with ceftazidime remained until completing 21 days. The patient had a rapid clinical improvement during hospitalization, with disappearance of heart failure clinical signs, normalization of pro-BNP levels at discharge (332 ng/l) and resolution of right costophrenic angle blunting in chest radiology.
effects. The scale proposed by Naranjo et al. was applied.,5 which resulted in a probable causal relationship (second strongest association category). The following factors were taken into account: existence of reported cases, temporality, clear clinical improvement after drug withdrawal and the presence of clinical and laboratory parameters consistent with CHF. Additionally, the combined causality/severity assessment scale proposed by Koh et al.6 was applied, of greater sensitivity, whereby the probable association was confirmed (second strongest association category) and, as it was necessary to withdraw the drug and treat CHF after hospital admission, a severity level of 3 was established (ascending severity level from 1 to 6). Furthermore, the involvement of other drugs was excluded from the clinical condition after reviewing other pharmacotherapy options. Conclusions This case reflects the association between administration of itraconazole and development of CHF. This causal relationship is difficult to prove and the limited scientific evidence on the subject is based on case reports and case series.2–4 Therefore, it is necessary to continue with pharmacovigilance and carry out observational studies targeting the assessment of this association. However, we believe that, with the available evidence, this adverse effect should be considered in clinical practice and even assess its contraindication in patients with a history of heart failure or left ventricular dysfunction. In these cases, voriconazole would be a reasonable alternative, since it is effective on Aspergillus sp. and has not been linked to the development of heart failure as an adverse effect. Conflict of interests The authors declare no conflict of interest.
Discussion The evidence supporting the association between itraconazole and development of CHF is limited and is based on cases reported after having marketed the drug.2–4 The mechanism by which itraconazole exerts its negative inotropic effect, which is not observed with other azoles, is unknown.3 This is a first episode of CHF in a patient with no evidence of significant structural heart disease upon echocardiographic examination, which led to the suspicion that itraconazole could be the cause of the heart condition. In addition, it is noteworthy that the patient has not had any new episodes of CHF to date (until the preparation of this work), with a total follow-up of 8 months. To eliminate subjective elements that could affect this analysis we decided to use algorithms validated on causality of adverse
References 1. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971;285:1441–6. 2. Vollenbroich R, Maeder MT, Weilenmann D. Congestive heart failure related to antifungal therapy with itraconazole. Int J Cardiol. 2014;172:170–1. 3. Ahmad SR, Singer SJ, Leissa BG. Congestive heart failure associated with itraconazole. Lancet. 2001;357:1766–7. 4. Fung SL, Chau CH, Yew WW. Cardiovascular adverse effects during itraconazole therapy. Eur Respir J. 2008;32:240. 5. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45. 6. Koh Y, Yap CW, Li SC. Development of a combined system for identification and classification of adverse drug reactions: Alerts Based on ADR Causality and Severity (ABACUS). J Am Med Inform Assoc. 2010;17:720–2.