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The Many Faces of Itraconazole Cardiac Toxicity

Open AccessPublished:August 15, 2020DOI:https://doi.org/10.1016/j.mayocpiqo.2020.05.006

      Abstract

      Itraconazole is well known for carrying a black-box warning for new or worsening congestive heart failure. Single cases of other cardiac- and fluid-related disturbances have been reported periodically since its issuance. We describe a large cohort of patients on itraconazole experiencing a breadth of cardiac- and fluid-related toxicities, ranging from new-onset hypertension to cardiac arrest. A retrospective, single-center, large case series at a large tertiary medical center was conducted. Patients with itraconazole and cardiac toxicity—including hypertension, cardiomyopathy, reduced ejection fraction, and edema—in medical record between January 1, 1999, and May 21, 2019, were identified and assigned a Naranjo score; 31 patients were included with a Naranjo score of 5 or higher. There were slightly more male subjects than female subjects, average age was 66, and all subjects were Caucasian. Median time until presentation of adverse effects was 4 weeks (range: 0.3 to 104 weeks). Most common symptom was edema (74% of patients), followed by heart failure without and with preserved ejection fraction (19.4% and 22.6% of patients, respectively). Worsening or new hypertension was also common (25.8% of patients). Rarer were pulmonary edema, pericardial effusion, and cardiac arrest that occurred in 1 patient. In most cases, clinicians stopped itraconazole (74%) or decreased itraconazole dose (19%), resulting in improvement or resolution of symptoms. In 4 cases, the adverse effect did not resolve. Itraconazole can cause a range of possible serious cardiac and fluid-associated adverse events. Dose decrease or cessation usually resulted in symptomatic improvement or reversal.

      Abbreviations and Acronyms:

      ADR (adverse drug event), CHF (congestive heart failure), CV (cardiovascular), CYP (Cytochrome-P), EF (ejection fraction), FDA (Food and Drug Administration), HFpEF (heart failure with preserved ejection fraction), HFrEF (heart failure with reduced ejection fraction)
      Itraconazole is a triazole antifungal commonly used to treat serious fungal infections. In 2001, the Food and Drug Administration (FDA) issued a black-box warning to itraconazole labeling about the risk of new or exacerbated congestive heart failure (CHF).
      • Ahmad S.
      • Singer S.
      • Leissa B.
      Congestive heart failure associated with itraconazole.
      The FDA warning stated that itraconazole should not be used for onychomycosis in patients with ventricular dysfunction because of negative inotrope activity seen in healthy human volunteers and dogs.
      Although not fully understood, proposed mechanisms of this effect include mitochondrial toxicity.
      • Cleary J.D.
      • Stover K.R.
      • Farley J.
      • Daley W.
      • Kyle P.B.
      • Hosler J.
      Cardiac toxicity of azole antifungals.
      Following the initial publication describing 58 cases of itraconazole-associated cardiac failure,
      • Ahmad S.
      • Singer S.
      • Leissa B.
      Congestive heart failure associated with itraconazole.
      related cases have periodically been reported.
      • Okuyan H.
      • Altin C.
      Heart failure induced by itraconazole.
      • Abraham A.O.
      • Panda P.K.
      Itraconazole induced congestive heart failure, a case study.
      • Paul V.
      • Rawal H.
      Cardiotoxicity with itraconazole.
      • Rodrigo-Troyano A.
      • Mediavilla M.
      • Garin N.
      • Guell R.
      Heart failure induced by itracaonazole.
      Particularly concerning are cases of CHF in the setting of no previous cardiac risk factors.
      • Abraham A.O.
      • Panda P.K.
      Itraconazole induced congestive heart failure, a case study.
      ,
      • Paul V.
      • Rawal H.
      Cardiotoxicity with itraconazole.
      Although CHF is the most commonly described form of cardiotoxicity, reports generally consisting of 1 to 2 patients suggest the scope of toxicity spans more widely. Case reports of cardiovascular (CV) or fluid disorders attributed to itraconazole include peripheral edema,
      • Lestner J.M.
      • Roberts S.A.
      • Moore C.B.
      • Howard S.J.
      • Denning D.W.
      • Hope W.W.
      Toxicodynamics of itraconazole: implications for therapeutic drug monitoring.
      polyuria,
      • Chiang C.-T.
      • Chan H.-L.
      Therapeutic and safety evaluation of 200 mg/day itraconazole for 7 days in the treatment of recalcitrant superficial mycoses: a preliminary report.
      hypertension,
      • Hoffmann W.J.
      • McHardy I.
      • Thompson G.R.
      Itraconazole induced hypertension and hypokalemia: Mechanistic evaluation.
      • Fung S.-L.
      • Chau C.-H.
      • Yew W.-W.
      Cardiovascular adverse effects during itraconazole therapy.
      • Denolle T.
      • Azizi M.
      • Massart C.
      • Zennaro M.C.
      HTA sous itraconazole: une nouvelle cause d’HTA iatrogène.
      and cardiac arrest:
      • Tsimogianni A.M.
      • Andrianakis I.
      • Betrosian A.
      • Douzinas E.
      Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report.
      the latter typically involving concomitant QT-prolonging medications.
      We sought to describe the patients seen at our institution in the last 2 decades with widely defined CV- or fluid-related adverse effects that we determined to be probably systematically related to the use of itraconazole and describe their outcomes.

      Methods

      This single-center retrospective, descriptive study was conducted at Mayo Clinic Rochester. Institutional review board approval was obtained. Charts of all adult patients with itraconazole orders were queried between January 1, 1999, and May 21, 2019, using the Mayo Clinic Unified Data Platform.
      • Chute C.G.
      • Beck S.A.
      • Fisk T.B.
      • Mohr D.N.
      The Enterprise Data Trust at Mayo Clinic: a semantically integrated warehouse of biomedical data.
      Patients without research authorization in Minnesota were excluded. Clinical notes were searched for terms itraconazole and hypertension, cardiomyopathy, reduced ejection fraction, or edema. Identified patients were reviewed, and the Naranjo adverse drug event (ADE) scoring tool
      • Naranjo C.A.
      • Busto U.
      • Sellers E.M.
      • et al.
      A method for estimating the probability of adverse drug reactions.
      was used to rate the likelihood of an itraconazole-associated ADE by 2 clinical pharmacists reviewing cases independently. If the pharmacist was unable to determine a score clearly, an infectious diseases physician provided input. Patients with Naranjo scores ≥5 (probable or definite ADE) were included. Patients scoring <5 (possible or doubtful ADE) were excluded. Data collected included patient age, sex, race, itraconazole indication, itraconazole- dosing history, itraconazole start date per prescription record and provider documentation for internal and the latter only for external initiation, itraconazole formulation at time of CV toxicity, clinician response, CV-toxicity resolution, itraconazole/hydroxy-itraconazole level, cardiac comorbidities, and pharmacogenomics results. Predefined cardiac comorbidities included cardiac arrhythmias, established coronary artery disease, cardiomyopathy, diabetes, hypertension, or hyperlipidemia. Concomitant medications were screened for potential alternative causes and Naranjo points assigned accordingly. CV toxicity was defined as complete resolution: no further signs, symptoms, or test results indicating adverse effect; partial resolution: ≥ 1 sign, symptom, or test result indicating adverse effect and severity has improved or number of symptoms decreased since presentation; no resolution: signs, symptoms, and/or test results continue at same frequency and severity or worsen.
      Serum drug levels were performed in the majority of patients at steady state (1 to 3 weeks following initiation of drug or change in dose). Itraconazole and its primary active metabolite— hydroxy-itraconazole—levels were assessed on site. Drug assay was performed by liquid chromatography-tandem mass spectrometry from a single serum sample. Laboratory reference suggests goals of >0.5 μg/mL for a localized infection and >1 μg/mL for systemic infections, with no defined upper limit. Results of each individual component were available via the electronic medical record laboratory section. Itraconazole and hydroxy-itraconazole results were summed and compared with the total to the aforementioned goal values. We reported the highest sum of itraconazole and hydroxy-itraconazole during a single assay recorded for each patient within the study time frame. This result was usually the serum level at the time of occurrence of the ADE.

      Results

      Of the initial 69 patients identified with itraconazole and a cardiac- or fluid-related ADE, 31 cases that scored ≥ 5 by Naranjo scale were included. Physician input on scoring was obtained on 1 of the included cases and 3 of the excluded cases. There were slightly more men than women, with an average age of 66, and all were Caucasian. The most common cardiac comorbidities were hypertension (22%) and cardiac arrhythmia (25%), whereas only 1 patient had baseline cardiomyopathy. The most common itraconazole indication was Histoplasmosis infection (48.4%) with pulmonary source (51.6%). Disseminated fungal infections were also frequent. In only 1 case was itraconazole used for prophylaxis (Table 1). The average total serum itraconazole level was 5.2 μg/mL (range: 1.8 to 11.7 μg/mL).
      Table 1Patient Characteristics
      CharacteristicTotal (N=31)

      N (%)
      Sex, Male17 (54.8)
      Age, median (IQR), years66 (56, 70)
      Race
       Caucasian31 (100)
      Cardiovascular comorbidities
       Cardiac arrhythmia8 (25.8)
       Cardiomyopathy1 (3.2)
       Coronary artery disease5 (16.1)
       Hypertension7 (22.6)
       Dyslipidemia3 (9.7)
      Indication
       Pulmonary16 (51.6)
       Disseminated12 (38.7)
       Tenosynovitis2 (6.5)
       Prophylaxis1 (3.2)
      Organism
      Histoplasma15 (48.4)
      Aspergillus2 (6.5)
      Coccidioides3 (9.7)
      Blastomyces5 (16.1)
      Prophylaxis1 (3.2)
      Cryptococcus1 (3.2)
      Other Fungal NOS4 (12.9)
      Naranjo Score, median (range) points7 (5-9)
      IQR = interquartile range; NOS = not otherwise specified.
      Table 2Summary of CV Toxicity Characteristics
      Percentages add up to >100%, as many patients had ≥1 CV toxicity.
      CharacteristicTotal (N=31)

      N (%)
      CV toxicity type
       CHF with reduced EF6 (19.4)
       CHF with preserved EF7 (22.6)
       Hypertension8 (25.8)
       Edema23 (74.2)
       Pericardial effusion1 (3.2)
       Other8 (25.8)
      Clinician initial action
       Continue itraconazole regimen2 (4.5)
       Discontinue itraconazole23 (74.2)
       Modify itraconazole dose6 (19.4)
      Outcome
       Complete resolution17 (54.8)
       Partial resolution9 (29)
       No resolution4 (12.9)
       Unknown1 (3.2)
      Clinician subsequent action taken
       Yes6 (19.4)
       No26 (80.6)
      CV = cardiovascular; CHF = congestive heart failure; EF = ejection fraction.
      a Percentages add up to >100%, as many patients had ≥1 CV toxicity.
      Table 3Descriptions of Patient Cases
      IDAgeSexCV comorbidities
      Defined risk factors include arrhythmia = 1, cardiomyopathy = 2, coronary artery disease = 3, diabetes = 4, hypertension = 5, or hyperlipidemia = 6.
      ITRA indicationCV toxicity typeNaranjo ScoreTime to ADE (weeks)ITRA oral dose
      Dose at time of adverse drug event.
      FormulationITRA Load
      200 mg PO TID for at least 3 days at beginning of therapy.
      ITRA + H-ITRA level
      Highest total (itraconazole + hydroxyitraconazole) level recorded.
      (μg/mL)
      Clinician action Regarding ITRAResolution
      170M3,5Pulmonary histoplasmosisright heart failure, edema96200 mg BIDcapsuleYes2Discontinuepartial
      267MDisseminated histoplasmosisHTN82200 mg BIDcapsuleYes2.9Discontinuecomplete
      333MDisseminated Blastomycespleural effusions, pulmonary edema, SOB88UnknownliquidUnknown6.2Discontinueunknown
      465MPulmonary histoplasmosisHFpEF, edema82200 mg BIDliquidYes11.5Modify dosecomplete
      584M3Pulmonary histoplasmosis and BlastomycesHTN85200 mg BIDcapsuleYes4.3Discontinuepartial
      677MPulmonary histoplasmosisedema, pleural effusion88200 mg BIDcapsuleUnknown10.1Discontinuecomplete
      752F5Pulmonary BlastomycesHTN, edema, hypokalemia, and metabolic acidosis87100 mg BIDcapsuleYes7.8Discontinuecomplete
      868F1Pulmonary AspergillusHFpEF, HTN, edema78200 mg BIDcapsuleNo4.8Modify dosepartial
      970FPisseminated histoplasmosisHTN, edema734200 mg BIDcapsuleNo5.9Discontinuecomplete
      1065M1,2Pisseminated BlastomycesHFpEF, edema, pulmonary edema73200 mg BIDcapsuleYes4.8Discontinuecomplete
      1166F1Pulmonary (NOS)HFpEF, edema71200 mg BIDcapsuleYes5.6Discontinuecomplete
      1272F1,5,6Pulmonary AspergillusHFpEF, edema73.5200 mg BIDcapsuleNo-Discontinuecomplete
      1369M1,6Penosynovitis (NOS)HFrEF, edema73200 mg BIDcapsuleNo4.5Discontinuecomplete
      1466FPisseminated Coccidioidesedema71200 mg BIDcapsuleYes3.1Discontinuecomplete
      1550MPulmonary histoplasmosisedema, SOB71.5200 mg BIDcapsuleNo5.9Discontinuecomplete
      1653F3,6Disseminated histoplasmosisHFrEF, edema74UnknownunknownUnknown2.3Discontinueno resolution
      1763MProphylaxisHFrEF, edema769300 mg BIDcapsuleYes2.5Discontinuecomplete
      1871F5Pulmonary histoplasmosisHTN, edema74200 mg BIDcapsuleNo5.6Discontinuepartial
      1957FPulmonary histoplasmosisedema63200 mg BIDcapsuleYes7.5Continue regimenno resolution
      2073M5Pulmonary CrytococcusHFrEF6104200 mg BIDcapsuleNo-Continue regimenno resolution
      2150F1Pulmonary Coccidioidesedema61200 mg BIDcapsuleYes3Discontinuecomplete
      2255F1Disseminated histoplasmosisHTN, pericardial effusion624200 mg BIDcapsuleYes4.3Modify dosepartial
      2354M3Pulmonary histoplasmosisedema60.3200 mg BIDcapsuleYes-Discontinuecomplete
      2469M5Pulmonary (NOS)HTN6unknownUnknownunknownUnknown-Discontinuecomplete
      2563MDisseminated Blastomycesedema, nocturia667200 mg BIDliquidNo3.5Modify dosepartial
      2666FPulmonary histoplasmosisHFrEF64200 mg QDliquidNo2.9Discontinuepartial
      2773F3Disseminated histoplasmosisedema6104200 mg BIDcapsuleYes6.8Modify doseno resolution
      2870MDisseminated BlastomycesHFpEF, edema52200 mg BIDcapsuleNo-Discontinuepartial
      2964M5Disseminated Coccidioidesedema52.5400 mg BIDcapsuleYes4.8Modify dosepartial
      3060F1Tenosynovitis histoplasmosisHFrEF, cardiac arrest530100 mg BIDliquidNo11.7Discontinuecomplete
      3121MDisseminated histoplasmosisedema53300 mg BIDliquidYes1.8Discontinuecomplete
      ADE = adverse drug event; BID = twice daily; CV = cardiovascular; HFrEF = heart failure with reduced ejection fraction (left-ventricular ejection fraction ≤40%); H-ITRA = hydroxy-itraconazole; HTN = hypertension; ID = identification; NOS = not otherwise specified; ITRA = itraconazole; SOB = shortness of breath.
      b Defined risk factors include arrhythmia = 1, cardiomyopathy = 2, coronary artery disease = 3, diabetes = 4, hypertension = 5, or hyperlipidemia = 6.
      c Dose at time of adverse drug event.
      d 200 mg PO TID for at least 3 days at beginning of therapy.
      e Highest total (itraconazole + hydroxyitraconazole) level recorded.
      The median time from itraconazole initiation until adverse effect presentation was 4 weeks (range: 0.3 to 104 weeks). The most common symptom was edema in 74% of patients, followed by heart failure with and without preserved ejection fraction (HFpEF and HFrEF, respectively) in just under a quarter of patients each. Worsening or new hypertension was present in 25.8% of patients. Rarer, but notable, were pulmonary edema and pericardial effusion; cardiac arrest occurred in 1 patient (Table 2). Most patients experienced more than 1 ADE, and, typically, these presented simultaneously.
      In most cases, clinicians stopped itraconazole (74%) or decreased itraconazole dose (19%) in response to perceived itraconazole toxicity. Complete resolution occurred in just over half the patients (54%) and partial resolution in 30%. In the cases with partial resolution, 20% of the time the clinician took an additional action in an attempt to resolve, most commonly discontinuing itraconazole after the dose had first been decreased. In 4 cases (12.9%), the identified toxicity did not resolve. Half the HFpEF cases resolved partially, and half resolved fully. For HFrEF, 2 patients had no resolution, 1 had partial resolution, and 3 had complete resolution. A summary of the 31 cases is presented in Table 3.
      We describe below 3 cases of heightened interest. Patient 1 demonstrates a combination of severe, concerning cardiac toxicities occurring at a moderate serum itraconazole level. Patient 7 experienced serious cardiac toxicity in the setting of elevated itraconazole levels, possibly related to her pharmacogenomic (CYP450) genotype. Patient 25 experienced dose-dependent nocturia, an effect not previously described in the literature.

      Patient 1

      A 70-year-old man from Minnesota, with a history of coronary artery disease requiring coronary artery bypass surgery in 2010 and pulmonary sarcoidosis diagnosed in 1996, was hospitalized for acute hypoxic respiratory failure. Bronchoscopy with transbronchial biopsy showed necrotizing granuloma and fungal elements consistent with Histoplasma capsulatum. Histoplasma urinary antigen results were positive. He started itraconazole liquid 200 mg every 8 hours for 3 days, followed by 200 mg orally every 12 hours. Five weeks later, the total serum itraconazole level was 3.1 μg/mL.
      Six weeks later, he was hospitalized with progressive shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, bilateral lower-limb swelling, and N-terminal-pro brain natriuretic hormone of 6066 pg/mL. A transthoracic echo revealed severe right-ventricular enlargement with moderate to severe decrease in systolic function, severely dilated inferior vena cava, and mild tricuspid regurgitation. Troponins were negative, whereas electrocardiogram revealed new evidence of prolonged QT interval and multifocal atrial tachycardia.
      Itraconazole was transitioned to voriconazole and later fluconazole for 1 year. Two years later, a repeat transthoracic echo showed improvement in the right-ventricular size but remained mildly dilated.

      Patient 7

      A 52-year-old former nurse from Minnesota with a history of hypertension presented with muscle weakness, bone pain, and diarrhea following a trip to Florida. Chest computed tomography demonstrated left lower-lobe cavitary lesion and right upper-lobe ground-glass nodule. Blastomyces urine antigen was low positive (0.35 ng/mL). Itraconazole (capsule formulation), 200 mg every 8 hours for 3 days, followed by 200 mg twice daily, was initiated for possible blastomycosis. Ten days later, the combined itraconazole/hydroxy-itraconazole serum level was 4.8 μg/mL. The itraconazole dose was decreased to 200 mg in the morning and 100 in the evening, resulting in a total itraconazole serum level of 7.8 μg/mL. The itraconazole dose was further reduced to 100 mg, twice daily.
      One month later, the patient reported increased blood pressure, new-onset dyspnea, slight swelling in her hands and feet, mouth ulcers, and poor appetite. Repeat total itraconazole level was 6.5 μg/mL. The itraconazole dose was further decreased to 100 mg daily. Shortness of breath progressed to dyspnea with minimal exertion and difficulty speaking. She reported chest pain, reported to emergency care, and was found to be in respiratory acidosis and hypokalemic, with serum potassium 2.8 mmol/L without known cause. Itraconazole was stopped, and subsequently her blood-pressure control improved, but dyspnea symptoms waxed and waned. Seventeen days later, her total itraconazole serum level was 1.4 μg/mL. Several months later, pharmacogenomics testing revealed CYP3A4 genotype∗1/∗22, which is associated with reduced 3A4 function. Approximately 2 years later, she was newly diagnosed with HFpEF at an outside institution.

      Patient 25

      A 63-year-old man from Wisconsin, with a history of pulmonary sarcoidosis, hyperlipidemia, benign prostate hypertrophy, and mild idiopathic low CD4, presented with a history of recurrent blastomycosis treated with itraconazole for 2 years, dosed at 100 mg twice daily. He had a pulmonary relapse of blastomycosis and was retreated with itraconazole capsules 200 mg twice daily, which now was associated with frequent nocturia of 4 to 5 times nightly. Because of the marked nocturia, the itraconazole was decreased to 100 mg twice daily. With this dose reduction, nocturia improved to 1 to 2 times per night. Total serum itraconazole on this dose was 3.5 μg/mL. His history was unremarkable for heart failure, fluid retention, or peripheral edema. Following completion of 18 months’ treatment dosing, the itraconazole dose was decreased to 100 mg, once daily, for lifelong secondary prophylaxis, which led to a decrease in nocturia to 1 time nightly. Nocturia completely resolved with itraconazole 100 mg, 3 times weekly. The patient was switched to fluconazole for secondary prophylaxis in early 2019.

      Discussion

      This study is the largest of its kind to detail itraconazole-related toxicity comprehensively at a single center since the FDA warning was issued nearly 20 years ago. Although the notion of cardiac- and fluid-related toxicity associated with itraconazole is known, the variety in patient presentations and specific sequelae were significant findings. Although some patients experience classic reduced ejection fraction, others demonstrated preserved ejection fraction. A possible mechanism is itraconazole damage to myofibroblasts or mitochondrial dysfunction, as seen with anthracycline cardiotoxicity.
      • Bollong M.J.
      • Yang B.
      • Vergani N.
      • et al.
      Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis.
      ,
      • Varga Z.V.
      • Ferdinandy P.
      • Liaudet L.
      • Pacher P.
      Drug-induced mitochondrial dysfunction and cardiotoxicity.
      In addition, fluid retention and hypertension, as experienced by Patient 25, may be related to mineralocorticoid excess. Thompson et al. have postulated that itraconazole inhibition of 11β-hydroxysteroid dehydrogenase 2 may lead to this effect.
      • Hoffman W.J.
      • McHardy I.
      • Thompson III, G.R.
      Itraconazole induced hypertension and hypokalemia: mechanistic evaluation.
      In a few cases, clinicians did not recognize itraconazole as a risk, and patients experienced ongoing negative outcomes.
      The clinical implications of pharmacogenomic variability on itraconazole metabolism have not been thoroughly explored. At this time, there are no Clinical Pharmacogenetics Implementation Consortium guidelines to direct clinician response to pharmacogenomic testing results on itraconazole use and dosing, although drug metabolic pathways suggest a potential influence.
      ,
      • Ashbee H.R.
      • Gilleece M.H.
      Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics.
      Itraconazole undergoes hepatic metabolism primarily by CYP3A4, forming more than 30 metabolites, including hydroxy-itraconazole, which has antifungal activity. All metabolites are also inhibitors of CYP3A4, having higher affinity for CYP3A4 than the parent drug.
      • Ashbee H.R.
      • Gilleece M.H.
      Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics.
      Patient 7’s pharmacogenomics indicated reduced CYP3A4 activity, which may have played a role in increased itraconazole exposure and, ultimately, cardiac toxicity.

      Limitations

      This study has several limitations, chiefly a lack of data on total itraconazole use during the study time frame to determine an exact rate of incidence. One-year sample revealed 316 unique patients issued itraconazole at Mayo Clinic Rochester, suggesting that these toxicities are infrequent. We did not seek to quantify specific patient risk factors or biochemical makers but see these as areas for future exploration. In addition, all the patients in this report were Caucasians, which may limit generalizability of our findings to non-Caucasian patient populations.

      Conclusion

      Over a 20-year span, itraconazole was the probable cause of 31 serious cardiac and fluid disorders at our institution.

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