RESUMO
OBJECTIVE: To assess the risk of select safety outcomes including endometrial cancer, endometrial hyperplasia, and breast cancer among women using conjugated estrogens/bazedoxifene (CE/BZA) as compared with estrogen/progestin combination hormone therapy (EP). METHODS: We conducted a new-user cohort study in five US healthcare claims databases representing more than 92 million women. We included CE/BZA or EP new users from May 1, 2014, to August 30, 2019. EP users were propensity score (PS) matched to users of CE/BZA. Incidence of endometrial cancer, endometrial hyperplasia, breast cancer, and eight additional cancer and cardiovascular outcomes were ascertained using claims-based algorithms. Rate ratios (RR) and differences pooled across databases were estimated using random-effects models. RESULTS: The study population included 10,596 CE/BZA and 33,818 PS-matched EP new users. Rates of endometrial cancer and endometrial hyperplasia were slightly higher among CE/BZA users (1.6 and 0.4 additional cases per 10,000 person-years), although precision was limited because of small numbers of cases (endometrial cancer: RR, 1.50 [95% confidence interval {CI}, 0.79-2.88]; endometrial hyperplasia: RR, 1.69 [95% CI, 0.51-5.61]). Breast cancer incidence was lower in CE/BZA users (9.1 fewer cases per 10,000 person-years; RR, 0.79; 95% CI, 0.58-1.05). Rates of other outcomes were slightly higher among CE/BZA users, but with confidence intervals compatible with a wider range of possible associations. CONCLUSIONS: CE/BZA users might experience slightly higher rates of endometrial cancer and endometrial hyperplasia, and a lower rate of breast cancer, than EP users in the first years of use.
Assuntos
Neoplasias da Mama , Neoplasias do Endométrio , Terapia de Reposição de Estrogênios , Estrogênios , Moduladores Seletivos de Receptor Estrogênico , Estrogênios/efeitos adversos , Estrogênios/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Terapia de Reposição de Estrogênios/efeitos adversos , Humanos , Feminino , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/epidemiologia , Neoplasias do Endométrio/induzido quimicamente , Neoplasias do Endométrio/epidemiologia , Hiperplasia Endometrial/induzido quimicamente , Hiperplasia Endometrial/epidemiologia , Incidência , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: There is limited real-world safety information on palbociclib for treatment of advanced stage HR+/HER2- breast cancer. METHODS: We conducted a cohort study of breast cancer patients initiating palbociclib and fulvestrant from February 2015 to September 2017 using the HealthCore Integrated Research Database (HIRD), a longitudinal claims database of commercial health plan members in the United States. The historical comparator cohort comprised patients initiating fulvestrant monotherapy from January 2011 to January 2015. Propensity score matching and Cox regression were used to estimate hazard ratios for various safety events. For acute liver injury (ALI), additional analyses and medical record validation were conducted. RESULTS: There were 2445 patients who initiated palbociclib including 566 new users of palbociclib-fulvestrant, and 2316 historical new users of fulvestrant monotherapy. Compared to these historical new users of fulvestrant monotherapy, new users of palbociclib-fulvestrant had a greater than 2-fold elevated risk for neutropenia, leukopenia, thrombocytopenia, stomatitis and mucositis, and ALI. Incidence of anemia and QT prolongation were more weakly associated, and incidences of serious infections and pulmonary embolism were similar between groups after propensity score matching. After adjustment for additional ALI risk factors, the elevated risk of ALI in new users of palbociclib-fulvestrant persisted (e.g. primary ALI algorithm hazard ratio (HR) = 3.0, 95% confidence interval (CI) = 1.1-8.4). CONCLUSIONS: This real-world study found increased risks of several adverse events identified in clinical trials, including neutropenia, leukopenia, and thrombocytopenia, but no increased risk of serious infections or pulmonary embolism when comparing new users of palbociclib-fulvestrant to fulvestrant monotherapy. We observed an increased risk of ALI, extending clinical trial findings of significant imbalances in grade 3/4 elevations of alanine aminotransferase (ALT).
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fulvestranto/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estados UnidosRESUMO
BACKGROUND: Detailed epidemiologic descriptions of large populations of advanced stage ovarian cancer patients have been lacking to date. This study aimed to describe the patient characteristics, treatment patterns, survival, and incidence rates of health outcomes of interest (HOI) in a large cohort of advanced stage ovarian cancer patients in the United States (US). METHODS: This cohort study identified incident advanced stage (III/IV) ovarian cancer patients in the US diagnosed from 2010 to 2018 in the HealthCore Integrated Research Database (HIRD) using a validated predictive model algorithm. Descriptive characteristics were presented overall and by treatment line. The incidence rates and 95% confidence intervals for pre-specified HOIs were evaluated after advanced stage diagnosis. Overall survival, time to treatment discontinuation or death (TTD), and time to next treatment or death (TTNT) were defined using treatment information in claims and linkage with the National Death Index. RESULTS: We identified 12,659 patients with incident advanced stage ovarian cancer during the study period. Most patients undergoing treatment received platinum agents (75%) and/or taxanes (70%). The most common HOIs (> 24 per 100 person-years) included abdominal pain, nausea and vomiting, anemia, and serious infections. The median overall survival from diagnosis was 4.5 years, while approximately half of the treated cohort had a first-line time to treatment discontinuation or death (TTD) within the first 4 months, and a time to next treatment or death (TTNT) from first to second-line of about 6 months. CONCLUSIONS: This study describes commercially insured US patients with advanced stage ovarian cancer from 2010 to 2018, and observed diverse treatment patterns, incidence of numerous HOIs, and limited survival in this population.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Platina/uso terapêutico , Taxoides/uso terapêutico , Idoso , Algoritmos , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Revisão da Utilização de Seguros , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Análise de Sobrevida , Tempo para o Tratamento , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: We conducted a study to assess whether testosterone therapy (TT) alters prostate cancer risk using a large U.S. commercial insurance research database. METHODS: From the HealthCore Integrated Research Database (HIRD), we selected men ages 30 years or greater who were new users of TT during 2007 to 2015. We selected two comparison groups: (i) unexposed (matched 10:1) and (ii) new users of phosphodiesterase type 5 inhibitor (PDE5i). Incident prostate cancer was defined as diagnosis of prostate cancer within 4 weeks following prostate biopsy. Propensity scores and inverse probability of treatment weights were used in Poisson regression models to estimate adjusted incidence rates, incidence rate ratios (IRR), and 95% confidence intervals (CI). Subgroup analyses included stratification by prostate cancer screening, hypogonadism, and follow-up time. RESULTS: The adjusted prostate cancer IRR was 0.77 (95% CI, 0.68-0.86) when comparing TT with the unexposed group and 0.85 (95% CI, 0.79-0.91) in comparison with the PDE5i group. Inverse associations between TT and prostate cancer were observed in a majority of subgroup analyses, although in both comparisons estimates generally attenuated with increasing time following initial exposure. Among TT users, duration of exposure was not associated with prostate cancer. CONCLUSIONS: Men who received TT did not have a higher rate of prostate cancer compared with the unexposed or PDE5i comparison groups. The inverse association between TT and prostate cancer could be the result of residual confounding, contraindication bias, or undefined biological effect. IMPACT: This study suggests that limited TT exposure does not increase risk of prostate cancer in the short term.
Assuntos
Hipogonadismo/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Neoplasias da Próstata/epidemiologia , Testosterona/uso terapêutico , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Adulto , Idoso , Biópsia , Bases de Dados Factuais/estatística & dados numéricos , Planos de Seguro com Fins Lucrativos/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Medição de Risco/estatística & dados numéricos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Although healthcare databases are a valuable source for real-world oncology data, cancer stage is often lacking. We developed predictive models using claims data to identify metastatic/advanced-stage patients with ovarian cancer, urothelial carcinoma, gastric adenocarcinoma, Merkel cell carcinoma (MCC), and non-small cell lung cancer (NSCLC). METHODS: Patients with ≥1 diagnosis of a cancer of interest were identified in the HealthCore Integrated Research Database (HIRD), a United States (US) healthcare database (2010-2016). Data were linked to three US state cancer registries and the HealthCore Integrated Research Environment Oncology database to identify cancer stage. Predictive models were constructed to estimate the probability of metastatic/advanced stage. Predictors available in the HIRD were identified and coefficients estimated by Least Absolute Shrinkage and Selection Operator (LASSO) regression with cross-validation to control overfitting. Classification error rates and receiver operating characteristic curves were used to select probability thresholds for classifying patients as cases of metastatic/advanced cancer. RESULTS: We used 2723 ovarian cancer, 6522 urothelial carcinoma, 1441 gastric adenocarcinoma, 109 MCC, and 12,373 NSCLC cases of early and metastatic/advanced cancer to develop predictive models. All models had high discrimination (Câ¯>â¯0.85). At thresholds selected for each model, PPVs were all >0.75: ovarian cancerâ¯=â¯0.95 (95% confidence interval [95% CI]: 0.94-0.96), urothelial carcinomaâ¯=â¯0.78 (95% CI: 0.70-0.86), gastric adenocarcinomaâ¯=â¯0.86 (95% CI: 0.83-0.88), MCCâ¯=â¯0.77 (95% CI 0.68-0.89), and NSCLCâ¯=â¯0.91 (95% CI 0.90 - 0.92). CONCLUSION: Predictive modeling was used to identify five types of metastatic/advanced cancer in a healthcare claims database with greater accuracy than previous methods.
Assuntos
Seguro Saúde/estatística & dados numéricos , Neoplasias/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sistema de Registros , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Prostate cancer is a commonly studied outcome in administrative claims studies, but there is a dearth of validated case identifying algorithms. The long-term development of the disease increases the difficulty in separating prevalent from incident prostate cancer. The purpose of this validation study was to assess the accuracy of a claims algorithm to identify incident prostate cancer among men in commercial and Medicare Advantage US health plans. METHODS: We identified prostate cancer in claims as a prostate cancer diagnosis within 28 days after a prostate biopsy and compared case ascertainment in the claims with the gold standard results from the Georgia Comprehensive Cancer Registry (GCCR). RESULTS: We identified 74,008 men from a large health plan claims database for possible linkage with GCCR. Among the 382 prostate cancer cases identified in claims, 312 were also identified in the GCCR (positive predictive value [PPV] = 82%). Of the registry cases, 91% (95% confidence interval = 88, 94) were correctly identified in claims. Claims and registry diagnosis dates of prostate cancer matched exactly in 254/312 (81%) cases. Nearly half of the false-positive cases also had claims for prostate cancer treatment. Thirteen (43%) false-negative cases were classified as noncases by virtue of having a biopsy and diagnosis >28 days apart as required by the algorithm. Compared to matches, false-negative cases were older men with less aggressive prostate cancer. CONCLUSIONS: Our algorithm demonstrated a PPV of 82% with 92% sensitivity in ascertaining incident PC. Administrative health plan claims can be a valuable and accurate source to identify incident prostate cancer cases.
Assuntos
Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Algoritmos , Neoplasias da Próstata/epidemiologia , Adulto , Idoso , California/epidemiologia , Estudos de Coortes , Bases de Dados Factuais , Georgia/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Reprodutibilidade dos TestesRESUMO
PURPOSE: Claims databases offer large populations for research, but lack clinical details. We aimed to develop predictive models to identify estrogen receptor positive (ER+) and human epidermal growth factor negative (HER2-) early breast cancer (ESBC) and advanced stage breast cancer (ASBC) in a claims database. METHODS: Female breast cancer cases in Anthem's Cancer Care Quality Program served as the gold standard validation sample. Predictive models were developed from clinical knowledge and empirically from claims data using logistic and lasso regression. Model performance was assessed by classification rates and c-statistics. Models were applied to the HealthCore Integrated Research Database (claims) to identify cohorts of women with ER+/HER2- ESBC and ASBC. RESULTS: The validation sample included 3184 women with ER+/HER2- ESBC and 1436 with ER+/HER2- ASBC. Predictive models for ER+/HER2- ESBC and ASBC included 25 and 20 factors, respectively. Models had robust discrimination in identifying cases (c-stat = 0.92 for ESBC and 0.95 for ASBC). Compared with a traditional a priori algorithm developed with clinical insight alone, the ER+/HER2- ASBC-predictive model had better positive predictive value (PPV) (0.91, 95% CI, 0.90-0.93, vs 0.69, 95% CI, 0.66-0.73) and sensitivity (0.54 vs 0.35). Models were applied to the claims database to identify cohorts of 33 001 and 3198 women with ER+/HER2- ESBC and ASBC. CONCLUSION: We conducted a validation study and developed predictive models to identify in a claims database cohorts of women with ER+/HER2- ESBC and ASBC. The models identified large cohorts in the claims data that can be used to characterize indications in the evaluation of targeted therapies.
Assuntos
Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Algoritmos , Neoplasias da Mama/epidemiologia , Modelos Biológicos , Adulto , Idoso , Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Estudos Retrospectivos , Medição de Risco/métodos , Estados Unidos/epidemiologiaRESUMO
Temozolomide (TMZ) is used to treat adult patients with glioblastoma multiforme (GBM). Cases of hepatotoxicity have been reported among patients using TMZ. The objective of the study was to assess the relation, if any, between exposure to TMZ and serious acute liver injury (SALI). We used the HealthCore Integrated Research Database to perform a case-control study nested within a retrospective cohort of adult patients aged 18-100 years with at least two diagnoses of brain cancer anytime between 2006 and 2014. Patients without continuous eligibility or with a SALI diagnosis within 6 months prior to the date of incident brain cancer diagnosis were excluded. Medical records were sought for potential SALI cases and reviewed by two hepatologists. Five controls were selected for each case using incidence density sampling, matched on age and calendar year of index date. The analysis included 61 confirmed SALI cases and 305 selected controls. Exposure to TMZ was classified according to dispensing date and days supply of medication dispensed. We estimated odds ratios using conditional logistic regression models. The odds ratio for any exposure to TMZ was 0.91 (95% CI 0.44-1.91), for recent exposure to TMZ was 0.62 (95% CI 0.21-1.85). There was no increased risk of SALI with increasing duration of exposure to TMZ. When patients with unconfirmed SALI were included in the analysis, results were similar (OR 1.04; 95% CI 0.70-1.54). In conclusion, this study did not find an association between TMZ and SALI risk among patients with brain cancer.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Dacarbazina/efeitos adversos , Bases de Dados Factuais/estatística & dados numéricos , Atenção à Saúde/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Temozolomida , Adulto JovemRESUMO
RATIONALE: Estimates of idiopathic pulmonary fibrosis (IPF) incidence and prevalence from electronic databases without case validation may be inaccurate. OBJECTIVES: Develop claims algorithms to identify IPF and assess their positive predictive value (PPV) to estimate incidence and prevalence in the United States. METHODS: We developed three algorithms to identify IPF cases in the HealthCore Integrated Research Database. Sensitive and specific algorithms were developed based on literature review and consultation with clinical experts. PPVs were assessed using medical records. A third algorithm used logistic regression modeling to generate an IPF score and was validated using a separate set of medical records. We estimated incidence and prevalence of IPF using the sensitive algorithm corrected for the PPV. MEASUREMENTS AND MAIN RESULTS: We identified 4,598 patients using the sensitive algorithm and 2,052 patients using the specific algorithm. After medical record review, the PPVs of these algorithms using the treating clinician's diagnosis were 44.4 and 61.7%, respectively. For the IPF score, the PPV was 76.2%. Using the clinical adjudicator's diagnosis, the PPVs were 54 and 57.6%, respectively, and for the IPF score, the PPV was 83.3%. The incidence and period prevalences of IPF, corrected for the PPV, were 14.6 per 100,000 person-years and 58.7 per 100,000 persons, respectively. CONCLUSIONS: Sensitive algorithms without correction for false positive errors overestimated incidence and prevalence of IPF. An IPF score offered the greatest PPV, but it requires further validation.
Assuntos
Fibrose Pulmonar Idiopática/epidemiologia , Prontuários Médicos/estatística & dados numéricos , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Comorbidade , Bases de Dados Factuais , Feminino , Humanos , Incidência , Revisão da Utilização de Seguros , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Distribuição por Sexo , Estados Unidos/epidemiologiaRESUMO
OBJECTIVES: Inflammatory bowel disease (IBD) is a chronic condition commonly requiring lifelong care. Both IBD and IBD-related treatments can cause significant morbidity, and it is often difficult to differentiate their relative etiologic contribution to adverse events (AEs). The objectives of this study were to assess the rates of select AEs among patients with IBD as a function of disease severity and of the use of anti-tumor necrosis factor alpha (anti-TNFα) medications. METHODS: We conducted a retrospective cohort study of IBD patients in the HealthCore Integrated Research Database (HIRD(TM)) between January 2004 and January 2011 to determine rates of AEs in patients with mild and moderate to severe IBD. Key study endpoints were select prespecified malignant neoplasms, infections, and other AEs of interest. RESULTS: A total of 33,386 IBD patients (52.7% ulcerative colitis; 47.3% Crohn's disease) met the inclusion criteria, and 60% had been followed for ≥1 year. Patients with moderate to severe IBD had increased rates of infections, lymphatic and digestive tract cancers, gastrointestinal (GI) perforations, and myocardial infarctions versus patients with mild IBD. Patients with IBD who used anti-TNFα therapies during the study had increased incidence of many types of infections, certain GI cancers (including rectal and anal cancer), intestinal perforations, and kidney stones compared with patients who had never used anti-TNFα therapies. CONCLUSIONS: Results from this large US cohort provide descriptive information on AE rates in a population of IBD patients undergoing routine care, estimating background incidence rates of AEs that are not readily available in the published literature. Our study findings may be limited owing to a lack of generalizability and potential for misclassification due to reliance on medical diagnosis and treatment and procedure codes to identify disease, comorbidities, and treatments. Further research and validation of our findings in other populations and databases are needed.
Assuntos
Abscesso , Colite Ulcerativa , Doença de Crohn , Doenças Retais , Viroses , Abscesso/epidemiologia , Abscesso/etiologia , Adulto , Idoso , Anticorpos Monoclonais , Estudos de Coortes , Colite Ulcerativa/complicações , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/epidemiologia , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Doença de Crohn/epidemiologia , Bases de Dados Factuais , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doenças Retais/epidemiologia , Doenças Retais/etiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Estados Unidos/epidemiologia , Viroses/epidemiologia , Viroses/etiologiaRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis is a life-threatening condition, and few data concerning the impact on healthcare utilization and associated costs are available. The objective of this study was to describe the burden of illness (comorbidity, healthcare resource utilization, and associated costs) in patients with idiopathic pulmonary fibrosis. METHODS: Two cohorts (patients with idiopathic pulmonary fibrosis and matched controls) were retrospectively identified from US claims databases between January 1, 2001 and September 30, 2008. Cases with idiopathic pulmonary fibrosis were defined by age of 55 years or older and either two or more claims with a code for idiopathic fibrosing alveolitis (ICD-9 516.3), or one claim with ICD 516.3 and a subsequent claim with a code for post-inflammatory pulmonary fibrosis (ICD-9 515). The prevalence and incidence of pre-selected comorbidities, healthcare resource utilization (hospital, outpatient, drugs), and direct medical costs were assessed in each cohort. RESULTS: A total of 9286 patients with idiopathic pulmonary fibrosis were identified. When compared with age- and gender-matched controls, these patients were at significantly increased risk for comorbidities including pulmonary hypertension and emphysema. The all-cause hospital admission rate (0.5 per person-year) and the all-cause outpatient visit rate (28.0 per person-year) were both â¼2-fold higher than in controls. Total direct costs for patients with idiopathic pulmonary fibrosis were $26,378 per person-year; the incremental costs over controls were $12,124 (2008 value). CONCLUSIONS: Patients with idiopathic pulmonary fibrosis experience increased comorbidity, healthcare resource utilization, and direct medical costs compared to controls.
Assuntos
Efeitos Psicossociais da Doença , Fibrose Pulmonar Idiopática/economia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Comorbidade , Bases de Dados Factuais , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Humanos , Fibrose Pulmonar Idiopática/mortalidade , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Topical retinoids have been in clinical use for the treatment of chronic skin conditions, including acne, photodamage, and psoriasis, for 30 years. OBJECTIVE: A systematic literature review was conducted to assess the incidence of noncutaneous adverse events (AE) among patients treated with topical retinoids with a focus on topical tretinoin studies reported before the Veterans Affairs Topical Tretinoin Chemoprevention trial. METHODS: Electronic literature searches were conducted in Embase and MEDLINE for literature reporting development of nonteratogenic, noncutaneous AE among patients treated with topical retinoids published through September 2008. RESULTS: The search yielded 2778 citations, of which 20 studies met inclusion criteria. Tretinoin was used in 14 of the studies. Other retinoids assessed included isotretinoin, adapalene, alitretinoin, and tazarotene. Within patients receiving topical tretinoin, 27.9% reported the occurrence of at least one noncutaneous AE. The majority of noncutaneous AE were transient and judged not to be related to tretinoin treatment. LIMITATIONS: The conclusions of this study apply largely to tretinoin compared with other topical retinoids. Many of the included trials were designed to evaluate the efficacy of topical treatment and reporting of safety events concentrated on incidence of localized AE, rather than systemic or noncutaneous events. CONCLUSION: We found no clear evidence of a relationship between the use of topical tretinoin and the development of noncutaneous AE before a recent report of excess mortality in a clinical trial. The majority of noncutaneous AE reported by patients receiving topical retinoids consisted of nonsevere, nonspecific symptoms that were judged not to be related to treatment.