Optimising Medical Management in CRS

Abstract

Purpose of Review

We assess the literature on different medical treatment options and their effectiveness in chronic rhinosinusitis (CRS).

Recent Findings

Although there is significant overlap in the management of CRS, not all therapies are equally effective within CRS phenotypes.

Summary

CRS is one of the most common chronic health problems affecting a large proportion of adult population and generating significant economic implications. Despite an unclear pathophysiology of this complex disorder, it is widely recognised that surgery alone does not resolve the chronic inflammation and that ongoing medical treatment remains the key to the successful management of patients with CRS.

http://bit.ly/2W3ip11

A case of erythema nodosum‐like panniculitis induced by nivolumab in a patient with oesophageal cancer

http://bit.ly/2AQr0Lu

Association of type 2 cytokines in severe rhinovirus bronchiolitis during infancy with risk of developing asthma: A multicenter prospective study

http://bit.ly/2TX6XSJ

Symptomatic involvement of the stomach and duodenum as initial presentation of AL amyloidosis

Primary systemic or amyloid light chain (AL) amyloidosis is a multisystem disorder with myriad presentations. Although it can involve the upper gastrointestinal tract in 8% of cases, symptomatic involvement is exceedingly rare. We chronicle here a case of postprandial epigastric pain associated with AL amyloidosis involving the stomach and duodenum. Pathological examination of endoscopic biopsy using Congo red staining confirmed the diagnosis. In order to establish the underlying aetiology of AL amyloidosis, the patient underwent extensive workup. Eventually, she was diagnosed with multiple myeloma based on the standard set of investigations. This paper underscores the importance of clinical suspicion of amyloidosis in patients presenting with non-specific gastrointestinal symptoms and highlights the role of endoscopic biopsy to confirm the amyloid deposition. Since gastrointestinal amyloidosis is a disease with a poor prognosis, early diagnosis and treatment are particularly warranted.

http://bit.ly/2HvAYrN

Overgrowth syndrome in neonates: a rare case series with a review of the literature

We present here two-term neonates presenting with right lower limb hypertrophy, a port-wine stain, acral abnormalities and clubfeet. These neonates had overlapping features of Klippel Trenaunay syndrome and congenital lipomatous overgrowth, vascular malformation, epidermal nevi and scoliosis/skeletal abnormalities. Such overgrowth syndrome has not been previously described in the literature. Both the neonates are doing well and are under regular follow-up.

http://bit.ly/2RRVHKa

Immune thrombocytopenic purpura presenting with spontaneous gingival haemorrhage in pregnancy

Gingival bleeding is a common intraoral finding, typically associated with inflamed tissues and periodontal disease. It is easily provoked by periodontal probing or toothbrushing. Spontaneous gingival bleeding rarely occurs and may be the only sign of systemic bleeding problems such as thrombocytopenia, leukaemia or coagulopathy. In pregnancy, acute onset of thrombocytopenia may occur in systemic disorders such as severe pre-eclampsia, HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) or the acute fatty liver of pregnancy. The diagnosis and management of such conditions may challenge physicians. It requires a systematic approach with a comprehensive history to exclude causes of gingival haemorrhage such as periodontal disease, anticoagulant therapy, maxillofacial trauma, haematological disorders or a bacterial infection. The authors describe a case of immune thrombocytopenic purpura presenting with spontaneous gingival haemorrhage in pregnancy. This case highlights the fact that medical intervention to correct the underlying aberration of haemostasis is necessary for local measures to stop the gingival bleeding successfully.

http://bit.ly/2HgpcRB

Lithium neurotoxicity presenting as dementia with therapeutic serum lithium levels

After 25 years of continuous lithium therapy, a woman with moderate intellectual disability and bipolar disorder developed symptoms suggestive of dementia. In fact, she had developed lithium neurotoxicity, but this was overlooked for 18 months as serial lithium levels were in the therapeutic range.

http://bit.ly/2RZu3uY

Resolution of asthmatic symptoms following successful endoscopic resection of tracheal mucoepidermoid carcinoma

Mucoepidermoid carcinoma (MEC) is a rare tumour of the trachea accounting for up to 0.2% of reported primary lung malignancy. We report a case of a 54-year-old man, ex-smoker, whose presentation mimicked adult onset asthma with cough and wheezing, which did not respond to conventional treatment. He had occasional haemoptysis and weight loss in which CT scan performed for malignancy screening showed a protruding mass in the distal trachea causing endobronchial obstruction. Bronchoscopic intervention was performed to relieve the obstruction that resulted in resolution of asthmatic symptoms. Histological diagnosis confirmed MEC. This case emphasised the importance of a high index of suspicion in an unusual presentation of a common disease and the pivotal role of bronchoscopic intervention in malignant central airway obstruction.

http://bit.ly/2HgpaJt

Solid papillary thyroid carcinoma with Hashimotos thyroiditis: description of a further case with challenging cytological features

Solid papillary thyroid carcinoma (SV-PTC) is a rare variant which is mainly observed in young patients with a history of exposure to ionising radiations. Neoplasms belonging to such category generally carry RET-PTC (REarranged during Transfection- Papillary Thyroid Carcinoma) fusions and seem to have a slightly worse prognosis with respect to classical and follicular variants of papillary thyroid carcinoma (PTC), though consistent prognostic and survival data are scarce. SV-PTC should be differentiated from trabecular-insular poorly differentiated thyroid carcinomas, which occur in a different age group and carry a dismal prognosis. These latter tumours do not show the typical nuclear features of PTC and show tumour necrosis with an high mitotic activity. In this report a further case of SV-PTC is described which was associated to Hashimoto's thyroiditis, a finding never described in the cytological literature up to now for SV-PTC; this association created further differential diagnostic problems. The neoplasm displayed RET-PTC1 fusion.

http://bit.ly/2RYQvnE

Fatal case of necrotising fasciitis due to Vibrio vulnificus in a patient with alcoholic liver disease and diabetes mellitus

Vibrio vulnificus is a halophilic Vibrio found globally. They are thought to be normal microbiome in the estuaries along the coasts associated with seawater and seashells. Infection usually results from consumption of raw oysters or shellfish or exposure of broken skin or open wounds to contaminated salt or brackish water. Clinical manifestations range from gastroenteritis to skin and subcutaneous infection and primary sepsis. Pathogen has the ability to cause infections with significant mortality in high-risk populations, including patients with chronic liver disease, immunodeficiency, diabetes mellitus and iron storage disorders. There is often a lack of clinical suspicion in cases due to Vibrio vulnificus leading to delay in treatment and subsequent mortality. Herein we report a case of necrotising fasciitis in a diabetic patient with alcoholic liver disease caused by Vibrio vulnificus which ended fatally.

http://bit.ly/2Hgp98n

Azygos vein cannulation after catheterisation of the left internal jugular vein in a toddler

Central venous catheterisation is routinely performed in paediatric patients to facilitate therapeutic management when long-term vascular access is needed. Misplacement of the catheter tip in thoracic vessels other than the superior vena cava has been described, along with related complications. Hereby, a case of a 15-month-old child is presented with a fully functional Hickman catheter introduced via the left internal jugular vein. The tip of the catheter was misplaced into the azygos vein. Intraoperative spot fluoroscopic images and anatomical explanations for the course of the catheter are presented. An understanding of the aetiology of the radiological appearance may help to increase recognition of such cases and avoid complications.

http://bit.ly/2RPsmjD

Monomicrobial necrotising soft tissue infection of the hand caused by a Panton-Valentine leukocidin-negative Staphylococcus aureus strain in a 66-year-old patient with diabetes

http://bit.ly/2HgpJTB

Rare presentation of iron deficiency anaemia with cerebral venous sinus thrombosis in a middle-aged woman

This is a case of a female patient presented with a mild headache associated with recurrent episodes of nausea and vomiting, confusion and right-sided hemiparesis, diagnosed of haemorrhagic venous infarction from the thrombosis of left transverse and sigmoid sinus and probably the left vein of Labbe. She had severe microcytic hypochromic anaemia due to iron deficiency, without any other risk factors for cerebral venous thrombosis such as trauma history, infections, coagulation disorders or autoimmune diseases. She had a good prognosis after iron supplementation and anticoagulation therapy.

http://bit.ly/2RTaW5r

Non-traumatic splenic rupture secondary to haemorrhagic infarct in diffuse large B-cell lymphoma

http://bit.ly/2HgpF6j

Paediatric presentation of intracranial haemorrhage due to thrombosis of a developmental venous anomaly

Developmental venous anomalies (DVAs) are the most commonly encountered cerebral malformations. While generally asymptomatic and discovered as incidental findings, there is a small number that can cause intracranial haemorrhage, usually attributed to associated cavernomas; however, venous thrombosis of the draining vein is a rare cause. A 10-year-old woman presented with seizure episodes. Angiographic evaluation revealed a collection of vessels draining into the superior sagittal sinus via the vein of Trolard, concerning for a DVA. The patient improved clinically with supportive care and antiepileptic treatment. Anatomically, DVAs represent dysplasia of primary capillary beds and smaller cerebral veins, resulting in abnormal venous drainage of the affected parenchyma. Several distinguishing radiological findings can help differentiate a DVA from other pathologies. Early radiological identification can help in the initiation of appropriate therapy and prevent incorrect surgical management leading to further neurological demise.

http://bit.ly/2RPsks1

Recurrent case of pregnancy-induced atypical haemolytic uremic syndrome (P-aHUS)

Pregnancy-induced atypical haemolytic uremic syndrome (P-aHUS) is a rare condition characterised by microangiopathic haemolytic anaemia, thrombocytopenia and renal failure. It accounts for approximately 7% of total HUS cases. Here, we present a case of recurrent P-aHUS in a 25-year-old Hispanic woman. Pregnancy was the clear trigger in both instances, and the disease manifested in first week of the postpartum period. Because of her significant obstetric history, a multidisciplinary approach was adopted to monitor her second pregnancy antepartum and post partum. As the patient developed recurrence of P-aHUS 4 days after her delivery, she was immediately administered eculizumab within few hours of disease manifestation. The patient normalised her haematological parameters within 1 week but sustained dialysis-requiring renal failure for a total of 6 weeks. This case highlights the advances as well as the ongoing uncertainties, especially with respect to the use of eculizumab, in this rare but morbid disease.

http://bit.ly/2HgpA2v

January is Thyroid Awareness Month

Thyroid Medication Among Most Prescribed in U.S.
Laura Rosbrow-Telem, Public News Service – MA

Dr. Elizabeth Pearce, president of the American Thyroid Association and a professor at Boston University's School of Medicine, says thyroid disorders, which affect the thyroid gland toward the bottom of the neck, particularly impact women, especially as they age.

Read Article…

The post January is Thyroid Awareness Month appeared first on American Thyroid Association.

http://bit.ly/2RVehRB

Relationship of Sociodemographic Factors and Outcomes in Functional Rhinoplasty

Facial plast Surg
DOI: 10.1055/s-0039-1677708

The objective of this article was to compare the effect of such sociodemographic factors as gender, age, marital status, employment status, race, and income on short- and long-term rhinoplasty outcomes using a validated disease-specific instrument—Nasal Obstruction Symptom Evaluation (NOSE) scale, as well as complication and revision rates. Patients who underwent a functional (+/− cosmetic) rhinoplasty with the senior author between January, 1 2012, and September 9, 2017, and had both a preoperative and at least one postoperative NOSE score, were included in the study. Sociodemographic variables of binary gender, age, marital status, employment status, race, and income based on zip code were collected. The primary outcomes were the differences between the preoperative and postoperative NOSE scores with short-term (less than 3 months) and longer-term (greater than 3 months) follow-up. Secondary outcomes were general complications and specifically revision surgery. Standard descriptive statistics, as well as univariable linear and logistic regressions, were conducted with each outcome measure. A total of 341 patients were included in this study. No individual patient-level variables were found to significantly affect the short- or longer-term average change in NOSE scores, although older age trended toward significance in longer-term average change in NOSE scores (p = 0.07). No factors significantly affected the rate of complications or revision surgery in this cohort. The authors found improvement in NOSE scores after rhinoplasty was not related to factors of age, gender, race, employment status, income, and marital status. This cohort also did not demonstrate differential rates in complications or revision surgery based on sociodemographic variables.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

http://bit.ly/2HkauJv

The Effect of Minocycline on Fat Graft Survival and Apoptotic Pathway

Facial plast Surg
DOI: 10.1055/s-0039-1677709

Variable absorption rate is one of the biggest problems of fat grafting and one of the most important causes of fat graft volume loss is apoptosis. Minocycline is a tetracycline derivative and besides its antibacterial capacity, it has been widely using for anti-apoptotic effects. This study was designed to investigate the effect of minocycline on fat graft survival and adipocyte apoptosis. A total of two main and eight subgroups were designed and a total of 48 experimental animals, 6 in each group, were used. Fat grafts are obtained from Wistar albino rats and implanted to dorsal area of rats. Local and systemic minocycline was applied in the study groups. On the 9th day, apoptotic cells were detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling method and on the 90th day morphologic characteristics and viability of adipocytes were evaluated using histologic and immunohistochemical methods and statistically compared. This study revealed that the fat grafts were bigger, and they kept their structures better and they were more vascular in the minocycline groups and apoptosis was significantly lower in the minocycline groups. The authors demonstrated that minocycline increases fat graft survival and statistical improvement in apoptosis inhibition via using minocycline therapy has been shown.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

http://bit.ly/2RUA7ET

The impact of implant abutment surface treatment with TiO2 on peri-implant levels of angiogenesis and bone-related markers: a randomized clinical trial

The goal of this randomized, blinded, split-mouth controlled clinical trial was to assess the influence of abutment surface treatment on tissue healing. Fifteen patients received two implants distributed randomly to two groups: test (TiO2 abutment surface), control (standard abutment surface). Levels of epidermal growth factor (EGF), bone morphogenetic protein 9 (BMP-9), endothelin 1 (ET-1), fibroblast growth factor (FGF), placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) were quantified in the peri-implant fluid after 3, 14, 30, and 60 days.

http://bit.ly/2CtCLYx

Necrotic ulcer on the chin

Necrotic ulcer on the chin of a previously healthy 38-year-old woman.

Simonsen S, Winther C, Zachariae C, Skov L.

Int J Dermatol. 2019 Jan 10. doi: 10.1111/ijd.14378. [Epub ahead of print] No abstract available.

PMID:

 

30632142

Persisting ulcer on the chin

Ned Tijdschr Geneeskd  

Meij V1, Kuijpers KC.

Author information

1

St. Antonius Ziekenhuis, Afd. Heelkunde, Nieuwegein, the Netherlands. v.meij@antoniusziekenhuis.nl

Abstract

A 62-year-old woman presented with an ulcerative lesion on the chin. She had not visited tropical regions, but she had been in Cyprus. A skin biopsy revealed coccoid micro-organisms resembling Leishmania. Subsequently a PCR was performed which showed Leishmania donovani and Leishmania infantum complex and the diagnose 'cutaneous leishmaniasis' was confirmed.

PMID: 22129807

Possible long-term sequelae in hand, foot, and mouth disease caused by Coxsackievirus A6

To the Editor: We read with interest a paper disclosing the enterovirus (EV) types responsible for hand, foot, and mouth disease (HFMD) in Chinese children.1 Among 2571 EV-positive cases, three quarters were attributed to 3 predominant types: Coxsackievirus (CV)-A16, CV-A6, and EV-A71. However, the report did not deal with EV-related atypical exanthems2 nor with the possible long-term consequences of these infections.

http://bit.ly/2SWbJ2J

Amyotrophic lateral sclerosis and anesthesia: a case series and review of the literature

Abstract

Purpose

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to death due to respiratory failure. This report describes the perioperative characteristics of ALS patients who underwent procedures with anesthesia at our institution.

Methods

We reviewed perioperative records of ALS patients who underwent procedures with anesthesia from January 1, 2014, through December 31, 2015.

Results

Seventy-eight patients underwent 89 procedures (71 procedures with monitored anesthesia care and 18 with general anesthesia), including 45 gastrostomy tube placements and 18 bone marrow biopsies. Three patients had prolonged duration of postoperative intubation related to preexisting respiratory muscle weakness, and one patient with bilateral pneumothorax required tracheal reintubation for respiratory distress. Four patients had prolonged duration of hospitalization. Three patients were hospitalized for ALS-related complications, and one patient was hospitalized for respiratory distress when pneumoperitoneum developed after gastrostomy tube placement. Three of these patients died of complications attributable to ALS within 30 days of the procedure. Twenty-nine (32.6%) procedures required minimal sedation (e.g., bone marrow biopsy, cataract surgery) and were performed on an ambulatory basis.

Conclusion

When caring for patients with ALS, the perioperative team must be prepared to treat potentially complex medical conditions that may not be directly related to the procedure and anesthetic management. However, minor procedures performed with minimal sedation may be safely performed on an ambulatory basis.

http://bit.ly/2CxpoX4

Health-Related Quality of Life After Diagnosis and Treatment of Differentiated Thyroid Cancer

This content analysis assesses health-related quality of life outcomes and adverse effects of different types of surgical treatment of differentiated thyroid cancer among patients in an Australian case-control study.

http://bit.ly/2ATMxmF

Association of Genetic vs Environmental Factors in Swedish Adoptees With Clinically Significant Tinnitus

This study uses Swedish national registry data to assess the association between genetic vs environmental factors and risk of tinnitus among adoptees.

http://bit.ly/2SZNFfv

Hearing Loss Research on Children Compared With Older Adults

This database study assesses areas of research on hearing loss in children and older adults.

http://bit.ly/2AQFM4Z

Heritability and Tinnitus

Genetic factors are fundamental in the molecular pathologic mechanisms of a number of auditory disorders that present throughout the lifespan. Historically, an understanding of the role of genetics in tinnitus has not been as straightforward because it can be viewed as a symptom of multiple diseases. Risk factors for tinnitus include hearing loss, aging, and noise exposure, most logically connecting its cause with environmental factors. This notion has been supported by a lack of heritability determined from early family-based questionnaire studies. In addition, previous studies that have primarily used genotyping in the pregenomics era have identified several candidate genes implicated in tinnitus (summarized by Lopez-Escamez et al) that have thus far lacked replication, and a recent pilot genome-wide association study also did not reveal significant associations. Throughout the course of genetics research in tinnitus, it has become increasingly clear that the lack of significance may have been hampered by an underappreciation of the clinical heterogeneity and subtypes that are inherent in tinnitus, which may have profoundly clouded true significant associations.

http://bit.ly/2T1RCQM

Incident Hearing Loss and Comorbidity

This retrospective, propensity-matched cohort study assesses the association between hearing loss and medical comorbidities.

http://bit.ly/2DgHQVC

January Issue Highlights

http://bit.ly/2TW3aoJ

Iodine Deficiency and Hearing Impairment

To the Editor On June 7, 2018, Scinicariello et al published a study in JAMA Otolaryngology–Head & Neck Surgery in which they analyzed data from 1198 adolescents (aged 12-19 years) from NHANES 2007 to 2010, with urinary iodine, audiometric measurements, and demographic and related variables. The authors concluded that this is the first study in which it was demonstrated at a national level that a urinary iodine concentration (UIC) less than 100 μg/L was a predictive risk factor for having speech-frequency hearing loss (SFHL) among adolescents, and more specifically among those with UIC less than 50 μg/L.

http://bit.ly/2Dfw5i1

Incidence of Thyroid Cancer Among Residents Within 5 Years of the 2011 Fukushima Nuclear Accident

This cohort study of 324 301 children and young adults in Fukushima, Japan, evaluates the number of detected thyroid cancers by age group within 5 years of the 2011 Fukushima Daiichi nuclear power station accident and compares basic clinical characteristics and demographic patterns in first-round and second-round examinations.

http://bit.ly/2TW34gR

Association of Age-Related Hearing Loss With Multiple Adverse Health Outcomes

Age-related hearing loss (ARHL) has recently received much attention owing to its recognition as a potential modifiable risk factor for dementia. An increasing number of observational studies, mostly published in the last decade, have associated ARHL with cognitive decline, cognitive impairment, and dementia, igniting increasing interest in ARHL. Livingston et al reported that interventions for peripheral hearing loss may reduce the prevalence of dementia by 9% globally, which is a result higher than that for any other modifiable risk factor. Interestingly, ARHL has also been associated with a higher risk for other common age-related conditions, including depression and falls, suggesting that ARHL is connected with a broader decline in health. However, the association of ARHL with adverse health outcomes other than dementia has been less well studied, despite the prevalence of ARHL as a chronic malady in older age (more than half of US adults older than 60 years have clinically meaningful hearing loss).

http://bit.ly/2DhSThv

Why the Data From the Fukushima Daiichi Nuclear Power Station Accident Are Important

On March 11, 2011, the Great East Japan Earthquake and subsequent giant tsunami led to catastrophic damage at the TEPCO (Tokyo Electric Power Company Holdings) Fukushima Daiichi nuclear power station. Radioactive materials spread into the Fukushima Prefecture. Although the estimated release of radioactive material was quite small, the accident caused great alarm within the population. In response, 4 months later, in July 2011, the Fukushima Health Management Survey was launched to monitor for potential radiation-induced health effects, including a large-scale thyroid surveillance program. In this issue of JAMA Otolaryngology–Head & Neck Surgery, Ohtsuru and colleagues provide data from the initial 2 rounds of ultrasound screening during the first 5 years after the accident, the first round between 2011 and 2013 and the second round between 2014 and 2015. Ultimately, 324 301 individuals who had been younger than 18 years at the time of the accident (the age group at higher risk of thyroid cancer after radiation exposure) were included in the analysis. During the 4 years after the accident that the screening rounds took place, 187 children and adolescents were diagnosed with thyroid cancer; the most common pathologic diagnosis was papillary thyroid cancer (98.0%).

http://bit.ly/2TW2Whn

Aggressive-Appearing Intratracheal Mass in an Older Woman

A woman in her early 70s presents with biphasic stridor and a report of dyspnea on mild exertion. Noncontrast computed tomography of the chest shows a lesion protruding into the right side of the tracheal region that appears to be contiguous with the right lobe of the thyroid gland. Examination of a biopsy specimen shows medullary thyroid cancer. What is your diagnosis?

http://bit.ly/2DhSNXb

Thyroid Cancer Screening After Nuclear Accidents

This guideline recommendation by an expert group convened by the International Agency for Research on Cancer outlines recommendations for thyroid screening after nuclear events.

http://bit.ly/2TWy4gS

Analysis of Clinical Features of Mammary Analog Secretory Carcinoma Using the SEER Database

This population-based study uses data from the Surveillance, Epidemiology, and End Results database to analyze the typical clinical characteristics of mammary analog secretory carcinoma.

http://bit.ly/2DdCXwo

Care of Patients With Endocrine Conditions

In this issue, we present the study by Ohtsuru and colleagues who analyzed clinical characteristics of thyroid cancers screened by ultrasonography in children and young adults during the first 5 years after the 2011 Fukushima Daiichi Nuclear Power Station accident. Along with the publication of this landmark study, I am excited to announce a new section editor in JAMA Otolaryngology–Head & Neck Surgery who will be dedicated to the care of patients with endocrine conditions. I invited Louise Davies, MD, MS, to serve as the first Endocrinology Section Editor. Dr Davies is an internationally recognized expert on thyroid cancer with a focus on appropriate treatment of adults diagnosed with small thyroid nodules and has methodologic expertise in epidemiology and mixed-methods research approaches. I am also excited to announce the appointment of Luc G. T. Morris, MD, MSc, to the editorial board. Dr Morris' research program straddles head and neck cancer genomics and the epidemiology of overdiagnosis, and he has methodologic expertise in biostatistics and bioinformatics. Together, they will provide breadth and depth to this renewed area of clinical focus.

http://bit.ly/2TWxT54

Utility of Routine Spirometry Measures for Surveillance of Idiopathic Subglottic Stenosis

This medical record review of 42 patients compares the use of peak expiratory flow, expiratory disproportion index, and total peak flow measures for monitoring disease progression in patients with idiopathic subglottic stenosis.

http://bit.ly/2APnDET

Association of Hospital Volume With Laryngectomy Outcomes in Patients With Larynx Cancer

This cross-sectional study of patients with a diagnosis of larynx cancer characterizes the hospital volume-outcome association specifically for laryngectomy surgery and identifies a minimum hospital volume threshold associated with improved outcomes.

http://bit.ly/2T05Phk

Failure to Accurately Disclose Conflicts of Interest in Article Published in JAMA Otolaryngology–Head & Neck Surgery

To the Editor I write to take full responsibility for failing to report appropriate conflict of interest disclosures in articles published in JAMA Otolaryngology–Head & Neck Surgery and the JAMA Network journals between 2015 and 2018, including "Cetuximab and Radiotherapy in Laryngeal Preservation for Cancers of the Larynx and Hypopharynx: A Secondary Analysis of a Randomized Clinical Trial," published online on April 9, 2016, and in the September 2016 issue of JAMA Otolaryngology–Head & Neck Surgery. In that article, I had reported nothing to disclose. In the interest of full disclosure, I now report the following financial interests and activities that I had been involved in from 2013 to the present, regardless of potential relevance:

http://bit.ly/2AKv3sX

Surgical Volumes and Outcomes

Practice makes perfect. Three words, easily conceptualized, and second nature for any surgeon. It is not surprising that an established and growing body of literature describes improved outcomes when complex surgery is performed by hospitals and surgeons who do those procedures frequently. Luft et al published the foundational study in 1979, reporting on 8 complex operations in almost 1 million patients. For some operations, they found a negative association between the number of procedures performed in a hospital and mortality rates. That general finding has been reproduced using a wide range of data sources for a variety of high-risk operations, including those done for head and neck cancer.

http://bit.ly/2SYr1Eo

JAMA Otolaryngology–Head & Neck Surgery

Mission Statement:JAMA Otolaryngology–Head & Neck Surgery provides timely information for physicians and scientists concerned with diseases of the head and neck. Given the diversity of structure and function based in this anatomic region, JAMA Otolaryngology–Head & Neck Surgery publishes clinical, translational, and population health research from an array of disciplines. We place a high priority on strong study designs that accurately identify etiologies, evaluate diagnostic strategies, and distinguish among treatment options and outcomes. Our objectives are to (1) publish original contributions that will enhance the clinician's understanding of otolaryngologic disorders, benefit the care of our patients, and stimulate research in our field; (2) forecast important advances within otolaryngology—head and neck surgery, particularly as they relate to the prevention, diagnosis, and treatment of disease through clinical and translational research, including that of the human genome and novel imaging techniques; (3) address questions of clinical outcomes and cost-effectiveness that result from clinical intervention, which grow in importance as health care providers are increasingly challenged to provide evidence of enhanced survival and quality of life; (4) provide expert reviews of topics that keep our readers current with true advances and also to provide a valuable educational resource for trainees in the several disciplines that treat patients with diseases of the head and neck; (5) serve as a forum for the concerns of otolaryngologists such as socioeconomic, legal, ethical, and medical issues; (6) provide helpful critiques that enable contributing authors to improve their submissions. We encourage a concise presentation of information and employ an abstract format that efficiently assesses validity and relevance from a clinical perspective. This approach promotes succinct yet complete presentation for our readers and electronic information resources. We believe this approach typifies the commitment of JAMA Otolaryngology–Head & Neck Surgery to providing important information that is easily interpreted by its diverse readership.

http://bit.ly/2AQDnaF

Association Between Lymph Node Ratio and Recurrence and Outcomes in Patients With Oral Cavity Cancer

This cohort study examines the association between lymph node ratio and tumor recurrence and survival outcomes in patients with oral cavity squamous cell carcinoma.

http://bit.ly/2SV9cpO

Trends in Health Care Costs and Utilization Associated With Untreated Hearing Loss Over 10 Years

This cohort study assesses whether untreated hearing loss is associated with increased health care costs and utilization.

http://bit.ly/2APgZ1c

Parental Perspectives and Concerns About Pediatric Tonsillectomy in Social Media

This study analyzes comments on Twitter from parents before, during, and after their children's tonsillectomy.

http://bit.ly/2SV8okM

The Invisible Costs of Hearing Loss

In this issue of JAMA Otolaryngology–Head & Neck Surgery, data from the administrative claims supplied by the OptumLabs database and analyzed by Reed et al indicate significantly longer inpatient stays, higher 30-day hospital readmission rates, and increased overall health care costs among persons with untreated hearing loss. The authors used data from this large, diverse medical claims database representing over 125 million individuals in the United States and found evidence that untreated hearing loss may be influencing health care in more ways than we previously imagined. The prevalence of hearing loss, which is strongly associated with age, is increasing as our population ages, with most US adults 75 years and older experiencing hearing loss. Coupled with the fact that hearing loss is not only common, but also connected with social isolation, reduced cognitive function, poorer physical and psychological health, increased risk of falls and hospitalization, and worse patient-clinician communication, the health care system should do more to improve screening and treatment of individuals with hearing loss.

http://bit.ly/2ASWPU3

Retained Nasal Trumpet for 20 Months

This case study examines a man in his 30s who presented 20 months after an emergency intubation with an iatrogenic retained nasal trumpet.

http://bit.ly/2SYfGE9

There is not an increased risk of intraocular hemorrhage associated with the use of novel antiplatelet therapy, but novel anticoagulants may decrease the hazard of bleeding compared with warfarin.

JAMA Ophthalmol. 2018 Feb; 136(2): 122–130.

Published online 2017 Dec 14. doi: 10.1001/jamaophthalmol.2017.5677

PMCID: PMC5838600

PMID: 29242919

Association of Novel Oral Antithrombotics With the Risk of Intraocular Bleeding

Katherine E. Uyhazi, MD, PhD,1 Todd Miano, PharmD, MSCE,2,3 Wei Pan, MS,3 and Brian L. VanderBeek, MD, MPH, MSCE1,2,3,4

Author information Article notes Copyright and License information Disclaimer

See commentary "Novel Antithrombotic Drugs and Intraocular Bleeding: The Importance of Observational Data and Future Perspectives." in JAMA Ophthalmol, doi: 10.1001/jamaophthalmol.2017.4179.

Associated Data

Supplementary Materials

Supplement: eTable 1. Intraocular Bleeding ICD-9 Codes

eTable 2. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Warfarin vs Dabigatran/Rivaroxaban Comparison

eTable 3. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Clopidogrel vs Prasugrel Comparison

jamaophthalmol-136-122-s001.pdf (100K)

Go to:

Abstract

Importance

Novel oral anticoagulation and antiplatelet therapies have become a mainstay of treatment for thromboembolic disease. However, the safety profile of these medications has not been completely characterized.

Objective

To determine the risk of developing intraocular hemorrhages with novel oral antithrombotic therapy compared with that of traditional antithrombotic agents.

Design, Setting, and Participants

In this retrospective cohort study, a large national insurance claims database was used to generate 2 parallel analyses. All patients with incident use of dabigatran etexilate or rivaroxaban between January 1, 2010, and September 30, 2015, were compared with patients with incident use of warfarin sodium. Similarly, patients with new use of prasugrel hydrochloride were compared with those with new use of clopidogrel bisulfate. Both analyses required the patient to be in the insurance plan for at least 24 months prior to initiation of therapy and excluded patients with any previous diagnosis of intraocular hemorrhages or any prescription for the comparator medications. Furthermore, the antiplatelet analysis required a diagnosis of acute coronary syndrome or a myocardial infarction within 60 days of initiation of pharmacologic therapy. The anticoagulant analysis excluded patients with end-stage renal disease, renal transplants, and those with heart valve disease.

Main Outcomes and Measures

Incident intraocular hemorrhages at 90 and 365 days. Multivariate Cox proportional hazards regression models were used to compare the hazard ratio (HR) of developing an intraocular hemorrhage in individuals taking novel agents compared with those taking traditional medications.

Results

A total of 146 137 patients taking warfarin (76 714 women and 69 423 men; mean [SD] age, 69.8 [11.8] years) were compared with 64 291 patients taking dabigatran or rivaroxaban (31 576 women and 32 715 men; mean [SD] age, 67.6 [11.7] years). Cox proportional hazards regression revealed a decreased hazard for developing an intraocular hemorrhage with dabigatran or rivaroxaban at 365 days (HR, 0.75; 95% CI, 0.58-0.97; P = .03), but not at 90 days (HR, 0.73; 95% CI, 0.22-2.63; P = .13). A total of 103 796 patients taking clopidogrel (37 578 women and 66 218 men; mean [SD] age, 68.0 [11.3] years) were compared with 8386 patients taking prasugrel (1988 women and 6380 men; mean [SD] age, 61.0 [9.6] years) and no increased hazard for developing an intraocular hemorrhage with prasugrel was seen at 90 days (HR, 0.75; 95% CI, 0.29-1.92; P = .55) or 365 days (HR, 1.19; 95% CI, 0.69-2.04; P = .53).

Conclusions and Relevance

These results suggest a decreased risk of intraocular hemorrhage associated with novel direct thrombin inhibitors and direct factor Xa inhibitors, but no difference for P2Y12 inhibitors compared with traditional vitamin K anticoagulation and antiplatelet therapy, respectively.

Go to:

Key Points

Question

Are novel anticoagulant and antiplatelet agents better, the same, or worse than traditional agents with regard to risk of intraocular hemorrhages?

Findings

In a cohort study using a large national insurance claims database, the novel anticoagulant agents dabigatran etexilate and rivaroxaban had a 25% decreased hazard of intraocular hemorrhages compared with warfarin sodium. No difference in the hazard of intraocular hemorrhages was identified for the antiplatelet agent prasugrel hydrochloride compared with clopidogrel bisulfate.

Meaning

These data suggest that novel antithrombotic agents are, at worst, equal in the risk of intraocular hemorrhages and in some instances are safer than their traditional counterparts.

Go to:

Introduction

Millions of patients worldwide are treated with oral anticoagulation and antiplatelet therapy to reduce the risk of thromboembolic events. Although traditional anticoagulation therapy has been with the vitamin K antagonist warfarin sodium, several newer agents have become increasingly popular. The direct thrombin inhibitor dabigatran etexilate and the direct factor Xa inhibitors rivaroxaban and apixaban have been shown to be noninferior to warfarin in the prevention of stroke in patients with atrial fibrillation. Unlike warfarin, which requires frequent blood tests and dose titration, these novel anticoagulants do not require routine monitoring. Owing to their predictable pharmacokinetics, shorter half-life, reduced drug-drug interactions, and overall ease of use, more patients are being started on these and similar agents in lieu of traditional vitamin K–based therapies.

Similarly, several novel antiplatelet agents are now available for patients who have had acute coronary syndrome or percutaneous coronary intervention. In lieu of traditional dual antiplatelet therapy with aspirin and clopidogrel bisulfate, the newer oral P2Y12 inhibitors prasugrel hydrochloride and ticagrelor are increasingly prescribed owing to improved efficacy, bioavailability, and onset of action compared with that of clopidogrel.

However, numerous reports of systemic hemorrhagic complications have brought the safety and adverse effect profiles of novel medications into question. Intraocular hemorrhages are a rare but potentially vision-threatening complication of systemic antithrombotic use. Previous studies have shown an increased risk for all types of intraocular hemorrhages in patients taking aspirin, clopidogrel, or warfarin, raising concerns over the safety of these medications.

An analysis using the World Health Organization's database of adverse events suggests that the odds of having a retinal or vitreous hemorrhage while taking dabigatran or rivaroxaban far exceeds that of warfarin. However, the results of this study are based strictly on voluntary physician report and do not quantify the number of patients using the medication. Contrasting these findings is a meta-analysis that found no increased risk of intraocular bleeding in patients taking novel anticoagulants vs those taking vitamin K antagonists, but this analysis was not geared toward finding eye complications.

Even less is known about the ocular risks of novel antiplatelet agents, as, to our knowledge, no studies have assessed intraocular hemorrhages in patients taking the newer oral P2Y12 inhibitors. Given the increasing number of patients using novel antithrombotics, the safety profile of these medications with regard to eye disease needs to be better understood. The goal of this study was to assess the risk of intraocular bleeding in patients taking novel oral antithrombotic agents compared with that of traditional antithrombotic agents.

Go to:

Methods

Data Set

Data were abstracted from the Clinformatics Data Mart Database (OptumInsight, Eden Prairie, MN), which contains the deidentified medical claims of all beneficiaries from a large private insurance network in the United States. The database includes all outpatient medical claims (office visits and associated diagnoses), all outpatient pharmaceutical prescriptions filled, and demographic data for each beneficiary during his or her enrollment in the insurance plan. The subset of data available for this study included all patients in the database from January 1, 2010, to September 30, 2015. The University of Pennsylvania institutional review board deemed this study exempt from review owing to the deidentified nature of the data.

Cohorts

For this study, the risk of intraocular bleeding was tested through comparing multiple cohorts of patients. To best assess the potential incremental risk of the novel medications, we compared them with the older medication that the novel drug intended to replace. Two separate analyses were performed. The index date for all comparison groups was the day the patient first filled a prescription. For all cohorts, patients were required to have been enrolled in the insurance plan for 24 months or more prior to the index date without a previous prescription for any of the study medications. Patients were also excluded if they had any previous diagnosis of intraocular hemorrhages or received a prescription for the comparator study medication prior to the index date.

Antiplatelet Cohort

The first analysis examined patients older than 40 years who had received at least 1 prescription for 1 of 2 P2Y12 receptor antagonists of interest: clopidogrel (older drug) or prasugrel (novel drug) during their time in the insurance plan. In addition, specific to the antiplatelet analysis, patients were required to have a history of acute coronary syndrome or a myocardial infarction within 60 days of initiation of therapy to ensure the medications were used for similar indications. Other novel antiplatelet agents (ie, ticagrelor and cangrelor) were not included owing to their limited use within the database. Patients receiving concomitant anticoagulation were either excluded from the analysis or censored at the initiation of anticoagulation. A sensitivity analysis was also performed with removal of patients with a history of ischemic stroke and transient ischemic attacks (TIAs).

Anticoagulant Cohort

The next analysis compared patients older than 40 years who filled at least 1 prescription for either rivaroxaban or dabigatran with patients who filled at least 1 prescription for warfarin. Other novel anticoagulants (ie, apixaban and edoxaban tosylate) were not tested owing to their limited use within the data set. Patients receiving concomitant P2Y12 receptor antagonists (ie, clopidogrel and prasugrel) were not excluded from the analysis; instead, concomitant exposure to P2Y12 receptor antagonists was measured and controlled for in the analysis. The novel anticoagulants studied (dabigatran and rivaroxaban) are cleared by renal elimination and are contraindicated in patients with end stage renal disease. Accordingly, patients with end stage renal disease or undergoing dialysis were excluded from the anticoagulant cohort. In addition, because the novel anticoagulants are approved only for the treatment of nonvalvular atrial fibrillation, patients with heart valve disease or valve replacement were also excluded. These latter exclusions were not applied to the antiplatelet analysis.

Follow-up

For all study cohorts, follow-up began on the date of filling the first prescription and continued until 1 of the following: occurrence of intraocular bleeding, a prescription was filled for a comparator group (ie, alternate antithrombotic), other bleeding (eg, gastrointestinal bleeding or hemorrhagic stroke), the patient's exit from the insurance plan, the end of the observation period, or a gap of more than 14 days in prescription coverage.

Outcomes of Interest

The primary outcome of interest was evidence of new intraocular hemorrhages, defined as having an incident diagnosis code for a new vitreous hemorrhage, nontraumatic intraocular hemorrhage, hyphema, retinal hemorrhage, or expulsive choroidal hemorrhage made by an eye care professional. Subconjunctival hemorrhages were not included. (See eTable 1 in the Supplement for all International Classification of Diseases, Ninth Revision, codes used in this study.)

Covariates

Confounding by indication is any association between a drug and an outcome that is owing to reasons underlying why the drug is actually prescribed, rather than a direct effect of the drug itself, and can limit these types of studies. Although using older antithrombotics as a comparator group reduces this confounding, additional covariates were evaluated for potential inclusion in multivariate analysis. These covariates included demographic information (age, sex, and race), year of initiation of treatment, indications for treatment (acute venous thrombosis, pulmonary embolism, atrial fibrillation, or atrial flutter), comorbid conditions (hypertension, types 1 and 2 diabetes, stroke, myocardial infarction, congestive heart failure, chronic liver disease, chronic pulmonary disease, peripheral vascular disease, and any malignant neoplasm) and eye disease states that are associated with bleeding (diabetic retinopathy, age-related macular degeneration, sickle cell anemia, or retinal vein occlusions). In addition, other classes of medications are known to potentiate or inhibit the effectiveness of anticoagulants and antiplatelet drugs, including selective serotonin reuptake inhibitors, statins, prescription nonsteroidal anti-inflammatory drugs (NSAIDs), and amiodarone. Other direct modulators were grouped into cytochrome P450 inhibitors (antifungals, antibiotics, fenofibrate, and calcium channel blockers) and cytochrome P450 inducers (corticosteroids, antiepileptics, rifampin, and leukotriene receptor antagonists). To assess the potential interaction between these medications and the study drugs at the time of a possible outcome, patients were considered to be users of these medications only if they had an active prescription at the time of outcome or censoring.

Statistical Analysis

Baseline demographic characteristics were assessed at the index date and were analyzed using descriptive statistics. Means and ranges were used for continuous variables and percentages were used for categorical variables. Cox proportional hazards regression models were used to analyze the time from prescription index date to either an outcome of interest that occurred or when the patient was censored. Hazard ratios (HRs) were estimated for 2 observation periods: days 1 to 90 after the index date and days 1 to 365 after the index date. All covariates were first assessed in a Cox univariate analysis. Each covariate with an association (defined as P < .20) with intraocular hemorrhages was then included for multivariate analysis. Backward variable selection was used for fitting the final multivariate models for each observation window in each analysis. Each of the multivariate models was assessed for multicolinearity; none was found. Furthermore, the proportional hazard assumption was tested for all variables using log-log plots and only prescription NSAIDs violated this assumption, which was not included in the multivariate analysis. All statistical analysis was performed with SAS, version 9.4 (SAS Institute Inc), software was used for all statistical analysis. P < .05 was considered significant.

Go to:

Results

A total of 146 137 patients prescribed warfarin and 64 291 patients prescribed dabigatran or rivaroxaban met the inclusion criteria (Figure). Approximately half of the patients were female in each cohort (76 714 [52.5%] in the warfarin cohort and 31 576 [49.1%] in the dabigatran or rivaroxaban cohort) and most patients were white (110 639 [75.7%] in the warfarin cohort and 50 523 [78.6%] in the dabigatran or rivaroxaban cohort) (Table 1). The mean (SD) age was 69.8 (11.8) years in the warfarin cohort and 67.6 (11.7) years in the dabigatran or rivaroxaban cohort. (See Table 1 for complete baseline demographic information.) The mean time to a censoring event (in the 365-day periods) was 124 days in the warfarin cohort and 193 days in the dabigatran or rivaroxaban cohort. The warfarin cohort had 81 incident intraocular hemorrhages at 90 days and 203 incident intraocular hemorrhages at 365 days. The novel therapeutic cohort had 33 incident intraocular hemorrhages at 90 days and 92 incident intraocular hemorrhages at 365 days. The longitudinal prevalence rate of an intraocular hemorrhage was 0.14% (205 of 146 137) among patients treated with traditional anticoagulants and was 0.14% (92 of 64 291) among patients treated with novel anticoagulants.

Figure.

Anticoagulation and Antiplatelet Prescriptions After Exclusion Criteria

aPatients were excluded if they had previous intraocular bleeding, end-stage renal disease, a kidney transplant, mitral valve disease, or a heart valve repair or replacement. ACS indicates acute coronary syndrome; MI, myocardial infarction.

Table 1.

Baseline Characteristics of Cohorts

Characteristic	Patients, No. (%)
	Anticoagulant		Antiplatelet
	Warfarin Sodium (n = 146 137)	Dabigatran Etexilate or Rivaroxaban (n = 64 291)	Clopidogrel Bisulfate (n = 103 796)	Prasugrel Hydrochloride (n = 8386)
Age, mean (SD), y	69.8 (11.8)	67.6 (11.7)	68.0 (11.3)	61.0 (9.6)
Female sex	76 714 (52.5)	31 576 (49.1)	37 578 (36.2)	1988 (23.7)
Race
White	110 639 (75.7)	50 523 (78.6)	76 842 (74.0)	6398 (76.3)
Black	13 680 (9.4)	4893 (7.6)	11 407 (11.0)	742 (8.8)
Other	21 818 (14.9)	8875 (13.8)	15 547 (15.0)	1246 (14.9)
Diagnosis
Types 1 and 2 diabetes	47 004 (32.2)	19 874 (30.9)	48 987 (47.2)	3354 (40.0)
Age-related macular degeneration	17 269 (11.8)	7612 (11.8)	12 248 (11.8)	543 (6.5)
Vein occlusions	2111 (1.4)	800 (1.2)	2046 (2.0)	73 (0.9)
Diabetic retinopathy	3203 (2.2)	1524 (2.4)	3150 (3.0)	203 (2.4)
Atrial fibrillation or flutter	44 395 (30.4)	27 714 (43.1)	12 659 (12.2)	607 (7.2)
Hypertension	109 758 (75.1)	49 849 (77.5)	96 481 (93.0)	7276 (86.8)
Chronic kidney disease	25 998 (17.8)	8665 (13.5)	21 809 (21.0)	948 (11.3)
Prior ischemic stroke or TIA	20 936 (14.3)	7194 (11.2)	22 271 (21.5)	609 (7.3)
Prior myocardial infarction	20 610 (14.1)	7232 (11.2)	103 796 (100)	8386 (100)
Congestive heart failure	37 439 (25.6)	13 856 (21.6)	41 159 (39.7)	2154 (25.7)
Any malignant neoplasm	30 343 (20.8)	11 618 (18.1)	16 911 (16.3)	921 (11.0)
Chronic pulmonary disease	55 311 (37.8)	23 513 (36.6)	46 044 (44.4)	2767 (33.0)
Peripheral vascular disease	36 592 (25.0)	13 738 (21.4)	41 344 (39.8)	1926 (23.0)
Acute venous thrombosis	34 825 (23.8)	7993 (12.4)	2704 (2.6)	138 (1.6)
Pulmonary embolism	19 414 (13.3)	3844 (6.0)	1027 (1.0)	45 (0.5)
Medications
Prescription NSAIDs	67 359 (46.1)	34 985 (54.4)	42 321 (40.8)	3918 (46.7)
Statins	78 965 (54.0)	34 338 (53.4)	96 228 (92.7)	8103 (96.6)
SSRIs	33 700 (23.1)	14 865 (23.1)	24 441 (23.5)	1681 (20.0)
Other metabolic inhibitors	110 699 (75.8)	50 838 (79.1)	80 352 (77.4)	6387 (76.2)
Other metabolic inducers	79 921 (54.7)	38 479 (59.9)	54142 (52.2)	4522 (53.9)
Amiodarone or dronedarone	12 284 (8.4)	7429 (11.6)	5590 (5.4)	234 (2.8)
Concurrent antiplatelet use	1032 (0.7)	0	NA	NA
Index year
2010	32 938 (22.5)	205 (0.3)	45 638 (44.0)	0
2011	28 000 (19.2)	5085 (7.9)	9767 (9.4)	0
2012	27 099 (18.5)	10 977 (17.1)	9057 (8.7)	3418 (40.8)
2013	26 223 (17.9)	19 124 (29.7)	23 681 (22.8)	2518 (30.0)
2014	17 721 (12.1)	15 808 (24.6)	8537 (8.2)	1489 (17.8)
2015	14 156 (9.7)	13 092 (20.4)	7116 (6.9)	961 (11.5)

Open in a separate window

Abbreviations: NA, not applicable; NSAIDS, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors; TIA, transient ischemic attack.

A total of 103 796 patients prescribed clopidogrel and 8386 patients prescribed prasugrel met the inclusion criteria (Figure). A minority of patients in both cohorts were female (37 578 [36.2%] in the clopidogrel cohort and 1988 [23.7%] in the prasugrel cohort) and most were white (76 842 [74.0%] in the clopidogrel cohort and 6398 [76.3%] in the prasugrel cohort) (Table 1). The mean (SD) age was 68.0 (11.7) years in the clopidogrel cohort and 61.0 (9.6) years in the prasugrel cohort. The mean time to a censoring event was 115 days in the clopidogrel cohort and 180 days in the prasugrel cohort. There were 68 new bleeding events in the traditional clopidogrel cohort at 90 days and 134 new bleeding events at 365 days. The novel antiplatelet cohort had 5 new bleeding events at 90 days and 16 new bleeding events at 365 days. The longitudinal prevalence rate for an intraocular hemorrhage was 0.13% (134 of 103 796) in patients treated with traditional agents and was 0.19% (16 of 8386) in patients treated with novel antiplatelet agents.

Cox univariate analysis revealed that, at 90 days, dabigatran and rivaroxaban were not associated with intraocular hemorrhages compared with warfarin (HR, 0.69; 95% CI, 0.46-1.04; P = .07). However, at 365 days, dabigatran and rivaroxaban were associated with a 32% decreased hazard (HR, 0.68; 95% CI, 0.53-0.87; P = .002). Univariate analysis of prasugrel at both 90 and 365 days showed no association with intraocular hemorrhages compared with clopidogrel (90-day HR, 0.72; 95% CI, 0.29-1.78; P = .47; 365-day HR, 0.98; 95% CI, 0.59-1.65; P = .95). (See eTables 2 and 3 in the Supplement for full univariate analysis results.)

Multivariate analysis again revealed no association for warfarin or dabigatran or rivaroxaban and intraocular hemorrhages in the 90-day period (HR, 0.73; 95% CI, 0.22-2.63; P = .13), but a 25% decreased hazard was seen at 365 days (HR, 0.75; 95% CI, 0.58-0.97; P = .03) (Table 2). No association was also found for developing an intraocular hemorrhage while taking clopidogrel compared with prasugrel in either of the observation windows (90-day HR, 0.75; 95% CI, 0.29-1.92; P = .55; 365-day HR, 1.19; 95% CI, 0.69-2.04; P = .53) (Table 3). A sensitivity analysis that removed all patients with a previous TIA or ischemic stroke from the antiplatelet cohorts found no difference in prasugrel's hazard for intraocular hemorrhages at either time point (90-day HR, 0.60; 95% CI, 0.19-1.93; P = .39; 365-day HR, 1.13; 95% CI, 0.63-2.02; P = .69). With the exception of retinal vein occlusions in the 90-day antiplatelet comparison, the ocular diseases most associated with bleeding (age-related macular degeneration HRs, 2.48-3.15; P < .001 for all comparisons; retinal vein occlusion HRs, 2.32-5.04; P < .009; and diabetic retinopathy HRs, 1.84-2.96; P < .04) were all found to have increased HRs for intraocular hemorrhages (Tables 2 and and33).

Table 2.

Multivariate Results for Significant Associations for Intraocular Hemorrhages in Warfarin vs Dabigatran or Rivaroxaban Comparison

Characteristic	No. (%)		HR (95% CI)	P Value
	Patients (n = 210 428)	Intraocular Hemorrhagesa
90-d Analysisb
Warfarin sodium	146 137 (69.4)	81 (0.06)	1 [Reference]	NA
Dabigatran etexilate or rivaroxaban	64 291 (30.6)	33 (0.05)	0.73 (0.22-2.63)	.13
Peripheral vascular disease	50 330 (23.9)	46 (0.09)	1.60 (1.09-2.36)	.02
Hypertension	159 607 (75.8)	103 (0.06)	2.13 (1.13-4.04)	.02
Metabolic inhibitors	161 537 (76.8)	83 (0.05)	0.62 (0.41-0.95)	.03
Retinal vein occlusion	2911 (1.4)	14 (0.48)	5.04 (2.78-9.12)	<.001
Age-related macular degeneration	24 881 (11.8)	39 (0.16)	2.48 (1.64-3.75)	<.001
Diabetic retinopathy	4727 (2.2)	14 (0.30)	2.96 (1.64-5.35)	<.001
365-d Analysis
Warfarin	146 137 (69.4)	203 (0.14)	1 [Reference]	NA
Dabigatran or rivaroxaban	64 291 (30.6)	92 (0.14)	0.75 (0.58-0.97)	.03
Statins	114 361 (54.3)	197 (0.17)	1.37 (1.07-1.75)	.01
Previous myocardial infarction	27 842 (13.2)	63 (0.23)	1.52 (1.14-2.02)	.004
Diabetic retinopathy	4796 (2.3)	25 (0.52)	1.98 (1.29-3.04)	.002
Retinal vein occlusion	2953 (1.4)	27 (0.91)	3.73 (2.46-5.64)	<.001
Age-related macular degeneration	25 176 (12.0)	106 (0.42)	3.16 (2.46-4.05)	<.001
Index year
2010	33 143 (15.8)	19 (0.06)	1 [Reference]	<.001
2011	33 085 (15.7)	21 (0.06)	1.14 (0.61-2.13)
2012	38 076 (18.1)	38 (0.10)	1.78 (1.03-3.10)
2013	45 347 (21.5)	77 (0.17)	1.12 (0.67-1.86)
2014	33 529 (15.9)	102 (0.30)	1.24 (0.75-2.05)
2015	27 248 (12.9)	38 (0.14)	0.54 (0.31-0.95)

Abbreviations: HR, hazard ratio; NA, not applicable.

aThere is a 1 to 1 correlation between number of patients and number of intraocular hemorrhages.

bTo prevent overfitting a model with a limited number of outcomes, a backward variable selection was used for fitting each of the final models with 1 variable per every additional 10 outcomes allowed to be included in the final model.

Table 3.

Multivariate Results for Significant Associations for Intraocular Hemorrhages in Clopidogrel vs Prasugrel Comparison

Characteristic	No. (%)		HR (95% CI)	P Value
	Patients (n = 112 182)	Intraocular Hemorrhagesa
90-d Analysisb
Clopidogrel bisulfate	103 796 (92.5)	68 (0.07)	1 [Reference]	NA
Prasugrel hydrochloride	8386 (7.5)	5 (0.06)	0.75 (0.29-1.92)	.55
Chronic kidney disease	22 757 (20.3)	26 (0.11)	1.88 (1.15-3.06)	.01
Age-related macular degeneration	12 791 (11.4)	23 (0.18)	2.87 (1.72-4.80)	<.001
diabetic retinopathy	3353 (3.0)	7 (0.21)	2.28 (1.03-5.08)	.04
Index year
2010	45 638 (40.6)	15 (0.03)	1 [Reference]	.05
2011	9767 (8.7)	8 (0.08)	3.15 (1.33-7.43)
2012	12 475 (11.1)	7 (0.06)	2.28 (0.91-5.72)
2013	26 199 (23.4)	25 (0.10)	2.15 (1.13-4.11)
2014	10 026 (8.9)	10 (0.10)	1.26 (0.56-2.82)
2015	8077 (7.2)	8 (0.10)	1.18 (0.50-2.81)
365-d Analysis
Clopidogrel	103 796 (92.5)	134 (0.13)	1 [Reference]	NA
Prasugrel	8386 (7.5)	16 (0.19)	1.19 (0.69-2.04)	.53
Types 1 or 2 diabetes	52 341 (46.7)	95 (0.18)	1.81 (1.29-2.54)	<.001
Congestive heart failure	43 313 (38.6)	73 (0.17)	1.43 (1.03-1.98)	.03
Retinal vein occlusions	2146 (1.9)	11 (0.51)	2.32 (1.23-4.39)	.009
Age-related macular degeneration	12 929 (11.5)	51 (0.39)	3.15 (1.23-4.39)	<.001
Diabetic retinopathy	3405 (3.0)	14 (0.41)	1.84 (1.04-3.26)	.04
Index year
2010	45 638 (40.6)	30 (0.07)	1 [Reference]	.03
2011	9767 (8.7)	10 (0.10)	1.93 (0.94-3.95)
2012	12 475 (11.1)	10 (0.08)	1.45 (0.70-3.04)
2013	26 199 (23.4)	55 (0.21)	1.57 (0.99-2.47)
2014	10 026 (8.9)	30 (0.30)	1.16 (0.69-1.95)
2015	8077 (7.2)	15 (0.19)	0.66 (0.35-1.24)

Open in a separate window

Abbreviations: HR, hazard ratio; NA, not applicable.

aThere is a 1 to 1 correlation between number of patients and number of intraocular hemorrhages.

bTo prevent overfitting a model with a limited number of outcomes, a backward variable selection was used for fitting each of the final models with 1 variable per every additional 10 outcomes allowed to be included in the final model.

Go to:

Discussion

Novel antithrombotic agents are established as safe and effective alternatives to traditional medications for the treatment of atrial fibrillation, thromboembolic disease, and acute coronary syndrome. The direct thrombin inhibitor dabigatran and the direct factor Xa inhibitor rivaroxaban are increasingly being prescribed owing to their ease of use and improved adverse effect profiles. Likewise, the oral P2Y12inhibitors prasugrel and ticagrelor are approved for use in patients with acute coronary syndrome and have demonstrated superior efficacy compared with clopidogrel.

To our knowledge, this study represents the first evaluation of the risk of intraocular bleeding with a novel antiplatelet agent. Our data suggest that prasugrel carries no additional ocular risk compared with its traditional counterpart, clopidogrel. Further inquiry will be needed on ocular safety profiles as more data become available for even newer antiplatelet and anticoagulation agents such as ticagrelor, cangrelor, apixaban, and edoxaban.

This study found a decreased hazard of intraocular hemorrhages at 365 days for dabigatran and rivaroxaban compared with warfarin. Our results, along with the recent meta-analysis of clinical trial data by Sun et alcontradict the concerns for intraocular bleeding raised by case reports and the World Health Organization adverse events database analysis. Information in the World Health Organization adverse events database results is based solely on voluntary reporting. This type of information can be misleading because it is susceptible to reporting bias and lacks the ability to control for confounding factors or to properly quantitate risk since the total number of prescriptions represented is unknown.

Although our results are similar to those reported in the meta-analysis by Sun et al, it is important to differentiate how each study arrived at its conclusions. Our study focuses on real-world use of anticoagulants, whereas the meta-analysis focused on results from clinical trial populations that may differ from our study in terms of baseline bleeding risk and how the drugs are dosed and monitored. We excluded people with a previous history of intraocular hemorrhages (to limit recurrences in those predisposed to intraocular hemorrhages) and controlled for eye diseases most frequently associated with bleeding. Unless they are specifically focused on ocular outcomes, clinical trials (and by extension, the meta-analysis by Sun et al) are unlikely to exclude patients with previous ocular bleeding or emphasize a history of diabetic retinopathy, retinal vein occlusions, or age-related macular degeneration during randomization. The importance of these risk factors is further highlighted in each of our final models, which show the significant hazard they represent for intraocular bleeding.

Furthermore, the a priori removal of patients predisposed to bleeding from our study also likely explains our lower rate of bleeding (0.14%) in the anticoagulant cohorts compared with that reported by Caldeira et al (0.21%-0.33%). Removal of these patients was needed to best equate the cohorts at baseline and allow for a direct assessment of the association of the medications with intraocular hemorrhages, independent of the underlying disease. Although this limits the generalizability of our results, our exceptionally low rate of intraocular hemorrhages throughout the study supports the safety of antithrombotics with regards to the eye in this population.

Strengths and Limitations

Other strengths of our study should be noted, including our ability to assess many other nonophthalmic factors that could mitigate or potentiate the effects of anticoagulants that may have been an issue in previous studies. In addition, the cohort design of the study minimizes the potential bias of convenience sampling that frequently occurs in case reports (and, by extension, the World Health Organization report) when rare outcomes spur publications that do not reflect the true rate seen in a larger population. Last, pharmacy records, not patient reports, determined medication use; thus, recall bias was eliminated.

Owing to the nature of our data and the inability to know if patients temporarily stopped their medication at or around the time of eye surgery, we are unable to comment on the safety profile of these drugs perioperatively. Although recent studies have shown no increased risk of perioperative vitreous hemorrhage with antithrombotic use, balancing the potentially life-threatening risk of stopping these medications and the low risk of hemorrhagic ocular complications is a difficult decision that should be made between the surgeon, the prescribing clinician, and the patient. Further work should be performed to better inform this decision.

Several limitations need to be considered when reviewing the results of our study. First, the rate of intraocular hemorrhages was exceedingly low, and the power of our study to detect subtle differences between antiplatelet cohorts was limited despite the large number of patients. In another context, however, this is reassuring, given the widespread use of antithrombotic agents. It could even be argued that since the incidence of an intraocular hemorrhage occurring while taking these medications is less than 0.2%, small differences between medication classes may not be clinically significant. Second, not all patients underwent an eye examination while taking the medications studied. Although patients with visually significant bleeding would have presumably been referred for care, it is possible that patients with clinically insignificant intraocular hemorrhages went undiagnosed, suggesting that our incidence rates may be an underestimate. Third, this study used administrative billing data that were unable to be verified with medical record–level data, nor have all the International Classification of Diseases, Ninth Revision codes used been specifically validated. Next, the database consists of claims from 1 insurance network and may not be generalizable to other patient populations.

Last, the database only includes data on prescription NSAIDs. We are unable to account for any over-the-counter use of NSAIDs or other factors that could influence the potency of the antithrombotic medications (ie, the effect of grapefruit juice on warfarin levels). Although this limitation certainly exists, the commonness of use of over-the-counter NSAIDs combined with the extremely low occurrence rate of bleeding found in this study suggest that the overall effect of this issue is likely low.

Go to:

Conclusions

Owing to the increasing use of novel antithrombotic medications for the treatment of coronary artery disease and atrial fibrillation, the ocular safety profile of these medications must be understood. Our study suggests that there is not an increased risk of intraocular hemorrhage associated with the use of novel antiplatelet therapy, but novel anticoagulants may decrease the hazard of bleeding compared with warfarin.

Go to:

Notes

Supplement.

eTable 1. Intraocular Bleeding ICD-9 Codes

eTable 2. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Warfarin vs Dabigatran/Rivaroxaban Comparison

eTable 3. Univariate Analysis of Association Between Parameters and Intraocular Bleeding for Clopidogrel vs Prasugrel Comparison

Click here for additional data file.(100K, pdf)

Go to:

References

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. ; RE-LY Steering Committee and Investigators . Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. [PubMed]

2. Patel MR, Mahaffey KW, Garg J, et al. ; ROCKET AF Investigators . Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. [PubMed]

3. Granger CB, Alexander JH, McMurray JJ, et al. ; ARISTOTLE Committees and Investigators .Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. [PubMed]

4. Shroff GR, Solid CA, Herzog CA. Temporal trends in ischemic stroke and anticoagulation therapy among Medicare patients with atrial fibrillation: a 15-year perspective (1992-2007). JAMA Intern Med. 2013;173(2):159-160. [PubMed]

5. Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128(12):1300-1305.e2. [PMC free article] [PubMed]

6. Wong CX, Brooks AG, Leong DP, Roberts-Thomson KC, Sanders P. The increasing burden of atrial fibrillation compared with heart failure and myocardial infarction: a 15-year study of all hospitalizations in Australia. Arch Intern Med. 2012;172(9):739-741. [PubMed]

7. Bavishi C, Panwar S, Messerli FH, Bangalore S. Meta-analysis of comparison of the newer oral P2Y12inhibitors (prasugrel or ticagrelor) to clopidogrel in patients with non–ST-elevation acute coronary syndrome. Am J Cardiol. 2015;116(5):809-817. [PubMed]

8. Sipahi I, Celik S, Tozun N. A comparison of results of the US Food and Drug Administration's mini-sentinel program with randomized clinical trials: the case of gastrointestinal tract bleeding with dabigatran. JAMA Intern Med. 2014;174(1):150-151. [PubMed]

9. Kiernan DF, Hariprasad SM, Rusu IM, Mehta SV, Mieler WF, Jager RD. Epidemiology of the association between anticoagulants and intraocular hemorrhage in patients with neovascular age-related macular degeneration. Retina. 2010;30(10):1573-1578. [PubMed]

10. Weir CR, Nolan DJ, Holding D, Hammer H. Intraocular haemorrhage associated with anticoagulant therapy. Acta Ophthalmol Scand. 2000;78(4):492-493. [PubMed]

11. Kuhli-Hattenbach C, Fischer IB, Schalnus R, Hattenbach LO. Subretinal hemorrhages associated with age-related macular degeneration in patients receiving anticoagulation or antiplatelet therapy. Am J Ophthalmol. 2010;149(2):316-321.e1. [PubMed]

12. Kang TS, Lord K, Kunjukunju N. Spontaneous choroidal hemorrhage in a patient on dabigatran etexilate (Pradaxa). Retin Cases Brief Rep. 2014;8(3):175-177. [PubMed]

13. Jun JH, Hwang JC. Association of rivaroxaban anticoagulation and spontaneous vitreous hemorrhage. JAMA Ophthalmol. 2015;133(10):1184-1186. [PubMed]

14. Shieh WS, Sridhar J, Hong BK, et al. Ophthalmic complications associated with direct oral anticoagulant medications [published online July 1, 2016]. Semin Ophthalmol. doi:10.3109/08820538.2016.1139738 [PubMed] [CrossRef]

15. Boyce MR, Barth BE, Singh A. Recurrent subretinal hemorrhage associated with rivaroxaban anticoagulation. Retin Cases Brief Rep. 2016;10(1):86-88. [PubMed]

16. Wang K, Ehlers JP. Bilateral spontaneous hyphema, vitreous hemorrhage, and choroidal detachment with concurrent dabigatran etexilate therapy. Ophthalmic Surg Lasers Imaging Retina. 2016;47(1):78-80. [PMC free article] [PubMed]

17. Talany G, Guo M, Etminan M. Risk of intraocular hemorrhage with new oral anticoagulants. Eye (Lond). 2017;31(4):628-631. [PMC free article] [PubMed]

18. Caldeira D, Canastro M, Barra M, et al. Risk of substantial intraocular bleeding with novel oral anticoagulants: systematic review and meta-analysis. JAMA Ophthalmol. 2015;133(7):834-839. [PubMed]

19. Olesen JB, Sørensen R, Hansen ML, et al. Non–vitamin K antagonist oral anticoagulation agents in anticoagulant naïve atrial fibrillation patients: Danish nationwide descriptive data 2011-2013. Europace. 2015;17(2):187-193. [PubMed]

20. Wallentin L, Becker RC, Budaj A, et al. ; PLATO Investigators . Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. [PubMed]

21. Wiviott SD, Braunwald E, McCabe CH, et al. ; TRITON-TIMI 38 Investigators . Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015. [PubMed]

22. Sun MT, Wood MK, Chan W, et al. Risk of intraocular bleeding with novel oral anticoagulants compared with warfarin: a systematic review and meta-analysis. JAMA Ophthalmol. 2017;135(8):864-870. [PMC free article] [PubMed]

23. Brown JS, Mahmoud TH. Anticoagulation and clinically significant postoperative vitreous hemorrhage in diabetic vitrectomy. Retina. 2011;31(10):1983-1987. [PubMed]

24. Grand MG, Walia HS. Hemorrhagic risk of vitreoretinal surgery in patients maintained on novel oral anticoagulant therapy. Retina. 2016;36(2):299-304. [PubMed]

25. Mason JO III, Gupta SR, Compton CJ, et al. Comparison of hemorrhagic complications of warfarin and clopidogrel bisulfate in 25-gauge vitrectomy versus a control group. Ophthalmology. 2011;118(3):543-547. [PubMed]