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

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

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

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)

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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.

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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.

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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.

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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.

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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)

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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)

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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.

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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.

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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.

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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)

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