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Πέμπτη 17 Ιανουαρίου 2019

Cobalt speciation and phytoavailability in fluvo-aquic soil under treatments of spent mushroom substrate from Pleurotus ostreatus

Abstract

Cobalt (Co) is a nutrient for soil microorganisms and crops, as well as a worldwide industrial pollutant. When the level of Co exceeds the acceptable limit, this heavy metal can lead to devastating consequences for soil environments. There is considerable attention and concern about elevated levels of Co contaminating soil and crops. Spent mushroom substrate (SMS) is a potential amendment for the adsorption of pollutants, which has potential for resolving Co-polluted soil that spans the world. To investigate the environmental behavior and risks associated with Co in fluvo-aquic soil under specific treatments of SMS from Pleurotus ostreatus, a lab-scale pot experiment was conducted. SMS and exogenous Co were added to soil, which was retained for approximately 30 days. Pakchois (Brassica chinensis L.) were planted in the treated soil for 28 days until harvest. The Co speciation in soil (modified BCR sequential extraction) and Co accumulation in pakchoi tissue were studied. When the SMS concentration was within a range of 0 to 9 g kg−1 (total amount = 0 to 2.7 g), Co in the acid-soluble fraction was transformed to the oxidizable fraction in soil, resulting from the mesh structure on the surface of SMS, as well as the amide and carboxyl in the SMS molecular structure. In this situation, the Co accumulation levels in the pakchois decreased significantly (P < 0.05), indicating the efficacy of SMS for reducing Co phytoavailability. However, when the SMS concentration reached 12 g kg−1, the phytoavailability increased again (P < 0.05). When the SMS concentration ranged from 8.86 to 9.51 g kg−1, the Co phytoavailability in soil reached a minimum, while the biomass of pakchoi reached a maximum. Conclusively, SMS from Pleurotus ostreatus are effective for reducing the Co phytoavailability, as well as for reducing the chance of Co transferring into a human's body through crops (i.e., food consumption). In order to achieve the optimum efficacy, the SMS concentration in soil should be maintained at a range of 8.86 to 9.51 g kg−1.



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



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Quality auditing in breast reconstruction using funnel plots and indicators: a semi-anonymous and practical method for your practice

Abstract

Background

In recent years, there is an increasing focus on the delivery of high-quality care in a cost-efficient fashion. A key strategy in improving practice is gaining insight in outcome differences. We present a simple and quick method of quality auditing in a local practice, aiming to start a discussion between surgeons and reduce complication rates by improving protocols.

Methods

Patients who underwent breast reconstruction with implants were evaluated on explantation rate within 60 days of insertion. Patients were traced using administrative data. Results were compared during yearly audits between 2014 and 2017. Each year, a meeting was held in which the data of all surgeons were compared using funnel plots in a semi-anonymous manner.

Results

At baseline, 6.1% (15/244) of all implants and 9.9% (9/91) of all tissue expanders had to be explanted, mainly due to infection (60.0% and 77.8%, resp.). Discussion at the audit led to the implementation of an anti-infection protocol. In the following years, explantation rates decreased to 3.8% (8/208) and 7.8% (8/102) in 2015 (infection 55.6% and 63%), and 3.4% (6/176) and 3.1% (2/64) in 2017 (infection 50% and 100%) and in 2016.

Conclusion

Audit feedback and the subsequent discussion about the causes of inter-surgeon differences led to a change in practice protocols for breast implant surgery and a reduction of breast implant explantation in our center.

Level of Evidence: Level III, risk / prognostic study



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A ubiquitous asthma monitoring framework based on ambient air pollutants and individuals’ contexts

Abstract

Air pollutants and allergens are the main stimuli that have considerable effects on asthmatic patients' health. Seamless monitoring of patients' conditions and the surrounding environment, limiting their exposure to allergens and irritants, and reducing the exacerbation of symptoms can aid patients to deal with asthma better. In this context, ubiquitous healthcare monitoring systems can provide any service to any user everywhere and every time through any device and network. In this regard, this research established a GIS-based outdoor asthma monitoring framework in light of ubiquitous systems. The proposed multifaceted model was designed in three layers: (1) pre-processing, for cleaning and interpolating data, (2) reasoning, for deducing knowledge and extract contextual information from data, and (3) prediction, for estimating the asthmatic conditions of patients ubiquitously. The effectiveness of the proposed model is assessed by applying it on a real dataset that comprised of internal context information including patients' personal information (age, gender, height, medical history), patients' locations, and their peak expiratory flow (PEF) values, as well as external context information including air pollutant data (O3, SO2, NO2, CO, PM10), meteorological data (temperature, pressure, humidity), and geographic information related to the city of Tehran, Iran. With more than 92% and 93% accuracies in reasoning and estimation mechanism, respectively, the proposed method showed remarkably effective in asthma monitoring and management.



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January is Thyroid Awareness Month

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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.



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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
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
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Efficient removal of oxytetracycline from aqueous solution by a novel magnetic clay–biochar composite using natural attapulgite and cauliflower leaves

Abstract

A novel magnetic attapulgite–biochar composite (MABC) derived from natural attapulgite, cauliflower leaves, and FeCl3 was successfully prepared as a low-cost adsorbent for oxytetracycline (OTC) removal from aqueous solution. Characterization experiments by different techniques suggested that attapulgite clay particles and Fe3O4 nanoparticles were successfully covered on the MABC surface. Compared with the pristine biochar (CLB) and attapulgite–biochar composite (ABC), MABC had the largest surface area, well-developed pore structure, and more surface oxygen-containing functional groups which could interact with organic pollutant via hydrogen bonding, π–π electron coupling, complexation, and ion exchange. The maximum adsorption capacity of MABC by the Langmuir model was 33.31 mg/g, which was dramatically higher than that of CLB and ABC. The effects of solution initial pH had little difference on the adsorption of OTC because of the buffering effect. Adsorbent-regeneration studies of MABC exhibited good reusability and separation property. All the results indicated that MABC could be used as a potential adsorbent because of its easy preparation and separation, high efficiency, wide pH range application, and abundant and cheap raw materials in the global ecosystem.

Graphical abstract


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Static decontamination of oil-based drill cuttings with pressurized hot water using response surface methodology

Abstract

Separating organic pollutants from oil-based drill cuttings (OBDC) is the current trend for its safe disposal. In this study, pressurized hot water extraction (PHWE) was adapted to decontaminate OBDC for the first time. Two typical OBDC samples, i.e., diesel-based drill cuttings (OBDC-A) and white oil-based drill cuttings (OBDC-B), were statically extracted in a homemade batch autoclave. Response surface methodology (RSM) with a central composite design (CCD) was applied to investigate the effects and interactive effects of three independent operating parameters (temperature, extraction time, and water volume) and to ultimately optimize the PHWE process. The results suggested that temperature is the dominant parameter, followed by water volume and extraction time. Interactive effects among the three parameters are present in the PHWE of OBDC-A but absent in the PHWE of OBDC-B. The suitable conditions for the effective PHWE of OBDC-A were found to be a temperature of 284–300 °C, water volume of 15–35 ml, and extraction time of 20–60 min. The corresponding conditions were 237–300 °C, 15–35 ml, and 20–60 min for the PHWE of OBDC-B. These different phenomena are caused by the different characteristics of the two OBDC samples. All of the polynomial models obtained from the RSM experiments are very valid and can adequately describe the relationship among the three independent operating parameters and responses. The experimental results also confirmed that PHWE is a more efficient separation technique for decontaminating OBDC than single organic solvent extraction or low-temperature thermal desorption because PHWE integrates the advantages of both these processes.



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Economic value of traffic noise reduction depending on residents’ annoyance level

Abstract

Noise is the most frequently encountered type of environmental pollution in everyday life and has a direct negative effect on humans. Individuals who are constantly exposed to noise tend to have a high incidence of cardiovascular disease and hypertension. Noise sources range from construction sites to political rallies and assemblies, but traffic is one of the most long-lasting and chronic sources of noise. Previously, researchers have conducted valuations of road traffic noise reduction, but they did not consider residents' annoyance levels in response to traffic noise. However, individuals' annoyance levels affect the economic value of noise reduction policies and thus must be considered to obtain an accurate estimate. Therefore, this study investigated residents' willingness to pay for traffic noise reduction depending on their annoyance level. We used the contingent valuation method and a survey to analyze how much 1022 respondents in Korea were willing to pay for noise reduction. We found that people who were annoyed and extremely annoyed by noise had a willingness to pay KRW 8422 (US $7.55) and KRW 9848 (US $8.83) annually per household, respectively, to reduce their annoyance level to zero. In addition, we determined the economic benefits of noise reduction policies using the respondents' willingness to pay to reduce noise by 1 dB(A), which totaled KRW 3.28 billion (US $2.91 million) per year. The results of this study provide estimates of the annual benefits of traffic noise reduction considering residents' annoyance level.



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Short-chain and medium-chain chlorinated paraffins in Canadian house dust and NIST SRM 2585

Abstract

A method for the analysis of short-chain and medium-chain chlorinated paraffins (SCCPs and MCCPs) in house dust was developed. The method is based on sonication extraction, sample cleanup by solid phase extraction (SPE), and separation and detection by gas chromatography coupled with mass spectrometry (GC/MS) operated in electron capture negative ion (ECNI) chemical ionization mode. The method is sensitive, with method detection limits (MDLs) down to 0.22 μg/g for SCCPs and 0.55 μg/g for MCCPs. The overall recoveries of the method were 104 (± 11)% and 108 (± 16)% for SCCPs and MCCPs, respectively. The method was successfully applied to the analysis of SCCPs and MCCPs in NIST standard reference material (SRM 2585, organic contaminants in house dust) and a subset of house dust samples collected under the Canadian House Dust Study (CHDS). Average concentrations of SCCPs and MCCPs in SRM 2585 (n = 12 replicates) were 7.58 (± 0.43) μg/g for SCCPs and 16.4 (± 2.1) μg/g for MCCPs, respectively. A comparison was made between CP concentrations in paired dust samples collected using two different methods from the same homes: fresh or "active" dust (FD) collected by technicians and a sample taken from the household vacuum cleaner (HD). Spearman rank analysis showed a significant positive correlation (p < 0.01) between FD and HD samples for both MCCPs and SCCPs. CPs were detected in every house dust sample (n = 48 HD samples), with median (range) concentrations of 6.2 (4.0 - 57) μg/g and 19 (5.9-901) μg/g for SCCPs and MCCPs, respectively. Widely scattered CP levels and 100% detection frequency in this preliminary set of 48 HD samples suggest a wide variability in Canadian household exposures to CPs.



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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, MSCEcorresponding author1,2,3,4
Author information Article notes Copyright and License information Disclaimer

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

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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.

An external file that holds a picture, illustration, etc. Object name is jamaophthalmol-136-122-g001.jpg
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
CharacteristicPatients, No. (%)
AnticoagulantAntiplatelet
Warfarin Sodium
(n = 146 137)		Dabigatran Etexilate or Rivaroxaban
(n = 64 291)		Clopidogrel Bisulfate
(n = 103 796)		Prasugrel Hydrochloride
(n = 8386)
Age, mean (SD), y69.8 (11.8)67.6 (11.7)68.0 (11.3)61.0 (9.6)
Female sex76 714 (52.5)31 576 (49.1)37 578 (36.2)1988 (23.7)
Race
White110 639 (75.7)50 523 (78.6)76 842 (74.0)6398 (76.3)
Black13 680 (9.4)4893 (7.6)11 407 (11.0)742 (8.8)
Other21 818 (14.9)8875 (13.8)15 547 (15.0)1246 (14.9)
Diagnosis
Types 1 and 2 diabetes47 004 (32.2)19 874 (30.9)48 987 (47.2)3354 (40.0)
Age-related macular degeneration17 269 (11.8)7612 (11.8)12 248 (11.8)543 (6.5)
Vein occlusions2111 (1.4)800 (1.2)2046 (2.0)73 (0.9)
Diabetic retinopathy3203 (2.2)1524 (2.4)3150 (3.0)203 (2.4)
Atrial fibrillation or flutter44 395 (30.4)27 714 (43.1)12 659 (12.2)607 (7.2)
Hypertension109 758 (75.1)49 849 (77.5)96 481 (93.0)7276 (86.8)
Chronic kidney disease25 998 (17.8)8665 (13.5)21 809 (21.0)948 (11.3)
Prior ischemic stroke or TIA20 936 (14.3)7194 (11.2)22 271 (21.5)609 (7.3)
Prior myocardial infarction20 610 (14.1)7232 (11.2)103 796 (100)8386 (100)
Congestive heart failure37 439 (25.6)13 856 (21.6)41 159 (39.7)2154 (25.7)
Any malignant neoplasm30 343 (20.8)11 618 (18.1)16 911 (16.3)921 (11.0)
Chronic pulmonary disease55 311 (37.8)23 513 (36.6)46 044 (44.4)2767 (33.0)
Peripheral vascular disease36 592 (25.0)13 738 (21.4)41 344 (39.8)1926 (23.0)
Acute venous thrombosis34 825 (23.8)7993 (12.4)2704 (2.6)138 (1.6)
Pulmonary embolism19 414 (13.3)3844 (6.0)1027 (1.0)45 (0.5)
Medications
Prescription NSAIDs67 359 (46.1)34 985 (54.4)42 321 (40.8)3918 (46.7)
Statins78 965 (54.0)34 338 (53.4)96 228 (92.7)8103 (96.6)
SSRIs33 700 (23.1)14 865 (23.1)24 441 (23.5)1681 (20.0)
Other metabolic inhibitors110 699 (75.8)50 838 (79.1)80 352 (77.4)6387 (76.2)
Other metabolic inducers79 921 (54.7)38 479 (59.9)54142 (52.2)4522 (53.9)
Amiodarone or dronedarone12 284 (8.4)7429 (11.6)5590 (5.4)234 (2.8)
Concurrent antiplatelet use1032 (0.7)0NANA
Index year
201032 938 (22.5)205 (0.3)45 638 (44.0)0
201128 000 (19.2)5085 (7.9)9767 (9.4)0
201227 099 (18.5)10 977 (17.1)9057 (8.7)3418 (40.8)
201326 223 (17.9)19 124 (29.7)23 681 (22.8)2518 (30.0)
201417 721 (12.1)15 808 (24.6)8537 (8.2)1489 (17.8)
201514 156 (9.7)13 092 (20.4)7116 (6.9)961 (11.5)

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
CharacteristicNo. (%)HR (95% CI)P Value
Patients
(n = 210 428)		Intraocular Hemorrhagesa
90-d Analysisb
Warfarin sodium146 137 (69.4)81 (0.06)1 [Reference]NA
Dabigatran etexilate or rivaroxaban64 291 (30.6)33 (0.05)0.73 (0.22-2.63).13
Peripheral vascular disease50 330 (23.9)46 (0.09)1.60 (1.09-2.36).02
Hypertension159 607 (75.8)103 (0.06)2.13 (1.13-4.04).02
Metabolic inhibitors161 537 (76.8)83 (0.05)0.62 (0.41-0.95).03
Retinal vein occlusion2911 (1.4)14 (0.48)5.04 (2.78-9.12)<.001
Age-related macular degeneration24 881 (11.8)39 (0.16)2.48 (1.64-3.75)<.001
Diabetic retinopathy4727 (2.2)14 (0.30)2.96 (1.64-5.35)<.001
365-d Analysis
Warfarin146 137 (69.4)203 (0.14)1 [Reference]NA
Dabigatran or rivaroxaban64 291 (30.6)92 (0.14)0.75 (0.58-0.97).03
Statins114 361 (54.3)197 (0.17)1.37 (1.07-1.75).01
Previous myocardial infarction27 842 (13.2)63 (0.23)1.52 (1.14-2.02).004
Diabetic retinopathy4796 (2.3)25 (0.52)1.98 (1.29-3.04).002
Retinal vein occlusion2953 (1.4)27 (0.91)3.73 (2.46-5.64)<.001
Age-related macular degeneration25 176 (12.0)106 (0.42)3.16 (2.46-4.05)<.001
Index year
201033 143 (15.8)19 (0.06)1 [Reference]<.001
201133 085 (15.7)21 (0.06)1.14 (0.61-2.13)
201238 076 (18.1)38 (0.10)1.78 (1.03-3.10)
201345 347 (21.5)77 (0.17)1.12 (0.67-1.86)
201433 529 (15.9)102 (0.30)1.24 (0.75-2.05)
201527 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
CharacteristicNo. (%)HR (95% CI)P Value
Patients
(n = 112 182)		Intraocular Hemorrhagesa
90-d Analysisb
Clopidogrel bisulfate103 796 (92.5)68 (0.07)1 [Reference]NA
Prasugrel hydrochloride8386 (7.5)5 (0.06)0.75 (0.29-1.92).55
Chronic kidney disease22 757 (20.3)26 (0.11)1.88 (1.15-3.06).01
Age-related macular degeneration12 791 (11.4)23 (0.18)2.87 (1.72-4.80)<.001
diabetic retinopathy3353 (3.0)7 (0.21)2.28 (1.03-5.08).04
Index year
201045 638 (40.6)15 (0.03)1 [Reference].05
20119767 (8.7)8 (0.08)3.15 (1.33-7.43)
201212 475 (11.1)7 (0.06)2.28 (0.91-5.72)
201326 199 (23.4)25 (0.10)2.15 (1.13-4.11)
201410 026 (8.9)10 (0.10)1.26 (0.56-2.82)
20158077 (7.2)8 (0.10)1.18 (0.50-2.81)
365-d Analysis
Clopidogrel103 796 (92.5)134 (0.13)1 [Reference]NA
Prasugrel8386 (7.5)16 (0.19)1.19 (0.69-2.04).53
Types 1 or 2 diabetes52 341 (46.7)95 (0.18)1.81 (1.29-2.54)<.001
Congestive heart failure43 313 (38.6)73 (0.17)1.43 (1.03-1.98).03
Retinal vein occlusions2146 (1.9)11 (0.51)2.32 (1.23-4.39).009
Age-related macular degeneration12 929 (11.5)51 (0.39)3.15 (1.23-4.39)<.001
Diabetic retinopathy3405 (3.0)14 (0.41)1.84 (1.04-3.26).04
Index year
201045 638 (40.6)30 (0.07)1 [Reference].03
20119767 (8.7)10 (0.10)1.93 (0.94-3.95)
201212 475 (11.1)10 (0.08)1.45 (0.70-3.04)
201326 199 (23.4)55 (0.21)1.57 (0.99-2.47)
201410 026 (8.9)30 (0.30)1.16 (0.69-1.95)
20158077 (7.2)15 (0.19)0.66 (0.35-1.24)

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

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