Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

The Prevalence of Adverse Ocular Hemorrhagic Events in Patients Utilizing Oral Anticoagulant and Antiplatelet Therapy in Routine Clinical Practice

Dattanand M. Sudarshana, BS; Eleni K. Konstantinou, MD; Sruthi Arepalli, MD; Fabiana Q. Silva, MD; Andrew P. Schachat, MD; Justis P. Ehlers, MD; Rishi P. Singh, MD

Abstract

BACKGROUND AND OBJECTIVE:

Previous literature assessing ocular hemorrhagic complications of anticoagulant/antiplatelet medications in routine clinical practice is limited. This study evaluates the prevalence of spontaneous ocular hemorrhagic events associated with anticoagulation/antiplatelet therapy.

PATIENTS AND METHODS:

A retrospective study was performed to identify patients taking anticoagulants (rivaroxaban [Xarelto; Janssen Pharmaceuticals, Beerse, Belgium], bivalirudin [Angiomax; The Medicines Company, Parsippany, NJ], lepirudin [Refludan; Bayer HealthCare Pharmaceuticals, Berlin, Germany], dabigatran [Pradaxa; Boehringer Ingelheim, Ingelheim am Rhein, Germany], and argatroban) and antiplatelet agents (clopidogrel [Plavix; Bristol-Myers Squibb, New York City, NY], prasugrel [Effient; Lilly Medical, Indianapolis, IN], and ticagrelor [Brilinta; AstraZeneca, Cambridge, UK]) who presented for an eye examination. Location of hemorrhage, relevant systemic and ocular comorbidities, baseline demographics, and concomitant aspirin use were noted.

RESULTS:

A total of 44 patients with spontaneous ocular hemorrhage were identified. Thirty patients had a single episode, whereas 14 patients had multiple episodes (two or more hemorrhagic events). Prevalence of spontaneous ocular hemorrhage on prasugrel (7.2%) and rivaroxaban (3.1%) was higher compared to dabigatran (1.9%), clopidogrel (2.0%), and ticagrelor (2.7%).

CONCLUSION:

Prevalence of spontaneous ocular hemorrhage with use of anticoagulant/antiplatelet agents is higher in routine clinical practice as compared to previously reported literature.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:27–34.]

Abstract

BACKGROUND AND OBJECTIVE:

Previous literature assessing ocular hemorrhagic complications of anticoagulant/antiplatelet medications in routine clinical practice is limited. This study evaluates the prevalence of spontaneous ocular hemorrhagic events associated with anticoagulation/antiplatelet therapy.

PATIENTS AND METHODS:

A retrospective study was performed to identify patients taking anticoagulants (rivaroxaban [Xarelto; Janssen Pharmaceuticals, Beerse, Belgium], bivalirudin [Angiomax; The Medicines Company, Parsippany, NJ], lepirudin [Refludan; Bayer HealthCare Pharmaceuticals, Berlin, Germany], dabigatran [Pradaxa; Boehringer Ingelheim, Ingelheim am Rhein, Germany], and argatroban) and antiplatelet agents (clopidogrel [Plavix; Bristol-Myers Squibb, New York City, NY], prasugrel [Effient; Lilly Medical, Indianapolis, IN], and ticagrelor [Brilinta; AstraZeneca, Cambridge, UK]) who presented for an eye examination. Location of hemorrhage, relevant systemic and ocular comorbidities, baseline demographics, and concomitant aspirin use were noted.

RESULTS:

A total of 44 patients with spontaneous ocular hemorrhage were identified. Thirty patients had a single episode, whereas 14 patients had multiple episodes (two or more hemorrhagic events). Prevalence of spontaneous ocular hemorrhage on prasugrel (7.2%) and rivaroxaban (3.1%) was higher compared to dabigatran (1.9%), clopidogrel (2.0%), and ticagrelor (2.7%).

CONCLUSION:

Prevalence of spontaneous ocular hemorrhage with use of anticoagulant/antiplatelet agents is higher in routine clinical practice as compared to previously reported literature.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:27–34.]

Introduction

Currently, more than 6 million patients receive long-term antithrombotic therapy in the United States.1 Newer oral anticoagulants such as dabigatran (Pradaxa; Boehringer Ingelheim, Ingelheim am Rhein, Germany), rivaroxaban (Xarelto; Janssen Pharmaceuticals, Beerse, Belgium), and apixaban act by directly inhibiting factor Xa or thrombin.2 Second- and third-generation oral antiplatelet medications include clopidogrel (Plavix; Bristol-Myers Squibb, New York City, NY), prasugrel (Effient; Lilly Medical, Indianapolis, Indiana), and ticagrelor (Brilinta; AstraZeneca, Cambridge, UK), which function as adenosine diphosphate (ADP)-receptor/P2Y12 antagonists and prevent ADP-induced platelet aggregation and subsequent thrombus formation.2 These medications are used for the management of venous thromboembolism, stroke prevention in atrial fibrillation, treatment of acute coronary syndrome, and secondary prevention of cardiovascular disease.3

The concomitant increase in newer antithrombotic drugs and patients undergoing long-term antithrombotic therapy poses theoretical challenges for ophthalmologists. Although these medications possess a wide therapeutic window and fewer serious adverse events, there are some disadvantages: the lack of reversal agents, inadequate clinical experience, and inability to measure the extent of anticoagulation.4 These somewhat uncontrollable characteristics can worsen hemorrhage in ocular conditions, such as hemorrhagic posterior vitreous detachment, exudative age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), and retinal vein occlusions, or at the time of intraocular surgery.

Further, the perioperative management of antithrombotic therapy is complex and relies on multiple demographic and medical factors.5 To avoid cerebrovascular and cardiovascular complications, ophthalmologists must heed the most recent perioperative guidelines regarding these newer medications. However, there have not been studies on perioperative ocular complication rates thus far.6 Thus, this study will investigate the prevalence of ocular hemorrhagic complications in patients with a history of anticoagulant and antiplatelet medication use in routine clinical practice.

Patients and Methods

Study Design

The study was performed at Cole Eye Institute, Cleveland, and received approval from the Cleveland Clinic Investigational Review Board. Because of the retrospective nature of the study, written informed consent was not required. All study-related procedures were performed in accordance with good clinical practice (International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use E6), applicable U.S. Food and Drug Administration (FDA) regulations, and the Health Insurance Portability and Accountability Act.

Participants and Data Collection

Patients seen at Cole Eye Institute and associated Cleveland Clinic ophthalmology departments, including the offices of Lakeland Eye and community outpatient eye offices, from December 2005 to April 2015 were included if they met the following criteria: 1) any record of use of rivaroxaban, bivalirudin, dabigatran, argatroban, clopidogrel, prasugrel, ticagrelor, abciximab, eptifibatide, or tirofban, and 2) had an ocular hemorrhagic event during the time of anticoagulant/antiplatelet therapy.

A total of 1,829 patients were identified through the electronic medical record system who are currently, or were at some previous point, prescribed anticoagulant/antiplatelet medications. In order to identify patients who presented with an ocular hemorrhagic event during their use of anticoagulation/antiplatelet medication, a complete review of the documentation during ophthalmic encounters was performed. History of present illness, physical exam, and assessment/plan were comprehensively reviewed. Search terms that incorporated the terminology involved with an ophthalmic assessment were queried within the office documentation for each patient. Search terms included “heme,” “hemorrhage,” and “bleeding.”

Of the initial 1,829 patients, 154 patients had confirmed ocular hemorrhagic episodes during treatment. These events were classified as spontaneous or related to surgery (intraoperative and perioperative). Spontaneous ocular hemorrhagic episodes were classified as the presence of blood at sites in and around the eye without prior trauma. Spontaneous hemorrhage was further subclassified into single episodes or multiple episodes: 1) multiple ocular hemorrhagic events (two or more episodes of ocular hemorrhage, either at the same site or in different sites, at different points in time), or 2) single episode (defined as an office visit when an ocular hemorrhage was noted. In the case of multiple office visits in which an episode of ocular hemorrhage was noted and subsequently resolved the following visit, it would still count as one ocular hemorrhagic episode.)

An ocular hemorrhagic episode related to surgery were also subclassified: 1) intraoperative hemorrhagic events were categorized as complications if the treating physician deemed the amount of hemorrhage excessive for a specific procedure, 2) postoperative complications including excessive hemorrhage occurring within 3 weeks after ocular surgery were included if deemed excessive by the treating physician. Due to identical evaluation criteria, intraoperative and postoperative complications were combined in the analysis.

A total of 44 patients were identified, and a comprehensive review of each patient's electronic chart was performed to identify and record demographic data, office encounters dates, type of anticoagulant medication used, and medication start and stop dates. Additionally, ocular hemorrhagic event characteristics such as date, anatomic location of hemorrhage, associated ocular/systemic comorbidities, concurrent aspirin use, indications for anticoagulation, and surgical management with anticoagulation were collected.

Patients were excluded if the ocular hemorrhage took place before the initiation of the anticoagulation/antiplatelet medication or the ocular hemorrhage was caused by trauma. By excluding those patients, it was possible to find patients whose hemorrhagic events could not be explained by an underlying etiology or associated procedure, highlighting these adverse events as ones most likely related to anticoagulant/antiplatelet therapy.

Time to ocular hemorrhagic event was calculated by recording the number of days from the start of the medication to the earliest date of the ocular complication. The data collection and analysis process are summarized in the Figure.

Flow diagram of data analysis. N = number of patients in that group.

Figure.

Flow diagram of data analysis. N = number of patients in that group.

Study End Points

The primary outcome measured in this study is the prevalence of ocular hemorrhagic complications in patients with a history of anticoagulants and antiplatelet medication use.

Statistical Analysis

Descriptive statistics were compiled to characterize population. Continuous variables were summarized using means and standard deviations. Comparison of time to ocular hemorrhagic event for patients taking ADP antagonists versus factor Xa inhibitor was performed using a two-sample t-test assuming unequal variance. A significance level of P = .05 was assumed for all tests.

Results

Of the 154 patients with hemorrhagic episodes and anticoagulant/antiplatelet use, 44 patients were noted to have a spontaneous ocular hemorrhagic event at the time of their anticoagulant/antiplatelet therapy. None of these events were due to excessive intraoperative and postoperative hemorrhage. Of the 44 patients with spontaneous hemorrhagic events, 30 experienced a single episode and 14 experienced multiple episodes.

The mean age for the hemorrhagic cohort was 73.9 years (Table 1). Ocular complications were only slightly higher in males (52%). Almost all patients had systemic comorbidities including hypertension (73%) and diabetes mellitus (32%). With respect to the ocular comorbidities, nonproliferative diabetic retinopathy was most common (14%), followed by proliferative diabetic retinopathy (9%), nonexudative AMD (9%), exudative AMD (7%), and preglaucoma/glaucoma (5%). Interestingly, three patients were found to have spontaneous hemorrhages without any of the aforementioned systemic or ocular comorbidity (Table 2). Ocular comorbidities that had the highest predisposition to hemorrhage (PDR, exudative AMD) were only seen patients who had multiple episodes of hemorrhage. Furthermore, most of the patients' hemorrhagic events had unilateral presentation (91%). In addition, the reason for anticoagulation was various with the majority needing anticoagulation for reasons such as heart disease, peripheral vascular disease, and arteriovenous malformation (pooled percentage: 45%) (Table 1) and coronary artery disease (23%).

Cohort Demographics Including Systemic/Ocular Comorbidities and Reason for Anticoagulation Therapy

Table 1:

Cohort Demographics Including Systemic/Ocular Comorbidities and Reason for Anticoagulation Therapy

Patients With Spontaneous Ocular Hemorrhage Without Systemic or Ocular Comorbidities

Table 2:

Patients With Spontaneous Ocular Hemorrhage Without Systemic or Ocular Comorbidities

The types of hemorrhage were categorized by location of the bleed (Table 3). Subconjunctival and intraretinal hemorrhagic episodes were the most prevalent locations of hemorrhage (51% and 25%, respectively). Many of the multiple hemorrhagic events seen were a combination of intraretinal, vitreous, subconjunctival, and subretinal/choroidal hemorrhages. There was a higher proportion of intraretinal and subretinal/choroidal hemorrhagic episodes in the multiple episode category as compared with single hemorrhagic episodes.

Types of Hemorrhage Associated With Anticoagulation

Table 3:

Types of Hemorrhage Associated With Anticoagulation

When determining the prevalence of hemorrhagic episodes by drug, those taking prasugrel and rivaroxaban had a higher ocular hemorrhagic event rates (7.2% and 3.1%, respectively) when compared to ticagrelor (2.7%), clopidogrel (2.0%), and dabigatran (1.9%) for an overall spontaneous hemorrhagic rate of 2.4% (Table 4). Concurrent aspirin use across all groups was 45% (Table 4). When evaluating patients that had a single hemorrhagic episode, a similar pattern persists (Table 4). Prasugrel has the highest hemorrhagic event rate (4.8%) followed by rivaroxaban (2.8%), ticagrelor (2.7%), clopidogrel (1.4%), and dabigatran (1.25%). The overall event rate for single episode spontaneous hemorrhagic episodes is 1.7%, with 37% of the patients concurrently on aspirin.

Patients With Spontaneous Ocular Hemorrhage During Anticoagulation

Table 4:

Patients With Spontaneous Ocular Hemorrhage During Anticoagulation

Multiple ocular hemorrhagic episodes occurred in 14 patients, among whom 10 patients were on clopidogrel (Table 4). Again, prasugrel had the highest event rate (2.4%), followed by clopidrogrel (0.77%), dabigatran (0.63%), and rivaroxaban (0.39%), with 64% of the patients concurrently taking aspirin. The overall event rate for this group was 0.77%.

With respect to time to ocular hemorrhagic event, medications were separated into adenosine diphosphate antagonists, Factor Xa inhibitors, and direct thrombin inhibitors. The initial start date was known for 30 of the 44 patients. The time to ocular hemorrhagic event was 466 days for adenosine diphosphate antagonists and 623 days for factor Xa inhibitor, with a standard deviation of 637 days and 344 days, respectively (Table 5). A two-sample t-test assuming unequal variances yielded a P value of .22, suggesting a statistically insignificant difference between the groups.

Time to Ocular Complication

Table 5:

Time to Ocular Complication

Discussion

The ocular hemorrhage risks related to novel anticoagulation and antiplatelet medications remain largely undefined. The understanding of the bleeding risks is derived from the phase 3 clinical trials for the approval of these medications (Table 6).7,8,9 However, these studies were designed for FDA approval and were powered for a cardiovascular/thrombotic outcome. Patients with a variety of comorbidities such as uncontrolled hypertension, recent history of myocardial infarction, and coronary revascularization typically were excluded from these studies and many times a detailed ophthalmology exam was not performed.7,8,9 Further, nonsignificant hemorrhagic events were likely not recorded, and patients in routine clinical practice might manifest with different outcomes than those enrolled in clinical studies, thus leading to underreporting of true ocular hemorrhage rates with these medications. Additionally, in routine clinical practice, patients are prescribed nonstandard doses of medications that do not reflect these standard of care studies. Due to these critical differences, the true rate of ocular bleeding would largely be unknown.

Previously Reported Ocular Adverse Events Related to Anticoagulant/Antiplatelet Medications

Table 6:

Previously Reported Ocular Adverse Events Related to Anticoagulant/Antiplatelet Medications

Within the current literature, two cases of spontaneous ocular hemorrhage (choroidal and subretinal) in patients undergoing newer anticoagulation have been previously described.10,11 Additionally, a meta-analysis of 17 randomized, controlled trials (RCTs) comparing ocular hemorrhage between newer anticoagulants and vitamin K antagonists found that the rate of substantial ocular hemorrhage, as defined by International Society on Thrombosis and Hemostasis, was quite low (< 0.4%).12

This study found an overall prevalence rate for ocular hemorrhage of 2.4%, with 45% reporting concomitant aspirin use. This is greater than previous reports from phase 3 clinical trials, which reported ocular hemorrhagic rates near 1% (Table 6).7,8,9 However, a critical point to note is that none of the hemorrhagic episodes that were reviewed in this study resulted in vision loss. This study fits in line with newly developing evidence regarding ocular complications from both newer medications and warfarin. A prospective study by Biyik et al. found that warfarin use was correlated with a higher prevalence of ocular hemorrhage.13 They also found a significant correlation between ocular hemorrhage and hypertension but no significant association with gender, international normalized ratio, duration of therapy, and diabetes mellitus.

It is well-known that systemic conditions such as hypertension and diabetes mellitus and ocular comorbidities such as AMD and diabetic retinopathy predispose patients to ocular hemorrhage.14 This phenomenon was observed in this study, as most of the patients that had a hemorrhagic episode had some kind of systemic or ocular comorbidity. In this cohort, 73% of patients had hypertension and 14% had nonproliferative diabetic retinopathy. It is important to note that there were three patients who had a single hemorrhagic episode without any history of systemic or ocular comorbidity. In the absence of any predisposing factors, the hemorrhagic events in this small group can be considered “truly spontaneous.”

Characterizing the location of the bleed provided valuable information regarding the true risk of the ocular hemorrhage. More than 50% of the hemorrhagic episodes that were noted were subconjunctival. These are generally not considered vision-threatening. Patients who had multiple hemorrhagic episodes had a greater involvement of vitreous and subretinal/choroidal locations. Time to ocular hemorrhagic event measurement demonstrated that ocular complications could take years after the initiation of the drug, with no significant differences detected between adenosine diphosphate antagonists and factor Xa inhibitors.

This study is not without limitations. The lack of a control group (eg, a warfarin-treated group) does not allow us to compare the hemorrhagic rates between the two groups and definitively establish treatment guidelines. Obtaining a comparable group will involve selecting patients with similar comorbidities and disease processes, posing a formidable challenge. The other limitation is that there is a selection bias in the population of patients that are present in the cohort. These patients presented for ophthalmic issues and may have more advanced ocular pathologies than seen in previous studies. A final limitation deals with the differentiation between what constitutes “excessive” versus normal hemorrhagic changes as part of a disease process like diabetic retinopathy or exudative AMD. The cohort of patients with spontaneous ocular hemorrhage was reviewed by an experienced ophthalmologist but the subjectivity of assessing what is “excessive” introduces a subjective bias.

Overall, this study is contributory in evaluating the spontaneous ocular hemorrhagic events in patients taking anticoagulant and antiplatelet medications. The event rate for this cohort is higher than what was observed in previous studies. However, it is reassuring to see that none of the hemorrhagic events were vision-threatening and further studies would be helpful in confirming these findings. Future studies are required to establish the difference in ocular bleeding rates between warfarin and newer anticoagulants/antiplatelet agents.

References

  1. Baron TH, Kamath PS, McBane RD. Management of antithrombotic therapy in patients undergoing invasive procedures. N Engl J Med. 2013;368(22):2113–2124. doi:10.1056/NEJMra1206531 [CrossRef]
  2. Parekh PJ, Merrell J, Clary M, Brush JE, Johnson DA. New anticoagulants and antiplatelet agents: A primer for the clinical gastroenterologist. Am J Gastroenterol. 2014;109(1):9–19. doi:10.1038/ajg.2013.228 [CrossRef]
  3. Kiire CA, Mukherjee R, Ruparelia N, Keeling D, Prendergast B, Norris JH. Managing antiplatelet and anticoagulant drugs in patients undergoing elective ophthalmic surgery. Br J Ophthalmol. 2014;98(10):1320–1324. doi:10.1136/bjophthalmol-2014-304902 [CrossRef]
  4. Bauer KA. Pros and cons of new oral anticoagulants. Hematology Am Soc Hematol Educ Program. 2013;1:464–470.
  5. Lip GYH, Durrani OM, Roldan V, Lip PL, Marin F, Reuser TQ. Peri operative management of ophthalmic patients taking antithrombotic therapy. Int J Clin Pract. 2011;65(3):361–371. doi:10.1111/j.1742-1241.2010.02538.x [CrossRef]
  6. Esparaz ES, Sobel RK. Perioperative management of anticoagulants and antiplatelet agents in oculoplastic surgery. Curr Opin Ophthalmol. 2015;26(5):422–428. doi:10.1097/ICU.0000000000000187 [CrossRef]
  7. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368:709–718. doi:10.1056/NEJMoa1113697 [CrossRef]
  8. Bauersachs R, Berkowitz SD, EINSTEIN Investigators et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–510. doi:10.1056/NEJMoa1007903 [CrossRef]
  9. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494–502. doi:10.1056/NEJMoa010746 [CrossRef]
  10. Kang TS, Lord K, Kunjukunju N. Spontaneous choroidal hemorrhage in a patient on dabigatran etexilate (Pradaxa). Retin Cases Brief Rep. 2014;8(3):175–177. doi:10.1097/ICB.0000000000000035 [CrossRef]
  11. Boyce MR, Bradley BE, Singh A. Recurrent subretinal hemorrhage associated with rivaroxaban anticoagulation. Retin Cases Brief Rep. 2015;10(1):86–88. doi:10.1097/ICB.0000000000000167 [CrossRef]
  12. Caldeira D, Canastro M, Barra M, et al. Risk of substantial ocular bleeding with newer oral anticoagulants: systematic review and meta-analysis. JAMA Ophthalmol. 2015;133(7):834–839. doi:10.1001/jamaophthalmol.2015.0985 [CrossRef]
  13. Wang K, Ehlers JP. Bilateral spontaneous hyphema, vitreous hemorrhage, and choroidal detachment with concurrent dabigatran etexilate therapy. Ophthalmic Surg Lasers Imaging Retina. 2016;47(1):78–80. doi:10.3928/23258160-20151214-13 [CrossRef]
  14. Spraul CW, Grossniklaus HE. Vitreous hemorrhage. Surv Ophthalmol. 1997;42(1):3–39. doi:10.1016/S0039-6257(97)84041-6 [CrossRef]

Cohort Demographics Including Systemic/Ocular Comorbidities and Reason for Anticoagulation Therapy

Total (N = 44)Spontaneous – Single Episode (N = 30)Spontaneous – Multiple Episodes (N = 14)

Mean Age (Years)73.974.771.3

Sex
  Male23 (52%)17 (57%)6 (43%)
  Female21 (48%)13 (43%)8 (57%)

Systemic Comorbidities*
  Hypertension32 (73%)23 (77%)9 (64%)
  Diabetes mellitus14 (32%)8 (27%)6 (43%)

Ocular Comorbidities*
  PDR4 (9%)04 (29%)
  NPDR6 (14%)3 (10%)3 (21%)
  Occlusion (BRVO/CRVO/RVO)000
  Ocular neoplasm000
  Pre-glaucoma/glaucoma2 (5%)2 (7%)0
  Nonexudative AMD4 (9%)3 (10%)1 (7%)
  Exudative AMD3 (7%)03 (21%)

No Comorbidities3 (7%)3 (10%)0

Laterality at Presentation
  Unilateral40 (91%)30 (100%)10 (71%)
  Bilateral4 (9%)04 (29%)

Reason for Anticoagulation*
  TIA3 (7%)3 (10%)0
  AF5 (11%)4 (13%)1 (7%)
  CAD10 (23%)5 (17%)5 (36%)
  MI6 (14%)3 (10%)3 (21%)
  Stroke4 (9%)3 (10%)1 (7%)
  Other20 (45%)15 (50%)5 (36%)

Patients With Spontaneous Ocular Hemorrhage Without Systemic or Ocular Comorbidities

ClassMedicationsIntraocular Bleeding Episode(s)Total # of People Taking MedicationEvent Rate (%)Concurrent Aspirin Use
Adenosine Diphosphate AntagonistsClopidogrel21,295 (71%)0.152
Prasugrel183 (5%)1.200
Ticagrelor037 (2%)0-
Factor Xa InhibitorRivaroxaban0254 (14%)0-
Direct Thrombin InhibitorsDabigatran0160 (9%)0-
Total31,8290.272 (80%)

Types of Hemorrhage Associated With Anticoagulation

HemorrhageTotal (N = 59)Intraoperative/Perioperative (N = 0)Spontaneous – Single Episode (N = 30)Spontaneous – Multiple Episodes (N = 29)
Subconjunctival30 (51%)01911
Hyphema1 (2%)001
Vitreous6 (10%)015
Pre-retinal0000
Intraretinal15 (25%)078
Subretinal/choroidal6 (10%)024
Extraocular1 (2%)010

Patients With Spontaneous Ocular Hemorrhage During Anticoagulation

Patients With a Single Ocular Bleeding EpisodePatients With Multiple Ocular Bleeding EpisodesTotal (Single + Multiple)
ClassMedicationsTotal # of Patients Taking This MedicationN/Event Rate (%)Concurrent Aspirin UseN/Event Rate (%)Concurrent Aspirin UseN/Event Rate (%)Concurrent Aspirin Use
Adenosine Diphosphate AntagonistsClopidogrel1,295 (71%)16/1.4510/0.77526/2.010
Prasugrel83 (5%)4/4.822/2.426/7.24
Ticagrelor37 (2%)1/2.701−/−-1/2.71
Factor Xa inhibitorRivaroxaban254 (14%)7/2.821/0.3918/3.13
Direct Thrombin InhibitorsDabigatran160 (9%)2/1.2511/0.6313/1.92
Total1,82930/1.711 (37%)14/0.779 (64%)44/2.420 (45%)

Time to Ocular Complication

MedicationsNumber of Patients (N)Mean (Days)Standard Deviation (Days)
Adenosine diphosphate antagonists(clopidogrel, prasugrel, ticagrelor)22465.8636.6*
Factor Xa inhibitor7622.6343.5*
Direct thrombin inhibitors157-

Previously Reported Ocular Adverse Events Related to Anticoagulant/Antiplatelet Medications

Antiplatelet/Anticoagulant DrugReported Ocular Adverse Events

Factor Xa Inhibitors
  Rivaroxaban (Xarelto)*Intraocular bleeding: N = 3 (< 0.1%) from EINSTEIN DVT/PE study

Direct Thrombin Inhibitors
  Bivalirudin (Angiomax)None reported
  Lepirudin (Refludan)None reported
  Dabigatran (Pradaxa)*Intraocular bleeding: N = 4 (0.3%) from RE-MEDY study
  ArgatrobanNone reported

Adenosine diphosphate antagonists
  Clopidogrel (Plavix)*Intraocular bleeding: N = 3 (0.05%) from CURE study
  Prasugrel (Effient)*None reported
  Ticagrelor (Brilinta)*Unspecified intraocular bleeding reported

Glycoprotein IIb/IIIa inhibitors
  Abciximab (Reopro)Abnormal vision (0.3%) from CAPTURE, EPILOG, and EPISTENT trials
  Eptifibatide (Integrilin)None reported
  Tirofban (Aggrastat)None reported
Authors

From the Department of Ophthalmology, Cole Eye Institute, Cleveland (DMS, SA, FQS, APS, JPE, RPS); and Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston (EK).

This study was presented at the Association for Research in Vision and Ophthalmology Annual Meeting, May 1–5, 2016, in Seattle.

Dr. Schachat is an employee of the Cleveland Clinic, a part-time employee of the State of Ohio, receives royalties from Elsevier, receives honorarium from the American Academy of Ophthalmology, and may receive future payments from Easton Capital outside the submitted work. Dr. Ehlers has received grants and personal fees from Thrombogenics and Alcon, grants from Genentech, and personal fees from Leica and Zeiss outside the submitted work. Dr. Singh has received grants and personal fees from Alcon, Genentech, and Regeneron; grants from Apellis; and personal fees from Optos and Zeiss outside the submitted work. The remaining authors report no relevant financial disclosures.

Address correspondence to Rishi P. Singh, MD, 9500 Euclid Avenue, Desk i32, Cleveland, OH 44195; email: singhr@ccf.org.

Received: March 20, 2017
Accepted: August 02, 2017

10.3928/23258160-20171215-04

Advertisement

Sign up to receive

Journal E-contents
Advertisement