Hematology

Anticoagulant, antiplatelet, and fibrinolytic (thrombolytic) therapy in patients at high risk for ocular hemorrhage

Anticoagulant, antiplatelet, and fibrinolytic (thrombolytic) therapy in patients at high risk for ocular hemorrhage
Author
John E Carter, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Stephen A Landaw, MD, PhD
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Wed Jun 16 00:00:00 GMT 2010 (More)

INTRODUCTION — Ocular hemorrhages usually originate from either the retina or the choroid. Normal retinal vessels can be damaged by an acute process (eg, trauma, retinal detachment), or by chronic disorders (eg, diabetes, retinal vein occlusion, sickle cell retinopathy, retinal macroaneurysms and retinal hemangiomas). Complete repair of such damage is not usually accomplished, since retinal neovascularization produces abnormal, fragile vessels prone to hemorrhage.

Similarly, choroidal neovascular membranes are abnormal networks of vessels that may complicate pathologic processes involving the retinal pigment epithelium and Bruch’s membrane including age-related macular degeneration (ARMD), myopic degeneration, angioid streaks, ocular histoplasmosis, multifocal choroiditis, punctate inner choroidopathy, and choroidal tumors. These membranes are also prone to bleed.

Most of the above noted ocular vascular conditions are chronic and are likely to coexist with conditions for which antithrombotic medications are prescribed, raising the question of whether their use might result in ocular hemorrhage. Hemorrhage into the preretinal (subhyaloid) space and vitreous are amenable to surgical treatment with generally good outcome; in comparison, hemorrhage into the retina or choroid is more likely to produce substantial, permanent visual impairment [1].

The use of anticoagulant, antiplatelet, and fibrinolytic therapy in patients at high risk for ocular hemorrhage will be reviewed here. There are a number of other high-risk settings in which patients may require anticoagulant or antiplatelet therapy. These issues are discussed separately and include patients with the following:

 

  • A primary or metastatic brain tumor. (See “Anticoagulant and antiplatelet therapy in patients with brain tumors”.)
  • An acute or prior intracerebral hemorrhage. (See “Anticoagulant and antiplatelet therapy in patients with an acute or prior intracerebral hemorrhage”.)
  • An unruptured intracranial aneurysm. (See “Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm”.)

 

The overall risk, diagnosis, and treatment of warfarin-associated ICH are also presented separately. (See “Risk of intracerebral hemorrhage in patients treated with warfarin” and “Management of warfarin-associated intracerebral hemorrhage”.)

INTRAOCULAR BLOOD SUPPLY — The retina is the innermost layer of the eye and receives blood supply and nourishment for its inner two-thirds from the central retinal artery and its branches. The choroid is separated from the retina by Bruch’s membrane and is a vascular structure acting to maintain intraocular pressure and also to provide nourishment to the outer one-third of the retina by diffusion across Bruch’s membrane. The choroidal blood supply comes from the posterior ciliary arteries, which are the terminal branches of the ophthalmic artery after the central retinal artery leaves to enter the optic nerve.

Neovascularization — Neovascularization of the retina, seen in diabetes mellitus and other disorders such as retinal vein occlusion and sickle cell anemia, involves the elaboration of angiogenesis factors as a result of retinal ischemia. The cause of choroidal neovascularization is less well understood, and includes theories involving ischemia or oxidative damage [2].

ANTIPLATELET AGENTS — Use of antiplatelet agents is associated with an increase in asymptomatic, superficial retinal hemorrhages over the optic disc. This was shown in a study of 32,918 residents of Malmo, Sweden, who were screened for glaucoma and retinal hemorrhage using fundus photography [3]. Only the use of antiplatelet agents was associated with a significant increase in the presence of retinal hemorrhages (odds ratio: 3.2). However, the hemorrhages noted in these photographs would not be expected to produce any clinical signs or symptoms.

Diabetic retinopathy — Most of the information on the use of antiplatelet agents in conditions associated with ocular hemorrhage relates to the treatment of patients with diabetes mellitus. Because ischemia contributes to the ocular complications of diabetes, the use of antiplatelet agents has been evaluated for both possible treatment and for safety of use. In general, aspirin appears to have no effect (either positive or negative) on the development or progression of proliferative retinopathy, vitreous bleeding, or visual loss. (See “Prevention and treatment of diabetic retinopathy”, section on ‘Antiplatelet agents’.)

In addition, aspirin does not appear to increase hemorrhagic complications in patients with diabetic retinopathy, even if advanced. In the Early Treatment Diabetic Retinopathy Study, patients with mild to severe nonproliferative or early proliferative diabetic retinopathy had one eye treated with scatter retinal photocoagulation. The 3711 participants were also randomly assigned to receive either aspirin (650 mg/day PO) or placebo. During the study, periodic fundus photography of the eyes not receiving photocoagulation detected vitreous or preretinal hemorrhages in 32 versus 30 percent of patients treated with aspirin or placebo, respectively [4].

Approximately 40 percent of these hemorrhages produced a loss of visual acuity to less than 20/40. However, the severity and rate of resolution of these hemorrhages were not different between the aspirin- and placebo-treated groups.

This study, as well as a meta-analysis of other randomized clinical trials, concluded that there were no ocular contraindications to the use of aspirin (650 mg/day) in persons with diabetes who require this medicine for treatment of cardiovascular disease or for other medical indications [4,5]. (See “Prevention and treatment of diabetic retinopathy”, section on ‘Antiplatelet agents’ and “Overview of medical care in adults with diabetes mellitus”, section on ‘Aspirin’.)

Age-related macular degeneration — There are few studies concerning the safety of antiplatelet agents in age-related macular degeneration (ARMD).

 

  • The use of aspirin was not associated with more ocular hemorrhage in trials conducted by the Macular Photocoagulation Study Group [6].
  • In the Physicians’ Health Study, a trend favoring aspirin was apparent both for reducing the occurrence of ARMD and for reducing the occurrence of visual loss to 20/30 or worse due to ARMD [7]. The beneficial effect of aspirin on prevention of myocardial infarction forced early termination of the trial before its effect on ocular hemorrhage could be adequately assessed.

 

When hemorrhages occur they may be more extensive. A report of 71 consecutive patients with ARMD complicated by acute subretinal hemorrhages found that the size of the hemorrhages was significantly larger in patients receiving antiplatelet agents or anticoagulants. Final visual outcomes were not reported [8].

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Recommendation — Considering diabetic retinopathy, ARMD, and other ocular conditions predisposing to ocular hemorrhage, the use of antiplatelet agents does not result in increased rates of symptomatic ocular hemorrhage and may reduce progression of the ocular pathology in some situations.

WARFARIN AND OTHER VITAMIN K ANTAGONISTS — Chronic anticoagulation with vitamin K antagonists has been successfully employed in a number of clinical settings, despite a relatively high rate of bleeding complications. (See “Therapeutic use of warfarin”, section on ‘Bleeding’.) This includes an approximately two- to fivefold increased risk of an initial intracranial hemorrhage (ICH) in elderly patients with achieved INRs of 2.0 to 3.0. (See “Risk of intracerebral hemorrhage in patients treated with warfarin”, section on ‘ICH risk with antithrombotic therapy’.)

The risk of ocular hemorrhage in unselected patients treated with warfarin is probably low. Of 126 patients from a large anticoagulation clinic who volunteered to undergo direct and indirect ophthalmoscopy, only four (3 percent) had small, visually insignificant, retinal hemorrhages [9]. The authors concluded that the risk of warfarin-induced retinal hemorrhage in patients without preexisting ocular disease, such as retinal neovascularization or choroidal vasculopathy, is so small that it should not deter physicians from prescribing this drug when indicated.

Age-related macular degeneration — The majority of reports concerning ocular hemorrhage during anticoagulation involve patients with age-related macular degeneration (ARMD). ARMD is common; nearly everyone over the age of 50 years has at least one macular drusen, which are localized deposits of extracellular material concentrated in the macula [10]. (See “Age-related macular degeneration: Epidemiology, etiology, and diagnosis”, section on ‘Definition and classification’.)

Early ARMD, consisting of large drusen and pigmentary abnormalities, is present in 30 percent of the population over 75 years of age. Advanced ARMD likely to produce visually significant damage is present in 7 percent of this age group. Most patients have the atrophic form (geographic or “dry” ARMD), with loss of photoreceptors, retinal pigment epithelium, and the choriocapillaris that may progress and produce mild or moderate visual loss. The remainder, about 10 to 20 percent, develop a central fibrovascular scar that may produce exudation or macular hemorrhage. At least 80 percent of patients with ARMD and vision 20/200 or worse have this neovascular or “wet” form [10-12].

A report commented on 109 patients ≥60 years of age with macular hemorrhage who were receiving antithrombotic or antiplatelet medications of some kind [13]. Presumably most of these patients had ARMD, but several had macular hemorrhage without choroidal neovascularization on fluorescein angiography. Six patients were receiving a vitamin K antagonist, while 60 percent of those not receiving a vitamin K antagonist were receiving aspirin, dipyridamole, or both, with the remainder receiving a variety of other antiplatelet medications. Two problems interfere with interpretation of this information:

 

  • No information was provided regarding visual outcome.
  • No information was provided concerning the number of patients seen during the same period who developed macular hemorrhage and were not receiving antithrombotic or antiplatelet medications.

 

A number of reports have described massive intraocular hemorrhage in ARMD. While unusual, the outcome in these cases is uniformly poor, often with residual vision reduced to the ability to see only hand motions or worse. In those reports with 10 or more patients, an average of 22 percent were receiving warfarin (range: zero to 30 percent) [14-20]. Fifteen of 21 patients, however, came from one study in which all patients had excessive degrees of anticoagulation, with INRs in the range of 3.0 to 4.0 [15].

In the latter case control study of patients with ARMD, 50 patients with massive subretinal hemorrhage were compared with 50 with small subretinal hemorrhage [15]. The percent of patients with massive or small subretinal hemorrhages who were receiving anticoagulation was 30 and 4 percent, respectively (relative risk 11.6). Use of aspirin was not different between the two patient groups.

Over one-half of the patients in the massive hemorrhage group were allowed to discontinue anticoagulant medication, suggesting that the indications for this agent may not have been sufficiently stringent. The authors concluded that physicians prescribing anticoagulant medication should be informed about the macular status of the patient. In patients with neovascular (or wet) ARMD, anticoagulant medication should be prescribed only for absolute systemic indications, and overanticoagulation should be strictly avoided through careful monitoring of the INR [21].

Recommendation — The use of warfarin and other oral anticoagulants results in increased risk for hemorrhagic complications in ARMD and perhaps other ocular conditions predisposing to ocular hemorrhage, but the absolute risk increase appears to be small. The outcome of preretinal (also called subhyaloid) and vitreous hemorrhage in diabetics is often good with appropriate treatment, but the outcome of subretinal hemorrhages in ARMD is often visually devastating.

Nevertheless, the high risk of stroke and pulmonary embolism in conditions for which warfarin is indicated provides a strong argument for its use despite the small risk of ocular complications.

FIBRINOLYTIC AGENTS — As with acute anticoagulation, there are only anecdotal reports of intraocular bleeding in patients with predisposing retinal conditions who have been treated with fibrinolytic agents [22,23]. Such complications occur in patients without predisposing ocular conditions as well, often with good outcomes following ocular surgery [24-27].

Diabetic retinopathy — Surveys have shown a variety of approaches among physicians for the use of fibrinolytic agents in patients with diabetes, with no difference in the occurrence of intraocular hemorrhage [28,29]. In the GUSTO-I trial of almost 41,000 patients, there was only one ocular hemorrhage (eyelid hematoma after a documented fall) and no intraocular hemorrhages among 6011 patients with diabetes [29]. It was estimated that about 2000 of the diabetic patients had nonproliferative retinopathy and about 300 had proliferative retinopathy. Although the risk of ocular hemorrhage was not as completely evaluated in other major fibrinolytic trials, an appreciable number of diabetics were included without reports of major intraocular bleeding [30].

Based upon these findings, the recommendation is that diabetic retinopathy, even if proliferative, should not be considered a contraindication to fibrinolytic therapy [29-33].

Age-related macular degeneration — Fibrinolytic therapy in patients with ARMD may be complicated by ocular hemorrhage. However, no reports of large groups of patients with ARMD treated with thrombolytics are available. One patient with exudative ARMD was reported to have a vitreous hemorrhage in the affected eye three hours after the intravenous administration of reteplase and eventually underwent vitrectomy [23]. Intraocular pressure was treated successfully, but the final visual acuity was only light perception.

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The visual outcome of ocular hemorrhage in patients with ARMD may not be as good as the outcome of vitreous hemorrhage in diabetics, but there is no reason to expect a substantially higher complication rate in patients with ARMD than in patients with diabetes. Given the serious conditions for which fibrinolytic drugs are given it is reasonable to use them, when indicated, in patients with ARMD.

Recommendation — Treatment of acute myocardial infarction or stroke with fibrinolytic agents will be uncommonly associated with ocular hemorrhages. The risk does not appear to be different in patients with and without ocular conditions complicated by hemorrhages. These ocular disorders are not a contraindication to the use of fibrinolytic therapy. (See “Fibrinolytic (thrombolytic) agents in acute ST elevation myocardial infarction: Therapeutic use”, section on ‘Diabetes mellitus’ and “Reperfusion therapy for acute ischemic stroke”.)

OPHTHALMIC SURGERY — Patients undergoing elective ophthalmic surgery may be taking aspirin or warfarin. Although use of these agents may increase the risk of bleeding with surgical procedures, interruption of such therapy may increase the risk of stroke or thromboembolism. (See “Management of anticoagulation before and after elective surgery”.)

This section will review the available information concerning these risks in patients undergoing ophthalmic surgery. A more detailed discussion concerning the use of aspirin or warfarin in patients undergoing cataract surgery is presented separately. (See “Cataract in adults”, section on ‘Antithrombotic agents’.)

In general, however, ocular surgical procedures have a very low risk of bleeding. Retinal surgeons manipulating the retina probably have the most hemorrhagic complications, primarily due to mechanical or technical reasons. However, it is not known whether the amount of bleeding that may be encountered is increased if the patient is taking an anticoagulant agent.

Anticoagulants — There is a concern that the use of anticoagulants may increase the likelihood of ocular hemorrhage during most forms of ophthalmic surgery. Available reports concerning such risks are mixed, with some studies showing [34-39] and others not showing [40-45] an excess bleeding risk following their use. The following observations in illustrate the range of findings:

 

  • An early report in 50 patients undergoing ophthalmic surgery showed a significant increase in perioperative hemorrhages in patients who had been receiving warfarin compared with a matched control group not receiving this agent (12 versus zero percent) [34]. There was no significant difference in hemorrhagic complications between patients in whom warfarin was continued and those in whom it was discontinued during the perioperative period.
  • A larger study of 541 patients undergoing vitreoretinal surgery indicated an increase in the rate of hemorrhagic complications in patients taking warfarin (relative risk: 6.2) [35]. The authors concluded that warfarin may be stopped prior to surgery if the patient’s thromboembolic risk is low.
  • A study of 347 patients undergoing glaucoma surgery included 21 patients on warfarin whose medication was continued and 19 patients whose warfarin was discontinued [38]. Patients on anticoagulants had a significantly higher complication rate than patients on antiplatelet agents or on no medication. Seven patients continuing anticoagulation during surgery had hemorrhagic complications while only 3 patients in whom anticoagulation was discontinued had such complications, but this result did not reach statistical significance.
  • A study of 367 patients undergoing trabeculectomy included only five patients on anticoagulants [39]. However, all five suffered significant hyphema and four had failure of the trabeculectomy within one year.
  • In contrast to these findings, the risk of hemorrhagic complications in patients continuing warfarin was not increased in a prospective cohort study of 19,584 cataract surgeries in patients ≥50 years of age [44]. Among patients routinely taking warfarin prior to surgery, 526 continued warfarin within four days of surgery and 208 discontinued warfarin [44]. There were no ocular hemorrhagic events in either group and no significant differences in overall medical event rates.

 

Similarly, a subsequent study of 48,862 patients undergoing 55,567 cataract operations included 5.1 percent who were taking warfarin [45]. There was an increase in subconjunctival hematoma related to the anesthesia block, but no ocular hemorrhagic complications.

In two phase III trials of intravitreal injection of the anti-vascular endothelial growth factor (anti-VEGF) agents bevacizumab and ranibizumab, 85 patients had 18 or more intravitreal injections without hemorrhagic complications [46].

Recommendation — Patients receiving warfarin for the prevention of major thromboembolic complications can undergo cataract surgery with reasonable safety. However, patients undergoing vitreoretinal and glaucoma surgery may experience an increase in visually significant bleeding complications. The decision to withhold warfarin prior to surgery should be made on an individual basis, depending upon the indication for the anticoagulation. Other factors to consider include whether the patient is monocular or binocular, or has risk factors for ocular hemorrhage, such as prior hemorrhage in the fellow eye.

Patients receiving intravitreal injections of anti-VEGF agents may continue anticoagulation safely.

Antiplatelet agents — Studies of patients receiving antiplatelet agents have shown no adverse effects in those undergoing cataract, glaucoma, or vitreoretinal surgery [35,38,39,44,45,47-49]. The complication rate in patients using or not using antiplatelet agents is very small. Use of antiplatelet drugs may be associated with an increase in minor hemorrhagic complications (eg, subconjunctival hemorrhage) related to retrobulbar block, but no increase in ocular hemorrhage complications and no visually significant complications. As examples:

 

  • In the prospective cohort study of 19,584 cataract surgeries cited above, routine users of aspirin who continued therapy had the same very low risk of ocular hemorrhage as those who did not use aspirin (0.59 versus 0.56 events per 1000 surgeries) [44].
  • In a review of 48,862 (55,567 extracted but only 48,862 analyzed in the study) cataract operations, 28.1, 5.1, 1.9, and 1.0 percent of the patients were taking aspirin, warfarin, clopidogrel, or dipyridamole, respectively [45]. Some patients were on combination antiplatelet therapy. The use of warfarin was associated with a significant increase in minor hemorrhagic complications of the anesthesia, mostly subconjunctival hemorrhage, but no sight-threatening complications and no ocular hemorrhagic complications were noted. Patients taking clopidogrel alone, but not those taking clopidogrel plus aspirin, also had an increase in subconjunctival hemorrhage but did not have visually significant ocular hemorrhagic complications.

 

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