Prevalence of ocular hemorrhage in patients receiving warfarin therapy

Prevalence of ocular hemorrhage in patients receiving warfarin therapy Rosanne Superstein, MD; Julius E.S . Gomolin, MD; Wahbi Hammouda, MD; Arthur Rosenberg, MD; Olga Overbury, PhD; Carmen Arsenault, COA ABSTRACT • RESUME Background: Wanarin, the drug most commonly used for outpatient anticoagulation therapy, has bleeding as its main side effect. The objective of this study was to determine the prevalence of ocular hemorrhage in patients receiving warfarin and to compare it to the prevalence in the general population. Methods: Patients receiving wanarin therapy who were attending the anticoagulation clinic at a tertiary care hospital in Montreal between October and December 1996 received a flyer inviting them to have their eyes examined to look for "ocular bleeding." Consenting patients were examined for subconjunctival hemorrhage, gross hyphema, and vitreous and retinal hemorrhages through external ocular examination and funduscopic examination with the pupils dilated using direct and indirect ophthalmoscopy. Results: Of the 1225 patients seen at the clinic 126 (10%) agreed to participate. Four patients (3%) were found to have intraretinal hemorrhage at the time of examination. All hemorrhages were Visually insignificant. Interpretation: The risk of retinal hemorrhage in patients without preexisting ocular disease, such as retinal neovascularization or choroidal vasculopathy, who are receiving warfarin therapy is so small that it should not deter physicians from prescribing this drug when indicated. Contexte: Le saignement est I'effet secondaire principal de la wanarine, medicament Ie plus utilise comme anticoagulant pour les patients externes. Cette etude a pour objet d'etablir la prevalence de I'hemorragie oculaire chez les patients recevant de la wanarine, comparativement a la population en general. Methodes: Les patients recevant une therapie de wanarine dans une clinique d'anticoagulation d'un h6pital de soins tertiaires de Montreal ont ret;u, entre octobre et decembre 1996, un feuillet les invitant a se faire examiner les yeux pour voir s'ils avaient des « saignements oculaires ». Les patients consentants ont ete examines pour hemorragie sous-conjonctivale, hyphema macroscopique et hemorragies du corps vitre ou de la retine, par I'entremise d'examens oculaires externes et d'examens du fond de I'reil avec pupilles dilatees, par ophtalmoscopie directe et indirecte. Resultats : Des 1225 patients vus a la clinique, 126 (10 %) ont accepte de

From Sir M ortimer B. Davis-Jewish General Hospital, McGi ll University, Montreal, Que.

Reprint requests to: Dr. Julius E.S. Gomolin, Department of Ophthalmology, SirMortimer B. Davis-Jewish General Hospital, 3755 C6te St. Catherine Rd., Montreal PQ H3T lE2; fax (51 4) 340-8215

Accepted for publication Aug. 15,2000

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Ocular hemorrhage with waJfarin-Superstein et al participer a I'etude. Parmi ces derniers, quatre (3 %) avaient une hemorragie de la retine au moment de I'examen. Les hemorragies etaient cependant toutes negligeables pour la vue. Interpretation: Chez les patients qui, n'ayant pas de maladie oculaire preexistante, telle une neoformation des vaisseaux sanguins ou une maladie vasculaire de la choro'ide, re~oivent une therapie de warfarine, Ie risque d'hemorragie de la retine est si faible qu'il ne devrait pas empecher les medecins de prescrire Ie medicament quand celui-ci est indique.

W

arfarin is the most commonly prescribed anticoagulant for oral use. It acts by inhibiting the synthesis of vitamin K-dependent coagulation factors (II, VII, IX and X).l With the increasing use of this drug in treating relatively common diseases such as atrial fibrillation, particularly in the elderly population, the side effects of therapy must be fully understood in order to evaluate the risk to benefit ratio in treating these disorders. The most serious adverse effect of warfarin therapy is hemorrhage, which has been reported in up to 39% of patients. 2,3 Bleeding complications related to warfarin include intracranial hemorrhage, subdural hemorrhage, gastrointestinal bleeding and ocular hemorrhage. 2- 6 Ocular bleeding described in the literature includes anterior chamber, subretinal and subconjunctival hemorrhages and has been reported more frequently in patients with preexisting ocular conditions. 7- 11 To our knowledge, there are no prospective studies evaluating the prevalence of intra- and extraocular hemorrhage in patients receiving warfarin. In two studies in the early 1960s the incidence of subconjunctival hemorrhage related to long-term anticoagulant therapy was 1.5% to 5%.5,6 In the Beaver Dam Eye Study retinal blot hemorrhages were three times more prevalent in patients receiving anticoagulant therapy than in normal subjects (4.5% vs. 1.5%).12 However, this finding was not statistically significant, and the investigators did not indicate which type of anticoagulant the patients were using. Hyphemas have been reported in patients with preexisting ocular problems, such as central retinal vein occlusion, proliferative diabetic retinopathy, optic nerve atrophy secondary to injury and iris-fixed intraocular lenses. 9- 11 Warfarin can theoretically cause subconjunctival, anterior chamber, retinal, choroidal and vitreous hemorrhages, which in some cases may be clinically unapparent. This may be particularly important in patients with underlying ocular disease, who may be predisposed to sight-threatening complications. The objective of this study was to determine the point prevalence of ocular hemorrhage in patients receiving warfarin thera-

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py and to compare it to the prevalence in the general population. METHODS

Patients receiving warfarin therapy who attended the anticoagulation clinic at Sir Mortimer B. DavisJewish General Hospital, Montreal, for follow-up appointments and blood tests on selected days between October and December 1996 received a flyer inviting them to undergo a 20-minute ocular examination to look for "ocular bleeding." Informed consent was obtained before the examination, and an interview was conducted. The consent form was approved by the hospital's Research Ethics Committee. Each patient was asked a series of questions regarding the reason for therapy, the duration of treatment, other medical and ocular diseases, prior bleeding complications and the use of other medications. The patients were also shown a standard picture of a subconjunctival hemorrhage and were asked whether they ever had one while using warfarin. An external ocular examination was then performed by an ophthalmology resident (R.S.) to look for subconjunctival hemorrhage and gross hyphema. Funduscopic examination with the pupil dilated was performed using direct and indirect ophthalmoscopy to screen for vitreous and retinal hemorrhages. Contact lens examination and fundus photography were done in patients with positive findings (any ocular bleeding in the absence of ocular disease). Positive findings were reviewed with an attending ophthalmologist (J.E.S.G.). Fluorescein angiography was done to differentiate between retinal dot hemorrhages and microaneurysms. Follow-up examinations were arranged when indicated. The intensity of anticoagulation was determined by means of the International Normalized Ratio (INR) , which standardizes reporting of the prothrombin time by adjusting for differences in thromboplastins used at different laboratories,l3 The INR was obtained on the day the patient was examined and 6 to 12 weeks before the examination, depending on available data from the patient's previous visit to the anticoagulation clinic.

Ocular hemorrhage with

No. (and %) of patients

Atrial fibrillation Cerebrovascular disease Deep vein thrombosis/pulmonary embolism Metal prosthetic heart valve Arterial embolism Vascular graft Mitral valve disease Inherited prothrombotic disorders (protein C deficiency, antithrombin III deficiency) Antiphospholipid antibodies Other Unknown

54 (43) 19 (15) 15(12) 14 (II) 5 (4) 3 (2) 3 (2)

2 2 5 4

et al

absence of other ocular disease: three had perimacular dot hemorrhages, two had subconjunctival hemorrhages, and one had a disc hemorrhage. No patient had gross hyphema or vitreous hemorrhage. The characteristics of the patients with ocular hemorrhages are shown in Table 2. Patient 1 had a dot hemorrhage approximately 1000 11 superonasal to the centre of the fovea. Warfarin therapy had been started 2 months earlier for treatment of deep vein thrombosis. Follow-up examination 4 months later showed resolution of the hemorrhage while the patient was still using warfarin. Patient 2 had a dot hemorrhage about 120011 superior to the centre of the fovea that was confirmed by fluorescein angiography. She also had a remote macroaneurysm in the fellow eye. Her INR 8 weeks before examination was 3.2, in the high therapeutic range. She reported having had nosebleeds. Patient 3 had one isolated 300-11 blot hemorrhage 1500 11 superior to the fovea. She had been receiving warfarin for 51f2 years for atrial fibrillation. Her INR 11 weeks before examination was 3.3. She reported nosebleeds and bruising easily. On further investigation it was found that 2 years earlier she had had vascular occlusion associated with foveal hemorrhage in the fellow eye. Patient 4 had a disc hemorrhage. Although diabetic, he had no evidence of diabetic retinopathy, glaucoma or other ocular disease. He had been receiving warfarin therapy for 18 months for an embolic cerebrovascular accident. His INR was in the high therapeutic

Table I-Indication for anticoagulation therapy with warfarin in 126 patients Indication

waifarin~Superstein

(2) (2) (4) (3)

RESULTS

Of the 1225 patients who attended the anticoagulation clinic 126 (10%) presented themselves to the ophthalmology clinic for examination. There were 65 men and 61 women with a mean age of71.5 (standard deviation 11.7) years (range 28 to 89 years). Ofthe 126,58 had hypertension and 28 had diabetes mellitus. The primary indication for anticoagulation therapy was atrial fibrillation (43 % of patients) (Table 1). Six patients were found to have ocular bleeding in the

Table 2-Characteristics of the six patients who had ocular hemorrhages

Patient no.

Age, yr

Hemorrhage location

International Normalized Ratio*

History of diabetes mellitus

History of hypertension

On examination

On previous examination

Reason for anticoagulation Vein thrombosis Atrial fibrillation Atrial fibrillation Atrial fibrillation Valve replacement Atrial fibrillation

2

70 76

Perimacular Perimacular

No No

No Yes

1.6 2.6

1.4 3.2

3

83

Perimacular

No

Yes

1.5

3.3

4

78

Disc

Yes

Yes

4.2

3.0

5

76

Subconjunctival

No

No

2.1

2.3

6

78

Subconjunctival

No

No

3.8

1.2

*Standardizes reporting of the prothrombin time by adjusting for differences in thromboplastins used at different laboratories. I)

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Ocular hemorrhage with waljarin-Superstein et al range. He reported bruising easily. Follow-up examination 1 month later showed partial resolution of the disc hemorrhage. Patients 5 and 6 had subconjunctival hemorrhages. Patient 5 was receiving acetylsalicylic acid (ASA) in addition to warfarin and had an INR at the therapeutic level. Patient 6 had an INR in the high therapeutic range. Prior subconjunctival hemorrhage was reported by 23 of the 126 patients, bruising by 15, nosebleeds by 14, hematochezia by 7, hematuria by 2, hemoptysis by 2, gastrointestinal bleeding by 2, and menorrhagia by 1. None of the patients had been admitted to hospital or had received a blood transfusion as a result of their bleeding complications. The mean INR of the 126 patients on the day of examination was 2.64 (standard deviation 0.96). The therapeutic goal was 2.5 to 3.5 for patients with metal prosthetic heart valves and 2.0 to 3.0 for all other patients. 14.1 5 The duration of treatment ranged from 1 week to 25 years (mean 3.97 [standard deviation 4.8] years). Eleven patients were also receiving ASA, and 1 was receiving ticlopidine hydrochloride. Other, incidental findings on fundus examination with the pupil dilated included choroidal nevi (in two patients), maculopathy, including cellophane maculopathy and macular geographic atrophy (two patients), nonexudative age-related macular degeneration (two patients), branch retinal artery occlusion (two patients) and, in one patient each, congenital hypertrophy of retinal pigment epithelium, peripheral drusen, a myelinated nerve fibre layer at the disc and a macroaneurysm. Four patients known to be diabetic had mild nonproliferati ve diabetic retinopathy, and one patient had central retinal vein occlusion. INTERPRETATION

We found that 6 of 126 patients receiving warfarin therapy had ocular bleeding; however, 2 of the 6 had only subconjunctival hemorrhages, which are not known to cause visual loss and are not generally clinically worrisome. The remaining four patients (3%) (1.6% of eyes) had retinal hemorrhages at the time of examination, all of which were visually insignificant. This rate is slightly higher than those observed in the nondiabetic populations in the Framingham and Beaver Dam Eye studies,12,16 but the difference is not statistically significantly different using the binomial probability of distribution. The Framingham Eye Study investigators found that 0.9% (44/4701) of eyes without a previous history of diabetes had micro-

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aneurysms or dot hemorrhages or both. 16 In the Beaver Dam Eye Study retinal blot hemorrhages were present in 1.5% (66/4311) of nondiabetic patients. 12 Since our patients were self-selected, a selection bias was introduced, which may have resulted in overestimation of the prevalence of visually significant hemorrhages. The patients who agreed to participate were more likely to have had prior bleeding or an eye problem than those who did not participate. The only data on the prevalence of retinal hemorrhages in patients receiving anticoagulant therapy are from the Beaver Dam Eye Study, which showed that 4.5% (3/67) of nondiabetic patients aged 65 years or more who were taking anticoagulants had blot hemorrhages. 12 This rate was three times that for subjects not taking anticoagulants; however, the difference was not statistically significant. The higher prevalence of retinal hemorrhages in the Beaver Dam Eye Study than in our study may have been due to the fact that the investigators used stereoscopic fundus photographs to assess for retinopathy, which is a more sensitive method than direct and indirect ophthalmoscopy, used in our study. However, the data from the Beaver Dam Eye Study for this subgroup are inconclusive because there were only 67 patients, the type and intensity of anticoagulation were not specified, and the results were not statistically significant. Two of our patients with retinal hemorrhages had preexisting ocular disease (retinal vascular disease in the fellow eye). Neither of our two patients with agerelated macular degeneration had massive hemorrhages, such as those reported by Brown and colleagues7 and el Baba and associates. 8 Although we did not find that patients with preexisting ocular disease are at greater risk for ocular hemorrhage, a study examining the risk of ocular hemorrhage in this subset of patients is warranted. Risk factors for systemic bleeding in patients receiving warfarin therapy include hypertension, increased age, longer duration of therapy, more intense anticoagulation and use of concurrent medications. 2,4,17-19 Three of our patients with retinal hemorrhages had hypertension. In the Framingham Eye Study the presence of an isolated retinal hemorrhage had a positive predictive value for hypertension of 74% in patients not receiving anticoagulant therapy.t 6 The positive predictive value in the Beaver Dam Eye Study was 48.5%.12 A study from the Mayo Clinic showed that patients with retinopathy and hypertension had a significantly lower 10-year survival rate than an age- and sex-matched normotensive population. 2o Although this

Ocular hemorrhage with wmjarin-Superstein et al

finding is controversial, it suggests the need to follow such patients closely and monitor their blood pressure control. Some studies suggest that the risk of bleeding is twice as great in older patients receiving anticoagulant therapy than in younger patients receiving such therapy?-4,18,19 In the Beaver Dam Eye Study retinal blot hemorrhages were associated with increasing age, regardless of coagulation statuS. 12 People aged 75 years or more were 9.5 times more likely than younger patients to have such hemorrhages. In our study the mean age of patients with retinal hemorrhages was higher than that of the overall group of patients (77 vs. 71 years). Bleeding is about three times as common in patients with an INR of 3.0 to 4.5 as in those with an INR of 2.0 to 3.0. 3 In our study the mean INR on the day of examination was similar for the patients with bleeding and for the overall group of patients. However, three of the four patients with retinal hemorrhages had INR values of 4.2, 3.2 and 3.3 on the day of examination, 8 weeks before examination and 11 weeks before examination respectively. ASA therapy has been reported to double the risk of bleeding in patients receiving warfarin. 10 None of our patients with retinal hemorrhages were taking ASA. However, one of our patients with a subconjunctival hemorrhage was taking this drug. Spandorfer and Merli 3 reported that the risk of bleeding becomes greater as the duration of warfarin therapy increases. Our findings are not consistent with this observation: the mean duration of therapy for the four patients with retinal bleeding was 1.9 years (range 2 months to 5.5 years), compared with 4.0 years for the overall group. In conclusion, the risk of retinal hemorrhage in patients receiving warfarin therapy is so small that it should not deter physicians from prescribing warfarin when indicated. However, patients with retinal hemorrhages should have their blood pressure monitored, and all patients, particularly those over 75 years of age, need to have their INR monitored closely.
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4. Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D' Angelo A, et ai, for the Italian Study on Complications of Oral Anticoagulant Therapy. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996;348: 423-8. 5. Pollard JW, Hamilton MJ, Christensen NA, Achor RW. Problems associated with long-term anticoagulant therapy. Circulation 1962;25:311-7. 6. Mosley DH, Schatz IJ, Breneman GM, Keyes JW. Longterm anticoagulant therapy. lAMA 1963;186:128-30. 7. Brown GC, Tasman WS, Shields JA. Massive subretinal hemorrhage and anticoagulant therapy. Can lOphthalmol 1982;17:227-30. 8. el Baba F, Jarrett WH II, Harbin TS Jr, Fine SL, Michels RG, Schachat AP, et al. Massive hemorrhage complicating age-related macular degeneration. Clinicopathologic correlation and role of anticoagulants. Ophthalmology 1986; 93:1581-92. 9. Koehler MP, Sholition DB. Spontaneous hyphema resulting from warfarin. Ann OphthalmoI1983;15:858-9. 10. Holder R. Spontaneous hyphaema as a result of systemic anticoagulation in previously abnormal eyes. Postgrad Med lI99l;67:1008-1O. 11. Taylor RH, Gibson JM. Warfarin, spontaneous hyphaemas, and intraocular lenses. Lancet 1988;1:762-3. 12. Klein R. Retinopathy in a population-based study. Trans Am Ophthalmol Soc 1992;90:561-94. 13. Hirsh J. Oral anticoagulants. N Engl 1 Med 1991;324: 1865-75. 14. Poller L. Therapeutic ranges for oral anticoagulation in different thromboembolic disorders. Ann Hematol 1992;64: 52-9. 15. Hirsh J. Guide to anticoagulant therapy: part 2. Oral anticoagulants. Circulation 1994;89: 1469-80. 16. Leibowitz HM, Krueger DE, Maunder LR, Milton RC, Kini MM, Kahn HA, et al. The Framingham Eye Study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975. Surv Ophthalmol 1980;24 (suppl):335-61O. 17. Fihn SD, McDonell M, Martin D, Henikoff J, Vermes D, Kent D, et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Ann Intern Med 1993; 118:511-20. 18. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am 1 Med 1989; 87:144-52. 19. Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med 1992;116:901-4. 20. Breslin DJ, Gifford RW, Fairbairn JF. Essential hypertension. Circulation 1966;33:87-97. Key words: warfarin, ocular hemorrhage, complications

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