Ocular Bleeding Related to Warfarin Anticoagulation in Patients with Mechanical Heart Valve and Atrial Fibrillation

Transcription

1 The Journal of International Medical Research 2007; 35: Ocular Bleeding Related to Warfarin Anticoagulation in Patients with Mechanical Heart Valve and Atrial Fibrillation I BIYIK 1, I MERCAN 2, O ERGENE 3 AND O OTO 4 1 Department of Cardiology and 2 Department of Ophthalmology, Uşak State Hospital, Uşak, Turkey; 3 Cardiology Clinics, Atatürk Education and Training Hospital, Izmir, Turkey; 4 Department of Cardiovascular Surgery, School of Medicine, Dokuz Eylül University, Izmir, Turkey We investigated the incidence of ocular bleeding in patients taking anticoagulant therapy (warfarin) and its association with other related factors. We examined 210 patients taking warfarin and 210 gender- and age-matched controls for ocular bleeding. Patients and controls were examined by external ocular examination and fundoscopic examination. The incidence of ocular bleeding was 11.4% in patients and 3.8% in controls. It was five times higher in patients with hypertension than in other patients. The incidence of ocular bleeding was higher in older than in younger patients. No association was found between ocular bleeding and factors such as gender, international normalized ratio, duration of warfarin therapy, concomitant aspirin use and diabetes mellitus. Thus, warfarin therapy increases the frequency of ocular bleeding. The higher incidence of ocular bleeding in the patients with hypertension and advanced age should be kept in mind and this subgroup of patients taking warfarin should be monitored closely. KEY WORDS: WARFARIN; ANTICOAGULANTS; MECHANICAL HEART VALVES; ATRIAL FIBRILLATION; OCULAR BLEEDING; HAEMORRHAGE Introduction Warfarin is the most effective drug in the primary and secondary prevention of stroke and other thromboembolic complications in patients with mechanical heart valves and atrial fibrillation. The anticoagulant effect of warfarin is due to the synthesis of vitamin K- dependent coagulation factors (factors II, VII, IX and X). 1 Mechanical heart valve thrombosis and systemic embolization are life-threatening complications in patients with prosthetic heart valves and atrial fibrillation, so it is crucial to treat these patients with warfarin, and also with aspirin. 2 Nevertheless, anticoagulation with warfarin has some risks because of its narrow therapeutic range, the effect of dietary levels of vitamin K, and racial/ethnic differences in response. While lower levels of anticoagulation may permit 143

2 thromboembolic events, higher levels may increase the risk of haemorrhagic complications. 3 The efficacy and safety of anticoagulation in patients with mechanical heart valves or atrial fibrillation depend on the maintenance of the international normalized ratio (INR), as recommended by current practice guidelines. 3 The most serious complication of warfarin anticoagulation is haemorrhage, which may be seen in up to 39% of patients receiving warfarin. 4 The haemorrhagic complications of warfarin therapy include gastrointestinal haemorrhage, intracranial haemorrhage, nasal and dental haemorrhage, skin bruising and ocular haemorrhage. 5,6 Warfarin may cause ocular bleeding complications such as subconjunctival, anterior chamber, vitreous, retinal and choroidal haemorrhages. These may lead to sight-threatening complications, especially in some patients with underlying ocular pathologies. The term ocular bleeding as it is used here refers to subconjunctival, anterior chamber, vitreous and retinal haemorrhages, and in the previous studies, the incidence of subconjunctival and retinal bleeding associated with anticoagulant therapy has been reported as 3 5% and retinal blot haemorrhages were three times higher in patients taking warfarin than in normal subjects. 7 We know of no prospective study examining the associations between ocular bleeding and other related factors, such as age, gender, INR, duration of warfarin therapy, concomitant aspirin use, hypertension and diabetes mellitus. In the present study, our aim was to investigate the incidence of ocular bleeding in patients undergoing warfarin anticoagulation therapy to prevent embolism in the presence of mechanical heart valves or atrial fibrillation, and the association of such bleeding with these other related factors. Patients and methods PATIENTS The study took place between July and December 2004 and was based upon patients undergoing warfarin therapy for cardiovascular disorders and attending the out-patient clinic of the Department of Cardiology of Uşak State Hospital. Indications for warfarin therapy in the study group were mechanical heart valves and atrial fibrillation resulting from heart disease. Patients attending the Cardiology Department and taking warfarin were examined for ocular bleeding, including subconjunctival haemorrhage, microscopic or gross hyphaema, and vitreous and retinal haemorrhages. Further cases presenting to the out-patient clinic of the Ophthalmology Department of Uşak State Hospital, with unconnected complaints and not undergoing anticoagulant or antithrombotic therapy, were evaluated as gender- and agematched controls. Almost all the patients taking warfarin and followed by the out-patient cardiology clinic were included in this study. Exclusion criteria for the study were very short duration of warfarin therapy (< 30 days), low intensity of anticoagulation (INR < 1.5), known ocular surgery, and underlying ocular disease, such as glaucoma. The study was planned in conjunction with the Department of Cardiology of Atatürk Education and Training Hospital, Uşak State Hospital s referral centre. The Institutional Review Board of Atatürk Education and Training Hospital approved the study protocol, and informed consent was obtained from all patients before examination. METHODS All examinations for ocular bleeding were performed by an experienced ophthalmologist by external ocular examination and fundo- 144

3 scopic examination, using direct and indirect ophthalmoscopy. All individuals in the warfarin-treated group were questioned to establish the reason for their warfarin therapy, the duration of the treatment, the presence of bleeding complications, concomitant drug use, and other concomitant diseases, such as diabetes mellitus and hypertension. The incidence of ocular bleeding and its association with other factors were investigated. Immediately before examination, the intensity of warfarin anticoagulation was measured as the INR by means of the CoaguChek S system (Roche Diagnostics, Indianapolis, Indiana, USA), a portable device which performs a prothrombin time blood test on a fresh whole-blood sample from a finger-stick and enables quick and easy INR measurement. 8 STATISTICAL ANALYSIS In the statistical analysis, ocular bleeding was considered as the dependent variable. The association between categorical variables and ocular bleeding was tested using the χ 2 test. Student s t-test was used to compare patients with and without ocular bleeding regarding average age, INR level and the duration of therapy. A P-value < 0.05 was considered to be statistically significant. Results The study included a total of 420 patients, comprising 210 patients who were undergoing warfarin therapy for cardiovascular disorders and a control group of 210 individuals attending the out-patient clinic with unconnected complaints and not undergoing anticoagulant or antithrombotic therapy. Patient characteristics and ocular bleeding frequency in the study group are summarized in Table 1. Of the 210 patients taking warfarin, 24 were found to have ocular bleeding (11.4%). Of the 210 age- and gender-matched controls, eight were found to have ocular bleeding (3.8%) (P = 0.003). There was significant correlation between ocular bleeding and hypertension (P < 0.001). Ocular bleeding was found approximately five times more frequently in hypertensive than in normotensive patients (23.9 and 5.0%, respectively). Increasing age may be a significant risk factor for ocular bleeding. In this study, the average age of patients with ocular bleeding was significantly higher than that of patients without ocular bleeding (mean ages were 61 ± 14 and 50 ± 15 years, respectively; P = 0.02). There was no gender difference in the percentage of subjects with ocular bleeding. Of the 24 patients with ocular bleeding, 15 (62.5%) were taking aspirin together with warfarin and nine (37.5%) were taking only warfarin. Thus, concomitant aspirin use slightly increased the incidence of ocular bleeding, but the difference was not statistically significant. Although the patients in the present study with mechanical heart valves were treated with more intense anticoagulation therapy and concomitant aspirin than the other patients, there was no significant increase in the frequency of ocular bleeding in these patients. The incidence of ocular bleeding was slightly higher in patients with diabetes mellitus than in others, but this difference was not statistically significant. The INR was 2.8 ± 1.1 (mean ± SD) and ranged from 1.5 to 8. There was no difference in the mean INR between patients with ocular bleeding and those without (2.8 and 2.8, respectively). The duration of warfarin therapy was 4.8 ± 4.4 years (mean ± SD), ranging from 45 days to 20 years. The mean duration of warfarin therapy was greater in patients with ocular bleeding than in others (6.0 and 4.7 years, respectively), but this difference was not statistically 145

4 TABLE 1: Patient characteristics and frequency of ocular bleeding among 210 patients undergoing warfarin therapy Number of Number with patients (%) ocular bleeding (%) P-value Gender Male 87 (41.4) 12 (13.8) Female 123 (58.6) 12 (9.8) Taking concomitant aspirin Yes 113 (53.8) 15 (13.3) No 97 (46.2) 9 (9.3) Prosthetic valve Yes 140 (66.7) 13 (9.3) No 70 (33.3) 11 (15.7) Hypertension < Yes 71 (33.8) 17 (23.9) No 139 (66.2) 7 (5.0) Diabetes mellitus Yes 15 (7.1) 3 (20.0) No 195 (92.9) 21 (10.8) Atrial fibrillation Yes 70 (33.3) 11 (15.7) No 140 (66.7) 13 (9.3) Antithrombotics Taking warfarin (cases) (11.4) Not taking any antithrombotic (controls) (3.8), not significant. significant. There was therefore no significant correlation between ocular bleeding and gender, INR in the therapeutic range, the duration of warfarin therapy, the presence of diabetes mellitus, or (interestingly) with concomitant aspirin use. Of the 24 patients with ocular bleeding in the group undergoing warfarin therapy, six had subconjunctival haemorrhage, two had subconjunctival and perimacular haemorrhages, one had subconjunctival and perimacular dot haemorrhages, 13 had perimacular haemorrhage, two had perimacular and disc haemorrhages, and two patients had vitreous haemorrhage. No patients had microscopic or gross hyphaema in the group undergoing warfarin therapy. Of the eight patients with ocular bleeding in the control group, five had subconjunctival haemorrhage and three had retinal haemorrhage. There were no disc or vitreous haemorrhages and no microscopic or gross hyphaema in the control group (Table 2). Discussion This study showed that the frequency of ocular bleeding in patients undergoing warfarin therapy was significantly higher than in patients not taking any 146

5 TABLE 2: Distribution of subjects according to site of ocular bleeding Subjects receiving warfarin Subjects not receiving warfarin Subconjunctival 9 5 Retinal 18 3 Vitreous 2 0 Hyphaema 0 0 anticoagulant or antithrombotic therapy, and that ocular bleeding was significantly associated with the presence of hypertension and increasing age. The incidence of ocular bleeding in this study was slightly higher than in previous studies. In the Beaver Dam Eye Study, 7 retinal haemorrhages were three times more frequent in patients undergoing anticoagulant therapy than in normal subjects (4.5% and 1.5%, respectively). The Beaver Dam Eye Study data for the subgroup of patients undergoing warfarin therapy are inconclusive since the group comprised only 67 patients and the type of anticoagulant taken by the patients was not stated. Superstein et al. 7 however found a 3% incidence of retinal bleeding in patients receiving warfarin therapy. Only 126 patients participated in their study and selection bias may have been introduced because the patients were self-selected. However, the present study was an observational study that comprised 210 patients, and almost all the patients who were taking warfarin and were followed by our out-patient cardiology clinic were included in the study. The study was conducted in a peripheral hospital, which provided data from a real-world clinical setting. In the present study, the incidence of ocular bleeding was significantly increased in the presence of hypertension and advanced age. Previous studies have shown that the incidence of retinal bleeding might increase with the presence of hypertension and advanced age. 7,9 In a recent study, Yang et al. 10 showed that ocular bleeding, especially massive spontaneous choroidal haemorrhage, might be associated with hypertension, advanced age, systemic anticoagulation, atherosclerosis and agerelated macular degeneration. Our data are therefore consistent with previously reported research. It is thought that a spontaneous rupture of small, friable vessels may cause haemorrhage in patients taking warfarin. 10 However, in the Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation (AFASAK 2) study, 11 there was no significant influence of age on the risk of bleeding. Abdelhafiz and Wheeldon 12 also reported that there was no significant association between age and bleeding. Ocular bleeding was not evaluated in these studies, however. There is controversy about whether advanced age is a risk factor for warfarinrelated haemorrhage. 13 Our results show that hypertension and advanced age might lead to ocular haemorrhage in patients receiving warfarin therapy, and that warfarin therapy should be considered as a risk factor for ocular bleeding. 10,14 In the present study we were not able to find any statistically significant association between ocular bleeding and gender, INR within the therapeutic range, the duration of warfarin therapy, the presence of diabetes 147

6 mellitus or concomitant aspirin use. Although the effect was not statistically significant, concomitant aspirin use was related to a slight increase in the incidence of ocular bleeding in the present study. Superstein et al. 7 pointed out that aspirin therapy might double the risk of bleeding in patients taking warfarin. A recent large study by Shireman et al. 15 reported that the risk of bleeding was moderately increased in elderly patients receiving combined warfarin and antiplatelet therapy. In trials investigating the combination therapy of warfarin and aspirin, the incidence of severe bleeding appears to be dose-dependent The NASPEAF study 18 showed that combined antiplatelet therapy and moderate intensity of warfarin anticoagulation therapy substantially decreased vascular events and proved to be safe. Ocular bleeding was not evaluated in any of these studies, however. Although a safe dose of aspirin cannot be determined, the guidelines for valvular prosthesis recommend mg/day aspirin in combined therapy. 19 In the present study, patients given combined therapy with warfarin and aspirin were receiving aspirin at an average dose of 100 mg/day, so our results are consistent with previous reports. The present study was not able to reveal any significant association between ocular bleeding and INR or between ocular bleeding and the duration of warfarin therapy. Recent studies have reported that a moderate intensity of anticoagulation therapy (INR 2 3) does not increase the incidence of bleeding complications. 6,18 In our study, the average INR of patients with ocular bleeding was 2.8. In an Italian study on the complications of oral anticoagulant therapy, it was reported that most bleeding events occur in the therapeutic range (INR < 3.0). 5 Kucher et al. 20 recently demonstrated that serial INRs are poor predictors of haemorrhagic complications of warfarin therapy, and that the INR may not accurately reflect anticoagulation status. In another recent study from Kucher and colleagues, 21 it is suggested that there is an increased incidence over time of warfarin-related haemorrhage, especially major and intracranial haemorrhage, but the study does not include data about ocular bleeding. Although the incidence of warfarin-related ocular bleeding was slightly higher in patients with diabetes than in other patients in our study, this result was not statistically significant. Diabetic retinopathy may facilitate this complication, but in our study the subgroup of patients having diabetes consisted of only 15 patients (7.1%); largescale studies may be needed to reveal such an association. Our study also was limited in that facilities at our hospital did not permit us to perform ocular angiographic examination, and few patients with retinal bleeding agreed to be referred to a tertiary centre because of its distance. This might have caused some overestimation of retinal bleeding rates. Nevertheless, to the best of our knowledge this study is the first observational study evaluating the associations between ocular bleeding and other related factors, such as age, gender, INR, duration of warfarin therapy, concomitant aspirin use, hypertension and diabetes mellitus in a real-world clinical setting. In conclusion, warfarin therapy increases the frequency of ocular bleeding. Although sight-threatening ocular bleeding, such as hyphaema and vitreous, disc and subconjunctival haemorrhages, may be noticed, other ocular bleedings may not attract attention. The higher incidence of ocular bleeding in patients with hypertension and advanced age should be kept in mind, and patients in this category who are taking warfarin should be monitored closely. 148

7 Acknowledgement We thank Dr Belgin Ünal for her help in the statistical analyses. Conflicts of interest No conflicts of interest were declared in relation to this article. Received for publication 7 July 2006 Accepted subject to revision 15 July 2006 Revised accepted 9 November 2006 Copyright 2007 Cambridge Medical Publications References 1 Hirsh J, Dalen JE, Deykin D, Poller L, Bussey H: Oral anticoagulants. Mechanisms of action, clinical effectiveness, and optimal therapeutic range. Chest 1995; 108: 231S 246S. 2 Larson RJ, Fisher ES: Should aspirin be continued in patients started on warfarin? A systematic review and meta-analysis. J Gen Intern Med 2004; 19: Reynolds MW, Fahrbach K, Hauch O, Wygant G, Estok R, Cella C, et al: Warfarin anticoagulation and outcomes in patients with atrial fibrillation. A systematic review and meta-analysis. Chest 2004; 126: Lewine MN, Raskob G, Landefeld S, Hirsh J: Hemorrhagic complications of anticoagulant treatment. Chest 1995; 108: 276S 290S. 5 Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D Angelo A, et al: Bleeding complications of oral anticoagulant treatment: an inceptioncohort, prospective collaborative study (ISCOAT): Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996; 348: Fang MC, Chang Y, Hylek EM, Rosand J, Greenberg SM, Go AS, et al: Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004; 141: Superstein R, Gomolin JES, Hammouda W, Rosenberg A, Overbery O, Arsenault C: Prevalence of ocular hemorrhage in patients receiving warfarin. Can J Ophthalmol 2000; 35: Gloster HM, Jr, Twersky J: Surgical pearl: the use of the CoaguChek S System for the preoperative evaluation of patients taking warfarin. J Am Acad Dermatol 2004; 50: Klein R: Retinopathy in a population-based study. Trans Am Ophthalmol Soc 1992; 90: Yang SS, Fu AD, McDonald HR, Johnson RN, Ai E, Jumper JM: Massive spontaneous choroidal hemorrhage. Retina 2003; 23: Gullow AL, Koefoed BG, Petersen P: Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: The AFASAK 2 study. Arch Intern Med 1999; 159: Abdelhafiz AH, Wheeldon NM: Results of an open label, prospective study of anticoagulant therapy for atrial fibrillation. Clin Ther 2004; 26: Sam C, Massaro JM, D Agostino RB, Sr, Levy D, Lambert JW, Wolf PA, et al: Framingham Heart Study. Warfarin and aspirin use and predictors of major bleeding complications in atrial fibrillation (the Framingham Heart Study). Am J Cardiol 2004; 94: Chu TG, Green RL: Suprachoroidal hemorrhage. Surv Ophthalmol 1999; 43: Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF: Combined anticoagulantantiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004; 35: Turpie AGG, Gent M, Laupacis A, Latour Y, Gunstensen J, Basile F, et al: A comparison of aspirin with placebo in patients treated with warfarin after heart valve replacement. N Engl J Med 1993; 329: Verheugt FW: Bleeding risk of combined oral anticoagulant and antiplatelet therapy in cardiovascular disease. J Cardiovasc Risk 1996; 3: Perez-Gomez F, Alegria E, Berjon J, Iriarte JA, Zumalde J, Salvador A, et al: NASPEAF investigators. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol 2004; 44: Stein PD, Alpert JS, Dalen JE, Horstkotte D, Turpie AJ: Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1998; 114: Kucher N, Connolly S, Beckman JA, Cheng LH, Tsilimingras KV, Fanikos J, et al: International normalized ratio increase before warfarinassociated hemorrhage: brief and subtle. Arch Intern Med 2004; 164: Kucher N, Castellanos LR, Quiroz R, Koo S, Fanikos J, Goldhaber SZ: Time trends in warfarin-associated hemorrhage. Am J Cardiol 2004; 94: Address for correspondence Dr I Biyik Ismetpafla Caddesi 75/1, Uşak, Turkey. ismailbiyikmd@yahoo.com 149