Aminocaproic Acid versus Prednisone for the Treatment of Traumatic Hyphema A Randomized Clinical Trial MARILYN D. FARBER, DrPH, 1 RICHARD FISCELLA, RPh, MPH, 2 MORTON F. GOLDBERG, MD3
Abstract: One hundred twelve patients who sustained hyphema after blunt trauma were enrolled in a double-blind randomized clinical trial to determine the relative efficacies of aminocaproic acid (Amicar®) and systemic prednisone for reducing the rate of secondary hemorrhage. Fifty-six patients received an oral dosage of 50 mgjkg of aminocaproic acid every 4 hours for 5 days, up to a maximum of 30 g daily, and 56 patients received an oral dosage of 40 mg of prednisone daily (adjusted for weight) in two divided doses. Placebo pills and liquids were given to each patient to mask the treatment schedules. There were no statistically significant differences between the patient populations for any demographic or clinical characteristic (e.g., visual acuity, intraocular pressure (lOP], initial hyphema size) measured in the study. Blacks comprised 53% of the study population, and the mean age of the patients was 23.5 years. Four patients in each of the treatment groups experienced a secondary hemorrhage; the rebleed rate was 7.1% in each group. Ophthalmology 1991 ; 98:279-286
Medical treatment to reduce secondary hemorrhage af ter traumatic hyphema has been the subject of much con troversy. Rebleeding usually occurs from 2 to 6 days after the initial hyphema and has been reported in 0.4 to 35% Originally received: September 27, 1990. Manuscript accepted: November 15, 1990. 1
Department of Ophthalmology, University of Illinois at Chicago Eye Center, University of Illinois at Chicago College of Medicine, Chicago. College of Pharmacy, University of Illinois at Chicago College of Medicine, Chicago. 3 The Wilmer Eye Institute, The Johns Hopkins Hospital, Baltimore.
2
Presented in part at the American Academy of Ophthalmology Annual Meeting, Atlanta, Oct/Nov 1990 Supported in part by core grant EY01792 from the National Eye Institute, Bethesda, Maryland, and an unrestricted grant from Research to Prevent Blindness, Inc, New York , New York (UIC Eye Center). Reprint requests to Marilyn D. Farber, DrPH, Department of Ophthalmology, University of Illinois at Chicago, 1855 W Taylor St. Chicago, IL 60612.
patients who have not received oral medication for treat ment.1 -26 It is recognized that rebleeding may predispose patients to corneal blood staining, elevated intraocular pressure (lOP) with subsequent optic atrophy, peripheral anterior synechiae formation, and possible decreased vi sual acuity; however, the rate of secondary hemorrhage (and, therefore, the risk to each patient) is so variable that confusion exists about the necessity of treatment. Several studies have reported the beneficial effect of epsilon-aminocaproic acid (Amicar®) in reducing sec ondary hemorrhages in humans. 8•9 •12·20·24·27 Three ran domized clinical trials that compared the rebleed rate in patients receiving this antifibrinolytic agent with a placebo control found that aminocaproic acid was successful in reducing rebleeds in the treated group. In 1976, Crouch and Frenkel24 reported a rebleed rate of 33.3% in their control population and 3.1 % in their treated group. In 1983 McGetrick and co-workers25 reported rebleeds in 33.3% of their control patients compared with 3.6% of their treated patients, results almost identical to those of 279
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Crouch and Frenkel. 24 Both studies were reported from our institution. Kutner et aJ2° found a 23% rebleed rate in their placebo group, compared with no rebleeds in the treated patients. Both Kutner et al 20 and McGetrick et al 25 limited the dosage of aminocaproic acid to 100 mg/kg every 4 hours up to a maximum of 30 g daily. In a forth study, Palmer and co-workers27 compared two dose regimens of aminocaproic acid, 100 mg/kg every 4 hours or 50 mg/kg every 4 hours, in a double-masked random ized clinical trial. There was no statistically significant difference in the rebleed rates in these two groups. Corticosteroids, given both topically and systemically, also have been advocated for the treatment of traumatic hyphema. 28- 32 Yasuna29 treated 50 patients with systemic prednisone and reported no rebleeds in his patients. Rynne and Romano 31 also used systemic corticosteroids andre ported no reb leeds. Romano 32- 35 has been a vigorous pro ponent ofcorticosteroid treatment but has not performed a randomized clinical trial. In 1980 Spoor and co workers15 conducted the first well-controlled randomized clinical trial of systemic prednisone compared with a pla cebo. They reported rebleed rates of 20% in the control group of 20 patients and 13% in the 23 treated patients. These results were not statistically significant, and they concluded that corticosteroids failed to reduce the risk of secondary hemorrhage. However, the power of their study to detect a difference between the prednisone group and the control group was very small, and their results should be treated with caution. The purpose of our study is to determine if systemic epsilon aminocaproic acid and systemic prednisone would have similar or dissimilar effects on the incidence of sec ondary hemorrhages after traumatic hyphema.
PATIENTS AND METHODS All patients with hyphema due to blunt trauma treated at the University of Illinois at Chicago (UIC) Eye Center from July 1985 through March 1990, who had no open globe or other injury requiring immediate surgery, and who consented to be in the study, were admitted to the hospital and were placed on a double-blind randomized clinical trial protocol. Excluded from the study were pa tients with sickle-cell trait or disease, intravascular coag ulopathy, gastric ulcer, or diabetes mellitus, or those who were intoxicated and had detectable blood in their stool. 36 Pregnant women also were excluded. A complete medical history, physical and ocular ex amination, and blood cell counts, including a differential white blood cell count, platelets, prothrombin time, partial thromboplastin time, and levels of serum creatinine, glu cose, sodium chloride, and blood urea nitrogen, were performed on each patient at the time of admission. Sickle-cell screening was done on all nonwhite patients. A slit-lamp examination and tonometry readings were performed daily by the admitting physician. The baseline and secondary hyphema levels were recorded in milli meters. Hyphemas were considered primary if the amount offresh or clotted blood remained unchanged or decreased 280
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from the baseline examination. A secondary hemorrhage was defined as a definite increase in the amount of fresh blood in the anterior chamber compared with admission levels or fresh red blood that was visible over darker, clot ted blood during the hospital course. If a patient com plained of a decrease in vision more than 1 day after ex periencing a traumatic injury, before presentation for treatment, that patient was considered to have a secondary hemorrhage. One person was excluded from the study on this basis. All patients (or the parent or adult guardian of a minor) gave informed consent after they received an explanation of the purpose of the study. The assignment to receive aminocaproic acid or prednisone was determined ran domly and in a double-masked fashion. Sixty-four patients were originally randomized to treatment with aminoca proic acid, and 58 patients were randomized to receive prednisone. After randomization, 8 patients were excluded from the aminocaproic acid group for the following rea sons: 4 patients were accidentally placed on a regimen of topical steroids by another member of the professional staff; 2 patients left the hospital against medical advice before treatment was completed; 1 patient had a seizure on the first day of follow-up (unrelated to medication aminocaproic acid was subsequently prescribed); and 1 patient had a drop in her platelet count and was taken off the protocol. Two patients randomized to prednisone were removed from the study: one who left the hospital against medical advice and one who was given topical corticosteroids. None of these patients developed rebleeds. Of the 112 patients who participated in the clinical trial, 56 (50%) were randomized to receive an oral aminoca proic acid dosage of 50 mg/kg every 4 hours, up to 30 g daily, and the remaining 56 patients received an oral prednisone dosage of 40 mg daily in two divided doses for persons over 60 kg of body weight and a reduced dos age for children and adults weighing less than 60 kg (ap proximately 0.6 mg/kg daily). All patients in the ami nocaproic acid group received, in addition to their treat ment drug, two daily doses of placebo. The prednisone group received, in addition to their treatment drug, six daily doses of liquid placebo. All of the treating physicians and nurses were masked to the identity of treatment. Routine admission orders, which were sequentially listed and entered into a computer (Technicon), consisted ofquiet activities, head ofthe bed elevated 30°, no reading, a patch and shield applied to the involved eye, topical application of 1% atropine sulfate four times a day to the involved eye, oral administration of acetaminophen (up to 650 mg) as needed for pain, and no aspirin. Individual weights were entered into the computer, the treatment medication was randomized, and the dosage was deter mined by the pharmacy for each patient. For an lOP greater than 25 mmHg, topical timolol maleate (0.25% or0.5%) and, ifnecessary, oral acetazolamide sodium were used. Prochlorperazine edisylate (5 or 10 mg orally or intramuscularly) was used as needed as an anti-emetic. Physicians were asked not to administer topical cortico steroids, and four patients who did receive topical corti costeroids were excluded from the study.
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AMINOCAPROIC ACID VERSUS PREDNISONE
Table 1. Demographic, Visual Acuity, and Rebleeds Compared by Treatment Group Aminocaproic Acid Group (n =56)
Total No. of Patients (n = 112)
Prednisone Group (n =56) No.
(%)
(36) (86)
28 40
(50) (71)
32 11 11 2
(57) (20) (20) (4)
27 14 14 1
(48) (25) (25) (2)
(39) (18) (17) (9) (6) (10) (1)
22 13 8 6 3 4 0
(39) (23) (14) (11) (5) (7) (0)
22 7 11 4 4 7 1
(39) (12) (20) (7) (7) (12) (2)
(51) (32) (5) (6) (4) (1) (1) (7.1)
26 20 3 5 2 0 0 4
(46) (36) (5) (9) (4) (0) (0) (7.1)
31 16 3 2 2 1 1 4
(55) (29) (5) (4) (4) (2) (2) (7.1)
(%)
No.
(%)
Variable
No.
Eye (right) Sex (male) Race Black White Hispanic Other Admission acuity 20/20-20/40 20/50-20/100 20/200-20/400 Count fingers Hand motions Light perception Central fixation Final acuity 20/20-20/40 20/50-20/100 20/200-20/400 Count fingers Hand motions Central fixation Unable to record Rebleed
48 88
(43) (79)
20 48
59 25 25 3
(53) (22) (22) (3)
44 20 19 10 7 11 1 57 36 6 7 4 1 1 8
Chi-square
p
0.15 0.12 0.62
0.49*
0.59*
1.00
*Visual acuities worse than 20/400 were combined. Table 2. Mean Age, Intraocular Pressure, and Hyphema Clearance Compared by Treatment Group Prednisone Group (n =56)
Aminocaproic Acid Group (n =56) Variable
Mean
so
Range
Mean
so
Range
P*
Age (yrs) lOP at admission (mmHg) lOP at discharge (mmHg) Clearance of hyphema (days)
23.8 17.8 13.1 4.5
13.8 6.8 4.8 1.3
4-64 5-50 3-27 3-6
23.3 17.7 13.3 3.5
13.4 6.9 4.1 1.7
1.5-62 6-43 6-23 2-6
0.84 0.84 0.88 0.39
SO = standard deviation; lOP = intraocular pressure. * Pvalues were derived from Student's t test.
The medical staff caring for the patients made daily inquiries about the patients' status, including any adverse drug reactions. Any pertinent finding was documented in the hospital progress notes. If a patient had an episode of rebleeding while receiving medication, the pharmacy was notified, and the randomization code was broken. All pa tients were then put on a regimen of aminocaproic acid, the standard treatment medication for the prevention of rebleeding at the UIC Eye Center before this study. One of the authors (MDF) examined every patient chart and completed the study forms. All questions about pos sible rebleeds at admission or during the course of the
study were adjudicated by a senior resident physician or the UIC Eye Center chief resident. Data analyses were performed using the chi-square test, Fisher's exact test, and Student's t test.
RESULTS A comparison of the two randomized groups is shown in Tables l and 2. There were no statistically significant differences between the study populations. Males made up 79% of the entire study population; 86% of the ami 281
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Table 3. Age of Patients and Rebleed Rates Aminocaproic Acid Group (n =56)
Age of Patients (yrs)
No.
(%)
Reb leeds
0-4 5-9 10-14 15-24 25-34 35+
2 7 9 14 14 10
(4) (12) (16) (25) (26) (18)
0 0 1 2 0 1
nocaproic acid group were male, and 71% of the pred nisone group were male. Trauma to the right eye was observed in 36% of the aminocaproic acid group and in 50% ofthe prednisone group. The mean age ofthe patients was 23.8 years (range, 4 to 64 years) in the aminocaproic acid group, and 23.3 years (range, 18 months to 62 years) in the prednisone group. Blacks made up 57% ofthe ami nocaproic acid group and 48% of the prednisone group. The remaining patients were almost evenly divided be tween whites and Hispanics. This ethnic composition re flects the UIC Eye Center's general population. Admission and final visual acuities were similar be tween the two groups. The one infant (18 months of age) had central steady fixation. Forty-seven patients (42%) had a visual acuity of 20/200 or worse at entry into the study (21, or 38%, in the aminocaproic acid group and 26, or 46.4%, in the prednisone group). After 5 days of hospitalization, 17 (15%) had a visual acuity of 20/200 or worse (10, or 18%, in the aminocaproic acid group and 7, or 12%, in the prednisone group). The distributions of visual acuity did not differ between the two study popu lations. The mean lOP values were almost identical be tween the study populations. The mean lOP in the ami nocaproic acid group was 17.8 mmHg at admission and 13.1 mmHg at discharge; for the prednisone group, the mean pressures were 17.7 mmHg and 13.3 mmHg, re spectively. A total of eight patients experienced rebleeds, four in each of the two groups (7.1% each). Six black patients, one white patient, and one Hispanic patient were in the rebleed group. When compared with the combined white and Hispanic population, there was no statistically sig nificant higher rate among black patients (P = 0.29, rel ative risk = 2.54, confidence interval = 0.53 to 12.07). The mean age of the patients with rebleeds was 26.9 years (range, 10 to 51 years) (Table 3) compared with a mean age of 23.5 years for the entire population. Seven (88%) of the eight patients with rebleeds were male. The average time to clearance of the rebleeds was 4.5 days for the aminocaproic acid group and 3.5 days for the prednisone group (P = 0.39). Of the four aminocaproic acid-treated patients who had rebleeds, one had blood clot on the iris, one had red blood cells only on the corneal endothelium, one had a 0.5-mm layered hyphema, and one had a total hyphema. In the prednisone group, one patient with a rebleed had endothelial red blood cells only, and the other 282
Prednisone Group (n =56) (%)
No.
(%)
Rebleeds
(11) (15)
3 4 9 17 11 12
(5) (7) (16) (30) (20) (21)
0 0 1 0 2 1
(10)
(%)
(11) (18) (8)
three had 1-, 2-, and 3-mm layered hyphemas, respec tively. The distribution of level of hyphema was almost iden tical between the two treatment groups at admission (P = 0.90) (Table 4). At discharge, only 43% of the ami nocaproic acid group compared with 75% of the predni sone group had complete resolution of their hyphemas. The distribution ofdischarge hyphema levels at discharge was statistically different between the two study popula tions (chi-square, P = 0.001). Causes of the traumatic hyphema are listed in Table 5. Projectiles were responsible for 33%, blows for 62%, and explosions for 4% ofall hyphemas in this study population. The most common weapon responsible for the injury was the fist ( 18%), followed by a flexible object, such as a belt or hose (12%), and a stick or board (12%). Balls (e.g., baseballs, racquetballs) accounted for 10% ofthe injuries. The locations where the injuries occurred are listed in Table 6. Thirty-nine percent of the hyphemas occurred in the street, 28% at home, and 12% during a sports ac tivity.
COMMENT There have been many forms of treatment used for patients with traumatic hyphema. These have ranged from no medication 3·719 · ·26 to miotics/ 8·37 mydriatics, 13•14·21 ·22·28 18 23 estrogens, · antifibrinolytics, 1·489 · · ·12·20·24·25 ·27·38·39 or cor ticosteroids.3·7·14·15·19·21·22·26·30·31 Most of the studies ad vocating either no systemic medication or the use of miotics, mydriatics, or estrogens were published between the years 1960 and 1976. All of the studies using antifi brinolytics have been reported since 1976, with the ma jority published during the last decade. Except for the one randomized clinical trial of corticosteroids published by Spoor and co-workers 15 in 1980, when they reported no beneficial effect of the treatment compared with controls for reducing the incidence of rebleeding, the majority of reports were published in 1979 or earlier. Most of the early reports advocate corticosteroids as treatment for the signs of iritis that are often associated with traumatic hy phemas. Adverse reactions to aminocaproic acid in humans in clude nausea, vomiting, muscle cramps, conjunctival suf
FARBER et al
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AMINOCAPROIC ACID VERSUS PREDNISONE
Table 4. Patients with Rebleeds, According to Grade of Hyphema Aminocaproic Acid Group (n =56)
Grade of Hyphema Admission Microscopic* 0.1-3.9 mm 4.0-5.9 mm 6.0-11.9 mm Total hyphema Discharge None Microscopict 0.1-3.9 mm 4.0-5.9 mm 6.0-11.9mm Total hyphema
Prednisone Group (n =56)
No.
(%)
Reb leeds
(%)
No.
(%)
Rebleeds
(%)
11 41 3 0 1
(19) (73) (6)
2 1 0
(18) (2)
13 39 1 2 1
(23) (70) (2) (4) (2)
1 3 0 0 0
(8) (8)
24 4 27 0 1 0
(43) (7) (48)
42 4 10 0 0 0
(75) (7) (18)
(2)
(100)
(2)
P* 0.90
0.001
*?values for hyphema levels were derived from chi-square analysis; hyphemas of 4.0 mm or greater were combined for analysis. t Includes red blood cells on the corneal endothelium and/or clots on the iris or in the angle but no layered hyphema. Table 6. Place of Occurrence of Traumatic Hyphema
Table 5. Causes of Traumatic Hyphema
All Patients (n = 112)
All Patients (n = 112) Cause
No.
(%)
Location
No.
(%)
Projectile Ball Egg Rock BB Nail Brick fragment Apple Snowball Bottle cap Other Blow Fist/foot Flexible object (e.g., belt, hose, strap) Stick/board Baseball bat (6), hockey stick (1) Inflexible object (e.g., metal, brick) Gun Bottle Other Explosion Firecracker Battery Unknown
37 11 4 4
(33) (10) (4) (4) (3) (3) (2) (2) (2) (2) (4) (62) (18) (12) (12) (6) (5) (3) (2) (4) (4) (4)
Street Home Game field/court Work Bar School Garage Other Unknown
44 31 14 5 4 3 3 6 2
(39) (28) (12) (4) (4) (3) (3) (5) (2)
3 3 2 2 2 2 4
69 20 13 14
7 6
3 2
4 5 4 1
1
(
Abstract: One hundred twelve patients who sustained hyphema after blunt trauma were enrolled in a double-blind randomized clinical trial to determine the relative efficacies of aminocaproic acid (Amicar®) and systemic prednisone for reducing the rate of secondary hemorrhage. Fifty-six patients received an oral dosage of 50 mgjkg of aminocaproic acid every 4 hours for 5 days, up to a maximum of 30 g daily, and 56 patients received an oral dosage of 40 mg of prednisone daily (adjusted for weight) in two divided doses. Placebo pills and liquids were given to each patient to mask the treatment schedules. There were no statistically significant differences between the patient populations for any demographic or clinical characteristic (e.g., visual acuity, intraocular pressure (lOP], initial hyphema size) measured in the study. Blacks comprised 53% of the study population, and the mean age of the patients was 23.5 years. Four patients in each of the treatment groups experienced a secondary hemorrhage; the rebleed rate was 7.1% in each group. Ophthalmology 1991 ; 98:279-286
Medical treatment to reduce secondary hemorrhage af ter traumatic hyphema has been the subject of much con troversy. Rebleeding usually occurs from 2 to 6 days after the initial hyphema and has been reported in 0.4 to 35% Originally received: September 27, 1990. Manuscript accepted: November 15, 1990. 1
Department of Ophthalmology, University of Illinois at Chicago Eye Center, University of Illinois at Chicago College of Medicine, Chicago. College of Pharmacy, University of Illinois at Chicago College of Medicine, Chicago. 3 The Wilmer Eye Institute, The Johns Hopkins Hospital, Baltimore.
2
Presented in part at the American Academy of Ophthalmology Annual Meeting, Atlanta, Oct/Nov 1990 Supported in part by core grant EY01792 from the National Eye Institute, Bethesda, Maryland, and an unrestricted grant from Research to Prevent Blindness, Inc, New York , New York (UIC Eye Center). Reprint requests to Marilyn D. Farber, DrPH, Department of Ophthalmology, University of Illinois at Chicago, 1855 W Taylor St. Chicago, IL 60612.
patients who have not received oral medication for treat ment.1 -26 It is recognized that rebleeding may predispose patients to corneal blood staining, elevated intraocular pressure (lOP) with subsequent optic atrophy, peripheral anterior synechiae formation, and possible decreased vi sual acuity; however, the rate of secondary hemorrhage (and, therefore, the risk to each patient) is so variable that confusion exists about the necessity of treatment. Several studies have reported the beneficial effect of epsilon-aminocaproic acid (Amicar®) in reducing sec ondary hemorrhages in humans. 8•9 •12·20·24·27 Three ran domized clinical trials that compared the rebleed rate in patients receiving this antifibrinolytic agent with a placebo control found that aminocaproic acid was successful in reducing rebleeds in the treated group. In 1976, Crouch and Frenkel24 reported a rebleed rate of 33.3% in their control population and 3.1 % in their treated group. In 1983 McGetrick and co-workers25 reported rebleeds in 33.3% of their control patients compared with 3.6% of their treated patients, results almost identical to those of 279
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Crouch and Frenkel. 24 Both studies were reported from our institution. Kutner et aJ2° found a 23% rebleed rate in their placebo group, compared with no rebleeds in the treated patients. Both Kutner et al 20 and McGetrick et al 25 limited the dosage of aminocaproic acid to 100 mg/kg every 4 hours up to a maximum of 30 g daily. In a forth study, Palmer and co-workers27 compared two dose regimens of aminocaproic acid, 100 mg/kg every 4 hours or 50 mg/kg every 4 hours, in a double-masked random ized clinical trial. There was no statistically significant difference in the rebleed rates in these two groups. Corticosteroids, given both topically and systemically, also have been advocated for the treatment of traumatic hyphema. 28- 32 Yasuna29 treated 50 patients with systemic prednisone and reported no rebleeds in his patients. Rynne and Romano 31 also used systemic corticosteroids andre ported no reb leeds. Romano 32- 35 has been a vigorous pro ponent ofcorticosteroid treatment but has not performed a randomized clinical trial. In 1980 Spoor and co workers15 conducted the first well-controlled randomized clinical trial of systemic prednisone compared with a pla cebo. They reported rebleed rates of 20% in the control group of 20 patients and 13% in the 23 treated patients. These results were not statistically significant, and they concluded that corticosteroids failed to reduce the risk of secondary hemorrhage. However, the power of their study to detect a difference between the prednisone group and the control group was very small, and their results should be treated with caution. The purpose of our study is to determine if systemic epsilon aminocaproic acid and systemic prednisone would have similar or dissimilar effects on the incidence of sec ondary hemorrhages after traumatic hyphema.
PATIENTS AND METHODS All patients with hyphema due to blunt trauma treated at the University of Illinois at Chicago (UIC) Eye Center from July 1985 through March 1990, who had no open globe or other injury requiring immediate surgery, and who consented to be in the study, were admitted to the hospital and were placed on a double-blind randomized clinical trial protocol. Excluded from the study were pa tients with sickle-cell trait or disease, intravascular coag ulopathy, gastric ulcer, or diabetes mellitus, or those who were intoxicated and had detectable blood in their stool. 36 Pregnant women also were excluded. A complete medical history, physical and ocular ex amination, and blood cell counts, including a differential white blood cell count, platelets, prothrombin time, partial thromboplastin time, and levels of serum creatinine, glu cose, sodium chloride, and blood urea nitrogen, were performed on each patient at the time of admission. Sickle-cell screening was done on all nonwhite patients. A slit-lamp examination and tonometry readings were performed daily by the admitting physician. The baseline and secondary hyphema levels were recorded in milli meters. Hyphemas were considered primary if the amount offresh or clotted blood remained unchanged or decreased 280
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from the baseline examination. A secondary hemorrhage was defined as a definite increase in the amount of fresh blood in the anterior chamber compared with admission levels or fresh red blood that was visible over darker, clot ted blood during the hospital course. If a patient com plained of a decrease in vision more than 1 day after ex periencing a traumatic injury, before presentation for treatment, that patient was considered to have a secondary hemorrhage. One person was excluded from the study on this basis. All patients (or the parent or adult guardian of a minor) gave informed consent after they received an explanation of the purpose of the study. The assignment to receive aminocaproic acid or prednisone was determined ran domly and in a double-masked fashion. Sixty-four patients were originally randomized to treatment with aminoca proic acid, and 58 patients were randomized to receive prednisone. After randomization, 8 patients were excluded from the aminocaproic acid group for the following rea sons: 4 patients were accidentally placed on a regimen of topical steroids by another member of the professional staff; 2 patients left the hospital against medical advice before treatment was completed; 1 patient had a seizure on the first day of follow-up (unrelated to medication aminocaproic acid was subsequently prescribed); and 1 patient had a drop in her platelet count and was taken off the protocol. Two patients randomized to prednisone were removed from the study: one who left the hospital against medical advice and one who was given topical corticosteroids. None of these patients developed rebleeds. Of the 112 patients who participated in the clinical trial, 56 (50%) were randomized to receive an oral aminoca proic acid dosage of 50 mg/kg every 4 hours, up to 30 g daily, and the remaining 56 patients received an oral prednisone dosage of 40 mg daily in two divided doses for persons over 60 kg of body weight and a reduced dos age for children and adults weighing less than 60 kg (ap proximately 0.6 mg/kg daily). All patients in the ami nocaproic acid group received, in addition to their treat ment drug, two daily doses of placebo. The prednisone group received, in addition to their treatment drug, six daily doses of liquid placebo. All of the treating physicians and nurses were masked to the identity of treatment. Routine admission orders, which were sequentially listed and entered into a computer (Technicon), consisted ofquiet activities, head ofthe bed elevated 30°, no reading, a patch and shield applied to the involved eye, topical application of 1% atropine sulfate four times a day to the involved eye, oral administration of acetaminophen (up to 650 mg) as needed for pain, and no aspirin. Individual weights were entered into the computer, the treatment medication was randomized, and the dosage was deter mined by the pharmacy for each patient. For an lOP greater than 25 mmHg, topical timolol maleate (0.25% or0.5%) and, ifnecessary, oral acetazolamide sodium were used. Prochlorperazine edisylate (5 or 10 mg orally or intramuscularly) was used as needed as an anti-emetic. Physicians were asked not to administer topical cortico steroids, and four patients who did receive topical corti costeroids were excluded from the study.
FARBER et al
•
AMINOCAPROIC ACID VERSUS PREDNISONE
Table 1. Demographic, Visual Acuity, and Rebleeds Compared by Treatment Group Aminocaproic Acid Group (n =56)
Total No. of Patients (n = 112)
Prednisone Group (n =56) No.
(%)
(36) (86)
28 40
(50) (71)
32 11 11 2
(57) (20) (20) (4)
27 14 14 1
(48) (25) (25) (2)
(39) (18) (17) (9) (6) (10) (1)
22 13 8 6 3 4 0
(39) (23) (14) (11) (5) (7) (0)
22 7 11 4 4 7 1
(39) (12) (20) (7) (7) (12) (2)
(51) (32) (5) (6) (4) (1) (1) (7.1)
26 20 3 5 2 0 0 4
(46) (36) (5) (9) (4) (0) (0) (7.1)
31 16 3 2 2 1 1 4
(55) (29) (5) (4) (4) (2) (2) (7.1)
(%)
No.
(%)
Variable
No.
Eye (right) Sex (male) Race Black White Hispanic Other Admission acuity 20/20-20/40 20/50-20/100 20/200-20/400 Count fingers Hand motions Light perception Central fixation Final acuity 20/20-20/40 20/50-20/100 20/200-20/400 Count fingers Hand motions Central fixation Unable to record Rebleed
48 88
(43) (79)
20 48
59 25 25 3
(53) (22) (22) (3)
44 20 19 10 7 11 1 57 36 6 7 4 1 1 8
Chi-square
p
0.15 0.12 0.62
0.49*
0.59*
1.00
*Visual acuities worse than 20/400 were combined. Table 2. Mean Age, Intraocular Pressure, and Hyphema Clearance Compared by Treatment Group Prednisone Group (n =56)
Aminocaproic Acid Group (n =56) Variable
Mean
so
Range
Mean
so
Range
P*
Age (yrs) lOP at admission (mmHg) lOP at discharge (mmHg) Clearance of hyphema (days)
23.8 17.8 13.1 4.5
13.8 6.8 4.8 1.3
4-64 5-50 3-27 3-6
23.3 17.7 13.3 3.5
13.4 6.9 4.1 1.7
1.5-62 6-43 6-23 2-6
0.84 0.84 0.88 0.39
SO = standard deviation; lOP = intraocular pressure. * Pvalues were derived from Student's t test.
The medical staff caring for the patients made daily inquiries about the patients' status, including any adverse drug reactions. Any pertinent finding was documented in the hospital progress notes. If a patient had an episode of rebleeding while receiving medication, the pharmacy was notified, and the randomization code was broken. All pa tients were then put on a regimen of aminocaproic acid, the standard treatment medication for the prevention of rebleeding at the UIC Eye Center before this study. One of the authors (MDF) examined every patient chart and completed the study forms. All questions about pos sible rebleeds at admission or during the course of the
study were adjudicated by a senior resident physician or the UIC Eye Center chief resident. Data analyses were performed using the chi-square test, Fisher's exact test, and Student's t test.
RESULTS A comparison of the two randomized groups is shown in Tables l and 2. There were no statistically significant differences between the study populations. Males made up 79% of the entire study population; 86% of the ami 281
OPHTHALMOLOGY
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MARCH 1991
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VOLUME 98
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NUMBER 3
Table 3. Age of Patients and Rebleed Rates Aminocaproic Acid Group (n =56)
Age of Patients (yrs)
No.
(%)
Reb leeds
0-4 5-9 10-14 15-24 25-34 35+
2 7 9 14 14 10
(4) (12) (16) (25) (26) (18)
0 0 1 2 0 1
nocaproic acid group were male, and 71% of the pred nisone group were male. Trauma to the right eye was observed in 36% of the aminocaproic acid group and in 50% ofthe prednisone group. The mean age ofthe patients was 23.8 years (range, 4 to 64 years) in the aminocaproic acid group, and 23.3 years (range, 18 months to 62 years) in the prednisone group. Blacks made up 57% ofthe ami nocaproic acid group and 48% of the prednisone group. The remaining patients were almost evenly divided be tween whites and Hispanics. This ethnic composition re flects the UIC Eye Center's general population. Admission and final visual acuities were similar be tween the two groups. The one infant (18 months of age) had central steady fixation. Forty-seven patients (42%) had a visual acuity of 20/200 or worse at entry into the study (21, or 38%, in the aminocaproic acid group and 26, or 46.4%, in the prednisone group). After 5 days of hospitalization, 17 (15%) had a visual acuity of 20/200 or worse (10, or 18%, in the aminocaproic acid group and 7, or 12%, in the prednisone group). The distributions of visual acuity did not differ between the two study popu lations. The mean lOP values were almost identical be tween the study populations. The mean lOP in the ami nocaproic acid group was 17.8 mmHg at admission and 13.1 mmHg at discharge; for the prednisone group, the mean pressures were 17.7 mmHg and 13.3 mmHg, re spectively. A total of eight patients experienced rebleeds, four in each of the two groups (7.1% each). Six black patients, one white patient, and one Hispanic patient were in the rebleed group. When compared with the combined white and Hispanic population, there was no statistically sig nificant higher rate among black patients (P = 0.29, rel ative risk = 2.54, confidence interval = 0.53 to 12.07). The mean age of the patients with rebleeds was 26.9 years (range, 10 to 51 years) (Table 3) compared with a mean age of 23.5 years for the entire population. Seven (88%) of the eight patients with rebleeds were male. The average time to clearance of the rebleeds was 4.5 days for the aminocaproic acid group and 3.5 days for the prednisone group (P = 0.39). Of the four aminocaproic acid-treated patients who had rebleeds, one had blood clot on the iris, one had red blood cells only on the corneal endothelium, one had a 0.5-mm layered hyphema, and one had a total hyphema. In the prednisone group, one patient with a rebleed had endothelial red blood cells only, and the other 282
Prednisone Group (n =56) (%)
No.
(%)
Rebleeds
(11) (15)
3 4 9 17 11 12
(5) (7) (16) (30) (20) (21)
0 0 1 0 2 1
(10)
(%)
(11) (18) (8)
three had 1-, 2-, and 3-mm layered hyphemas, respec tively. The distribution of level of hyphema was almost iden tical between the two treatment groups at admission (P = 0.90) (Table 4). At discharge, only 43% of the ami nocaproic acid group compared with 75% of the predni sone group had complete resolution of their hyphemas. The distribution ofdischarge hyphema levels at discharge was statistically different between the two study popula tions (chi-square, P = 0.001). Causes of the traumatic hyphema are listed in Table 5. Projectiles were responsible for 33%, blows for 62%, and explosions for 4% ofall hyphemas in this study population. The most common weapon responsible for the injury was the fist ( 18%), followed by a flexible object, such as a belt or hose (12%), and a stick or board (12%). Balls (e.g., baseballs, racquetballs) accounted for 10% ofthe injuries. The locations where the injuries occurred are listed in Table 6. Thirty-nine percent of the hyphemas occurred in the street, 28% at home, and 12% during a sports ac tivity.
COMMENT There have been many forms of treatment used for patients with traumatic hyphema. These have ranged from no medication 3·719 · ·26 to miotics/ 8·37 mydriatics, 13•14·21 ·22·28 18 23 estrogens, · antifibrinolytics, 1·489 · · ·12·20·24·25 ·27·38·39 or cor ticosteroids.3·7·14·15·19·21·22·26·30·31 Most of the studies ad vocating either no systemic medication or the use of miotics, mydriatics, or estrogens were published between the years 1960 and 1976. All of the studies using antifi brinolytics have been reported since 1976, with the ma jority published during the last decade. Except for the one randomized clinical trial of corticosteroids published by Spoor and co-workers 15 in 1980, when they reported no beneficial effect of the treatment compared with controls for reducing the incidence of rebleeding, the majority of reports were published in 1979 or earlier. Most of the early reports advocate corticosteroids as treatment for the signs of iritis that are often associated with traumatic hy phemas. Adverse reactions to aminocaproic acid in humans in clude nausea, vomiting, muscle cramps, conjunctival suf
FARBER et al
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AMINOCAPROIC ACID VERSUS PREDNISONE
Table 4. Patients with Rebleeds, According to Grade of Hyphema Aminocaproic Acid Group (n =56)
Grade of Hyphema Admission Microscopic* 0.1-3.9 mm 4.0-5.9 mm 6.0-11.9 mm Total hyphema Discharge None Microscopict 0.1-3.9 mm 4.0-5.9 mm 6.0-11.9mm Total hyphema
Prednisone Group (n =56)
No.
(%)
Reb leeds
(%)
No.
(%)
Rebleeds
(%)
11 41 3 0 1
(19) (73) (6)
2 1 0
(18) (2)
13 39 1 2 1
(23) (70) (2) (4) (2)
1 3 0 0 0
(8) (8)
24 4 27 0 1 0
(43) (7) (48)
42 4 10 0 0 0
(75) (7) (18)
(2)
(100)
(2)
P* 0.90
0.001
*?values for hyphema levels were derived from chi-square analysis; hyphemas of 4.0 mm or greater were combined for analysis. t Includes red blood cells on the corneal endothelium and/or clots on the iris or in the angle but no layered hyphema. Table 6. Place of Occurrence of Traumatic Hyphema
Table 5. Causes of Traumatic Hyphema
All Patients (n = 112)
All Patients (n = 112) Cause
No.
(%)
Location
No.
(%)
Projectile Ball Egg Rock BB Nail Brick fragment Apple Snowball Bottle cap Other Blow Fist/foot Flexible object (e.g., belt, hose, strap) Stick/board Baseball bat (6), hockey stick (1) Inflexible object (e.g., metal, brick) Gun Bottle Other Explosion Firecracker Battery Unknown
37 11 4 4
(33) (10) (4) (4) (3) (3) (2) (2) (2) (2) (4) (62) (18) (12) (12) (6) (5) (3) (2) (4) (4) (4)
Street Home Game field/court Work Bar School Garage Other Unknown
44 31 14 5 4 3 3 6 2
(39) (28) (12) (4) (4) (3) (3) (5) (2)
3 3 2 2 2 2 4
69 20 13 14
7 6
3 2
4 5 4 1
1
(
