Antifibrinolytic therapy in the acute period following aneurysmal subarachnoid hemorrhage

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J Neurosurg 61:225-230, 1984 Antifibrinolytic therapy in the acute period following aneurysmal subarachnoid hemorrhage Preliminary observations from the Cooperative Aneurysm Study NEAL F. KASSELL, M.

1 J Neurosurg 61: , 1984 Antifibrinolytic therapy in the acute period following aneurysmal subarachnoid hemorrhage Preliminary observations from the Cooperative Aneurysm Study NEAL F. KASSELL, M.D., JAMES C. TORNER, M.S., AND HAROLD P. ADAMS, JR., M.D. Department of Surgery, Division of Neurosurgery, and Department of Neurology, College of Medicine, The University of Iowa, Iowa City, Iowa v" Antifibrinolytic therapy remains a controversial issue in the management of subarachnoid hemorrhage (SAH). The relationship of antifibrinolytic therapy with mortality, rebleeding, ischemia, hydrocephalus, and clotting abnormalities was studied in 672 patients in the International Cooperative Study on the Timing of Aneurysm Surgery. The patients with antifibrinolytic therapy had a significantly lower rebleeding rate, but higher rates of ischemic deficits and hydrocephalus. The net result was no difference in mortality in the 1 st month following the initial SAH. Further clinical trials are needed to determine the overall effects of antifibrinolytic therapy. KEY WORDS " aneurysm 9 subarachnoid hemorrhage 9 antifibrinolytic therapy 9 hydrocephalus 9 Cooperative Aneurysm Study T HE value of antifibrinolytic agents in the management of patients with ruptured intracranial aneurysms remains controversial. 7,9 Not only is the effectiveness of these drugs in preventing rebleeding uncertain, but their relationship to the genesis of a variety of complications, including focal ischemic neurological deficits, hydrocephalus, thrombophlebitis, and pulmonary embolus, also remains to be elucidated. Furthermore, the influence of antifibrinolytic therapy on survival has not been established. The purpose of this investigation was to study the effect of antifibrinolytic agents on mortality, rebleeding, ischemic neurological deficits, and other complications of aneurysmal subarachnoid hemorrhage (SAH) in the acute period following aneurysm rupture. Case Material Clinical Material and Methods Between January, 1980, and September, 1982, 2265 patients were admitted on Days 0 to 3 following their frst aneurysmal SAH to one of the 68 centers participating in the International Cooperative Study on the Timing of Aneurysm Surgery (see Appendix). Day 0 is defined as the day of the hemorrhage. Of these, 672 had surgery planned for the period 7 to 14 days after hemorrhage, and these patients serve as the study population. All patients had computerized tomography (CT) performed within 5 days of SAH. Four hundred and sixty-seven patients (69%) received antifibrinolytic agents and are hereafter referred to as the "antifibrinolytic group," and 205 patients (31%) did not receive antifibrinolytic agents and are hereafter referred to as the "no-antifibrinolytic group." While the details of antifibrinolytic therapy for each individual patient were not recorded, the protocol suggested that either aminocaproic acid or tranexamic acid be administered until at least 14 days after SAH or until operation, whichever came first. The suggested dose of aminocaproic acid was 36 gmday and of tranexamic acid was 6 to 12 gmday, both by continuous intravenous infusion. Study Methods On admission, patients were examined for prognostic factors for rebleeding and death in the acute period following SAH. These factors included time of admission, neurological status on admission, sex, age, and blood pressure on admission) In addition, the amount ofsubarachnoid blood on CT, interval to surgery, preex- J. Neurosurg. Volume 61August,

N. F. Kassell, J. C. Torner and H. P. Adams, Jr. 50- (3 I m Ld 40- [~ NO ANTIFIBRINOLYTIC THERAPY ~,PY () z I~ NO ANTIFIBRINOLYTIC THERAPY I A kltlrlodlkl~l VTI~ TU~D A DV 7g.7 80 I, 0 30- I-- C.

2 N. F. Kassell, J. C. Torner and H. P. Adams, Jr. 50- (3 I m Ld 40- [~ NO ANTIFIBRINOLYTIC THERAPY ~,PY () z I~ NO ANTIFIBRINOLYTIC THERAPY I A kltlrlodlkl~l VTI~ TU~D A DV 7g.7 80 I, I-- C.) 20-13" l_d 13_ 10- I J_ 0 l-- z o n~ 13_ o DAYS FROM SAH FIG. 1. Distribution of interval to admission by antifibrinolytic THIN THICK TOTAL FIG. 3. Incidence of subarachnoid hemorrhage on computerized tomography by antifibrinolytic group. isting hypertension, and use of adjunctive medicinal agents were recorded. The results were compared between the antifibrinolytic and no-antifibrinolytic groups. The rates of mortality, rebleeding, ischemic neurological deficits, hydrocephalus, deep-vein thrombosis, pulmonary embolus, and bleeding disorders were then assessed for the two groups. Life table techniques were used to adjust the rebleeding rate for interval to admission, interval to surgery, and interval to death, and to adjust the ischemic neurological deficit rate for interval to admission and interval to death. The other outcome measures were compared by proportional analysis, since the exact date of onset of these complications was not recorded. Statistical significance was accepted at p < Cause of death was assessed for patients who died within 30 days of SAH, including delayed deaths after rebleed or ischemia. Rebleeding was documented by CT or cerebrospinal fluid (CSF) examination. In the International Cooperative Study on the Timing of Aneurysm Surgery, the term "ischemic neurological deficit" is used in preference to "vasospasm" due to the inevitable difficulty of determining whether any specific neurological impairment in the acute period following bleeding was due to the arterial narrowing which occurs after aneurysm rupture or to other etiologies. Vasospasm was, however, accepted as an estimated cause of death. Hydrocephalus was diagnosed by clinical signs and confirmed by ventricular enlargement visible on CT scanning. 40-3S.1 60 P'-'I ANTIFIBRINOLYTIC THERAPY 30- =~-~l II NO ANTIFIBRINOLYTIC THERAPY (3 l--- Ld 40 I'lC THERAPY THERAPY z4.= 2= 21.6 I, o l--- Ld c..) ry ILl IX. 20 ~L~ _ 107,.a ,7 44 S*4 CONSCIOUSNESS LEVEL FIG. 2. Distribution of admission consciousness level by antifibrinolytic group. FIG. 4. Distribution of interval to surgery by antifibrinolytic 226 J. Neurosurg. Volume 61August, 1984

3 Antifibrinolytic therapy in subarachnoid hemorrhage 25~!! ---# 22.3 >_ 2o I ~ I,' 20.0 m < m 15 O or n i-- z 10- I.d TIC THERAPY rf X NO ANTIFIBRINOLYTIC THERAPY ILl 13_ 5-0;~ I I I I FIG. 5. Cumulative probability of death by antifibrinolytic TABLE 1 Comparison of prognostic factors* Factors Antifibrinolytic No Antifibrinolytic Therapy Therapy no. of cases interval to admission _< 1 day 76.1% 79.7% consciousness: stupor or coma 12.4% 13.2% sex: female 60.4% 65.8% systolic blood pressure _> 170 mm Hg 17.1% 22.4% preexisting hypertension 20.6% 20.0% subarachnoid blood on CT 80.0% 79.7% surgical treatment 78.4% 82.4% day of surgery (median days) age (yrs) * None of the factors showed a significant intergroup difference. CT = computerized tomography. Comparability of Groups Results Despite the fact that the antifibrinolytic and noantifibrinolytic groups were not selected randomly, there was remarkable similarity in the prognostic factors for death and rebleeding in the acute period following SAH between the two groups (Figs. 1 to 4 and Table 1). There were no significant differences in time of admission, neurological status on admission, sex, age, or elevated blood pressure on admission. Furthermore, there were no significant differences in the amount of subarachnoid blood on CT, timing of surgery, or preexisting hypertension. No difference in use of antihypertensive drugs, mannitol, or diuretic agents was found 50 to 40 -r" between the two groups. However, the antifibrinolytic group had a greater percentage of patients receiving sedatives, analgesics, and steroids (Table 2). Mortality Rate The overall mortality rate was essentially identical in both groups (Fig. 5 and Table 3). The mortality rate at 14 days for the antifibrinolytic group was 13.2%, and at 30 days it was 22.3%. For the no-antifibrinolytic group, the mortality rate was 13.0% and 20.0%, respectively. In the no-antifibrinolytic group, the estimated cause of death at 30 days was rebleeding in 45% and vasospasm in 24%. The situation was almost identically reversed in those patients who did receive antifibrinolytic agents where the estimated cause of death was rebleeding in 24% and vasospasm in 42% (Fig. 6). Rebleeding and Focal Ischemic Neurological Deficits The 14-day rebleeding rate was 11.7% in the antifibrinolytic group and 19.4% in the no-antifibrinolytic group. This difference was statistically significant (Fig. 7 and Tables 3 and 4). However, the rebleeding rates I--- r~ rl E] REBLEEDING ISCHEMIA NO YES ANTIFIBRINOLYTIC THERAPY FIG. 6. Primary causes of death up to 30 days after subarachnoid hemorrhage by antifibrinolytic group. TABLE 2 Adjunctive medical management Antifi- No Antifi- Signifi- Drugs brinolytic brinolytic cance* Therapy Therapy (p value) analgesics antihypertensives 32.5% 35.8% 21.0% 32.2% NS diurdtics 11.8% 13.2% NS mannitol 15.8% 13.2% NS sedatives 49.5 % 38.5 % 0.01 steroids total cases 63.0% % * NS = not significant. J. Neurosurg. Volume 61August,

4 N. F. Kassell, J. C. Torner and H. P. Adams, Jr. TABLE 3 Mortality and morbidity rates iy w 5- EL O I I I I I I I I I I I I I I O FIG. 7. Cumulative probability of rebleeding by antifibrinolyric PY Antifi- No Antifi- Signifi- Outcome brinolytic brinolytic cance* Therapy Therapy (p value) no. of cases day mortality 13.2 % 13.0% NS 30-day mortality 22.3% 20.0% NS 14-day rebleed 11.7% 19.4% day focal ischemic 32.4% 22.7% 0.01 deficit hydrocephalus 13.5% 6.8% 0.02 bleeding disorder 0.9% 1.0% NS pulmonary embolism 0.9% 0.5% NS thrombophlebitis 2.8% 1.5% NS * NS = not significant. m.< r'r, O nr" EL I-- 4o] 2O Ld (D p,.,,- LIJ 10 EL I ' ~.,,,,,,~ 32.4 ~ 22.7 A ANT IFIB RIN 0 LYTIC TH ER_ APY ><NO ANTIFIBRINOLYTIC THERAPY on Days 0 and 1 in the two groups were essentially identical. Focal ischemic deficits were found to be significantly different by 14 days after the initial hemorrhage (Table 3). The antifibrinolytic group had a rate of 32.4% while the no-antifibrinolytic group had only a 22.7% rate (Fig. 8). The time course of the development of deficits was similar for both groups (Table 4). Figure 9 shows the time course of rebleeding and the onset of ischemic neurological deficits for both antifibrinolytic groups combined. The peak incidence of rebleeding occurred on Days 0 and 1, while the peak incidence of ischemic neurological deficits occurred on Day 7. P~I~------'~-I T T I I I ] T I I i l T ~ FIG. 8. Cumulative probability of focal ischemic deficit by antifibrinolytic ~ FOCAL ]SCHEMIC DEFICIT m o < N \ \ 2- IM L.d \ \ REBLEEDING 0 I I I I I I 1 I ; 6 ; ' DAYS FROM FIRST SAH FIG. 9. Daily probabilities of onset of rebleeding and focal ischemic deficit for both antifibrinolytic groups combined. SAH = subarachnoid hemorrhage. Hydrocephalus Fourteen percent of the patients who received antifibrinolytic agents developed hydrocephalus compared to 7% of the patients who did not receive antifibrinolytic agents. This difference was statistically significant (Table 3). Thrombophlebitis In the antifibrinolytic group, the thrombophlebitis rate was 2.8% versus 1.5% in the no-antifibrinolytic group. This difference was not statistically significant (Table 3). Pulmonary Embolus The pulmonary embolus rate was 0.9% in the antifibrinolytic group versus 0.5 % in the no-antifibrinolytic group. This difference was not statistically significant (Table 3). Discussion In the present study, there were no obvious biases for or against the use of antifibrinolytic agents since the primary objective of the project was to investigate the influence of the timing of surgery on outcome following 228 J. Neurosurg. Volume 61August, 1984

5 Antifibrinolytic therapy in subarachnoid hemorrhage aneurysmal SAH. Furthermore, there were remarkable similarities between the antifibrinolytic and the noantifibrinolytic groups in prognostic factors of rebleeding and mortality rate in the acute period following SAH. Antifibrinolytic therapy patients were more likely to be treated with analgesics, sedatives, and steroids, but no relationship between these agents and rebleeding, ischemia, or mortality rates has been reported. Since the results are from an observational clinical trial, only associations can be demonstrated and causality cannot be proven. In this study, the cumulative mortality rate was the same in both the antifibrinolytic and the no-antifibrinolytic groups. Small differences were noted in the daily mortality rates suggesting different causes of death during this interval. In essence, it appears that the reduction in mortality rates resulting from antifibrinolytic therapy is achieved at the expense of a proportional increase in mortality from ischemic neurological deficits. The differences in the time course of the onset of focal ischemic neurological deficits and rebleeding further suggest that this interpretation is correct (Fig. 9). In other studies, mortality rates have been reported to be higher, lower, or the same in patients receiving antifibrinolytic agents when compared to those who did not receive this form of therapy. 7 Particularly noteworthy is a randomized study of tranexamic acid reported by Fodstad, et al.,2 where the mortality rate was higher in patients who received antifibrinolytic therapy, despite a lower rebleeding rate. More of their patients in the antifibrinolytic group developed cerebral infarction, and they concluded that tranexamic acid may produce cerebral ischemic complications. Possible explanations for the increased rate of ischemic neurological deficits in patients receiving antifibrinolytic therapy include the following. These agents do not increase the severity of vasospasm but may aggravate the intravascular sludging, platelet fibrin emboli, and microthrombosis that accompany the arterial narrowing. Another possibility is that antifibrinolytic agents do increase the severity of vasospasm. The severity of vasospasm is related to the amount and duration of blood in the basal cisterns, and it has been shown that tranexamic acid prolongs the clearance of blood from the subarachnoid space. 2 Both of these explanations may coexist. In the present study there was a marked difference in the rebleeding rates between the antifibrinolytic and the no-antifibrinolytic groups, except during the first 48 hours of therapy when the rebleeding rates were essentially identical. It has been suggested that it takes approximately this period of time for the antifibrinolyric agents to exert their desired actions and this observation would seem to confirm the therapeutic effectiveness of these drugs? The rate of hydrocephalus was twice as high in the antifibrinolytic group compared to the no-antifibrinolytic group. Hydrocephalus that occurs after SAH is TABLE 4 Timing ofevents* No. With Days from No. With Focal Ische- Deaths No. of No. Surgery With SAH Rebleeding mic Deficit antifibfinolytic therapy no antifibfinolytic therapy I II * This table contains the raw data; the direct proportions do not correspond to the life table-adjusted percentages in the text (see Methods). SAH = subarachnoid hemorrhage. caused by mechanical obstruction of the CSF pathways. 5 Prolongation of the subarachnoid clot may account for the increase in hydrocephalus in patients receiving antifibrinolytic therapy. A higher incidence of ventricular dilatation has been reported in other series of patients receiving antifibrinolytic therapy, 4'6 although this observation has not been made uniformly. 2 The rates of pulmonary embolism and deep-vein thrombophlebitis were not statistically significant between the two groups. These fndings reconfirm the previous experience of the Cooperative Aneurysm Study.l Despite the large number of previous studies and the abundant literature on antifibrinolytic therapy, the safety and effectiveness of these agents in patients with SAH from ruptured aneurysm remains unsettled. This is due in large part to suboptimal study design with inadequate numbers of cases: deficiencies that may not, in a pragmatic sense, be completely rectifiable. Also, important therapeutic hypotheses such as this usually require several independent trials by different groups of J. Neurosurg. Volume 61August,

6 N. F. Kassell, J. C. Torner and H. P. Adams, Jr. investigators using dissimilar study designs for confirmation. It is suggested that another trial of the effectiveness of antifibrinolytic therapy in the management of patients with ruptured aneurysms is desirable. Many of the design and technical problems in prior studies appear to have been corrected in the Rotterdam- Amsterdam-Glasgow-London randomized, controlled, double-blind study of tranexamic acid, the results of which are anxiously awaited. Summary The results of this study suggest that antifibrinolytic therapy does not alter the mortality rate in the acute period following aneurysmal SAH. Antifibrinolytic agents appear to decrease rebleeding, but seem to be associated with increased ischemic neurological complications and hydrocephalus. These findings further emphasize the need for developing effective therapies for dealing with the arterial narrowing and the ischemic neurological deficits that occur following aneurysm rupture. APPENDIX Participating Institutions United States. Albert Einstein College of Medicine, Bronx, New York; Barrow Neurological Institute, Phoenix, Arizona; Case Western Reserve Institute, Cleveland, Ohio; Duke University Medical Center, Durham, North Carolina; Indiana University, Indianapolis, Indiana; Louisiana State University, New Orleans, Louisiana; Massachusetts General Hospital, Boston, Massachusetts; Mayfield Neurological Institute, Cincinnati, Ohio; New York University Medical Center, New York, New York; Ohio State University, Columbus, Ohio; Pennsylvania Hospital, Philadelphia, Pennsylvania; University of California Medical Center, San Diego, California; University of California at San Francisco, San Francisco, California; University of Florida, Gainesville, Florida; University of Iowa, Iowa City, Iowa; University of Minnesota, Minneapolis, Minnesota; University of Michigan, Ann Arbor, Michigan; University of Mississippi, Jackson, Mississippi; University of Pittsburgh, Pittsburgh, Pennsylvania; University of Southern California, Los Angeles, California; University of Tennessee, Memphis, Tennessee; University of Texas Health Science Center, Dallas, Texas; Vanderbilt University, Nashville, Tennessee; Washington University School of Medicine, St. Louis, Missouri. Outside United States. Monash University, Victoria, Australia; North Shore Medical Centre, Sydney, Australia; Royal Adelaide Hospital, Adelaide, Australia; Royal Prince Alfred Hospital, Sydney, Australia; Universitatsklinik fur Neurochirurgie in Graz, Graz, Australia; University of Alberta, Edmonton, Alberta, Canada; University of Toronto, Toronto, Ontario, Canada; University of Western Ontario, London, Ontario, Canada; Rigshospitalet, Copenhagen, Denmark; Central Middlesex Hospital, London, England; National Hospital, Queens Square, London, England; Newcastle General Hospital, Newcastle, England; Royal Hallamshire Hospital, Sheffield, England; University of Paris VI, Paris, France; Central Regional Hospital of Bordeaux, Bordeaux, France; National Institute of Neurosurgery, Budapest, Hungary; Bellaria Hospital, Bologna, Italy; Neurosurgical Institute of Milan, Milan, Italy; University Hospital, Brescia, Italy; University of Milan, Milan, Italy; University of Padova, Padova, Italy; University of Rome, Rome, Italy; University of Verona, Verona, Italy; University of Vicenza, Vicenza, Italy; Juntendo University, Tokyo, Japan; Kitano Hospital, Osaka, Japan; Kyoto University, Kyoto, Japan; Kyushu University, Fukuoka, Japan; Mihara Memorial Hospital, Gunma, Japan; Nagoya University, Nagoya, Japan; National Cardiovascular Center, Osaka, Japan; Okayama University, Okayama, Japan; Research Institute for Brain and Blood Vessels, Akita, Japan; Shinshu University, Matsumoto, Japan; Tohoku University Institute of Brain Disease, Sendai, Japan; University of Tokyo, Tokyo, Japan; University of Amsterdam, Amsterdam, The Netherlands; Western General Hospital, Edinburgh, Scotland; Groote Schuur Hospital, Capetown, South Africa; Karolinska Hospital, Stockholm, Sweden; University of Lund, Lund, Sweden; University of Essen, Essen, West Germany; Medical Hospital, Hannover, West Germany; University of Ljubljana, Ljubljana, Yugoslavia. Executive Committee. C. Drake, M. Dyken, E. Flamm, R. Frankowski, N. Kassell, J. Kurtzke, S. Peerless, A. Sahs, J. Torner, M. Goldstein (ex officio), M. Walker (ex officio). References 1. Adams HP Jr, Nibbelink DW, Torner JC, et al: Antifibrinolytic therapy in patients with aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. Arch Neurol 38:25-29, Fodstad H, Forssell A, Liliequist B, et al: Antifibrinolysis with tranexamic acid in aneurysmal subarachnoid hemorrhage: a consecutive controlled clinical trial. Neurosurgery 8: , Fodstad H, Pilbrant A, Schannong M, et al: Determination of tranexamic acid (AMCA) and fibrinfibrinogen degradation products in cerebrospinal fluid after aneurysreal subarachnoid haemorrhage. Acta Neurochir 58:1-13, Knibestrl M, Karadayi A, Tovi D: Echo-encephalographic study of ventricular dilatation after subarachnoid hemorrhage, with special reference to the effect of antifibrinolytic treatment. Acta Neuroi Scand 54:57-60, Laurent JP: Subarachnoid hemorrhage, in Wood JH (ed): Neurobiology of Cerebrospinal Fluid. New York: Plenum Press, 1980, pp Park BE: Spontaneous subarachnoid hemorrhage complicated by communicating hydrocephalus: epsilon amino caproic acid as a possible predisposing factor. Surg Neurol 11:73-80, Ramirez-Lassepas M: Antifibrinolytic therapy in subarachnoid hemorrhage caused by ruptured intracranial aneurysm. Neurology 31: , Torner JC, Kassell NF, Wallace RB, et al: Preoperative prognostic factors for rebleeding and survival in aneurysm patients receiving antifibrinolytic therapy: report of the Cooperative Aneurysm Study. Neurosurgery 9: , Vermeulen M, Muizelaar JP: Do antifibrinolytic agents prevent rebleeding after rupture of a cerebral aneurysm? A review. Clin Neurol Neurosurg 82:25-30, 1980 Manuscript received November 3, This work was supported by Public Health Services Grant NS This paper was presented at the Annual Meeting of the American Association of Neurological Surgeons in Washington, D.C., April 24-28, Address reprint requests to: Neal F. Kassell, Department of Neurosurgery, The University of Iowa College of Medicine, Iowa City, Iowa J. Neurosurg. Volume 61August, 1984

Treatment of Acute Hydrocephalus After Subarachnoid Hemorrhage With Serial Lumbar Puncture

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