:Acta N6urochirurglca
Acta Neurochir (Wien) (1990) 107:11-15
9 by Springer-Verlag 1990
Dose Escalation Trial of a Novel Calcium Antagonist, AT877, in Patients with Aneurysmal Subarachnoid Haemorrhage M. Shibuya, Y. Suzuki, K. Sugita, I. Saito 1, T. Sasaki 1, K. Takakura 1, S. Okamoto 2, H. Kikuchi 2, T. Takemae 3, and H. Hidaka 4 Departments of Neurosurgery: Nagoya University, 1Tokyo University, 2 Kyoto University, 3Shinshu University, 4Department of Pharmacology, Nagoya University, Japan
Summary
o u t c o m e it did n o t p r e v e n t the d e v e l o p m e n t o f a n g l o -
The initial dose-escalating clinical trial of a novel calcium antagonist, AT877, in patients with aneurysmal subarachnoid haemorrhage is reported. AT877 is characterized by its strong spasmolytic activity, its inhibition of intracellular calcium ion activity, and the inhibiton of several protein kinases. A total of 113 patients (Hunt and Hess grades I to IV) who had undergone surgery within 3 days of aneurysmal rupture entered the study. Patients were divided into 5 groups according to the total daily dose of AT877: I: 20rag; II: 40rag; III: 60rag; IV: 90mg; and V: 120-180 mg. AT877 was given by intravenous infusion over 30 min two or three times a day for 14 days after surgery. Although AT877 did not completely abolish angiographic vasospasm, severe vasospasm was seen less frequently in patients given higher doses. Vasospasm was the cause of a poor clinical outcome (Glasgow outcome scale rating 3 or greater) in 19%, 7%, 9%, 8%, and 6% of the patients in groups I to V, respectively. The results indicated a favourable clinical effect of AT877 at doses above 40 mg per day. Only mild hypotension was seen, even when 60 mg of AT877 was infused over 30 rain. AT877 appears to be effective in patients with subarachnoid haemorrhage. Part of its effect may be attributable to protection of the brain from ischaemic insults due to chronic cerebral vasospasm. However, the drug still needs to be evaluated in a placebo-controlled double-blind trial (which is currently being carried out).
graphic vasospasm. A T 8 7 7 is a n o v e l c a l c i u m a n t a g o n i s t w h i c h is n o t a c a l c i u m e n t r y b l o c k e r , b u t i n h i b i t s the i n t r a c e l l u l a r ac-
Keywords: Subarachnoid haemorrhage; chronic cerebral vasospasta; calcium antagonist; AT877; HA 1077.
Introduction D e l a y e d n e u r o l o g i c a l deficits d u e to c h r o n i c c e r e b r a l v a s o s p a s m are still l e a d i n g cause o f a p o o r o u t c o m e in p a t i e n t s w h o are o p e r a t e d o n for r u p t u r e d i n t r a c r a n i a l a n e u r y s m s 11. T h e effectiveness o f a d i h y d r o p y r i d i n e c a l c i u m a n t a g o n i s t , n i m o d i p i n e , i n such p a t i e n t s h a s been established by placebo-controlled double-blind trials 9,13-15. H o w e v e r , a l t h o u g h it i m p r o v e d the clinical
t i o n o f c a l c i u m i o n s in the s m o o t h m u s c l e cells 2. W e h a v e p r e v i o u s l y s h o w n its a n t i v a s o s p a s t i c activity i n a n e x p e r i m e n t a l a n i m a l m o d e l o f c h r o n i c c e r e b r a l vas o s p a s m , w h i c h was s t r o n g e r t h a n t h a t o f a n y previo u s l y r e p o r t e d c a l c i u m a n t a g o n i s t , 17' 18. T h i s p a p e r rep o r t the results o f a n o p e n , d o s e - e s c a l a t i n g trial o f A T 8 7 7 i n p a t i e n t s w h o h a d their a n e u r y s m s c l i p p e d w i t h i n 3 days after the o c c u r r e n d e o f s u b a r a c h n o i d haemorrhage (SAH).
Material and Methods This study was performed with the cooperation of four Japanese universities (Nagoya, Tokyo, Kyoto, and Shinshu) and their affiliated hospitals. Patients with Hunt and Hess SAH grades 8 from I to IV who underwent operation for ruptured aneurysms whithin 3 days after SAH were entered the study. This study was the first clinical trial of AT877 [(1-(5-isoquinolinesulfonyl)-homopiperazine],which was developed by the Asahi Chemical Co. of Tokyo. The drug is identical with HAl077 which has been the designation in previous reports. AT877 was started from a small dose of 10 mg intravenously twice daily (b.i.d.). After each group of patients were completed, the trial of a higher dose was used for the next group (20 mg b.i.d., 30 mg b.i.d., 30mg three times a day (t.i.d.) and then 40 to 60mg t.i.d.). Altogether, 5 groups of patients were created, each given a different daily dose of AT877. The drug was dissolved in 100ml of saline which was administered intravenously over 30 minutes. Blood pressure was carfully monitored, especially during first administration, since the hypotensive effect could vary depending conditions such as malnutrition and dehydration as well as individual differences. Patients or their next of kin were given an explanation of the nature of the drug and the purpose of the study and consent was obtained for each patient entered in the trial.
12
M. Shibuya et al.: Calcium Antagonist in Subarachnoid Haemorrhage
Table 1. Data of Patients Entered in an Open Trial o f AT877 Sex and Mean Age: Male 42 (37%) 51.2:k 10.5 years Female 71 (63%) 57.3 :t: 10.1 years Location of Aneurysms: Acorn 41 (36%), IC 33 (29%), MC 30 (27%), AC 4 (4%), V-B 5 (4%) Clinical Grade: Hunt I 16 (14%), II 54 (48%), III 32 (28%), IV 11 (10%) CT Grade: Fisher I 1 (1%), II 25 (22%), III 73 (65%), IV 14 (12%) Abbreviations: Acorn, anterior communicating artery; IC, internal carotid artery; MC, middle cerebral artery; AC, anterior cerebral artery other than Acorn; V-B, vertebro-basilar system
The background data of the patients are shown in Table 1. For the purpose of the study, the entry of patients with minor SAH was limited and patients with severe SAH were selected whenever possible. As a result, 38% of the patients were Hunt and Hess grade III or IV, two-thirds of the patients had dense SAH and 12% of them had intracerebral haematoma. AT877 was started within 24 hours after surgery and continued for 14 consecutive days. The diagnosis of vasospasm was made by either angiography, CT scan, or clinically. Postoperative angiography was performed between the 5th and 14th days after the haemorrhage in 60 patients. The extent of angiographic vasospasm was used to divide patients into 4 groups (none, mild, moderate and severe). Clinical outcome was assessed at one month after the haemorrhage according to the Glasgow outcome scale ~~
tively. Better results were obtained with higher doses of AT877 (40 mg or more per day) and the highest dose of AT877 (120 to 180 mg/day) gave the best results. Overall, 69% of patients had a good outcome, 9% had moderate deficits but were still independent for daily living, 16% had severe deficits and needed assisN=6
100 -
llllll~l~l
75-
11
15
15
13
:::::::::::: :;;:;:;::::: :::::::::::: :::::::::::: :::::::::::: :::::::::::: :::::::::::: ::::::::::::
:::::::::: :::::::::: :m::.':.':
"6
Results Angiographic vasospasm: Figure 1 shows the incidence and severity of angiographic vasospasm between days 5 and 14 after SAH. Though AT877 did not completely prevent its occurrence, higher doses reduced the incidence of severe vasospasm. Severe vasospasm was found in 50%, 27%, 27%, 13%, and 0% of the patients in groups I (AT877 20, rag/day), II (40 rag), III (60 rag), IV (90 rag), and V (120 to 180 rag), respectively. Symptomatic vasospasm: Vasospasm which caused overt neurological deficit also decreased with higher doses of the drug, from 52% of the patients in group I to 31% of both groups IV and V (Fig. 2). Symptomatic vasospasm which caused neurological deficit of GOS 2 or more at one month after SAH decresed with increasing doses of the drug from 24% in group I to 12% in group IV. However, it increased again to 19% in group 5. Clinical outcome: The clinical status of the patients as assessed by the Glasgow outcome scale (GOS) one month after the SAH is shown in Fig. 3. Patients who were functioning independently in their daily life accounted for 76%, 68%, 73%, 88%, and 81% of groups I to V, respectively. The causes of poor coutcome were divided into vasospasm and other causes. Vasospasm was the cause of a poor outcome in 19%, 7%, 9%, 8%, and 6% of the patients in groups I to V, respec-
:;:::::::: :::::::::: ::::::::::
iiiiiiiiii ;::::::::: 50moEl_
Z 25-
mncl or
Rone
0X2
20X2
30X2
30x3
~40x3
AT877 mg/day
Fig. 1. Angiographic vasospasm and daily dose of AT877. Number of patients are shown as a percentage on the ordinate, sev. severe angiographic vasospasm; rood. moderate vasospasm; mild mild vasospasm; > 40 x 3, includes 40 x 3, 50 x 3, and 60 x 3mg of AT877
.= 5 0 -
2S-
E
.= 10x2
20x2
30x2
30x3
>=40x3
AT877 mg/day
Fig. 2. Occurrence of symptomatic vasospasm and daily dose of AT877. Total number of patients in each group are the same as those in Fig. 1. "transient": patients who showed neurological deficits due to vasospasm which had resolved at the time of follow-up one month after the haemorrhage. "GOS > 2": patients who had neurological deficits of GOS 2 or more due to vasospasm at 1 month follow-up examination
M. Shibuya etal.: Calcium Antagonist in Subarachnoid Haemorrhage N=21
28
22
26
13 Table 2. Results and Causes o f a Poor Outcome
16
100-
/
Outcome: GR78 (69%), MD 10(9%), SD 18 (16%), PVS4(4%),
D3(3%) Vasospasm: Severe (GOS ~> 3) 12 (11%) Mild (GOS = 2) 4 (4%)
"6 ga 5o GOS 1&2
/ 10x2
20x2
30x2
30xa
>40x3
AT877 mg/day
Other causes: Operative complications Intracranial haemorrhge Initial bleeding Rebleeding Cardiac failure Hydrocephalus Others
4 3 2 2 2 1 5
Fig. 3. Clinical outcome at one month after the subarachnoid haemorrhage. "GOS 1 & 2": patients who could manage independent living (open region of columns). "GOS > 3": patients who were dependent on others, for their daily care. They were divided by the cause of the deficit into "spasm" (dotted regions) and "other causes" (gray regions)
Abbreviations: GOS, Glasgow outcome scale; GR, good result or GOS 1 ; MD, moderate deficit or GOS 2; SD, severe deficit or GOS 3; PVS, permanent vegetative state or GOS 4; D, died or GOS 5
tance in daily life, 4% were in a permanently vegetative state, and 3 patients (3%) died. Vasospasm was the cause of severe neurological deficit (GOS > 3) in 11% of the patients. While another 4% had mild deficits (GOS 2) due to vasospasm. The other causes of neurological deficit are listed in Table 2. All of these were problems normally encountered in patients with ruptured aneurysms and there were no specific side effects which could be attributed to the use of AT877. Among the 3 patients who died two deaths were due to vasospasm. (1) A 75-year-old female patient in group I (20 mg of AT877/day) was in a poor condition (Hunt & Hess grade IV). Vasospasm worsened her condition and she died on day 17. (2) A 32-year-old female patient, with a ruptured aneurysm in the anterior communication artery, in group V (AT877
120 mg/day) was in excellent condition until day 9 when her symptoms suddenly deteriorated. CT scan showed a prominent low density area in the right cerebral hemisphere. Despite surgical decompression she died on day 13. (3) A 39-year-old male patient (Fisher's grade IV) in group II (AT877 40 mg/day) with arteriosclerosis was doing well until day 15, when his condition deteriorated due to an acute epidural haematoma which was evacuated. He suffered repeated episodes of intraventricular haemorrhage and died on day 28. The relationship between use of AT877 and this patient's haemorrhagic tendency was unclear. Effects on blood pressure." Blood pressure (BP) was measured regularly during infusion of AT877. Figure 4 shows the average changes in BP when the drug was given for the first time to patients. With a dose of 10 mg
+10 E E 10 mg (n=23-2s)
1O 0 o m .=_
~ (n=37-40)
=~ fO
-10
I 15 4 AT877 infusion
1 30
T i m e : rain
I 60
Fig. 4. Effects of AT877 on blood pressure is shown as the mean change from control values before starting infusion of the drug. The hypotensive effect was mild; 60rag of AT877 reduced blood pressure by 14mmHg at the completion of infusion and by 9 mmHg at 60 rain after the infusion
14 of AT877, there was no change in the average BP. Thirty milligrams of AT877 produced a minimal decrease of BP during infusion and it returned to the control level at 60 rain after infusion was commenced. A mild decrease in BP was seen with 60 mg of AT877 ( - 1 4 m m H g at 30min, - 9 m m H g at 60rain). There was neither tachyphylaxis nor any cumulative effect when the drug was used for 14 days.
Discussion In 1983, Allen e t a l ) first showed the effectiveness of nimodipine for treatment of ischaemic neurologic deficits after SAH by a placebo-controlled double-blind trial. Auer etal. 3 and Ljunggren etal. 12 also found evidence of effectiveness in patients who had undergone early surgery for ruptured aneurysms in open trials of the drug. Its efficacy was then confirmed by Philippon e t a l ] 4, Jan etal. 9, Petruk etal. 13, and Pickard etal. 15 by placebo-controlled double-blind trials. However, the results of nimodipine treatment have not been entirely satisfactory. It does not prevent the development of angiographic vasospasm. The effects of nimodipine have been attributed to its protection of the brain from ischaemic insult or to the vasodilation of small arteries that are invisible on angiograms. A trial of nicardipine performed by Flamm et al. 6 gave similar results. Further trials using other drugs having different mechanisms of action or other forms of therapy, such as with tissue plasminogen activators 4,16 appeared to be necessary to obtain better results in patients with ruptured aneuryms. AT877 differs from most other calcium entry blockers in that it inhibits calcium ion activity intracellularly2. It has been shown to inhibit cyclic nucleotides-dependent protein kinases 7 which are considered to be deeply implicated in smooth muscle contraction. AT877 has been shown to dilate arteries in spasm following systemic administration in experimental animal models 17' 18. Such a strong antivasospastic action has not been demonstrated with the other calcium entry blockers; nimodipine, nifedipine, and nicardipine. Statistical analysis was not performed in this trial since it was an open tiral which cannot be free from biases and since the number of the patients in each group was too small. However, the results indicate that severe angiographic vasospasm decreased with higher doses of AT877, and appear to confirm its vasodilatory effect in human SAH. The death due to vasospasm of 1 patient who was given 40mg t.i.d, of AT877 suggests that higher doses may be necessary in
M. Shibuyaetal.: CalciumAntagonistin SubarachnoidHaemorrhage some patients with a tendency to develop severe vasospasm. There are many factors which lead to the development of vasospasm, such as the amount of subarachnoid clot, the lenght of time that the clot or its lysates remain in contact with the artery, coagulability or lysability of the clot, and vascular responsiveness to the drug. The adequate dose of the drug may have to be decided individually by considering the factors which contribute to vasospasm. In the present trial, 10 to 60 mg of AT877 was used since 30mg/60kg/30min corresponded to 0.5 mg/kg/30min, the lowest significantly effective dose in animal experiments which had littel effect on blood pressure iv. As with other calcium antagonists, AT877 seem to protect the ischaemic brain. Preliminary data from our laboratory have shown that AT877 increases cerebral blood flow both in dogs and rats and prevents neuronal loss in the uncus of ischaemic rat brain (unpublished data). Thus, some part of the favourable clinical outcome in the present trial was probably attributable to the protective effect of AT877 against brain ischaemia. We had an impression that even patients who developed angiographic vasospasm showed relatively mild signs of ischaemia or showed surprisingly good recovery from ischaemic neurological deficits. The results of this early clinical trial of AT877 in SAH patients appear encouraging. Higher doses of AT877 reduced the percentage of patients with severe angiographic vasospasm and improved the clinical outcome. The adverse effects encountered were not different form those usually found in the manangement of SAH patients. Among the doses of AT877 used in this study, the intravenous infusion of 30 rag/30 min, t.i.d, produced the most favourable results. The reduced effectiveness above this dose may have been related to this agent's hypotensive effect. A large-scale, placebo-controlled, double-blind trial of AT877 is currently being carried out.
Acknowledgements This trial was performedwith the cooperation of the following universities and their affiliatedhospitals in Japan. Tokyo University,Kyoto Unversity,ShinsuUniversity,Nagoya University, Handa City Hospital, Yokkaichi City Hospital, Ichinomiya City Hospital, Kainan Hospital, Seguchi Neurosurgical Clinic, OhgakiCity Hospital, Okazaki City Hospital, ChukyoHospital, ShizuokaSaiseikaiHospital,ToyohashiCityHospital,Nagoya First Red Cross Hospital, YokohamaShintoshiNeurosurgicalHospital, HamamatsuRosaiHospital,MaizuruCityHospital,Tominaga Neurosurgical Hospital, Kobe Central Hospital, Kohritsu Showa Hospital, Kantoh Rosai Hospital, Fuji Brain InstituteHospital,Kameda General Hospital, and Aizawa Hospital.
M. Shibuya et al.: CaIcium Antagonist in Subarachnoid Haemorrhage
References l. Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SG, Chou SN, Kelly DL, Weir BK, Crabbe RA, Lavik PJ, Rosenbloom SB, Dorsey FC, Ingram CR, Mellits De, Bertsch LA, Boisvert DP, Hundley MB, Johnson RK, Strom JA, Transou CR (1983) Cerebral arterial spasm - A controlled trial ofnimodipine in patients with subarachnoid hemorrhage. N Engl J Med 308:619-624 2. Asano T, Ikegaki I, Satoh S, Suzuki Y, Shibuya M, Takayasu M, Hidaka H (1987) Mechanism of action of a novel antivasospastic drug, HA 1077. J Pharmacol Exp Ther 241:1033-1040 3. Auer LM, Scneider GH, Auer T (1986) Computerized tomography and prognosis in early aneurysm surgery. J Neurosurg 65:217-221 4. Findlay JM, Weir BKA, Steinke D, Tanabe T, Gordon P, Grace M (1988) Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of subarachnoid hemorrhage. J Neurosurg 69:723-735 5. Fisher CM, Kistler JP, Davis JM (1980) Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6:1-9 6. Flamm ES, Adams ES Jr, Beck DW, Pinto RS, Marler JR, Walker MD, Godersky JC, Loftus CM, Biller J, Boarine D J, O'Dell C, Banwart K, Kongable G (1988) Dose-escalation study of intravenous nicardipine in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 68:393-400 7. Hidaka H, Inagaki M, Kawamoto S, Sasaki Y (1984) Isoquinoline sulfonamides, novel and potent inhibitors of cyclic nucelotide dependent protein kinase and protein kinase C. Biochemistry 23:5036-5041 8. Hunt WE, Hess R (1968) Surgical risk as related to time of intervention in the repair ofintracranial aneurysms. J Neurosurg 28:14-20 9. Jan M, Buchheit F, Tremoulet M (1988) Therapeutic trial of intravenous nimodipine in patients with established cerebral vasospasm after rupture of intracranial aneurysms. Neurosurgery 23:154-157 10. Jennett B, Bond M (1975) Assessment of outcome after severe brain damage. A practical scale. Lancet h 480-484
15 11. Kassell NF, Sassaki T, Colohan ART, Nazar G (1985) Cerebra1 vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 16:562-572 12. Ljunggren B, Brandt L, Saveland H, Nilsson PE, Cronqvist S, Andersson KE, Vinge E (1984) Outcome in 60 patients treated with early aneurysm operation and intravenous nimodipine. J Neurosurg 61:864-873 i3. Petruk KC, West M, Mohr G, Weir BKA, Benoit BG, Gentili F, Disney LB, Khan MI, Grace M, Holness RO, Karwon MS, Ford RM, Cameron GS, Tucker WS, Purves GV, Miller JDR, Hunter KM, Richard MT, Durity FA, Chan R, Clein LJ, Maroun FB, Godon A (1988) Nimodipine treatment in poor-grade aneurysm patients. J Neurosurg 68:505-517 14. Philippon J, Grob R, Dagreou F, Guggiari M, Rivierez M, Viars P (1986) Prevention of vasospasm in subarachnoid haemorrhage: A controlled study with nimodipine. Acta Neurochir (Wien) 82: 110-114, 1986 15. Pickard JD, Murray GD, Illingworth R, Shaw MDM, Teasdale GM, Foy PM, Humphrey PRD, Lang DA, Nelson R, Richards P, Sinar J, Bailey S, Skene A (1989) Effect of oral nimodipine on cerebral infarction and outcome after subarachuoid haemorrhage: British aneurysm nimodipine trial. Br Med J 298: 636-642 i6. Seifert V, Eisert WG, Stolke D, Goetz C (1989) Efficacy of single intracisternaI bolus injection of recombinant tissue plasminogen activator to prevent delayed cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery 25:590-598 17. Shibuya M, Suzuki Y, Takayasu M, Asano T, Harada T, Ikegaki I, Satoh S, Hidaka H (1988) The effects of an intracellular calcium antagonist, HA1077, on delayed cerebral vasospasm in dogs. Acta Neurochir (Wien) 90:53-59 18. Takayasu M, Suzuki Y, Shibuya M, Asano T, Kanamori M, Okada T, Kageyama N, Hidaka H (1986) The effects of HA compound calcium antagonists on delayed cerebral vasospasm in dogs. J Neurosurg 65:80-85 Correspondence and Reprints: Masato Shibuya, M.D., Department of Neurosurgery, Nagoya University, 466 Nagoya, Japan.
Acta Neurochir (Wien) (1990) 107:11-15
9 by Springer-Verlag 1990
Dose Escalation Trial of a Novel Calcium Antagonist, AT877, in Patients with Aneurysmal Subarachnoid Haemorrhage M. Shibuya, Y. Suzuki, K. Sugita, I. Saito 1, T. Sasaki 1, K. Takakura 1, S. Okamoto 2, H. Kikuchi 2, T. Takemae 3, and H. Hidaka 4 Departments of Neurosurgery: Nagoya University, 1Tokyo University, 2 Kyoto University, 3Shinshu University, 4Department of Pharmacology, Nagoya University, Japan
Summary
o u t c o m e it did n o t p r e v e n t the d e v e l o p m e n t o f a n g l o -
The initial dose-escalating clinical trial of a novel calcium antagonist, AT877, in patients with aneurysmal subarachnoid haemorrhage is reported. AT877 is characterized by its strong spasmolytic activity, its inhibition of intracellular calcium ion activity, and the inhibiton of several protein kinases. A total of 113 patients (Hunt and Hess grades I to IV) who had undergone surgery within 3 days of aneurysmal rupture entered the study. Patients were divided into 5 groups according to the total daily dose of AT877: I: 20rag; II: 40rag; III: 60rag; IV: 90mg; and V: 120-180 mg. AT877 was given by intravenous infusion over 30 min two or three times a day for 14 days after surgery. Although AT877 did not completely abolish angiographic vasospasm, severe vasospasm was seen less frequently in patients given higher doses. Vasospasm was the cause of a poor clinical outcome (Glasgow outcome scale rating 3 or greater) in 19%, 7%, 9%, 8%, and 6% of the patients in groups I to V, respectively. The results indicated a favourable clinical effect of AT877 at doses above 40 mg per day. Only mild hypotension was seen, even when 60 mg of AT877 was infused over 30 rain. AT877 appears to be effective in patients with subarachnoid haemorrhage. Part of its effect may be attributable to protection of the brain from ischaemic insults due to chronic cerebral vasospasm. However, the drug still needs to be evaluated in a placebo-controlled double-blind trial (which is currently being carried out).
graphic vasospasm. A T 8 7 7 is a n o v e l c a l c i u m a n t a g o n i s t w h i c h is n o t a c a l c i u m e n t r y b l o c k e r , b u t i n h i b i t s the i n t r a c e l l u l a r ac-
Keywords: Subarachnoid haemorrhage; chronic cerebral vasospasta; calcium antagonist; AT877; HA 1077.
Introduction D e l a y e d n e u r o l o g i c a l deficits d u e to c h r o n i c c e r e b r a l v a s o s p a s m are still l e a d i n g cause o f a p o o r o u t c o m e in p a t i e n t s w h o are o p e r a t e d o n for r u p t u r e d i n t r a c r a n i a l a n e u r y s m s 11. T h e effectiveness o f a d i h y d r o p y r i d i n e c a l c i u m a n t a g o n i s t , n i m o d i p i n e , i n such p a t i e n t s h a s been established by placebo-controlled double-blind trials 9,13-15. H o w e v e r , a l t h o u g h it i m p r o v e d the clinical
t i o n o f c a l c i u m i o n s in the s m o o t h m u s c l e cells 2. W e h a v e p r e v i o u s l y s h o w n its a n t i v a s o s p a s t i c activity i n a n e x p e r i m e n t a l a n i m a l m o d e l o f c h r o n i c c e r e b r a l vas o s p a s m , w h i c h was s t r o n g e r t h a n t h a t o f a n y previo u s l y r e p o r t e d c a l c i u m a n t a g o n i s t , 17' 18. T h i s p a p e r rep o r t the results o f a n o p e n , d o s e - e s c a l a t i n g trial o f A T 8 7 7 i n p a t i e n t s w h o h a d their a n e u r y s m s c l i p p e d w i t h i n 3 days after the o c c u r r e n d e o f s u b a r a c h n o i d haemorrhage (SAH).
Material and Methods This study was performed with the cooperation of four Japanese universities (Nagoya, Tokyo, Kyoto, and Shinshu) and their affiliated hospitals. Patients with Hunt and Hess SAH grades 8 from I to IV who underwent operation for ruptured aneurysms whithin 3 days after SAH were entered the study. This study was the first clinical trial of AT877 [(1-(5-isoquinolinesulfonyl)-homopiperazine],which was developed by the Asahi Chemical Co. of Tokyo. The drug is identical with HAl077 which has been the designation in previous reports. AT877 was started from a small dose of 10 mg intravenously twice daily (b.i.d.). After each group of patients were completed, the trial of a higher dose was used for the next group (20 mg b.i.d., 30 mg b.i.d., 30mg three times a day (t.i.d.) and then 40 to 60mg t.i.d.). Altogether, 5 groups of patients were created, each given a different daily dose of AT877. The drug was dissolved in 100ml of saline which was administered intravenously over 30 minutes. Blood pressure was carfully monitored, especially during first administration, since the hypotensive effect could vary depending conditions such as malnutrition and dehydration as well as individual differences. Patients or their next of kin were given an explanation of the nature of the drug and the purpose of the study and consent was obtained for each patient entered in the trial.
12
M. Shibuya et al.: Calcium Antagonist in Subarachnoid Haemorrhage
Table 1. Data of Patients Entered in an Open Trial o f AT877 Sex and Mean Age: Male 42 (37%) 51.2:k 10.5 years Female 71 (63%) 57.3 :t: 10.1 years Location of Aneurysms: Acorn 41 (36%), IC 33 (29%), MC 30 (27%), AC 4 (4%), V-B 5 (4%) Clinical Grade: Hunt I 16 (14%), II 54 (48%), III 32 (28%), IV 11 (10%) CT Grade: Fisher I 1 (1%), II 25 (22%), III 73 (65%), IV 14 (12%) Abbreviations: Acorn, anterior communicating artery; IC, internal carotid artery; MC, middle cerebral artery; AC, anterior cerebral artery other than Acorn; V-B, vertebro-basilar system
The background data of the patients are shown in Table 1. For the purpose of the study, the entry of patients with minor SAH was limited and patients with severe SAH were selected whenever possible. As a result, 38% of the patients were Hunt and Hess grade III or IV, two-thirds of the patients had dense SAH and 12% of them had intracerebral haematoma. AT877 was started within 24 hours after surgery and continued for 14 consecutive days. The diagnosis of vasospasm was made by either angiography, CT scan, or clinically. Postoperative angiography was performed between the 5th and 14th days after the haemorrhage in 60 patients. The extent of angiographic vasospasm was used to divide patients into 4 groups (none, mild, moderate and severe). Clinical outcome was assessed at one month after the haemorrhage according to the Glasgow outcome scale ~~
tively. Better results were obtained with higher doses of AT877 (40 mg or more per day) and the highest dose of AT877 (120 to 180 mg/day) gave the best results. Overall, 69% of patients had a good outcome, 9% had moderate deficits but were still independent for daily living, 16% had severe deficits and needed assisN=6
100 -
llllll~l~l
75-
11
15
15
13
:::::::::::: :;;:;:;::::: :::::::::::: :::::::::::: :::::::::::: :::::::::::: :::::::::::: ::::::::::::
:::::::::: :::::::::: :m::.':.':
"6
Results Angiographic vasospasm: Figure 1 shows the incidence and severity of angiographic vasospasm between days 5 and 14 after SAH. Though AT877 did not completely prevent its occurrence, higher doses reduced the incidence of severe vasospasm. Severe vasospasm was found in 50%, 27%, 27%, 13%, and 0% of the patients in groups I (AT877 20, rag/day), II (40 rag), III (60 rag), IV (90 rag), and V (120 to 180 rag), respectively. Symptomatic vasospasm: Vasospasm which caused overt neurological deficit also decreased with higher doses of the drug, from 52% of the patients in group I to 31% of both groups IV and V (Fig. 2). Symptomatic vasospasm which caused neurological deficit of GOS 2 or more at one month after SAH decresed with increasing doses of the drug from 24% in group I to 12% in group IV. However, it increased again to 19% in group 5. Clinical outcome: The clinical status of the patients as assessed by the Glasgow outcome scale (GOS) one month after the SAH is shown in Fig. 3. Patients who were functioning independently in their daily life accounted for 76%, 68%, 73%, 88%, and 81% of groups I to V, respectively. The causes of poor coutcome were divided into vasospasm and other causes. Vasospasm was the cause of a poor outcome in 19%, 7%, 9%, 8%, and 6% of the patients in groups I to V, respec-
:;:::::::: :::::::::: ::::::::::
iiiiiiiiii ;::::::::: 50moEl_
Z 25-
mncl or
Rone
0X2
20X2
30X2
30x3
~40x3
AT877 mg/day
Fig. 1. Angiographic vasospasm and daily dose of AT877. Number of patients are shown as a percentage on the ordinate, sev. severe angiographic vasospasm; rood. moderate vasospasm; mild mild vasospasm; > 40 x 3, includes 40 x 3, 50 x 3, and 60 x 3mg of AT877
.= 5 0 -
2S-
E
.= 10x2
20x2
30x2
30x3
>=40x3
AT877 mg/day
Fig. 2. Occurrence of symptomatic vasospasm and daily dose of AT877. Total number of patients in each group are the same as those in Fig. 1. "transient": patients who showed neurological deficits due to vasospasm which had resolved at the time of follow-up one month after the haemorrhage. "GOS > 2": patients who had neurological deficits of GOS 2 or more due to vasospasm at 1 month follow-up examination
M. Shibuya etal.: Calcium Antagonist in Subarachnoid Haemorrhage N=21
28
22
26
13 Table 2. Results and Causes o f a Poor Outcome
16
100-
/
Outcome: GR78 (69%), MD 10(9%), SD 18 (16%), PVS4(4%),
D3(3%) Vasospasm: Severe (GOS ~> 3) 12 (11%) Mild (GOS = 2) 4 (4%)
"6 ga 5o GOS 1&2
/ 10x2
20x2
30x2
30xa
>40x3
AT877 mg/day
Other causes: Operative complications Intracranial haemorrhge Initial bleeding Rebleeding Cardiac failure Hydrocephalus Others
4 3 2 2 2 1 5
Fig. 3. Clinical outcome at one month after the subarachnoid haemorrhage. "GOS 1 & 2": patients who could manage independent living (open region of columns). "GOS > 3": patients who were dependent on others, for their daily care. They were divided by the cause of the deficit into "spasm" (dotted regions) and "other causes" (gray regions)
Abbreviations: GOS, Glasgow outcome scale; GR, good result or GOS 1 ; MD, moderate deficit or GOS 2; SD, severe deficit or GOS 3; PVS, permanent vegetative state or GOS 4; D, died or GOS 5
tance in daily life, 4% were in a permanently vegetative state, and 3 patients (3%) died. Vasospasm was the cause of severe neurological deficit (GOS > 3) in 11% of the patients. While another 4% had mild deficits (GOS 2) due to vasospasm. The other causes of neurological deficit are listed in Table 2. All of these were problems normally encountered in patients with ruptured aneurysms and there were no specific side effects which could be attributed to the use of AT877. Among the 3 patients who died two deaths were due to vasospasm. (1) A 75-year-old female patient in group I (20 mg of AT877/day) was in a poor condition (Hunt & Hess grade IV). Vasospasm worsened her condition and she died on day 17. (2) A 32-year-old female patient, with a ruptured aneurysm in the anterior communication artery, in group V (AT877
120 mg/day) was in excellent condition until day 9 when her symptoms suddenly deteriorated. CT scan showed a prominent low density area in the right cerebral hemisphere. Despite surgical decompression she died on day 13. (3) A 39-year-old male patient (Fisher's grade IV) in group II (AT877 40 mg/day) with arteriosclerosis was doing well until day 15, when his condition deteriorated due to an acute epidural haematoma which was evacuated. He suffered repeated episodes of intraventricular haemorrhage and died on day 28. The relationship between use of AT877 and this patient's haemorrhagic tendency was unclear. Effects on blood pressure." Blood pressure (BP) was measured regularly during infusion of AT877. Figure 4 shows the average changes in BP when the drug was given for the first time to patients. With a dose of 10 mg
+10 E E 10 mg (n=23-2s)
1O 0 o m .=_
~ (n=37-40)
=~ fO
-10
I 15 4 AT877 infusion
1 30
T i m e : rain
I 60
Fig. 4. Effects of AT877 on blood pressure is shown as the mean change from control values before starting infusion of the drug. The hypotensive effect was mild; 60rag of AT877 reduced blood pressure by 14mmHg at the completion of infusion and by 9 mmHg at 60 rain after the infusion
14 of AT877, there was no change in the average BP. Thirty milligrams of AT877 produced a minimal decrease of BP during infusion and it returned to the control level at 60 rain after infusion was commenced. A mild decrease in BP was seen with 60 mg of AT877 ( - 1 4 m m H g at 30min, - 9 m m H g at 60rain). There was neither tachyphylaxis nor any cumulative effect when the drug was used for 14 days.
Discussion In 1983, Allen e t a l ) first showed the effectiveness of nimodipine for treatment of ischaemic neurologic deficits after SAH by a placebo-controlled double-blind trial. Auer etal. 3 and Ljunggren etal. 12 also found evidence of effectiveness in patients who had undergone early surgery for ruptured aneurysms in open trials of the drug. Its efficacy was then confirmed by Philippon e t a l ] 4, Jan etal. 9, Petruk etal. 13, and Pickard etal. 15 by placebo-controlled double-blind trials. However, the results of nimodipine treatment have not been entirely satisfactory. It does not prevent the development of angiographic vasospasm. The effects of nimodipine have been attributed to its protection of the brain from ischaemic insult or to the vasodilation of small arteries that are invisible on angiograms. A trial of nicardipine performed by Flamm et al. 6 gave similar results. Further trials using other drugs having different mechanisms of action or other forms of therapy, such as with tissue plasminogen activators 4,16 appeared to be necessary to obtain better results in patients with ruptured aneuryms. AT877 differs from most other calcium entry blockers in that it inhibits calcium ion activity intracellularly2. It has been shown to inhibit cyclic nucleotides-dependent protein kinases 7 which are considered to be deeply implicated in smooth muscle contraction. AT877 has been shown to dilate arteries in spasm following systemic administration in experimental animal models 17' 18. Such a strong antivasospastic action has not been demonstrated with the other calcium entry blockers; nimodipine, nifedipine, and nicardipine. Statistical analysis was not performed in this trial since it was an open tiral which cannot be free from biases and since the number of the patients in each group was too small. However, the results indicate that severe angiographic vasospasm decreased with higher doses of AT877, and appear to confirm its vasodilatory effect in human SAH. The death due to vasospasm of 1 patient who was given 40mg t.i.d, of AT877 suggests that higher doses may be necessary in
M. Shibuyaetal.: CalciumAntagonistin SubarachnoidHaemorrhage some patients with a tendency to develop severe vasospasm. There are many factors which lead to the development of vasospasm, such as the amount of subarachnoid clot, the lenght of time that the clot or its lysates remain in contact with the artery, coagulability or lysability of the clot, and vascular responsiveness to the drug. The adequate dose of the drug may have to be decided individually by considering the factors which contribute to vasospasm. In the present trial, 10 to 60 mg of AT877 was used since 30mg/60kg/30min corresponded to 0.5 mg/kg/30min, the lowest significantly effective dose in animal experiments which had littel effect on blood pressure iv. As with other calcium antagonists, AT877 seem to protect the ischaemic brain. Preliminary data from our laboratory have shown that AT877 increases cerebral blood flow both in dogs and rats and prevents neuronal loss in the uncus of ischaemic rat brain (unpublished data). Thus, some part of the favourable clinical outcome in the present trial was probably attributable to the protective effect of AT877 against brain ischaemia. We had an impression that even patients who developed angiographic vasospasm showed relatively mild signs of ischaemia or showed surprisingly good recovery from ischaemic neurological deficits. The results of this early clinical trial of AT877 in SAH patients appear encouraging. Higher doses of AT877 reduced the percentage of patients with severe angiographic vasospasm and improved the clinical outcome. The adverse effects encountered were not different form those usually found in the manangement of SAH patients. Among the doses of AT877 used in this study, the intravenous infusion of 30 rag/30 min, t.i.d, produced the most favourable results. The reduced effectiveness above this dose may have been related to this agent's hypotensive effect. A large-scale, placebo-controlled, double-blind trial of AT877 is currently being carried out.
Acknowledgements This trial was performedwith the cooperation of the following universities and their affiliatedhospitals in Japan. Tokyo University,Kyoto Unversity,ShinsuUniversity,Nagoya University, Handa City Hospital, Yokkaichi City Hospital, Ichinomiya City Hospital, Kainan Hospital, Seguchi Neurosurgical Clinic, OhgakiCity Hospital, Okazaki City Hospital, ChukyoHospital, ShizuokaSaiseikaiHospital,ToyohashiCityHospital,Nagoya First Red Cross Hospital, YokohamaShintoshiNeurosurgicalHospital, HamamatsuRosaiHospital,MaizuruCityHospital,Tominaga Neurosurgical Hospital, Kobe Central Hospital, Kohritsu Showa Hospital, Kantoh Rosai Hospital, Fuji Brain InstituteHospital,Kameda General Hospital, and Aizawa Hospital.
M. Shibuya et al.: CaIcium Antagonist in Subarachnoid Haemorrhage
References l. Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SG, Chou SN, Kelly DL, Weir BK, Crabbe RA, Lavik PJ, Rosenbloom SB, Dorsey FC, Ingram CR, Mellits De, Bertsch LA, Boisvert DP, Hundley MB, Johnson RK, Strom JA, Transou CR (1983) Cerebral arterial spasm - A controlled trial ofnimodipine in patients with subarachnoid hemorrhage. N Engl J Med 308:619-624 2. Asano T, Ikegaki I, Satoh S, Suzuki Y, Shibuya M, Takayasu M, Hidaka H (1987) Mechanism of action of a novel antivasospastic drug, HA 1077. J Pharmacol Exp Ther 241:1033-1040 3. Auer LM, Scneider GH, Auer T (1986) Computerized tomography and prognosis in early aneurysm surgery. J Neurosurg 65:217-221 4. Findlay JM, Weir BKA, Steinke D, Tanabe T, Gordon P, Grace M (1988) Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of subarachnoid hemorrhage. J Neurosurg 69:723-735 5. Fisher CM, Kistler JP, Davis JM (1980) Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6:1-9 6. Flamm ES, Adams ES Jr, Beck DW, Pinto RS, Marler JR, Walker MD, Godersky JC, Loftus CM, Biller J, Boarine D J, O'Dell C, Banwart K, Kongable G (1988) Dose-escalation study of intravenous nicardipine in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 68:393-400 7. Hidaka H, Inagaki M, Kawamoto S, Sasaki Y (1984) Isoquinoline sulfonamides, novel and potent inhibitors of cyclic nucelotide dependent protein kinase and protein kinase C. Biochemistry 23:5036-5041 8. Hunt WE, Hess R (1968) Surgical risk as related to time of intervention in the repair ofintracranial aneurysms. J Neurosurg 28:14-20 9. Jan M, Buchheit F, Tremoulet M (1988) Therapeutic trial of intravenous nimodipine in patients with established cerebral vasospasm after rupture of intracranial aneurysms. Neurosurgery 23:154-157 10. Jennett B, Bond M (1975) Assessment of outcome after severe brain damage. A practical scale. Lancet h 480-484
15 11. Kassell NF, Sassaki T, Colohan ART, Nazar G (1985) Cerebra1 vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 16:562-572 12. Ljunggren B, Brandt L, Saveland H, Nilsson PE, Cronqvist S, Andersson KE, Vinge E (1984) Outcome in 60 patients treated with early aneurysm operation and intravenous nimodipine. J Neurosurg 61:864-873 i3. Petruk KC, West M, Mohr G, Weir BKA, Benoit BG, Gentili F, Disney LB, Khan MI, Grace M, Holness RO, Karwon MS, Ford RM, Cameron GS, Tucker WS, Purves GV, Miller JDR, Hunter KM, Richard MT, Durity FA, Chan R, Clein LJ, Maroun FB, Godon A (1988) Nimodipine treatment in poor-grade aneurysm patients. J Neurosurg 68:505-517 14. Philippon J, Grob R, Dagreou F, Guggiari M, Rivierez M, Viars P (1986) Prevention of vasospasm in subarachnoid haemorrhage: A controlled study with nimodipine. Acta Neurochir (Wien) 82: 110-114, 1986 15. Pickard JD, Murray GD, Illingworth R, Shaw MDM, Teasdale GM, Foy PM, Humphrey PRD, Lang DA, Nelson R, Richards P, Sinar J, Bailey S, Skene A (1989) Effect of oral nimodipine on cerebral infarction and outcome after subarachuoid haemorrhage: British aneurysm nimodipine trial. Br Med J 298: 636-642 i6. Seifert V, Eisert WG, Stolke D, Goetz C (1989) Efficacy of single intracisternaI bolus injection of recombinant tissue plasminogen activator to prevent delayed cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery 25:590-598 17. Shibuya M, Suzuki Y, Takayasu M, Asano T, Harada T, Ikegaki I, Satoh S, Hidaka H (1988) The effects of an intracellular calcium antagonist, HA1077, on delayed cerebral vasospasm in dogs. Acta Neurochir (Wien) 90:53-59 18. Takayasu M, Suzuki Y, Shibuya M, Asano T, Kanamori M, Okada T, Kageyama N, Hidaka H (1986) The effects of HA compound calcium antagonists on delayed cerebral vasospasm in dogs. J Neurosurg 65:80-85 Correspondence and Reprints: Masato Shibuya, M.D., Department of Neurosurgery, Nagoya University, 466 Nagoya, Japan.
