Fumio Gotoh

Cilostazol Stroke Prevention Study: A Placebo-Controlled Double-Blind Trial for Secondary Prevention of Cerebral Infarction

Cilostazol, an antiplatelet drug that increases the cyclic adenosine monophosphate (AMP) levels in platelets via inhibition of cyclic AMP phosphodiesterase, has been used in chronic arterial occlusive disease. The purpose of the present study was to examine the effects of cilostazol on the recurrence of cerebral infarction using a multicenter, randomized, placebo-controlled, double-blind clinical trial method. Patients who suffered from cerebral infarction at 1 to 6 months before the trial were enrolled between April 1992 and March 1996. Oral administration of cilostazol (100 mg twice daily) or placebo was randomly assigned to the patients and continued until February 1997. The primary endpoint was the recurrence of cerebral infarction. In total, 1,095 patients were enrolled. An analysis based on 1,052 eligible patients (526 given cilostazol and 526 given placebo) showed that the cilostazol treatment achieved a significant relative-risk reduction (41.7%; confidence interval [CI], 9.2% to 62.5%) in the recurrence of cerebral infarction as compared with the placebo treatment (P=.0150). Intention-to-treat analysis of 1,067 patients also showed a significant relative-risk reduction (42.3%; CI, 10.3% to 62.9%, P=.0127). No clinically significant adverse drug reactions of cilostazol were encountered. Long-term administration of cilostazol was effective and safe in the secondary prevention of cerebral infarction.

Inhibition of nitric oxide synthesis induces a significant reduction in local cerebral blood flow in the rat

The effect of intravenous administration of NG-monomethyl-L-arginine (L-NMMA, 30 mg/kg), a specific inhibitor of nitric oxide synthesis, on local cerebral blood flow (lCBF) was examined in the rat using the [14C]iodoantipyrine autoradiographic method. L-NMMA induced a statistically significant reduction in lCBF in the cerebral cortices as well as in various deep structures of the brain. This reduction in lCBF was accompanied by a clear increase in mean arterial blood pressure, suggesting that the cerebral resistance vessels constricted significantly beyond the autoregulatory response following L-NMMA administration. These findings indicate that the basal cerebral circulation may be closely related to nitric oxide production.

Stroke in systemic lupus erythematosus.

We investigated the clinical and pathologic characteristics of stroke in 234 patients with systemic lupus erythematosus. Thirteen patients (5.6%) developed cerebrovascular disease. Cerebral infarction was noted in eight, cerebral hemorrhage in two, and subarachnoid hemorrhage in three. In seven (54%) of these 13 patients, stroke occurred less than or equal to 5 years after systemic lupus erythematosus was diagnosed. Among the predisposing risk factors for stroke, hypertension was the most important. Lupus anticoagulant was detected in three (38%) and anticardiolipin antibody in three (43% of seven investigated) of the patients with infarction. Evaluation of the clinical manifestations and autoantibodies indicated that renal involvement and high titers of anti-deoxyribonucleic acid antibody were more frequent in the stroke group than in the non-stroke group. Autopsy studies on six of the patients with stroke revealed small infarcts and hemorrhages in all, but in no case was true angiitis observed. Libman-Sacks endocarditis was found in two of the three patients with infarction. In conclusion, the important contributory factor to the development of stroke in patients with systemic lupus erythematosus is considered to be hypertension mediated by immunologic abnormalities. Antiphospholipid antibodies and Libman-Sacks endocarditis are closely associated with occlusive cerebrovascular disease.

Prognostic Value of Admission Blood Pressure in Patients With Intracerebral Hemorrhage Keio Cooperative Stroke Study

BACKGROUND AND PURPOSE Patients with acute stroke on admission to the hospital are often found to have high blood pressure. The purpose of the present study was to investigate the prognostic value of admission blood pressure in patients with acute intracerebral hemorrhage, including putaminal, thalamic, subcortical, cerebellar, and pontine hemorrhage. METHODS A total of 1701 patients with intracerebral hemorrhage of the putamen (n = 776; mean +/- SD age, 58 +/- 14 years) thalamus (n = 538; 63 +/- 12 years), subcortex (n = 153; 61 +/- 16 years), cerebellum (n = 110; 64 +/- 11 years), and pons (n = 124; 59 +/- 13 years) were examined. The mean blood pressure on admission in patients with a fatal outcome was compared with that in patients who survived. RESULTS The mean age in each patient group (putaminal, thalamic, subcortical, cerebellar, and pontine hemorrhage) with fatal outcome was older than that with nonfatal outcome, while ANCOVA indicated no correlation between age and blood pressure on admission or age and volume of hematoma. The mean arterial blood pressure on hospital admission was 126.9 +/- 25.8 mm Hg (+/-SD) in cases of putaminal. 127.4 +/- 22.6 mm Hg in thalamic, 116.4 +/- 20.6 mm Hg in subcortical, 123.5 +/- 23.9 mm Hg in cerebellar, and 133.0 +/- 26.0 mm Hg in pontine hemorrhage. The mean blood pressure on admission in patients with a fatal outcome among those with putaminal (136.0 +/- 36.3 mm Hg) and thalamic (133.2 +/- 22.1 mm Hg) hemorrhage was significantly higher than that in those with a nonfatal outcome (123.8 +/- 20.6 mm Hg for putaminal, 101.6 +/- 22.5 mm Hg for thalamic) (P < .01). No correlation between mean blood pressure and outcome was observed in the patients with subcortical (116.5 +/- 22.2 mm Hg for nonfatal, 114.9 +/- 22.0 mm Hg for fatal outcome), cerebellar (125.2 +/- 22.2 mm Hg, 116.9 +/- 28.8 mm Hg), and pontine (129.9 +/- 23.8 mm Hg, 136.0 +/- 27.7 mm Hg) hemorrhage. The volume of hematoma on admission in patients with fatal outcome with putaminal (58.2 +/- 24.4 mL), thalamic (27.0 +/- 13.1 mL), subcortical (32.9 +/- 14.4 mL), and cerebellar (31.4 +/- 28.6 mL) hemorrhage was greater than that in those with nonfatal outcome (20.8 +/- 11.4 mL, 7.1 +/- 4.8 mL, 18.3 +/- 10.6 mL, and 8.1 +/- 4.2 mL, respectively; P < .01), while no correlation between volume of hematoma and outcome was observed in patients with pontine hemorrhage. CONCLUSIONS The above data suggest that an increased mean blood pressure and volume of hematoma on admission in putaminal and thalamic hemorrhage were related to increased mortality, while in patients with subcortical, cerebellar, and pontine hemorrhage, the mean blood pressure was not related to the clinical outcome.

Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS): A randomized, double-blind, aspirin-controlled trial.

Background and Purpose— The antiplatelet agent sarpogrelate is a selective inhibitor of 5-hydroxytryptamine receptors. The purpose of this study was to compare the efficacy and safety of sarpogrelate with those of aspirin in Japanese ischemic stroke patients. Methods— In total, 1510 patients with recent cerebral infarction (1 week to 6 months after onset) were randomly assigned to receive either sarpogrelate (100 mg TID) or aspirin (81 mg/d). Mean follow-up period was 1.59 years. The primary efficacy end point was recurrence of cerebral infarction. Clusters of serious vascular events (stroke, acute coronary syndrome, or vascular event–related death) were selected as secondary end points. The aim of the primary efficacy analysis was to demonstrate the noninferiority of sarpogrelate with respect to aspirin, with the criterion that the upper limit of the 95% CI of the hazard ratio (sarpogrelate vs aspirin) for recurrence of cerebral infarction should not exceed 1.33. Results— Cerebral infarction recurred in 72 patients (6.09%/y) in the sarpogrelate group and in 58 (4.86%/y) in the aspirin group (hazard ratio=1.25; 95% CI, 0.89 to 1.77; P=0.19). A serious vascular event occurred in 90 (7.61%/y) and in 85 (7.12%/y) patients, respectively (hazard ratio=1.07; 95% CI, 0.80 to 1.44; P=0.65). The overall incidences of bleeding events were 89 (11.9%) and 131 (17.3%), respectively (P<0.01). Conclusions— Sarpogrelate was not noninferior to aspirin for prevention of recurrence of cerebral infarction. Bleeding events were significantly fewer with sarpogrelate than aspirin. The effect of aspirin in Japanese patients was similar to that in Western studies.

Effects of a selective inhibitor of cyclic AMP phosphodiesterase on the pial microcirculation in feline cerebral ischemia.

We evaluated the effects of cilostazol, a selective inhibitor of cyclic adenosine monophosphate phosphodiesterase, on the pial vessels of adult cats subjected to endothelial damage followed by middle cerebral artery occlusion. Six cats were treated with cilostazol and four with 30% N,N-dimethylformamide in 70% saline (solvent). The brain surface was irradiated with ultraviolet rays through a cranial window for 3 minutes to selectively damage the endothelium of the pial vessels in both groups. Beginning 32 minutes after termination of the irradiation, the middle cerebral artery was occluded for 30 minutes. Thirty minutes before occlusion, intravenous infusion of 30 micrograms/kg/min cilostazol or 0.1 ml/kg/min solvent was begun and continued until the end of the study. Before occlusion, the infusion of cilostazol induced a significant (p less than 0.05) dilatation while the infusion of solvent produced no significant changes in the diameter of the pial arteries. The pial veins of solvent-treated cats showed significant (p less than 0.05) constriction during occlusion, whereas cilostazol-treated cats exhibited only mild constriction of the pial veins. The formation of platelet thrombi after occlusion was significantly (p less than 0.05) inhibited in the pial veins of cilostazol-treated compared with solvent-treated cats. Similarly, the microcirculation of the pial veins was effectively restored after reopening of the middle cerebral artery in cilostazol-treated compared with solvent-treated cats. Our data suggest that cilostazol is an effective antithrombotic agent as well as a potent vasodilator acting on vascular smooth muscle.

Effects of anoxia on cerebral metabolism and electrolytes in man

THE OXYGEN tension (PO,) of brain tissue obeys the law of supply and demand. Supply is influenced by arterial oxygen content, cerebral blood flow, and cerebral blood pH (by the Bohr effect), and demand depends soleIy on the functional state of brain metabolism. If the oxygen tension of the blood is reduced (for example, by anoxic anoxia of nitrogen inhalation), presumably a value will be reached below which capillary PO, is insufficient to maintain oxygen diffusion into brain tissue; functional impairment with signs of cerebral anoxia will result. Such thresholds for oxygen tension have been determined for brain preparations; below these cerebral oxygen consumption became decreased and thresholds for cerebral venous PO,-at which electroencephalographic slowing and decreased cerebral metabolism occurred-have also been estimated in animals by several investigators.1-5 There is as yet no comparable data available in man except a few determinations of the levels of oxygen saturation in the internal jugular vein at which loss of consciousness occurred during nitrogen breathing and postural hypotension.6 It has been reported in animals that when tissue or capillary venous pOz fell below threshold during induced anoxia the extracellular sodium ions of the brain decreased and there was an increase of extracellular potassium. This ionic change was said to correlate with electroencephalographic slowing.5,7rs Such data support the notion that anoxic symptoms and signs are due to failure of the mechanism for active sodium transport in brain, which is apparently dependent on cerebral energy metabolism. The present study reports for the first time in man similar observations concerning the threshold for cerebral venous oxygen tension

Stroke Prevention by Cilostazol in Patients with Atherothrombosis: Meta-analysis of Placebo-controlled Randomized Trials

BACKGROUND Cilostazol is an antiplatelet agent that inhibits phosphodiesterase III in platelets and vascular endothelium. Previous randomized controlled trials of cilostazol for prevention of cerebrovascular events have garnered mixed results. We performed a systematic review and meta-analysis of the randomized clinical trials in patients with atherothrombotic diseases to determine the effects of cilostazol on cerebrovascular, cardiac, and all vascular events, and on all major hemorrhagic events. METHODS Relevant trials were identified by searching MEDLINE, EMBASE, and the Cochrane Controlled Trial Registry for titles and abstracts. Data from 12 randomized controlled trials, involving 5674 patients, were analyzed for end points of cerebrovascular, cardiac, and major bleeding events. Searching, determination of eligibility, data extraction, and meta-analyses were conducted by multiple independent investigators. RESULTS Data were available in 3782, 1187, and 705 patients with peripheral arterial disease, cerebrovascular disease, and coronary stenting, respectively. Incidence of total vascular events was significantly lower in the cilostazol group compared with the placebo group (relative risk [RR], 0.86; 95% confidence interval [CI], 0.74-0.99; P=.038). This was particularly influenced by a significant decrease of incidence of cerebrovascular events in the cilostazol group (RR, 0.58; 95% CI, 0.43-0.78; P < .001). There was no significant intergroup difference in incidence of cardiac events (RR, 0.99; 95% CI, 0.83-1.17; P=.908) and serious bleeding complications (RR, 1.00; 95% CI, 0.66-1.51; P=.996). CONCLUSIONS This first meta-analysis of cilostazol in patients with atherothrombosis demonstrated a significant risk reduction for cerebrovascular events, with no associated increase of bleeding risk.

Enhanced erythrocyte aggregability in occlusive cerebrovascular disease.

We measured the rate of erythrocyte aggregation using our whole-blood aggregometer in 80 patients with occlusive cerebrovascular disease during the acute and chronic phases. We compared the data with values for 38 age-matched healthy controls. Mean +/- SD erythrocyte aggregability of the patients during both the acute phase (0.145 +/- 0.21/sec, n = 35) and the chronic phase (0.139 +/- 0.21/sec, n = 45) was higher than that in the controls (0.123 +/- 0.21/sec, n = 38; p less than 0.01). Erythrocyte aggregability was positively correlated with the plasma concentration of globulin and fibrinogen and inversely correlated with the albumin:globulin ratio. However, these correlations did not necessarily exclude the possibility that some unknown substance(s) released from ischemic tissue might enhance erythrocyte aggregability.

Low perfusion hyperemia following middle cerebral arterial occlusion in cats of different age groups.

Thirty-one cats were divided by age into 3 groups, young (Y), middle (M) and old (O). Continuous recordings of local cerebral blood volume (CBV) and frequent measurements of mean transit time of blood (I) were made from the Sylvian opercula after ischemia was produced by transorbital clipping of the middle cerebral artery at its origin (MCA occlusion). Control recordings were made simultaneously from the corresponding area of the contralateral cerebral hemisphere. MCA occlusion temporarily stopped cerebral blood flow (CBF) in the area supplied by the ipsilateral MCA, as indicated by a rapidly decreasing CBV and complete disappearance of hemodilution curves. Within 30 sec, CBF resumed with a dilatation of the vascular bed and reappearance of hemodilution curves through newly developed collateral channels. Despite a low CBF, below half the control, CBV recovered, overshooting the control level. The appearance of hyperemia In the iscbemic area was statistically significant. Such “low perfusion hyperemia” was slower in appearance and of more diverse magnitude in group O than in group Y. This suggested that aging may lead to a decrease in rapidity of the vascular response to ischemia and impair the in-tegrity of collateral vessels.