A. Lowenthal

European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.

In 1988, we undertook a randomized, placebo-controlled, double-blind trial to investigate the safety and efficacy of low-dose acetylsalicylic acid (ASA), modified-release dipyridamole, and the two agents in combination for secondary prevention of ischemic stroke. Patients with prior stroke or transient ischemic attack (TIA) were randomized to treatment with ASA alone (50 mg daily), modified-release dipyridamole alone (400 mg daily), the two agents in a combined formulation, or placebo. Primary endpoints were stroke, death, and stroke or death together. TIA and other vascular events were secondary endpoints. Patients were followed on treatment for two years. Data from 6,602 patients were analysed. Factorial analysis demonstrated a highly significant effect for ASA and for dipyridamole in reducing the risk of stroke (p < or = 0.001) and stroke or death combined (p < 0.01). In pairwise comparisons, stroke risk in comparison to placebo was reduced by 18% with ASA alone (p = 0.013); 16% with dipyridamole alone (p = 0.039); and 37% with combination therapy (p < 0.001). Risk of stroke or death was reduced by 13% with ASA alone (p = 0.016); 15% with dipyridamole alone (p = 0.015); and 24% with the combination (p < 0.001). The treatment had no statistically significant effect on the death rate alone. Factorial analysis also demonstrated a highly significant effect of ASA (p < 0.001) and dipyridamole (p < 0.01) for preventing TIA. The risk reduction for the combination was 36% (p < 0.001) in comparison with placebo. Headache was the most common adverse event, occurring more frequently in dipyridamole-treated patients. All-site bleeding and gastrointestinal bleeding were significantly more common in patients who received ASA in comparison to placebo or dipyridamole. We conclude that (1) ASA 25 mg twice daily and dipyridamole, in a modified-release form, at a dose of 200 mg twice daily have each been shown to be equally effective for the secondary prevention of ischemic stroke and TIA; (2) when co-prescribed the protective effects are additive, the combination being significantly more effective than either agent prescribed singly; (3) low-dose ASA does not eliminate the propensity for induced bleeding.

Guanidino compounds in serum and cerebrospinal fluid of non-dialyzed patients with renal insufficiency

Twelve guanidino compounds were determined in simultaneously sampled serum and cerebrospinal fluid of eight non-dialyzed patients with renal insufficiency. Liquid cation exchange chromatography with a highly sensitive fluorescence detection method was used. In patients with serum urea levels about 10 times higher than in controls, the levels of guanidinosuccinic acid, creatinine, guanidine and methylguanidine, in serum as well as in cerebrospinal fluid, are at least 10 times higher than in control subjects. The levels of argininic acid and N-alpha-acetylarginine (in serum) and gamma-guanidinobutyric acid (in cerebrospinal fluid) are slightly increased (less than 10 X). The levels of the other guanidino compounds are close to normal values. A significant positive correlation exists between the guanidinosuccinic acid, creatinine and guanidine levels in serum and cerebrospinal fluid. The accumulation of several experimentally proven toxic guanidino compounds could contribute to the complex nervous system symptomatology and the hematological complications seen in renal insufficiency.

European stroke prevention study: effectiveness of antiplatelet therapy in diabetic patients in secondary prevention of stroke.

Background and Purpose The European Stroke Prevention Study was a multicenter trial comparing the effect of a combination of 75 mg dipyridamole and 330 mg acetylsalicylic acid three times a day with the effect of a placebo in the prevention of stroke or death in 1,861 patients after one or more episodes of recent transient ischemic attack or cerebral infarction. Methods The present study represents a secondary analysis of the efficacy of study medication in diabetic (n=216) and nondiabetic (n=1,645) patients. Results The risk of end point events was greater in diabetic than in nondiabetic subjects. Total end point reduction in individuals receiving the combination of dipyridamole and acetylsalicylic acid was 39% in nondiabetic subjects and 23% in diabetic subjects in the explanatory analysis, and the reduction in the risk of stroke was 48% and 32%, respectively. However, a statistically significant reduction of risk was obtained only in nondiabetic subjects. Conclusions The combination of dipyridamole and acetylsalicylic acid appeared to be more effective in nondiabetic subjects than in diabetic subjects in the prevention of death and stroke although the low number of diabetic patients may at least in part explain this result

Antiplatelet treatment does not reduce the severity of subsequent stroke

Objective: To assess the the effect of antiplatelet therapy on the severity of subsequent stroke in patients with stroke and TIA. Background: The Second European Stroke Prevention Study (ESPS2) recruited 6,602 patients in four treatment groups: placebo, 2 × 25 mg acetylsalicylic acid (ASA), 2 × 200 mg dipyridamole (DP), and the combination of 50 mg ASA and 400 mg DP per day. Seventy-six percent of the patients had had a stroke as the qualifying event, whereas 24% had a TIA. All patients were followed at 3-month intervals for 2 years. ESPS2 showed a benefit from antiplatelet treatment compared with placebo and an additional benefit using ASA and DP together compared with either of these antiplatelet agents alone. Methods: In the ESPS2, the study protocol included assessment of severity of end point stroke with the modified Rankin scale once the stroke had clinically stabilized, and no further impairment was observed. There were 824 new stroke events during follow-up. In 701 of them, the initial Rankin scale was known, and this was also evaluated after each nonfatal recurrent stroke. The difference in Rankin scale between treatment groups was analyzed after recurrent stroke, and the progress in Rankin scale between entry and recurrent stroke was quantified by calculating the number of patients with a change of one or more degrees in the scale. Results: There were no significant differences in these changes in Rankin scale between the treatment groups. The mean time to reach an end point of stroke was longest in patients who used ASA + DP (p = 0.057). However, there was no difference among the treatment groups in the time to death during follow-up. Conclusion: This study suggests that antiplatelet therapy does not influence the severity of recurrent stroke as evaluated with the Rankin scale. However, antiplatelet therapy seems to lengthen the time the patient remains free from a recurrent stroke.

Serum guanidino compound levels and the influence of a single hemodialysis in uremic patients undergoing maintenance hemodialysis.

Guanidino compounds are increased in uremia and are highly suspected to be uremic toxins. The serum levels of 11 guanidino compounds and the influence of a single hemodialysis were evaluated in 30 steady-state uremic patients undergoing maintenance hemodialysis. Guanidino compound levels were detected using liquid cation exchange chromatography with a highly sensitive fluorescence detection method. Highly standardized dialysis procedures were performed. Before hemodialysis, high levels were found for guanidinosuccinic acid, N-alpha-acetylarginine, argininic acid, creatinine, gamma-guanidinobutyric acid, guanidine and methylguanidine. Guanidinosuccinic acid reached levels associated with toxic effects in vitro. After hemodialysis, although lowered, guanidinosuccinic acid, creatinine, guanidine and methylguanidine were still markedly increased. No differences in the percent decrease, during a single hemodialysis, of the studied compounds were found using different membranes such as cellulose acetate, cuprophane and polyacrylonitrile membranes. Substantial differences, however, in the percent decrease of the different guanidino compounds were found, ranging from 25 +/- 13% for arginine to 74 +/- 7.5% for guanidinosuccinic acid. Data reported here show that guanidino compounds are raised in serum of uremic patients undergoing maintenance hemodialysis, before as well as after a single hemodialysis, while substantial differences in the percent decrease of the different guanidino compounds are found.

Increased GFAp levels in CSF as a marker of organicity in patients with Alzheimer's disease and other types of irreversible chronic organic brain syndrome

SummaryGlial fibrillary acidic protein (GFAp), an astrocyte-specific protein, was determined in cerebrospinal fluid (CSF) of adults and children with global cognitive dysfunction. In children CSF-GFAp values were not closely associated with organic brain disease. However, GFAp values in CSF were increased in 65 of 121 samples of adults with dementia, independent of its cause. GFAp values were not correlated with the severity of the dementia. Increaed levels in the CSF are believed to indicate reactive gliosis in most patients with dementia, whereas GFAp levels in encephalitic patients normalize after clinical recovery.

Glial cells identified by anti-alpha-albumin (anti-GFA) in human pineal gland

Abstract: α‐Albumin, a CNS specific protein, identical to GFA protein and specific for glial cells, has been found in the human pineal gland using histoimmunological and quantitative methods. The significance of its presence in the pineal gland is discussed.

The European Stroke Prevention Study: results according to sex.

The European Stroke Prevention Study was a multicenter trial comparing the effect of a combination of 75 mg dipyridamole and 330 mg acetylsalicylic acid tid with placebo in the prevention of stroke or death after one or more attacks of recent transient ischemic attack or stroke of atherothrombotic origin. From the 2,500 patients in the intention-to-treat analysis, the proportion of women was 42%, and from the 1,861 patients in the explanatory analysis it was 44%. The endpoint incidence was significantly higher in men than in women. The endpoint reduction was statistically significant in men in both types of analyses with total endpoints (stroke or death) and in the risk of stroke, while in women it was statistically significant only in the intention-to-treat analysis with total endpoints. However, there was a marked percentage reduction of endpoints in both men and women in explanatory analysis. The risk reduction of strokes was 49% for men and 41% for women, and the reduction of total endpoints was 39% in men and 30% in women. Thus, antiplatelet therapy is effective in the prevention of stroke or death in both sexes.

Comparative Study of Guanidino Compounds in Serum and Brain of Mouse, Rat, Rabbit, and Man

Abstract: The levels of 12 guanidino compounds were determined in the serum and brain of mouse, rat, rabbit, and man using cation‐exchange column chromatography with the fluorescence ninhydrin detection method. A comparative study of these compounds was made in the four groups studied, for serum and brain. In rabbit and man the different guanidino compounds were also determined in various brain regions. This study provides basic analytical data that could facilitate the interpretation of further biochemical and neurochemical studies dealing with guanidino compounds that are identified as being toxins in hyperargininemia and uremia.

Second European Stroke Prevention Study: antiplatelet therapy is effective regardless of age

Background ‐ The Second European Stroke Prevention Study (ESPS2) was a randomized, placebo‐controlled trial that investigated the efficacy of low‐dose acetylsalicylic acid (ASA) and modified‐release dipyridamole (DP), alone or in combination, in the secondary prevention of ischemic stroke. The trial demonstrated that the combination was significantly more effective than either agent used alone. The aim of the present study was to evaluate the influence of age on the efficacy of ASA and DP, alone or in combination, in the secondary prevention of stroke in the ESPS2 population. Methods and results ‐ A total of 6602 patients were recruited to the ESPS2 and there were 4 treatment groups: ASA (25 mg twice daily), DP (200 mg twice daily), ASA and DP in a combined formulation, or placebo. Primary endpoints were stroke, death, and stroke or death together. The endpoints evaluated in the present study were stroke, stroke and/or death, and vascular events. Stroke was the qualifying event in 76% of the patients, while 24% had a transient ischaemic attack. Patients were reviewed at 3‐month intervals for 2 years. The study population consisted of 2565 (39%) patients aged less than 65 years, 2240 (34%) patients aged between 65 and 74 years, and 1797 (27%) patients aged 75 years and over. Advancing age was associated with an increased incidence of endpoints in all 4 treatment groups. The combination of ASA and DP significantly reduced the incidence of all endpoints, compared with placebo, in each age group. There was no influence of age on the efficacy of antiplatelet therapy for any of the evaluated endpoints. Relative risk reductions of treatment compared with placebo were 11.1–27.6% in the ASA group, 8.0–18.7% in the DP group, and 20.3–45.2% in patients receiving combination therapy. Conclusion ‐ This study clearly demonstrates that combination therapy with DP and ASA is superior to either agent used alone in the secondary prevention of ischemic stroke, irrespective of the age of the patient.