STROKE (THROMBOTIC)

Hakim AA; Ross GW; Curb JD; Rodriguez BL; Burchfiel CM; Sharp DS; Yano K; Abbott RD
Division of Biostatistics and Epidemiology, University of Virginia School of Medicine, Charlottesville 22908, USA.
J Clin Epidemiol (England) Jun 1998, 51 (6) p487-94

OBJECTIVE: To examine the association between coffee consumption and the development of stroke in men at high risk for cardiovascular disease.

METHODS: Coffee intake was observed from 1965 to 1968 in a cohort of men enrolled in the Honolulu Heart Program with follow-up for incident stroke over a 25-year period. Subjects were 499 hypertensive men (having systolic or diastolic blood pressures at or above 140 and 90 mm Hg, respectively) in older middle-age (55 to 68 years) when follow-up began. Past and current cigarette smokers were excluded from follow-up.

RESULTS: In the course of follow-up, 76 men developed a stroke. After age-adjustment, risk of thromboembolic stroke increased significantly with increases in coffee consumption (P = 0.002). No relationships were observed with hemorrhagic stroke. When adjusted for other factors, the risk of thromboembolic stroke was more than doubled for men who consumed three cups of coffee per day as compared to nondrinkers of coffee (RR = 2.1; 95% CI = 1.2-3.7).

CONCLUSIONS: Although in need of further confirmation, consumption of coffee appears to be positively associated with an increased risk of thromboembolic stroke in hypertensive men in older middle-age. Findings suggest that it may be prudent to advise older middle-aged men with hypertension who consume large amounts of coffee to consider reducing their coffee intake.

Belch J; McLaren M; Hanslip J; Hill A; Davidson D
University Department of Medicine, Ninewells Hospital & Medical School, Dundee, Scotland.
Int Angiol (Italy) Jun 1998, 17 (2) p120-4

OBJECTIVES: Thrombotic stroke is a common disorder with considerable mortality and morbidity. Risk factors for stroke include cigarette smoking, hypertension and hyperlipidaemia and these have been linked to abnormalities of haemorrheology and coagulation such as increased fibrinogen. Other haemorrheological abnormalities have also been documented. These include an elevation in the white blood cell (WBC) count. The aim of our study was to evaluate plasma fibrinogen, WBC aggregation and the release of free radicals in thrombotic stroke.

EXPERIMENTAL DESIGN: Thirty-four patients with thrombotic stroke were enrolled in the study. The data were compared to 58 matched controls.

SETTING: This study was carried out in Ninewells Hospital, Dundee on patients previously admitted to the medical wards with acute stroke.

MEASURES: Plasma fibrinogen, WBC aggregation and plasma malondialdehyde (MDA) were measured in this study.

RESULTS: As expected, the stroke patients have a significantly higher fibrinogen level (4.3+/-1.2 g/dl versus 3.1+/-0.6, p<0.001). WBC aggregation is also increased in the patient group (47.5+/-10.4% versus 42.7+/-10.6, p=0.036), as is plasma MDA (8.6+/-2.0 micromol/l versus 7.1+/-1.07, p<0.001). The factor VIII von Willebrand factor antigen measured as a marker as vascular damage was also significantly higher in the patient group (251+/-87% versus 182+/-64, p<0.001). There was also a statistically significant correlation between fibrinogen level and WBC aggregation, and fibrinogen and MDA. These are both statistically significant p=0.012 and p<0.001 respectively.

CONCLUSIONS: We believe our study suggests that enhanced WBC aggregation/adhesion with release of free radicals may be another mechanism whereby fibrinogen exerts its known detrimental effect in stroke development. This may allow planning of therapeutic strategies as yet undeveloped.

Kumari KT; Augustine J; Leelamma S; Kurup PA; Ravikumar A; Sajeesh K; Eapen S; Nair AR; Vijayalekshmi N; Karthikeyan S; et al
Department of Biochemistry, University of Kerala.
Indian J Med Res (India) Mar 1995, 101 p115-9

Elevated levels of serum glycosaminoglycans (GAG), associated with hypomagnesemia were observed in patients of proven CAD and thrombotic stroke in Kerala. Serum lipid profile was normal in the majority of these patients, indicating that elevated serum GAG may be an even more reliable indicator of atherosclerosis than elevated serum total cholesterol or LDL cholesterol. Autopsy samples of carotid artery and aorta which had atheroma showed significantly higher GAG when compared to samples which showed no atheroma. Serum Mg levels were significantly lower in CAD and thrombotic stroke patients as compared to controls. Mg deficiency may be one of the factors involved in the increased level of GAG.

Shieh SM; Shen MM; Tsai WJ; Shiuan LR; Wang DJ
Proc Natl Sci Counc Repub China [B] (Taiwan) Oct 1985, 9 (4) p298-304

The main purpose of this report is to demonstrate the presence of subfractions in serum HDL and to explore their role in the pathogenesis of thrombotic stroke Preparative untracentrifugation was used to isolate the differing density fractions of serum lipoproteins, and 2-27% polyacrylamide gradient gel electrophoresis was used to identify the character of the HDL subfractions. The study was performed on 59 Chinese males, in whom 31 were patients with thrombotic stroke affecting the cerebral cortex diagnosed by neurological examination and computed tomography; and the others grouped as healthy control. The age and Broca index of both groups were similar. The serum levels of total cholesterol and LDL-cholesterol were normal. However, in the thrombotic stroke group HDL-cholesterol was significantly lower and correlated inversely with both significantly higher levels of VLDL-cholesterol (r=-0.5392, p less than 0.01) and VLDL-triglyceride (r=-0.5866, p less than 0.01). The serum levels of total triglycerides and LDL-triglyceride were also significantly higher in patient with thrombotic stroke. The mean area percentage of HDL2b subfraction measured in the diameter range as determined by gradient gel electrophoresis was significantly lower and HDL2 also showed the same tendency in patients with thrombotic stroke. Our finding was consistent with the postulation that HDL2 or HDL2b in in particular, probably played a more protective role than any other HDL subfractions against thrombotic stroke, one of the major atherosclerotic complications.

Enderby P, Broeckx J, Hospers W, Schildermans F, Deberdt W
Speech and Language Therapy Research Unit, Frenchay Hospital, Bristol, England.
Clin Neuropharmacol 1994 Aug;17(4):320-31

The nootropic agent piracetam has been shown to improve learning and memory, and it may, by this means, facilitate recovery and rehabilitation after a stroke. We report the results of a pilot study exploring its effects in patients undergoing rehabilitation after acute cerebral infarction in the carotid artery territory. We compared piracetam and placebo, each given for 12 weeks, in a multicenter, double-blind, randomized trial of parallel-group design; testing was performed at baseline (6-9 weeks poststroke), weeks 5 and 12, and, in fewer patients, 12 weeks after termination of treatment. Standardized tests of activities of daily living (Barthel Index, Kuriansky Test), aphasia (Aachen Aphasia Test), and perception (Rivermead Perception Assessment Battery) were the primary efficacy variables. Of 158 patients, 137 (81 males, 56 females) were studied after treatment and 88 at 24-week follow-up. Thirty patients on piracetam (45%) and 37 on placebo (53%) were aphasic on entry. Both groups, including the subgroups with aphasia, were well matched at baseline for demographic data, stroke sequelae, type and severity of aphasia, and prognostic parameters. Multivariate analysis of Aachen Aphasia subtest scores showed a significant overall improvement relative to baseline in favor of piracetam (p = 0.02) at 12 weeks. This was not seen at 24 weeks when, however, fewer patients were available for evaluation so that we could neither confirm nor deny whether improvement was maintained after cessation of piracetam. We were unable to demonstrate an effect on tests of activities of daily living and could neither confirm nor exclude an effect on perceptual deficit. We have shown an improvement in aphasia in patients undergoing rehabilitation after a stroke after 12 weeks' treatment with piracetam that requires confirmation in further studies.

Huber W
Department of Neurology and School of Logopedics, Rheinisch-Westfalische Hochschule (RWTH), Aachen, Germany.
Pharmacopsychiatry 1999 Mar;32 Suppl 1:38-43

Piracetam has been shown to improve speech in aphasic patients. This paper reviews the evidence for this benefit in aphasic patients with acute stroke and, in conjunction with language treatment, in post-acute and chronic aphasia. Early double-blind, placebo-controlled trials in acute stroke showed improvement in several neurologic parameters including aphasia. Subsequently two randomized double-blind placebo-controlled studies were performed which utilised the Aachen Aphasia Test (AAT), a validated and standardized procedure, to assess language function. Patients received placebo or piracetam 4.8g daily for 12 weeks in one study and for 6 weeks in the other. In both studies patients received concomitant intensive speech therapy; one included patients 6-9 weeks after stroke while in the other the duration of aphasia varied between 4 weeks and 3 years. Compared with placebo there was improvement in both studies on piracetam in all 5 subtests of the AAT and significant overall improvement in aphasia. This indicated that, given in conjunction with language therapy, piracetam improved speech in patients with post-acute and chronic aphasia. In the Piracetam in Acute Stroke Study (PASS), of 927 patients treated within 12 hours of the onset of acute ischemic stroke, 373 were aphasic. Treatment consisted of placebo or an intravenous bolus of 12g piracetam, 12g piracetam daily for 4 weeks and 4.8 g daily for a further 8 weeks. After 12 weeks significantly more patients (approximately 10%, P=0.04) had recovered from aphasia on piracetam than placebo while in 197 patients treated within 7 hours of stroke onset, the difference in favor of piracetam was 16% (P= 0.02). These studies indicate that piracetam improves aphasia in acute stroke and, as an adjuvant to language therapy, in post-acute and chronic aphasia.

De Reuck J, Van Vleymen B
Department of Neurology, University Hospital, Ghent, Belgium.
Pharmacopsychiatry 1999 Mar;32 Suppl 1:33-7

Recent post-marketing surveillance reports have confirmed the benign safety profile and lack of organ toxicity shown by piracetam during its 25 years of clinical usage. Tolerance has proved equally good with the more recent use of larger doses (up to 24 g/day) for the long-term control of cortical myoclonus and when given intravenously to patients with acute stroke. This paper provides a brief review of these findings and records the safety of piracetam as found in the Piracetam in Acute Stroke Study (PASS), a randomized multicenter placebo-controlled study in 927 patients with acute ischemic stroke. Patients receive one intravenous bolus injection of placebo or 12 g piracetam, piracetam 12 g daily for 4 weeks and maintenance treatment for 8 weeks. The major results have been reported (De Deyn et al., Stroke 28 [1997] 2347-2352). Safety was assessed taking into account adverse events including abnormal laboratory test results and mortality. Death within 12 weeks occurred more frequently in the piracetam group but the difference from placebo was not significant. Of many potential risk, prognostic and treatment-related factors examined by logistic regression, 6 contributed significantly to death of which the most important were initial severity of stroke and age. Neither treatment nor any treatment-related factor contributed significantly to death. Adverse events were similar in frequency, type and severity in piracetam and placebo groups. Events of cerebral, non-cerebral and uncertain origin likewise occurred with similar frequency. Few patients discontinued because of adverse events. There was no difference between treatments in the frequency of events associated with bleeding, including hemorrhagic transformation of infarction. An important finding was that, of 31 patients with primary hemorrhagic stroke enrolled, 3 piracetam-treated patients died compared with 6 on placebo. The results suggest that piracetam in high dosage may be given to patients with acute stroke without significant adverse effects.

Hickenbottom SL, Grotta J
Department of Neurology, University of Texas at Houston Medical School, 77030, USA.
Semin Neurol 1998;18(4):485-92

The concept of neuroprotection relies on the principle that delayed neuronal injury occurs after ischemia. The phenomenon of the "ischemic cascade" has been described, and each step along this cascade provides a target for therapeutic intervention. In animal models of global and focal cerebral ischemia, numerous preclinical studies have demonstrated various agents to be neuroprotective at different steps along this cascade. A wide variety of drugs has also been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They include calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilizad, anti-intercellular adhesion molecule-1 (ICAM-1) antibody, GM-1 ganglioside, clomethiazole, the sodium channel antagonist fosphenytoin, and piracetam. In the future, clinicians may have an armamentarium of treatments for acute ischemic stroke at their disposal, with a combination of agents directed at different sites in the ischemic cascade being the ultimate goal.

De Deyn PP, Orgogozo JM, De Reuck J
Lancet 1998 Jul 25;352(9124):326

No abstract.

Tomczykiewicz K, Domzal T
Kliniki Neurologicznej Centralnego Szpitala Klinicznego Wojskowej Akademii Medycznej, Warszawie.
Neurol Neurochir Pol 1997 Nov-Dec;31(6):1101-9
Comment on Lancet 1998 May 16;351(9114):1447-8

The increase of interest in piracetam in the treatment of stroke has been noticed lately. The reason of that is the unique double-action of this drug which depends on: 1. its effect on vascular system, and 2. improving of the metabolic process in a nerve cell. The purpose of our work was the evaluation of the therapeutic action of piracetam in comparison with other drugs, which are applied in treating stroke. 171 patients were examined, and piracetam was given to 40 of them. The effects of the treatment were evaluated after 14 days of using piracetam in dose of 12.0 g i.v. The authors estimate, that this drug is efficient in ischaemic stroke. However, its definite superiority over other drugs has not been firmly stated.

De Deyn PP, Reuck JD, Deberdt W, Vlietinck R, Orgogozo JM
Department of Neurology, Middelheim Hospital, Antwerp, Belgium.
Stroke 1997 Dec;28(12):2347-52

BACKGROUND AND PURPOSE: Piracetam, a nootropic agent with neuroprotective properties, has been reported in pilot studies to increase compromised regional cerebral blood flow in patients with acute stroke and, given soon after onset, to improve clinical outcome. We performed a multicenter, randomized, double-blind trial to test whether piracetam conferred benefit when given within 12 hours of the onset of acute ischemic stroke to a large group of patients.

METHODS: Patients received placebo or 12 g piracetam as an initial intravenous bolus, 12 g daily for 4 weeks and 4.8 g daily for 8 weeks. The primary end point was neurologic outcome after 4 weeks as assessed by the Orgogozo scale. Functional status at 12 weeks as measured by the Barthel Index was the major secondary outcome. CT scan was performed within 24 hours of the onset of stroke but not necessarily before treatment. Analyses based on the intention to treat were performed in all randomized patients (n = 927) and in an "early treatment" population specified in the protocol as treatment within 6 hours of the onset of stroke but subsequently redefined as less than 7 hours after onset (n = 452).

RESULTS: In the total population, outcome was similar with both treatments (the mean Orgogozo scale after 4 weeks: piracetam 57.7, placebo 57.6; the mean Barthel Index after 12 weeks: piracetam 55.8, placebo 53.1). Mortality at 12 weeks was 23.9% (111/464) in the piracetam group and 19.2% (89/463) in the placebo group (relative risk 1.24, 95% confidence interval, 0.97 to 1.59; P = .15). Deaths were fewer in the piracetam group in those patients in the intention-to-treat population admitted with primary hemorrhagic stroke. Post hoc analyses in the early treatment subgroup showed differences favoring piracetam relative to placebo in mean Orgogozo scale scores after 4 weeks (piracetam 60.4, placebo 54.9; P = .07) and Barthel Index scores at 12 weeks (piracetam 58.6, placebo 49.4; P = .02). Additional analyses within this subgroup, confined to 360 patients with moderate and severe stroke (initial Orgogozo scale score < 55), showed significant improvement on piracetam in both outcomes (P < .02).

CONCLUSIONS: Piracetam did not influence outcome when given within 12 hours of the onset of acute ischemic stroke. Post hoc analyses suggest that piracetam may confer benefit when given within 7 hours of onset, particularly in patients with stroke of moderate and severe degree. A randomized, placebo-controlled, multicenter study, the Piracetam Acute Stroke Study II (PASS II) will soon begin.

[Article in German]
Stoppe G, Sandholzer H, Staedt J, Kiefer J, Winter S, Kochen MM, Ruther E
Psychiatrische Klinik und Poliklinik, Universitat Gottingen.
Dtsch Med Wochenschr 1995 Nov 24;120(47):1614-9

AIM OF INVESTIGATION: To discover (1) to what extent patients' wishes and the extent of any abnormality of brain performance influence the frequency with which "nootropic" drugs (those thought to affect brain activity, e.g. piracetam, pyritinol, or improve cerebral circulation, e.g. xanthine derivatives, Ginkgo biloba, secale alkaloids, calcium antagonists) are prescribed; (2) the medical practitioner's expectations of the effectiveness of such medications.

METHOD: In a personal interview, 145 family doctors and 14 neurologists in private practice in the Gottingen area of Germany (participation rate: 83.2% of those asked to participate) were questioned about fictitious cases (case 1: mild memory problem with or without expressed wish for medication; case 2: moderate dementia, of Alzheimer or multi-infarct type). The previously arranged interviews, which took place in the doctors' practice rooms, consisted of standardized open questions to the written case reports.

RESULTS: Regardless of the wish of the patient and the extent and type of the abnormal brain function about 70% of all participating doctors would prescribe those drugs, even though about 56% had doubts about their effectiveness. About 28% expected a positive effect on brain performance. A nearly equal proportion of doctors would continue an existing drug regimen as would prescribe one.

CONCLUSION: The prescription of the named group of drugs is influenced less by medical criteria than by factors which concern doctor-patient relationship.

Alberts MJ
Stroke Acute Care Unit, Duke University Medical Center, Durham, NC 27710, USA.
Neurology 1998 Sep;51(3 Suppl 3):S53-5

The approval of tissue plasminogen activator (tPA) for treatment of patients with ischemic stroke in the United States marked the first therapy proven to reverse or limit the effects of an acute stroke. Despite this approval and the lack of an alternative therapy, the use of tPA in stroke has been quite low. Several explanations for this underutilization have been identified, including lack of patient awareness, potential complications, infrastructure deficiencies, and physician concerns. This article explores these issues and suggests strategies for improving the use of tPA as an acute therapy in stroke.

ESPS Investigators.
European Stroke Prevention Study. Forbes CD University of Dundee Medical School, Scotland, United Kingdom.
Thromb Res 1998 Sep 15;92(1 Suppl 1):S1-6

Patients who had survived a stroke or transient ischaemic attacks (TIA) were admitted to a trial of low-dose aspirin (50 mg) alone, sustained release dipyridamole (400 mg/day) alone, or a combination of the two agents, and results compared with a placebo over 24 months. This low-dose aspirin regimen produced in pairwise comparisons a significant risk reduction of 18% for stroke, 13% for stroke and/or death but no reduction in all cause mortality. The sustained release dipyridamole produced a significant risk reduction of 16% for stroke, 15% for stroke and/or death but no significant reduction of mortality. In combination, aspirin and dipyridamole produced a risk reduction of 37% in stroke, 24% in stroke and/or death, and no reduction in mortality. Similar findings were found in TIA, which was a secondary endpoint. These results are highly significant in comparison with placebo. As expected, there were enhanced reports of alimentary side-effects in the aspirin groups and also enhanced bleeding. Dipyridamole was associated with a slight increase in headache, which resolved in most patients if therapy was continued. The conclusions are that 50 mg/day of aspirin alone or 400 mg/day of sustained release dipyridamole alone are equally effective in stroke and TIA prevention. When used in combination the effects were additive and were significantly more effective than the single agents.

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