Dipyridamole plus aspirin versus aspirin alone in secondary prevention after TIA or stroke: a meta-analysis by risk.

OBJECTIVES: To study the effect of combination therapy with aspirin and dipyridamole (A+D) over aspirin alone (ASA) in secondary prevention after transient ischaemic attack (TIA) or minor stroke of presumed arterial origin and to perform subgroup analyses to identify patients that might benefit most from secondary prevention with A+D. DATA SOURCES: The previously published meta-analysis of individual patient data was updated with data from ESPRIT (n = 2,739); trials without data on the comparison of A+D versus ASA were excluded. REVIEW METHODS: A meta-analysis was performed using Cox regression, including several subgroup analyses and following baseline risk stratification. RESULTS: A total of 7612 patients (five trials) were included in the analyses, 3800 allocated to A+D and 3812 to ASA alone. The trial-adjusted hazard ratio (HR) for the composite event of vascular death, non-fatal myocardial infarction and non-fatal stroke was 0.82 (95% confidence interval (CI) 0.72 to 0.92). HRs did not differ in subgroup analyses based on age, sex, qualifying event, hypertension, diabetes, previous stroke, ischaemic heart disease, aspirin dose, type of vessel disease and dipyridamole formulation, nor across baseline risk strata as assessed with two different risk scores. A+D were also more effective than ASA alone in preventing recurrent stroke; HR 0.78 (95% CI 0.68 to 0.90). CONCLUSION: The combination of aspirin and dipyridamole is more effective than aspirin alone in patients with TIA or ischaemic stroke of presumed arterial origin in the secondary prevention of stroke and other vascular events. This superiority was found in all subgroups and was independent of baseline risk.

Enhancement of cholesteryl ester metabolism in cultured human monocyte-derived macrophages by verapamil.

The effect of the Ca2+ entry blocker, verapamil, on the biosynthesis of cholesterol and the metabolism of low-density lipoprotein (LDL) was studied in cultured human monocyte-derived macrophages. Addition of verapamil (50 microM) of monocyte-derived macrophages enhanced 125I-LDL and 125I-labelled acetyl-LDL binding and internalization, and increased [2-14C]acetate incorporation into cholesterol. Since higher levels of LDL and modified lipoproteins may be implicated in atherogenesis, the more efficient processing of these lipoproteins by monocyte-derived macrophages in the presence of Ca2+ blocker warrants further assessment for its potential as an antiatherogenic agent.

Receptor-mediated uptake and 'retroendocytosis' of high-density lipoproteins by cholesterol-loaded human monocyte-derived macrophages: possible role in enhancing reverse cholesterol transport.

Human monocyte-derived macrophages (MDM) are cholesterol-loaded, and the rates of uptake, degradation and resecretion of high-density lipoproteins are measured and compared to the rates in control cells. Results show the binding activity of these lipoproteins is upregulated in cholesterol-loaded cells; the bound and internalized lipoproteins are not degraded to any appreciable extent but primarily resecreted as a larger particle. The enhancement of binding activity for high-density lipoproteins is arrested when cycloheximide is added to the medium, suggesting that protein synthesis is involved. Preliminary evidence also indicates that HDL3 (without apoE) after internalisation is converted intracellularly to a larger apoE-containing HDL2-like particles. Thus, MDM appears to possess specific receptors for HDL3 without apoE that may function to facilitate HDL-mediated removal of excess cholesterol from cells.

A critical appraisal of ticlopidine, a new antiplatelet agent. Effectiveness and clinical indications for prophylaxis of atherosclerotic events.

BACKGROUND: Recommendations are broadening for the prophylaxis of atherosclerotic disorders, but aspirin is the only widely used agent. Ticlopidine hydrochloride, a new antiplatelet medication, has recently been approved for prescription in North America. We reviewed the major clinical trials of ticlopidine and derived guidelines for its use. METHODS: Studies of ticlopidine were sought through MEDLINE for 1980 to 1990 and through bibliographies of retrieved articles. All published, randomized trials of ticlopidine were appraised if they reported major morbidity and mortality as primary end points. All eligible studies were formally reviewed by an expert panel according to published principles for critical appraisal of the medical literature. Both benefits and risks were quantified. RESULTS: Four randomized trials reported major clinical end points. In these, ticlopidine was more effective than placebo for preventing recurrences after completed stroke; was more effective than aspirin for patients with transient ischemic attacks and partial strokes; and reduced vascular death and nonfatal myocardial infarction in an open trial among patients with unstable angina. For patients with intermittent claudication ticlopidine, was not significantly better than placebo for preventing myocardial infarction or stroke. Side effects were more common with ticlopidine than with aspirin or placebo. CONCLUSIONS: Ticlopidine should be prescribed in place of aspirin for stroke prophylaxis or unstable angina if the patient is unable to tolerate aspirin. Ticlopidine may also benefit patients who experience new ischemic events while taking aspirin or, probably, patients with peripheral vascular disease. A complete blood cell count should be performed every 2 weeks during the first 3 months of therapy to check for leukopenia.

Herpes zoster ophthalmicus and delayed ipsilateral cerebral infarction.

We studied five patients who had acute cerebral infarctions 5 weeks to 6 months after herpes zoster ophthalmicus (HZO). All had infarcts of the cerebral hemisphere ipsilateral to the HZO, and one also had a cerebellar infarct. Cerebral arteriography in one patient disclosed narrowing of the middle cerebral artery, occlusion of the anterior cerebral artery ipsilateral to the HZO and narrowing of the opposite anterior cerebral artery. In another case, arteriography revealed occlusion of the distal internal carotid artery on the side of the HZO.

HMG-CoA reductase inhibitors (statins): a promising approach to stroke prevention.

Statins represent a promising class of agents to prevent stroke. In randomized trials of middle-aged patients with coronary artery disease, statins reduce the incidence of stroke. The reduction in stroke may not be solely related to cholesterol or low-density lipoprotein reduction but may involve nonsterol mechanisms effects on endothelial cells, macrophages, platelets, and smooth muscle cells. Statins also reduce the size of cerebral infarction in a murine stroke model, suggesting a neuroprotective effect. The best current evidence for stroke prevention is with pravastatin and simvastatin. Pravastatin reduces the risk of stroke in patients with coronary artery disease and average cholesterol levels; simvastatin reduces the risk of the combined endpoint of stroke and transient ischemic attack in hypercholesterolemic patients with coronary artery disease. Future studies of statins are needed in stroke populations, particularly the elderly.

Prostacyclin infusion in acute cerebral infarction.

We gave prostacyclin infusions to seven patients with acute cerebral infarction. Patients without CT evidence of infarction improved, but those who already had hypodensities on CT did not benefit. Increased platelet activity, measured by plasma beta-thromboglobulin, decreased significantly (p less than 0.01) during prostacyclin administration to normal levels, but rose again after the infusion. These results indicate that prostacyclin can be given safely in doses adequate to suppress platelet function. Our findings encouraged us to proceed with a controlled trial of its clinical efficacy.

Thromboxane, prostacyclin, and leukotrienes in cerebral ischemia.

Our understanding of the biochemistry and biologic actions of AA metabolites has been greatly expanded in recent years. The discoveries of TXA2, PGI2, and LTs have fostered new concepts of the pathophysiology of cerebral ischemia. New approaches to treatment of ischemia include seeking an optimal dose of aspirin, developing drugs that selectively inhibit or antagonize TXA2 or LTs, and administering PGI2 or its analogues. Altering the dietary content of essential fatty acids for prophylaxis is also being studied. Though the results of this thrust are still preliminary, the exploration of these therapeutic strategies in cerebrovascular disorders based on further understanding of the pathophysiologic roles of TXA2, PGI2, LTs and probably other AA metabolites is anticipated with some optimism.

Prediction of carotid stenosis progression by lipid and hematologic measurements.

We followed 19 men and 19 women with asymptomatic carotid stenosis up to 30 months to determine whether hematologic or lipid abnormalities could identify those individuals developing progressing carotid atherosclerosis (defined as an increase in mean percent stenosis greater than or equal to 19% or an increase in a single region of greater than or equal to 23%) on B-mode carotid ultrasonography performed at 2- to 6-month intervals. Our patients demonstrated increased beta-thromboglobulin, platelet factor 4, and fibrinogen compared with age-matched controls. Eight patients developed progression of carotid stenosis, and this group had higher baseline low-density lipoprotein (LDL) and fibrinogen than the 30 nonprogressing patients. Multiple regression analyses of age, sex, smoking, coronary artery disease, peripheral vascular disease, diabetes, hypertension, and baseline high-density lipoprotein (HDL), HDL2, HDL3, LDL, beta-thromboglobulin, platelet factor 4, and fibrinogen identified coronary artery disease and elevated LDL and fibrinogen as the only independent variables significantly associated with the progressing group. We conclude that, in patients with carotid atherosclerosis, a combination of coronary artery disease and elevated LDL and fibrinogen will predict with 88% accuracy whether the patient will have progressing carotid stenosis.

Cholesteryl ester hydrolase activity in mononuclear cells from patients with type II hypercholesterolemia.

Cholesteryl ester hydrolase (CEH) activity was measured in freshly isolated mononuclear cells from patients with primary Type II hypercholesterolemia, heterozygous familial hypercholesterolemia (FH) and familial combined hyperlipidemia (CFH). CEH activity was significantly lower in mononuclear cells from Type II patients than in cells from matched normolipidemic individuals. Moreover, the reduced CEH activity in cells from the hypercholesterolemic patients was accompanied by significant accumulation of cholesteryl ester. This pattern of reduced CEH activity and cholesteryl ester accumulation was identical for cells from both the FH and CFH patients. Since low density lipoprotein (LDL) cholesterol concentrations were higher in the Type II patients, we incubated mononuclear cells from normolipidemic individuals with high concentrations of LDL-cholesterol (greater than 150 mg/dl). Under these conditions CEH activity was significantly decreased, cholesteryl ester content increased, and cholesterol linoleate, in particular, accumulated. These data suggest that the intracellular accumulation of cholesteryl esters is determined in part by the extracellular concentrations of LDL-cholesterol and by the activity of CEH within the cells.

The community hospital-based stroke programs in North Carolina, Oregon and New York--V. Stroke diagnosis: factors influencing the diagnostic evaluation of patients following acute stroke.

Among the 4129 patients of the Community Hospital-based Stroke Program, 30% had an unspecified stroke diagnosis. Since specific diagnosis and, perhaps, eventual treatment, derives in part from diagnostic testing, we examined the effect of clinical condition, geographic and demographic factors on the incidence of certain diagnostic tests after acute stroke. In this multivariable analysis, race, sex, history of hypertension and history of diabetes did not influence the chance of having any test, but older age strongly reduced the chances of receiving extensive evaluation. When CT scanning was available, the utilization of a CT as well as other diagnostic studies including cerebral angiography, radionuclide brain scan, EEG and EKG was increased. The odds of receiving a CT scan increased if the patient was married, and decreased with a history of previous stroke. A history of previous TIA increased the chance of having a cerebral angiogram while a history of cardiac disease decreased the chance. There were striking regional geographic differences in the use of CT, radionuclide brain scanning and cerebral angiography which may, in part, reflect differences between the availability of these technologies in urban and rural hospitals. These results indicate that evaluation of stroke patients remains heterogenous.

Molecular biological studies in atherothrombotic brain infarction.

Strokes due to atherosclerosis are the most prominent neurological disease affecting adults, and efforts to reduce stroke occurrence, in addition to stroke-risk reduction, will require insights into molecular mechanisms. Our studies showing abnormal metabolism of low and high density lipoproteins (LDL and HDL) in vivo and of RFLP in apoprotein AI, the major protein of HDL, in stroke-prone subjects suggest that greater exploration of fundamental mechanisms of atherothrombotic brain infarction (ABI) should yield preventative strategies, the ultimate treatment for strokes.

Pharmacologic protection against ischemic brain damage.

Pharmacologic protection should be used cautiously. The author reviews its rationale, use, and recommendations in three clinical conditions associated with ischemic brain damage: stroke, cardiac arrest, and head trauma.

The effect of oral contraceptives on mononuclear cell cholesteryl ester hydrolase activity.

The influence of sex steroids on mononuclear cell cholesteryl ester hydrolase (CEH) activity in premenopausal women and women on combined estrogen-progestin oral contraceptives has been studied. In addition, plasma and mononuclear cell cholesterol and esters were measured along with plasma estrogen and progesterone levels. Mononuclear cell CEH activity in control women is highest on Day 20 of their menstrual cycle. The control women had significantly higher CEH activities than women on oral contraceptives. Plasma esters were higher in the oral contraceptive group. However, in mononuclear cells, free cholesterol but not cholesteryl esters were higher in women on oral contraceptives.

PIP: Premenopausal women, 1 control group (n=9) taking no medication or using no oral contraceptives (OCs) and 1 treated group (n=10) receiving OCs for contraception, were studied to determine any effects OCs have on mononuclear cell cholesteryl ester hydrolase (CEH) activity. 9 of the 10 medicated women were taking Ortho Novum 1/50 and the other person was receiving Norlestrin 1/50. Normally menstruating women (controls) showed a significant rise in CEH levels on Day 20 of the menstrual cycle (P .05). The enzyme activity in women on OCs was significantly lower than control women in 3 of 4 testing periods. In addition, plasma and mononuclear cell cholesterol and esters were measured along with plasma estrogen and progesterone levels. Although free cholesterol levels in normal cycling (control) women and in the OC group did not vary significantly during the menstrual cycle between the 2 groups, the women on OCs had significantly higher ester levels than the control women in 3 of the 4 test periods P .05-.005). When paired ratios of plasma cholesterol to esterified cholesterol were compared between control and OC groups, the ratio of free/esterified was significantly higher in the control group in 3 of 4 tests. In the mononuclear cells, on the other hand, the cholesterol/cholesteryl ester ratio was significantly lower in the control group during the 4 test periods. No association between levels of endogenous sex hormones (estradiol, progesterone) and CEH activity were found. CEH levels may be related to incidence of atherosclerosis, and women taking OCs may have increased chances of developing this disease.

Cholesteryl ester hydrolase activity in human symptomatic atherosclerosis.

Acid cholesteryl ester hydrolase (CEH) activity was assayed in mononuclear cells of patients with symptomatic atherosclerosis (transient ischemic attacks, TIA) and in age-matched controls showing no evidence of atherosclerosis. The acid CEH level of TIA patients was significantly lower than that of controls (1074 +/- 128 vs 2113 +/- 255 pmol/mg P/hr, mean +/- SE). Neither mononuclear cell nor plasma cholesterol and cholesteryl ester concentrations differed significantly between atherosclerotic and control groups. TIA women had lower mononuclear cell concentrations of free cholesterol than men.

Pilot study of nicardipine for acute ischemic stroke.

The author performed a pilot study of nicardipine (NC), a Ca(+)+ channel blocker, to study its dosing, toxicity, and possible efficacy for hemispheric cerebral infarction within 12 hours (mean 6.9 hr) of onset to determine the advisability of proceeding with a multi-centered controlled trial. NC was administered IV (3 to 7 mg/hr) X 72 hours by titrating dose to mean arterial blood pressure (MABP not less than 10% of baseline), then orally X 30 days. Forty-three patients have been entered; mean age 63 (range 34-89), 25 male and 18 female. Only 3 had CT evidence of infarct on entry. Results have shown improvement in a 100-point (pt) graded exam (40 pts at entry, 68 pts at 3 months). Of 20 patients completing 3 months' evaluation, 17 improved and none worsened. Sixteen out of 20 were at home and 8 had minimal or no impairment. Mean Barthel's index was 72. Mean maximal serum NC level was 75 ng/mL. MABP decreased from 103 (entry) to 83 (72 hours). A larger controlled study is warranted to determine the efficacy of NC for acute cerebral infarct.