Volume 2, Number 2: February 1999

Antiplatelet therapy for acute ischaemic stroke

Does Dietary Fiber Really Protect against Colorectal Cancer?

Effect of the Novel Antiplatelet Agent Cilostazol on Plasma Lipoproteins in Patients With Intermittent Claudication

Effects of a single local administration of cilostazol on neointimal formation in balloon-injured rat carotid artery

 Antiplatelet therapy for acute ischaemic stroke

Reference:http://som.flinders.edu.au/fusa/cochrane/cochrane/revabstr/ab000029.htm

Objectives: To determine whether antiplatelet therapy is safe and effective in the acute stages of definite or presumed ischaemic stroke.

Search strategy: Cochrane Stroke Review Group search strategy plus searching of the trials' register of the Antiplatelet Trialists' Collaboration and contacting pharmaceutical companies.

Selection criteria: All completed and unconfounded, truly randomised controlled trials comparing antiplatelet therapy started within 14 days of the stroke with control in patients with definite or presumed ischaemic stroke.

Data collection and analysis: The following outcomes were assessed: death or dependency at the end of follow up; death during follow-up and during the treatment period; vascular deaths during follow-up; deep venous thrombosis; pulmonary embolism; recurrent stroke; intracranial haemorrhage; major extracranial haemorrhage; myocardial infarction.

Main results: Five trials including 501 patients with a maximum of six months follow-up were included in this review. One trial
contributed 309 patients. The numbers of outcome events were too small to provide reliable evidence on the benefits or risks of antiplatelet therapy with respect to any of the outcomes measured. There were promising reductions in the risks of death or dependency at the end of follow up (OR 0.75, 95% CI 0.47-1.20) and death alone (OR 0.63, 95% CI 0.40-1.00) but these results were very dependent on the single largest trial and were based on few outcome events.

Conclusions: There were too few patients and outcome events in the five small trials included in the current version of this
review to draw any reliable conclusions. However, two large trials (IST and CAST), which together included more than 40,000
patients, have recently been reported and have provided reliable evidence that aspirin, started within 48 hours of onset of
presumed ischaemic stroke, is beneficial; for every 1000 patients treated, 9 avoided death or non-fatal stroke in the acute phase, and in the long term, about 13 avoided death or dependency (and an additional 10 per 1000 made a complete recovery from their stroke). The next version of this review will include the data from these two trials.

Citation: Counsell C, Sandercock P. Antiplatelet therapy for acute ischaemic stroke (Cochrane Review). In: The Cochrane
Library, Issue 1, 1999. Oxford: Update Software.

Does Dietary Fiber Really Protect against Colorectal Cancer?

Reference: N Engl J Med 1999;340:169 -176

Summary: Colorectal carcinoma is common in the Western world, but rare in Africa. This observation has led to the hypothesis that a high-fiber diet is protective against colorectal carcinoma. In addition, there are a number of intuitively sensible explanations for how this effect might be mediated. A number of case-control studies have shown a reduced risk of colonic carcinoma with increasing fiber consumption, as has a meta- analysis. However, most studies looking at this issue have been retrospective (with the risk of recall bias) and have not been designed to distinguish between the effects of the fiber itself and those of other constituents of plant foods. Five prospective studies have shown weak or nonexistent inverse associations between the risk of colon cancer and dietary fiber intake, and three placebo controlled randomized trials found no significant reduction in incidence of colorectal tumors in subjects who received fiber supplements. The present study is a large prospective analysis of the incidence of colorectal carcinoma and adenoma in a cohort of women who kept detailed dietary records.

The study used a cohort of 121,700 female registered nurses who were between 30 and 55 years of age at recruitment in 1976. They were followed up by questionnaire every 2 years. In 1980, 1984 and 1986 dietary questions were included in the questionnaire to assess subjects' fiber intake. The responses to the dietary questions in the questionnaire were validated by comparing the responses with detailed food diaries in a subgroup of 173 women. Women with incompletely filled in questionnaires, a history of cancer at baseline, ulcerative colitis, Crohn's disease or familial polyposis were excluded from the analysis leaving a total of 88,757 women who were followed up between 1980 and 1996. The population was divided into quintiles based on their reported fiber intake. Subjects were asked to report new cases of colorectal carcinoma on each questionnaire. Cases occurring in people who had died were identified from the National Death Index. Cases of adenoma were analyzed for a subgroup of 27,530 women who were eligible for screening and reported having colonoscopy or sigmoidoscopy during the study period.

The intake of dietary fiber between top and bottom quintiles differed by a factor of 2.5. Women who consumed more fiber were older, less likely to have smoked cigarettes, more likely to exercise regularly, to have a family history of colon cancer and to undergo screening endoscopy. 787 cases of colorectal carcinoma were identified. There was no significant relation between the incidence of colorectal carcinoma and dietary fiber intake. This remained true if the intake of fiber was analyzed as a continuous variable rather than in quintiles. Subgroup analysis based on the source of the fiber also failed to show any appreciable reduction in risk. There was, however, a small significant increase in risk associated with greater consumption of vegetable fiber (RR 1.35; 95% CI: 1.05 to 1.72; P for trend = 0.004). In addition there was no evidence of an inverse association between amount of fiber in the diet and colorectal cancer in any population subgroup defined by age, family history of colorectal cancer, aspirin use, physical activity, body mass index, cigarette smoking total intake of fat, intake of alcohol, red meat, methionine, calcium and vitamin D. The only association found was for women in the lowest third of the group with respect to folate consumption with respect to fruit fiber only (RR 0.59; 95% CI: 0.35 to 0.99; P for trend = 0.06) which is most likely due simply to chance.

The analysis for adenoma also showed no relation between fiber intake and the risk of developing colonic adenomas, although these results are not reported in detail in the paper. This study shows no reduction in risk of colorectal cancer and adenoma with increasing fiber consumption. Indeed increased consumption of vegetable fiber seemed to increase the risk.

Studies such as this are difficult to conduct. It is possible that the food questionnaires did not reflect true exposure to fiber (although a good attempt at validating the questionnaire was made). The study would not show an effect of fiber in early life or an influence of the consumption of more than 30 to 35g of fiber a day (this is three times the daily fiber average consumption in the USA). There are possible confounding variables too, such as the fact that women who consumed more fiber were more likely to have a family history of colorectal cancer and therefore may be at higher baseline risk than others. This study also only looked at women and it is possible that the findings would have been different for men. Nonetheless, the study was large and conducted over 16 years and so provides an important addition to the building evidence about the association (or lack of it) between dietary fiber intake and colorectal cancer.

 Effect of the Novel Antiplatelet Agent Cilostazol on Plasma Lipoproteins in Patients With Intermittent Claudication

Reference:Arteriosclerosis, Thrombosis, and Vascular Biology. 1998;18:1942-1947

Abstract—Cilostazol is an antiplatelet agent and vasodilator marketed in Japan for treatment of ischemic symptoms of
peripheral vascular disease. It is currently being evaluated in the United States for treatment of symptomatic intermittent
claudication (IC). Cilostazol has been shown to improve walking distance in patients with IC. In addition to its reported
vasodilator and antiplatelet effects, cilostazol has been proposed to have beneficial effects on plasma lipoproteins. We
examined the effect of cilostazol versus placebo on plasma lipoproteins in 189 patients with IC. After 12 weeks of therapy with 100 mg cilostazol BID, plasma triglycerides decreased 15% (P<0.001). Cilostazol also increased plasma high density
lipoprotein cholesterol (HDL-C) (10%) and apolipoprotein (apo) A1 (5.7%) significantly (P<0.001 and P<0.01, respectively). Both HDL3 and HDL2 subfractions were increased by cilostazol; however, the greatest percentage increase was observed in HDL2. Individuals with baseline hypertriglyceridemia (>140 mg/dL) experienced the greatest changes in both HDL-C and triglycerides with cilostazol treatment. In that subset of patients, HDL-C was increased 12.2% and triglycerides were decreased 23%. With cilostazol, there was a trend (3%) toward decreased apoB as well as increased apoA1, resulting in a significant (9.8%, P<0.002) increase in the apoA1 to apoB ratio. Low density lipoprotein cholesterol and lipoprotein(a) concentrations were unaffected. Cilostazol treatment resulted in a 35% increase in treadmill walking time (P=0.0015) and a 9.03% increase in ankle-brachial index (P<0.001). These results indicate that in addition to improving the symptoms of IC, cilostazol also favorably modifies plasma lipoproteins in patients with peripheral arterial disease. The mechanism of this effect is currently unknown.

This study demonstrates that, in addition to its vasodilator and antiplatelet properties, the phosphodiesterase inhibitor
cilostazol also favorably modifies plasma lipoproteins. Specifically, plasma levels of HDL-C and apoA1 are significantly
increased and plasma triglycerides are decreased. Both the triglyceride-lowering and HDL-raising effects of cilostazol are
more pronounced in individuals with baseline hypertriglyceridemia. The only previous report of the lipid-modifying effect of
cilostazol is a study of a limited number of diabetic subjects in the Japanese literature.4 This prior study reported effects of
cilostazol on plasma lipoproteins, which were comparable to those reported here.

Current treatment guidelines recommend aggressive cholesterol lowering and risk-factor modification in individuals with known coronary heart disease and other symptomatic vascular disease, including PAD.9 Individuals with PAD are at high risk of death and disability from coronary and cerebrovascular disease, in addition to the morbidity associated with PAD itself. The risk of fatal cardiovascular events in subjects with PAD is increased from 2- to 15-fold, depending on the severity of the underlying PAD.10 11 12 Therefore, patients with IC have great potential to benefit from lipoprotein modification, not only to alter the clinical course of PAD itself, but also to modify coexisting atherosclerotic vascular disease. The ability of cilostazol to favorably modify plasma triglycerides and HDL-C is particularly significant for patients with IC, in that both hypertriglyceridemia and low HDL-C are observed with increased frequency in such patients.13 14 15 16 17 Reduced plasma triglycerides may be desirable in this patient population, as elevated plasma triglyceride levels are associated with increased risk of cardiovascular disease independent of HDL-C.18 19

The exact mechanisms involved in the ability of cilostazol to lower plasma triglycerides and increase HDL are at present unknown. The lipoprotein effects of cilostazol that we have observed appear to be independent of changes in physical activity or glucose tolerance and are unaffected by concomitant ?-antagonist therapy. It is likely that the lipoprotein effects of cilostazol are a result of its ability to inhibit cyclic nucleotide phosphodiesterase and thereby elevate intracellular cAMP. Cyclic nucleotide phosphodiesterases regulate intracellular levels of cAMP (and cGMP) by catalyzing their degradation.20 There are several possible mechanisms by which increased cAMP might result in lowered plasma triglycerides. One possible mechanism is by reducing hepatic triglyceride (ie, VLDL) secretion, either directly, or indirectly by potentiating the effect of glucagon to inhibit VLDL secretion.21 On the other hand, increased cAMP levels have been shown to promote release of lipoprotein lipase from rat adipocytes,22 which could reduce plasma triglycerides. Although plasma lipoprotein lipase was not measured as part of the present study, increased plasma lipoprotein lipase has been observed in streptozotocin diabetic rats treated with cilostazol (Otsuka America Pharmaceutical, unpublished data, 1994).

In the present study, the time course of the effect of cilostazol on HDL-C differed from that of its effect on triglycerides. In addition, the change in HDL-C was not correlated with the decrease in triglycerides during cilostazol treatment. This suggests that different mechanisms may be responsible for the effect of cilostazol on triglycerides and HDL. In this regard, there are no published studies of the effect of cAMP on expression of apoA1 by the liver or gut. On the other hand, the previous observation that increased cAMP levels enhance HDL3-mediated sterol efflux from cholesterol-loaded human skin fibroblasts23 indicates 1 possible mechanism for increased HDL-C after phosphodiesterase inhibitor treatment.

The observed beneficial lipoprotein-modifying effect of cilostazol, in addition to its previously reported antiplatelet properties, offers the possibility that long-term therapy with this agent will not only alleviate the symptoms of IC but may also favorably alter the clinical course of atherosclerotic peripheral vascular disease. This remains to be determined and will require long-term study of the effects of cilostazol.

Effects of a single local administration of cilostazol on neointimal formation in balloon-injured rat carotid artery.

Reference:Atherosclerosis 1999 Jan;142(1):41-6


To elucidate if locally administered cilostazol, an inhibitor of cyclic AMP phosphodiesterase III, suppresses neointimal
formation in balloon-injured carotid artery of the rat, 20 mg of cilostazol was topically applied using pluronic gel at the time of
balloon injury. Rats were sacrificed 14 days after balloon injury to measure the extent of neointimal formation. Plasma and
tissue concentrations of cilostazol were also measured at 1, 3, 7 and 14 days after topical application. The 5-bromo-2'-deoxyuridine (BrdU, a thymidine analogue) was given intraperitoneally to detect proliferation of smooth muscle
cells in the injured media at 3 days after balloon injury. At 1 day after injury, plasma and tissue concentrations were
0.147+/-0.043 microg/ml and 1380 microg/g tissue. Although the plasma concentration of cilostazol was undetectable ( <
0.02 microg/ml), a significant amount of cilostazol (46 microg/g tissue) was still detected in the tissue at the site of application even after 2 weeks. The intimal area of the injured carotid after 2 weeks was significantly smaller in the cilostazol-treated group than in the gel-treated control group (0.06+/-0.01 vs 0.15+/-0.02 mm2, P<0.001). BrdU-positive smooth muscle cells in the injured media after 3 days were also significantly fewer in the cilostazol-treated group than in the gel-treated control group (4.3+/-0.5 vs 9.1+/-0.9% of total cells, P < 0.001). These results suggest that local administration of cilostazol using pluronic gel maintains a high concentration of the drug at the application site, has an anti-proliferative effect on smooth muscle cells, and may have potential for clinical therapeutic use for the prevention of restenosis following arterial
intervention.

In clinical studies, systemic administration of cilostazol prevented restenosis after balloon angioplasty and events following coronary stent implantation.Local drug delivery in pluronic gel may be useful for surgical bypass grafting, since pluronic gel can be easily administered during the operation and the delayed development of stenosis of the graft is also due to intimal hyperplasia. Other local administration of cyclic AMP and PDE inhibitors (aminophylline and amrinone) to rats markedly inhibited neointima formation after balloon injury in vivo and in smooth muscle cells in vitro. In conclusion, a single local administration of cilostazol suppressed both medial SMC proliferation and neointimal formation in balloon-injured rat carotid artery. Although the plasma concentration of cilostazol was very low, the tissue concentration remained at a high level even at 2 weeks after application. Local administration of cilostazol might be useful in preventing restenosis by suppressing neointimal formation at the site of anastomosis of bypass grafts with no systemic adverse effects.