STROKE:TAKE TWO ASPIRIN?

Few disorders are as devastating and frightening for an individual as stroke. Often without warning, life can be torn apart by the sudden loss of basic physical or mental skills. Equally, no disorder is more confounding to medical science since stro

Stroke is the third most common cause of death in the West and the most important cause of adult disability (Lancet, 1992; 339:342-4). Among those over 65 it is the second most common cause of death after heart disease.

Stroke is a non specific, collective term for symptoms, such as paralysis, perceptual loss, speech difficulties and visual problems, which are the result of trauma to the brain tissue. Trauma can be caused either by loss of blood supply (infarction), and thus death of the surrounding tissue caused by blockage or occlusion (closure) of a vessel. It can also be caused by cerebral hemorrhage.

In the West, 85 per cent of strokes result from cerebral infarction after arterial occlusion (Lancet, 1992; 339:533-6). Cere bral infarction can be the result of atherosclerosis (narrowing of the arteries) or occlusion caused by cerebral thrombosis (blood clot in the brain). Often the two are present together since the formation of blood clots in the brain can be the result of platelets forming in response to the damaged lining of the blood vessels. Cerebral embolism, where a clot which has formed in another part of the body usually the heart or the deep veins in the legs travels up into the brain, has the same effect.

High blood pressure (hypertension) can cause hemorrhage usually through aneurysm (a local “ballooning” of an artery causing it to burst). The extreme force of blood leaking from an artery damages the delicate brain tissue as well as compressing and impairing the function of adjacent tissues. A similar effect can be produced by water retention (edema) around the brain. The degree of disability after a stroke depends largely on the duration and the site of the trauma.

Over the years research has taken a circular route of proving and disproving the same old theories. As a result, many commentaries come to the same conclusion, namely that in spite of vast amounts of money which have been poured into the study of stroke and related vascular disorders, there is still very little known about this devastating disorder (BMJ, 1995; 311:139-40). Much of the research concerns itself with finding the single most effective prophylaxis (preventative) for primary or secondary strokes, the most popular options being anti coagulants, anti platelets, anti hypertensives, diuretics and surgery. Too often treatment ends up being a combination of any or all of these things.

It is also important to note that “effective” in stroke research generally means “cost effective” and that prevention usually has the aim of reducing the cost of patients requiring hospital admission and treatment for stroke, rather than improving the quality of life for victims of stroke (JAMA, 1995; 274:1839-45).

The “magic bullet” philosophy upon which modern medicine is built does not benefit stroke patients. Perhaps the best example of this can be seen in the wholesale administration of aspirin (an anti platelet) as a treatment for and prophylactic measure against stroke. Aspirin thins the blood as well as having an anti hypertensive effect, so for many physicians it has long seemed a logical way of preventing stroke in patients with constricted blood vessels, those who have suffered heart attacks or those who have experienced transient ischaemic attacks (or TIAs, minor strokes of short duration). The fact that it was cheap, readily available and familiar to patients was also in its favour. Evidence for the use of aspirin in the treatment of stroke has been accumulating for years but was perceived as having been given the definitive thumbs up by the Antiplatelet Trialists’ Collaboration (ATC) in a series of articles in 1994 (BMJ, 1994; 308:81-106; BMJ, 1994; 308: 159-68; BMJ, 1994; 308:235-46). These findings echoed many of the group’s findings six years before (BMJ, 1988; 296:320-31). Although, on closer inspection the group’s findings were more circumspect than many were willing to acknowledge at the time, aspirin quickly became hailed as the conquering hero of stroke treatment and has since been prescribed widely (almost recklessly), throughout the world regardless of patient’s individual “risk” factors.

But the side effects of aspirin in the high doses in which it is prescribed for stroke treatment are debilitating and sometimes fatal. Aspirin is usually prescribed in doses ranging from 75-325mg daily. Although this is lower than the megadoses of between 1-4g daily not uncommon 15 years ago, it is not without risk.

Dyspepsia (stomach upset, nausea and vomiting) and gastrointestinal hemorrhage can occur in 10-20 per cent of cases (Lancet, May 31, 1980). Even in low doses it can increase the risk of cerebral hemorrhage. This increase is not statistically great in high risk patients, but in the low risk group the increase may be as high as 21 per cent (Drugs and Therapeutics Bulletin, Jan 20, 1994).

There is continuous debate over the optimum duration of aspirin therapy (BMJ, 1994; 308:71-3). Certainly long term use can cause serious side effects. Aspirin may slow blood clotting, but it can also deplete the body of certain essential vitamins and minerals, especially iron. Not surprisingly, one of the effects of long term aspirin therapy is anemia, a condition which can complicate hemorrhagic disorders. Others include ulcers (particularly in elderly persons), liver damage and allergic reactions such as hives, wheezing, tinnitus, chronic catarrh, headache, confusion and, more rarely, hypotension followed by collapse. Asthmatics can die from severe attacks brought on by aspirin consumption. In combination with thrombolytics such as warfarin or heparin it may augment either the risks or the benefits of those agents, depending on which research one chooses to believe.

In addition, recent commentary on the ATC findings suggests that the researchers got it all wrong. Less than a year after the anti platelet research was published, a small review appeared in the BMJ questioning earlier findings (BMJ, 1994; 308:1213-5). Researchers Alexander Cohen, et al, from the Thrombosis Research Institute took a closer look at the Collaboration’s figures for the third arm of the trial, which looked at the efficacy of aspirin in reducing venous thrombosis and pulmonary embolism in patients after surgery. They found that not only was some of the ATC arithmetic substantially lacking, but that they had applied their “meta analysis” (the comparison of like research to produce an informed overview) to trials which were not comparable.

The ATC study had also chosen to “skirt” the issue of substantial side effects such as internal bleeding, because in many of the trials analyzed these side effects were not recorded. But as Cohen and colleagues comment, “This information is not optional data for completeness but is absolutely essential to determine risk-benefit ratios, which must always be clearly defined before any general recommendations are made.” These problems served to highlight several important issues, including the poor quality of research hitherto published in medical journals regarding stroke, its treatment and prevention, and the superficial, eager beaver way in which practitioners latch on to any research, however inadequate, presented in an authoritative manner.

Not surprisingly, in the same issue the authors of the ATC study defended their position, saying in effect that their data was not intended to recommend aspirin as a wholesale measure; that “treatment recommendations depend on a variety of considerations, of which trial results are only one part”; that it was up to individual physicians to familiarize themselves with all available data and the variety of treatments in current use; and to plead that the best they could do was to rely on whatever research has been produced to date (BMJ, 1995; 309:1215-7).

To some extent they were justified. Aspirin cannot claim to prevent primary strokes and has never been proven effective as a prophylaxis in low risk patients with no history of cardiovascular disorders (N E J Med, 1992; 327:175-81; BMJ, 1988; 296:313-6). Even as secondary prevention, for which there is some evidence, there is disagreement about the optimum dose (Lancet, 1991; 338:1345-9). One trial comparing treatment with aspirin, warfarin, or no treatment at all was revealing. In patients with a low risk of stroke there was no significant difference in life expectancy between the three groups. In high risk patients, life expectancy over the following 10 year period was 6.27 years for the aspirin group, 6.51 for warfarin users and 6.01 for those receiving no treatment at all a statistically significant difference but close enough to provide food for thought (JAMA, 1995; 274:1839-45).

With hindsight, the BMJ’s response in the editorial which prefaced the ATC reports was telling: “aspirin seems as effective as any other single agent or combination of agents [our emphasis].” (BMJ, 1994; 308:71-3). In the end, that’s not saying much since most other single agents or combination of agents produce devastating side effects particularly in low to medium risk patients (see box p2).

Since the ATC trial, the Cochran Database of Systematic Reviews has published on disc the first set of overviews from the Cochrane Stroke Review Group. Among these, four trials of anti platelet agents showed no significant advantage in rates for death, deep vein thrombosis or intracerebral hemorrhage when compared to other methods of treatment (Stroke Module, Cochrane database of systematic reviews, Updated 9 March 1995).

!APat Thomas