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 stroke cannot be pinned down to one single, treatable cause. Instead, it is influenced by a number of different factors – organic and iatrogenic. As a result, stroke prevention often takes a rather haphazard course.
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). Cerebral 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).
Sidebar: Drugs that cause strokes
A number of classes of drugs can cause cerebral hemorrhage or infarction. These include:
- Sumatripan, the migraine drug (Intensive Care Med, 1995; 21: 82-3).
- Beta blockers (Revist Clinica Espan, 1993;192: 228-30).
- Nefedipine (causing cortical blindness) (BMJ, 1992; 305: 693).
- Chemotherapy or hormones given during chemotherapy (Am J Clin Onc, 1992; 15:168-73).
- Contraceptive pill (Acta Neurol Belg, 1992;92: 45-7).
- Oral anticoagulant therapy (The Lancet, 1991; 338: 1158).
- Excessive use of nasal decongestants (J Neurol, Neurosurg & Psychiatry; 1989; 52: 541-3).
- Blood pressure lowering drugs (Med J Australia, 1987; 146: 412-4).
- Phenylpropanolamine, a drug available over the counter in weight loss, nasal congestants and cold preparations (Am J Emerg Med, 1987; 5: 163-4).
- Recreational drugs, like Ecstacy, cocaine and methamphetamines (European Neuro, 1995; 35: 193; South Med J, 1995; 88: 352-4; Europ Neuro, 1994; 34: 16-22).
- Anabolic steroids (Neuro, 1994; 44: 2405-6).
Stroke or thrombosis clot thinning medication can itself cause stroke. This includes:
- Streptokinase/subcutaneous heparin therapy, combination therapy, (Circulation,1995; 92 : 2811-8) and recombinant tissue type plasminogen activator (Circulation;1991; 83: 448-59).
- Anticoagulant medication (Arch of Neuro, 1985; 42: 1033-5).
- Stroke can also be brought on by:
- Ingesting hydrogen peroxide (Stroke; 1994;25: 1065-7).
- Lumbar myelography (Nervenarzt, 1994;65: 125-7).
- Heavy drinking in men (Stroke; 1996; 27:1033-9).
Sidebar: Death or disability?
It’s not just aspirin which has come under fire recently. Other standard treatments such as thrombolysis are also being questioned after trials revealed a higher death rate. When thrombolysis is used after cerebral infarction the likely result is another stroke this time caused by cerebral hemorrhage. Heparin and warfarin are both indicated in increased incidence of cerebral hemorrhage, but the most recent debate has been over the use of agents such as streptokinaise (SK) and recombinent tissue plasminogen activator (rtPA).
Three large SK trials have been terminated because of early high mortality due to intracerebral hemorrhage. One trial for rtPA also showed increased mortality. In none of these four trials was there any benefit for subsequent disability that could offset the excess early mortality (Lancet, 1996; 347:391). Thrombolysis is a high risk strategy in stroke, especially if administered “late” (three to six hours after the stroke). The National Institutes of Neurological Disorders and Stroke (NINDS) trial showed an even smaller “therapeutic window” (under three hours) for the administration of rtPA (N J Med, 1995; 333:1581-7).The MAST-I trial (Lancet, 1995; 346:1509-14) was abandoned when high death rates were revealed amongst those receiving these drugs. Mortality was increased from 24.3 per cent to 35.8 per cent in the first six months, though disability over the longer term decreased from
53.4 per cent to 41.8 per cent. Commentary on the trial asked, among other things, whether it was ethical to ask patients whether they would rather be dead or disabled. (Lancet, 1995; 347:391-3). The MAST-I results were not unique (Circulation, 1995; 92:2811-8; NE J Med, 1995; 335: 1581-7; NE J Med, 1996; 336:145-60).
Different thrombolitic drugs given in different ways may have different effects (JAMA, 1995; 274:1017-25) and it is the elderly (in other words, the majority of stroke patients) who are more likely to experience cerebral hemorrhage and have a higher mortality rate (Circulation, 1995; 92:2811-8).
Sidebar: Women and stroke
There is a perception among physicians and the public that stroke and heart disease are disorders affecting men, usually elderly men (NE J Med, 1991, 325:274-6). Although in middle age the death rate from coronary heart disease is five times higher for men than women, in old age the rates become similar when heart disease is the leading cause of death for women as well as men.
Women live longer than men and comprise 64 per cent of the population over the age of 75 (JAMA, 1992; 268:1417-22). Yet women and those over 65 are often excluded from research into heart disease and stroke. Several of the most well known research projects into cardiovascular disease have not included women (Women and Health Research, National Academy Press, 1994). Older people and women are often passed over by researchers because they complicate things: older people may have other health problems and may be taking other medicines which would interfere with the “purity” of a study’s findings; women have a different chemical make up from the male “gold standard”).Women, in particular are at risk of stroke from an increased number of medical causes. For instance, it has long been known that the contraceptive pill increases the likelihood of stroke. A low dose pill (50 micrograms of estrogen) can treble a woman’s risk of thromboembolism (BMJ, 1996; 312:83-8; Lancet, 1995; 346:1375-82; see also WDDTY, vol 4 no 7). HRT carries a similar risk. According to US research, women taking drugs for heart conditions run a greater risk of developing torsades de pointes a sudden quickening of the heart beat rate (JAMA, Dec 1, 1993). There may also be a gender bias in the way women are treated for heart disease (NE J Med, 1991; 325:129-35; NE J Med, 325:221-5). Women are less likely to be offered surgery and more likely to be offered drugs (thrombolytics, diuretics, anti platelets) for treatment of heart disease, and these have been shown to increase the likelihood of a fatal stroke (see box, p 2).
Sidebar: Everyday alternatives: what really works
Stroke prevention, like heart disease prevention, is largely a matter of common sense. Lifestyle changes may be unlikely to produce immediate benefits; one study, for instance, concluded that dietary changes take about four years to significantly reduce blood pressure (JAMA, May 22, 1996). However, they are also unlikely to produce harmful or fatal side effects and may provide those with low to moderate risk of stroke with a better quality of life for longer.
Change your diet:
A diet rich in fruit and vegetables can help protect against stroke. For every extra three servings (a serving is defined as half a cup) per day of fruit and vegetables you could reduce the risk of stroke by 22 per cent (JAMA, 1995; 273:1113-7). Vegetables provide the greatest protection, perhaps because of their high fibre content (known to lower blood pressure). Fruit and vegetables contain a number of beneficial elements including carotenoids and vitamin C as well as antinutrients such as tannins, phytic acid, flavonoids, phyto estrogens, all which have a cholesterol lowering effect (BMJ, 1996; 312:1479; BMJ, 1996; 312:478-81; JAMA, 1995; 274:1197).
The same substances can be found in things like red wine and tea, and moderate amounts of these may offer a protective effect. One Danish study of 6051 men and 7234 women aged 30-70 showed that those who have a moderate intake of red wine (three to five glasses a day) cut their risk of heart disease and stroke by half (BMJ, May 6, 1995). The flavonoids found in fruit, vegetables, wine and tea are potent antioxidants and have an anti platelet effect (Biochem Pharmacol, 1987; 36:317-22). Although platelet inhibiting factors in flavonoids have a more direct effect on ischaemic stroke it has also been shown to reduce the risk of hemorragic stroke (JAMA, 1995; 273:317-22). The Danish study showed that abstainers had the highest risk, but the use of alcohol as a preventative needs to be weighed carefully against other debilitating side effects such as depletion of minerals such as magnesium, liver damage and, in some cases, cancer (NE J Med, May 11, 1995).
Eating walnuts has also been shown to help reduce the risk of stroke (JAMA, 1995, 273:1563). Walnuts, along with soya bean or canola oil, provide a source of the essential fatty acid alpha lineolic acid. Research shows that for every 0.13 per cent increase in alpha lineolic acid in the blood, the risk of stroke dropped 37 per cent. The reasons why are not fully understood, but it is thought that it may reduce the formation of blood clots that contribute to stroke.
Exercise:
Researchers at Birmingham University’s department of geriatric medicine looked at 125 men and women aged between 35-74 who had suffered their first stroke, together with a comparable of healthy controls. They found that vigorous exercise between the ages of 15-25 gave the most protection and that this was irrespective of other “risk” factors such as social class, smoking and alcohol consumption, family history of stroke, hypertension or diet. Continued vigorous exercise later in life also helped reduce the risk (BMJ, July 24, 1993). American research agrees: analysis of data from the 11 year national health and nutrition examination study showed clear evidence of benefit. In men and women with a sedentary lifestyle the relative risk of stoke was almost double that of their active counterparts (Am J Epidemiology, 1996; 143:860-9.)
Increase antioxidants:
Stroke victims with a high level of vitamin A in the blood recover more quickly and are less likely to die than patients with lower levels (Lancet, 1992; 339:1562-5). In fact antioxidant vitamins such as A, C and E may help reduce the level of free radicals the toxic by products of metabolism. In elderly people in particular higher levels of vitamin C can act as a protective agent against stroke (BMJ, 1995; 310:1563-4).
Lose weight:
Obesity can lead to hypertension. Analysis of one 36 year follow up study suggests that one in four adults in the United States has hypertension and that 78 per cent of the hypertension in men and 65 per cent in women is directly related to obesity (NE J Med, 1996; 334:1571-6).
Eat garlic:
Garlic taken over a few months can reduce levels of cholesterol in the blood by 15 per cent and heart attack risk by 30 per cent. It also thins the blood, reducing the risk of thrombosis. Just half a clove of garlic will reduce the stickiness in the blood (Int J Clin Pharm Ther Tox, 1991; 29:151-5).
Sidebar: WDDTY verdict
Stroke is a bewildering experience for everyone. Much of the research into its prevention and treatment remains confused. Well it is generally thought that addressing the classical causes such as high blood pressure and raised cholesterol levels provides the most effective prevention, this account for only 50% of the total risk factors.
Those who have had major surgery, especially to the heart or lower limbs, have a greatly increased risk of developing thrombosis, which can eventually translate into stroke. Drugs which are currently administered to combat thrombosis cause greater morbidity and mortality is common especially in elderly patients. Often these patients, or their family members or asked, in the grip of acute stroke, to make the impossible choice between the risk of early death or the possibility of less disability in the longer term.
Physicians and researchers need to direct their attention away from concerns about what it might cost to hospitalise and treat patients, and look to the evidence about the cost, in human terms, of inappropriate treatments, which save only a handful of lives out of every thousand patients treated and leave many more with a substantially reduced quality of life. A more positive step would be sharpening of their clinical skills and a return to “whole person” medicine as the ultimate prevention.
- This article first appeared in the December 1996 (Volume 7 Number 6) edition of What Doctors Don’t Tell You.
