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The author: Professor Yasser Metwally

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ASPIRIN: DOSE AND INDICATIONS IN MODERN STROKE PREVENTION

” Aspirin is relatively safe and is used probably more than any other drug”, was written in 1968, 36 and that statement is as true now as it was then. But the closing sentence of that same paper, “nobody knows whether it decreases thrombosis or not” reminds us of how much research has been done in the intervening years.

Our current knowledge about the application of aspirin in stroke prevention has been guided by the evolving insights into the pharmacologic actions of aspirin on hemostasis, particularly on platelet function, and it is appropriate to consider these fundamental aspects first. Nevertheless, management of patients should be based on clinical studies. I shall separately review the clinical evidence about stroke prevention in patients with transient ischemic attacks (TIAs) or minor strokes, in patients with other kinds of atherosclerotic disease, and in the healthy population. The final sections are devoted to the question of side effects and to the “ideal” dose of aspirin in stroke prevention from the point of view of efficacy as well as side effects.

ASPIRIN AND PLATELETS

Salicylic acid has been used as an antipyretic agent for centuries, as an extract first from the bark of the white willow (Salix alba) and later from meadow sweet (Spiraea ulmaria). An acetylated form, which caused less irritation of the stomach than sodium salicylate, was developed as early as 1853 , 35 but was not marketed until the turn of the century (by Hoffmann, from the Bayer company, whose father was tortured by rheumatism). Only in the last two decades have we come to understand why acetylsalicylic acid, or aspirin, has not only fewer adverse effects but also more powerful anti-inflammatory properties than the deacetylated form. An important step was the discovery that aspirin blocks the synthesis of Prostaglandins in many tissues, 57 including blood platelets. 49 This also made clear why aspirin interferes with hemostasis. Blatrix noted in 1963 that aspirin increases bleeding time, 5 and in 1968 O’Brien described a specific inhibitory effect of aspirin on the aggregation response of blood platelets, even in doses as low as 150 mg, which were at that time considered subclinical. 36

• Pharmacologic Action

It is to some extent reassuring that scientific curiosity of pharmacologists alone, without the driving force of commercial interests, has given us so much new insight into the way the old drug aspirin affects the aggregation response of platelets. Pivotal contributions have come from the groups of FitzGerald, 41, Patrono, 38 and Weksler 59. Much of what follows in this section is the result of their work.

The target through which aspirin interferes with the synthesis of prostaglandins is the enzyme cyclo-oxygenase. 47 This enzyme is found not only in platelets but also in endothelial cells, mucosal cells of the intestinal tract, glomeruli of the kidney, smooth muscle cells, and other tissues. Its action is to convert the ubiquitous prostaglandin precursor arachidonic acid into cyclic endoperoxides. Aspirin selectively and permanently inhibits this enzyme by a 1:1 reaction at the molecular level, by which the acetyl group-which was added only to reduce the irritation of the stomach by salicylates is transferred to the hydroxyl group of a single serine residue at position 530 within the enzyme 48, 56. In platelets, the cyclic endoperoxides are normally converted into thromboxane A, (TXA,), an unstable compound that enhances platelet aggregation. Thus, blocking of cyclo-oxygenase by aspirin leads to a reduced production of TXA, and in this way to an impairment in the aggregation of blood platelets and, it is hoped, also to an impairment in the formation of thrombi in the arterial system.

It should not be assumed, however, that “aspirinated” platelets are at all incapable of sticking together. Despite the absence of TXA,, strong stimuli such as thrombin and collagen can still induce a full response of platelet aggregation. Apparently other biochemical pathways for the activation of platelets are still open. In addition, aspirin has been shown to affect platelet function in some other way, independent of the acetylation of cyclo-oxygenase. 19, 33 The salicylate moiety has been shown to have antithrombotic properties of its own but also to antagonize the effects of aspirin. 13 The biologic importance of the effects of aspirin other than on cyclo-oxygenase is unknown, let alone the clinical relevance.

• Low-dose Aspirin and Platelets

If it is assumed that the antithrombotic effects of aspirin are mediated by the inhibition of TXA,, at least 95% of all circulating platelets need to be acetylated, since even a fraction of 10% normal platelets is sufficient to produce a full aggregation response. 9, 45

A single tablet of aspirin, in any dose that exceeds 100 mg, virtually abolishes (98% inhibition) the production of TXA, in all circulating platelets. This degree of inhibition is reached in less than I hour and lasts as long as 2 days. 39 The time lag of 2 days suggests that cyclo-oxygenase is acetylated not only in platelets but also in megakaryocytes and that the entry of normal platelets into the circulation requires the resynthesis of the enzyme in megakaryocytes as well as the formation of the platelets themselves. 40 A single administration of an even smaller dose, from 12 mg upward, causes an incomplete inhibition of platelets (as measured from the concentration of TXB2 the stable metabolite of TXA, after whole blood clotting), the degree of which is proportional to the dose. 37, 40 The rapidity with which a fraction of platelets is acetylated (within 5 minutes) and also the absence of aspirin in the systemic circulation during that initial phase suggest that the first contact between aspirin and platelets takes place in the portal circulation. 13, 42

If low-dose aspirin is given daily, the cumulative effects of doses as low as 20 mg per day are sufficient for attaining complete inhibition of TXA, in all platelets. The reasons for the cumulative action are that the acetylation of cyclooxygenase is permanent and aspirinated platelets apparently have a normal life span. In other words, the minimum daily dose of aspirin (in terms of TXA2 suppression) is the dose needed to acetylate the fraction of new platelets formed each day (10% to 15% ). 40 The studies that have demonstrated complete suppression of TXA2 by daily doses of aspirin between 20 and 50 mg have included not only volunteers,18, 28,33,37,44,46 but also patients with TIAs, 58, or myocardial ischemia. 12, 59

A disadvantage of the use of low-dose aspirin is that it takes several days to reach a steady state of complete TXA, suppression. With doses between 20 and 40 mg, this interval ranges between 6 and 12 days, 40, which is unattractive for patients in whom immediate antithrombotic protection is indicated. From the preceding paragraphs it is clear, however, that with a loading dose of at least 100 mg of aspirin, a complete antiplatelet effect can be reached within 1 hour. 11, 39 This degree of inhibition can then be sustained by daily administration of doses between 20 and 40 mg. On the other hand, it should be kept in mind that much of the effects of these low maintenance doses takes place in the portal circulation. This implies that the megakaryocytes in the bone marrow are probably not acetylated and that omission of one daily minidose of aspirin may result in the appearance of a critical fraction of normal platelets in the blood-until the next dose is taken.

• The Aspirin Dilemma

The dosage of aspirin is not simply a game of “how low can you go” compared by some to the limbo dance that was popular in the 1960s. High doses of aspirin acetylate cyclo-oxygenase not only in platelets but also in many other tissues: cells in the gastric mucosa, kidney glomeruli, smooth muscle, and vascular endothelium. In contrast, low-dose aspirin affects mainly platelets and not the other sites where Prostaglandins are enzymatically produced from arachidonic acid. Two factors are responsible for the sparing of extraplatelet cyclo-oxygenase by low-dose aspirin: (1) the exposure of platelets to the intact drug in the portal blood rather than in the systemic circulation (presystemic acetylation of platelet cyclo-oxygenase) 13,24 and (2) the capacity of nucleated cells to resynthesize cyclo-oxygenase, even if some degree of suppression has occurred. This selective inhibition of cyclo-oxygenase in platelets but not in other tissues has the definite advantage of fewer side effects and the possible advantage of retaining the antithrombotic action of some Prostaglandins other than TXA2 .

The adverse effects of aspirin on the gastrointestinal tract are well known and can be broadly divided into hemorrhagic complications and less specific but sometimes no less serious symptoms of gastric discomfort. The interference with the production of prostacyclins in the mucosal lining affects the integrity of the gastrointestinal wall in a dose-dependent fashion. 38 Even with low-dose aspirin this contact obviously cannot be avoided, but it can be minimized by taking a soluble form of the drug with water on an empty stomach. 20 If enteric-coated aspirin is used instead of the regular form, the required minimum dosage for complete inhibition of TXA2 may increase because prolonged contact with the intestinal juice enhances hydrolysis of the drug. For a slow-release preparation the necessary dose was 50 me 46; for a granular form it was 80 mg. 27

The “aspirin dilemma” has been created by the finding that the prostaglandin derivative produced in endothelial cells, PGI, or prostacyclin, has a potent antiaggregant action as well as vasodilatory properties, 34 and that the synthesis of this beneficial prostacyclin is also suppressed by aspirin, at least by doses of 100 mg or more. That prostacyclin might act as a natural antiplatelet agent is perhaps supported by the finding that the urine of some patients with severe peripheral atherosclerosis and biochemical evidence of platelet activation also contains an increased amount of the major metabolite of prostacyclin in the urine, 2,3-dinor-6-keto-PGF-1-alpha. 17

For the reasons given above (presystemic acetylation of platelets and resynthesis of cyclo-oxygenase), the use of 20 to 40 mg of aspirin per day might theoretically offer a therapeutic window through which the dilemma could be escaped. Judged from the urine, there is indeed no decrease in the concentration of 6-keto-PGF-1-alpha after daily doses of 30 or 35 mg of aspirin. 11, 28, 37 With 50 mg as a daily dose, some diminution of this metabolite of renal prostacyclin was found in one study, 46 but not in another that used 60 mg in women at risk of pregnancy-induced hypertension. On the other hand. more direct methods of assessing the production of prostacyclin suggest that this is affected to some extent by the as little as 20 mg of aspirin per day. These methods consist in determining the concentration of PGI-M, a metabolite of extrarenal prostacyclin, or measuring prostacyclin itself in punch biopsies from the aorta and leg veins in patients who underwent coronary bypass surgery. 59 Fortunately, recovery of cyclo-oxygenase in endothelium may take place within 6 hours. 23

In conclusion, 20 mg of aspirin seems to be the minimal daily dose needed for complete inhibition of the aggregant factor TXA, in platelets, and even at this minimum there is probably some temporary interference with the action of the antiaggregant factor prostacyclin. Whether this ideal dose of aspirin is clinically relevant can be determined only by clinical trials.

ASPIRIN AND STROKE PREVENTION IN PATIENTS WITH TIA OR MINOR STROKE

• Diagnosis

Aspirin should be prescribed not as an excuse to stop thinking about a patient, but only if there is enough evidence (positive or negative) that the symptoms are the result of ischemia and that atherosclerosis is the most likely cause of this.

It is particularly when the symptoms are transient that diagnosis is most difficult. Many other disorders can resemble a TIA, the most common of which are migraine, syncope, hyperventilation, postural vertigo, hypoglycemia, and epilepsy. 15 The criteria that have been adopted to define true TIAs are worded in rather abstract terms, which may result in a disappointing interobserver reliability. 31 Structured checklists in plain language may help to improve this. 30

The arbitrary time limits of 24 hours and 6 weeks that have been devised to separate TIAS, reversible ischemic neurological deficits (RINDs), and minor strokes have little value in terms of management. What really counts is what the patient might lose in the future, and little help can be expected from criteria derived from astronomy rather than from biology. Most attacks that resolve within I day do so within 60 minutes, 32, but even with these short-lived deficits the CT scan may later show a relevant infarct; in one large series, the proportion of patients with an infarct on CT scanning that was appropriate to the symptoms gradually increased with the duration of the (longest) attack: 10% with symptoms for less than 30 minutes, 20% if recovery took between 5 and 24 hours, 40% if this took between 1 and 6 weeks, and 50% with deficits persisting beyond 6 weeks. 29 Further evidence comes from the Oxford Community Stroke Project, in which the prevalence of antecedent risk factors and the risk of subsequent stroke or death was similar in patients with TIAs or minor stroke. 14 In other words, the differences between TIAs, RINDs, and minor strokes are quantitative rather than qualitative.

• Clinical Trials with 300 to 1300 mg of Aspirin

Since late 1970s, a great many placebo-controlled trials with aspirin have been performed in patients with cerebrovascular disease. The pioneering study was done in Canada, with Dr. Barnett as principal investigator. 8 It involved almost 600 patients and showed that 1300 mg of aspirin per day reduced the incidence of stroke or death by 31%. It is remarkable not only because it was the first large study in the field but also because it exemplifies two important principles that have become well recognized in the meantime. The first is that the final analysis should include not only strokes but also deaths, at least vascular deaths. Two thirds of the deaths in patients with TIA or minor stroke are caused by ischemic heart disease, 1, 25 which makes some sense because atherosclerosis tends to be a generalized condition. It is more common now than it was then for neurologists to adopt the patient’s perspective-that what counts is not only not having a stroke but also being alive.

The second principle brought home to neurologists in the meantime is that individual trials can be misleading, however careful the work that has gone into them, and that subgroups of single trials can be even more misleading. It is in subgroup analyses, with limited numbers of events, that random variations are most likely to occur. Conventional significance tests are of limited use in this context; if they are performed often enough, some difference may emerge by chance alone, whereas with small numbers true differences may easily be missed . Even megatrials may contain particular subgroups with false-negative results, as has been shown by analysis according to astrological birth sign. 26 A well-known example of the vagaries of subgroups in the field of stroke prevention is the false notion that aspirin is not effective in women, which prevailed for some time after the Canadian trial. 8 In other cases positive differences emerge in single trials which cannot be reproduced in other studies. For instance, one might be led to believe that aspirin protects against nonvascular death if this idea had not been rejected from the outset by the investigators themselves. 55 Or one might think that the benefits of aspirin are enhanced by combining it with some other drug, particularly sulfinpyrazonel or dipyridamole. 16 Despite the limitations of individual trials, I shall review three other large studies before considering the collective evidence. 16,55,8,26

A study conducted in France in 604 patients showed that 1000 mg daily of aspirin significantly reduced the risk of stroke (point estimate 40%) in both sexes. 6 Myocardial infarction also occurred significantly less often in the treated group, but death was not reduced. Cotreatment with dipyridamole did not offer additional benefits. 6

The European Stroke Prevention Study, conducted in 16 centers in 6 countries, compared 1250 patients who took 1000 mg of aspirin plus 325 mg of dipyridamole per day after TIA or stroke, with a similar number of placebo- treated patients, and found a 33% reduction in the occurrence of stroke or death. 16

The first trial that tested a daily dose of aspirin substantially lower than the “conventional” quantity of at least 1 g was the UK-TIA trial, in which 2435 patients with TIA or minor stroke were randomized to treatment with 300 mg of aspirin, 1200 mg of aspirin, or placebo. 55 In the two groups allocated aspirin, the odds* of suffering death, major stroke, or myocardial infarction were significantly reduced (point estimate 18%), but the more relevant but less frequent composite event of vascular death or disabling stroke was reduced by only 7%, which was not significantly different from zero. There was no demonstrable difference between the two doses of aspirin with regard to any of the outcome events. 55

• Low-dose Aspirin

In the last year, two clinical trials have been completed in which doses of less than 100 mg of aspirin were tested in patients with TIA or minor stroke. The Dutch TIA trial randomized 3131 patients (one third after a TIA, two thirds with minor stroke) between 30 mg of aspirin (experimental dose) and 300 mg (reference dose). 52 In the group on 30 mg the risk for vascular death, stroke, or myocardial infarction was 228/1555 (14.7%), versus 240/1576 (15.2%) in the patients on 300 mg. 53 The risk ratio for these event rates is 0.96, the risk reduction 0.04 (-O.14;0.19). Expressed in terms of the hazard- ratio, which takes account of the time at which the events occurred, and adjusted for slight imbalances of randomization with respect to sex and age, the risk reduction was 9% (95% confidence interval -9% to 24%). The bleeding complications and other adverse effects are discussed below, together with those in the medium-dose and high-dose trials. 52,53

In the Swedish Aspirin Low-dose Trial (SALT), the effects of 75 mg of aspirin were compared with those of placebo in 1360 patients. The event rates (again for vascular death, stroke, or myocardial infarction) were 151/676 in the aspirin group and 184/684 in the placebo group. 50 The risk ratio for these numbers is 0.83, and the risk reduction 0.17 (95% confidence interval 0.00;0.30). Despite the range of this interval, the results of both the Dutch and Swedish trials are quite consistent with the idea that low, medium, and high doses of aspirin are equivalent with regard to stroke prevention. 50

ASPIRIN AND STROKE PREVENTION IN OTHER GROUPS OF PATIENTS

• lschemic Heart Disease

One of the striking findings in the overview of 29,000 patients by the Antiplatelet Trialists’ Collaboration was that antiplatelet agents (usually aspirin) averted similar proportions of occlusive vascular events in several different categories of patients. 2 The odds reduction for the composite end point vascular death, stroke or myocardial infarction was, as we saw, 22% (SD 5%) for trials in patients with cerebrovascular disease; it was of similar magnitude, i.e., 25% (SD 4%), in patients after myocardial infarction; and it was as large as 36% (SD 13%) in trials of unstable angina. On analysis of separate outcome events it was clear that the protective actions of aspirin crossed the traditional boundaries between specialties. Not only was nonfatal myocardial infarction reduced by 35% in patients with cerebrovascular disease, but also strokes were avoided in patients with myocardial infarction, and to an even greater extent: 42% (SD 11%). Until that time, most trials in patients with coronary disease used doses of aspirin around 1000 mg. 26

In the second cycle of the Antiplatelet Trialists’ Collaboration, involving more than 100,000 patients, the value of aspirin in preventing stroke in patients with ischemic heart disease or peripheral arterial disease has been further confirmed and has also been extended to medium doses of aspirin, 100 to 300 Mg. 3 Particularly important is the ISIS-2 trial, in which 160 mg of enteric-coated aspirin given to patients with suspected myocardial infarction reduced nonfatal stroke in hospital from 0.6% to 0.3%, in a total of 17,187 patients. 26,3

• Primary Prevention

Two primary prevention trials with aspirin have been performed so far, both in physicians. The British Doctors’ Trial randomized 5139 male physicians initially aged 50 to 78 years in an open design between 500 mg of aspirin daily and the advice to avoid aspirin. 43 After 6 years, there was no statistically significant difference between the two groups, either for the combined outcome event vascular death, stroke or myocardial infarction, or for any of these events alone. If anything, disabling strokes were somewhat more common among those allocated aspirin; there were only limited data available on which of the strokes were hemorrhagic and which thrombotic, but these showed no excess of any particular type of stroke with aspirin. 43

The US Physicians’ Health Study was a double-blind, placebo-controlled trial of 325 mg of aspirin taken every other day, conducted among 22,071 US male physicians initially aged 40 to 84 years, with an average follow-up of 5 years. 54 For the three combined vascular outcome events, there was a statistically significant (18%, SD 7%) reduction among those on aspirin. On analysis of the separate events, myocardial infarction (fatal or nonfatal) appeared to account for most of this effect (44% risk reduction), and this was the reason for early termination of the study. However, there was no difference for other deaths of cardiac origin, and a nonsignificantly increased risk of stroke (all types), particularly for the small subgroup of hemorrhagic strokes (23 versus 12).

An overview of these two trials of primary prevention showed a 32% (SD 8%) reduction in the odds of suffering a nonfatal myocardial infarct, and a 13% (SD 6%) reduction of the combined vascular events, but a nonsignificant increase for nonfatal stroke (18% SD 13%). 24 If these uneven benefits, in subjects who already are at low risk of vascular disease, are weighed against the small but definite chance of adverse effects (see below), it is not surprising that the prophylactic use of aspirin has not really caught on. 24

DOSE OF ASPIRIN AND SIDE EFFECTS

It was known before its second life as an antithrombotic agent that the incidence of hemorrhagic complications and gastrointestinal symptoms with aspirin was dose-dependent. It is difficult, however, to compare the incidence of these side effects between different studies because the criteria tend to be less precise and the auditing procedures less rigid than for the main outcome events. A comparison of bleeding complications or gastrointestinal symptoms between different groups within one study gives at least some idea of the relative frequency of side effects, as these have been recorded without knowledge of treatment allocation.

In placebo-controlled trials with 1000 to 1300 mg of aspirin, the incidence of side effects was two to three times greater than in patients on placebo. 6, 8, 16, 55 The most detailed report is from the UK-TIA study: gastrointestinal bleeding occurred in 1.6% of the patients on placebo, 2.6% on 300 mg of aspirin, and 4.7% on 1200 mg; approximately half of the patients in each group required admission to hospital. Indigestion, nausea, heartburn, vomiting, or constipation was reported by 24% of the patients on placebo, 29% of those on 300 mg of aspirin, and 39% of those on 1200 mg. 55

Thus, the gastrointestinal symptoms from 300 mg of aspirin per day seem to be rather modest, whereas there is a distinct increase in the small risk of a hemorrhage. This is borne out by the Physicians Health Study, with the alternate-day regimen (the doctors took beta-carotene on the other day, as a potential agent against cancer, and this part of the study still continues). Gastrointestinal discomfort was reported by one fourth of both the subjects on placebo and those who took 325 mg of aspirin every other day, and gastrointestinal symptoms by about one third in each group. Only ulcers were slightly more common in the aspirin group (risk ratio 1.22). With respect to bleeding, the risk ratio for minor bleeds was 1.32 (easy bruising, hematemesis, melena, unspecified gastrointestinal bleeding, epistaxis), and that for hemorrhages requiring transfusion was 1.71. 24

With low-dose aspirin, the incidence of hemorrhagic complications can be decreased even further. In the 30-mg group of the Dutch TIA trial, major bleeding complications (requiring hospitalization) were slightly less common than in the 300-mg group (hazard ratio 0.77; 95% confidence interval 0.51- 1.16), and significantly fewer minor bleeds occurred (relative risk 0.58, 95% confidence interval 0.41-0.83). Even gastric discomfort or unspecified side effects were reported less often with 30 mg than with 300 mg (15% versus 17%), although this difference was not significant on its own. 53

SUMMARY: THE IDEAL DOSE OF ASPIRIN

Several pieces of evidence can now be fitted together to fill at least some of the blanks in our knowledge about the optimal dose and indications for stroke prevention with aspirin.

1. The antiplatelet effects of aspirin are mediated mainly by acetylation of the enzyme cyclo-oxygenase, which controls a vital step in the synthesis of TXA,, a powerful promoter of platelet aggregation. Any dose of aspirin above 100 mg rapidly and fully suppresses the production of TXA, in more than 95% of circulating platelets and megakaryocytes in the bone marrow. A maintenance dose of 20 to 40 mg of aspirin per day is sufficient to sustain this degree of platelet inhibition. Most of the effects of such low doses of aspirin on platelets take place in the portal circulation, and the drug hardly reaches the systemic circulation to interfere with the production of prostacyclins in other tissues (endothelial cells, gastrointestinal mucosa, glomeruli in the kidney).

2. Placebo-controlled clinical trials of aspirin in patients with TIAs or minor stroke have shown approximately a 20% reduction for the-composite outcome event vascular death, myocardial infarction, or stroke. This has been achieved with doses as widely different as 1000 to 1300 mg, 300 mg, and 75 mg, although the confidence interval is much wider for the medium and low doses than for the high dose.

3. In patients with myocardial infarction or unstable angina, doses of aspirin between 100 and 300 mg have prevented not only cardiac events (fatal and nonfatal), but also stroke, in similar proportions as in patients with TIAs or minor stroke.

4. In a direct comparison of 30 mg and 300 mg of aspirin in more than 3000 patients with TIA or minor ischemic stroke, the occurrence of vascular death, stroke or myocardial infarction was similar (in fact slightly less common) with the low dose.

5. In middle-aged male physicians without overt cardiovascular disease, aspirin (in high or medium dose) has been shown to prevent myocardial infarction (fatal or nonfatal) at the expense of slightly more strokes.

6. The side effects of aspirin are dose-dependent. For gastrointestinal discomfort or symptoms the incidence is substantially greater for the high dose than for the medium dose or placebo, but the difference between the medium dose and the low dose or placebo is very small. The risk of bleeding complications (half of which require transfusion, cauterization, or tamponade) seems more directly proportional to the dose, but the actual incidence rates are difficult to compare between studies.

In conclusion, 20 to 40 mg of aspirin per day is sufficient for complete suppression of the aggregant agent TXA2 in blood platelets, preferably after a loading dose of at least 100 mg. In two recent clinical trials of patients with transient ischemic attacks or minor stroke, 30 and 75 mg of aspirin per day conferred a similar degree of protection against stroke as did doses between 300 and 1300 mg, and with fewer side effects. Nevertheless, the rate of reduction of vascular outcome events by aspirin, which is in the order of 20% to 25%, leaves much room for improvement, and the search for other preventive measures should be vigorously pursued.

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