Dr. Ralph RossRussell: Before I begin, may I as a representative of the primeval species, the old worldneurologist, express my pleasure and thanks at beingasked to this meeting. We particularly appreciate theinformality of the gathering and the fact that we arenot time-constrained. This is quite a change for someof us.
We have heard a characteristically well-balancedreview from BillFields with which I entirelyagree andIhave very little to add. I would just emphasize one ortwo of the points that he has made. I think we wouldall concur that arguments based on in vitro tests or onmechanisms of biochemical action are irrelevant. Weare talking about a clinical problem and a patient response; we do not have to understand how quinineworks to know that it cures malaria. Aspirin, even insmall doses, is superior to placebo, and the argumentreally is whether a high or a low dose is superior. Iwould accept what he has just told us; the evidencesuggests that high-dose aspirin is better than lowdose aspirin, and the stroke rate in a number of trialsfavors the high-dose group. On the other hand, weare dealing with long-term therapy, offering patientsprotection against recurrence of stroke, so the patientis required to take the drug for many years. Itis no useprescribing an effective drug if the patient is not goingto take it.
The second point he made is that high-dose aspirincauses more serious side effects in the form of hemorrhage and also more trivial side effects, which may beequally important to the patient, in the form of gastrointestinal dyspepsia and constipation. In all the trials,the notable feature has been the difference in compliance between those given high-dose aspirin and thosegiven low-dose aspirin. Patients are much more likely to stop taking aspirin if the dose is high. I suggestthat in many cases the possible small additional benefit from high dosage is obviated by the fact that manypatients do not take the prescribed drug, and we muststrike a balance between efficacy and patient compliance. Now, as he has told us, no trial has directlycompared high- and low-dose except the UK-TIAtrial, in which no clear difference could be foundbetween the two groups, which were 300 mg/dayand1,200 mg/day, and the recent Dutch trial did not really
help very much because it compared very-low-dosewith low-dose and again found no difference. Itwas apity that this trial did not include a high-dose group.So I suggest a typical British compromise: we shouldrecommend to our patients that 600-900 mg a day isthe desired dose, but they should be allowed to reduce it if they find that this is unacceptable. I reallyfeel that to start off on yet another trial would beunwise, I feel that money could be better spent inother ways.
Dr. John Brust: I jotted down five controversies thatswirl around antiplatelet agents that I want to quicklyreview. The first is the one that we are already in themiddle of-dosage. I would make two points: one isthat, in the Physicians'Health Study, the frequency ofstroke in the doctors not getting aspirin was muchlower than expected, and so it may be that aspirinreally did not get a chance to show what it could do inthat exceptional population. As far as the differencebetween the coronary and the carotid arteries goes, itwas brought out in Don Easton's breakfast symposium the other day that perhaps the difference in thesize of these arteries is important. The carotid is a lotbigger, the plaques are a lot bigger, there is morecollagen, so perhaps this is why one might see a differential effect, if indeed in these studies there is a differential effect.
I would guess that a lot of patients will do fine onlow-dose or very-low-dose and others will not and wehave precedent for this. Not everybody takes thesame dose of anticonvulsants or of maintenancemethadone, and what I wonder is: What would be thecumbersomeness or cost of simply starting everybody at a low dose and then measuring something?Can you send the patients' blood through an agrigometer and find out if platelets are being appropriatelyinhibited? I do not think we need more than cyclooxygenase to explain aspirin's effects. If there is adifference between low- and high-dose, I expect it isa difference in what aspirin is doing to cycle-oxygenase in a particular patient. So, is there something wecan measure that would allow us, as we do withhypertension, to start with a low dose and follow thepatient and then increase the dose if we need to, butnot if we do not?
End pointsStroke, myocardial infarction, deathDeath (vascular)
ESPS 1
32.725.5
UK-TIA
15.85.1
CATS
20.421.5
SALT
14.50.1
Controversial question number two involves prostacyclin. Nobody knows how important prostacyclinis. So is it worth sparing? None of the low doses, tomy knowledge, have effectively spared prostacyclin.There was a paper a year ago by Clarke in which a controlled-release aspirin, a 75-mg pill that released 10mg/h into the prehepatic circulation, knocking outthe platelets and then getting metabolized in the liverand not getting in the systemic circulation to affectprostacyclin, did produce a dissociation. That is as faras the study went. Is that worth a trial?
Question number three involves dipyridamole. Atone of the sessions at a recent meeting, dipyridamolereared its head in a fashion that reminded me ofmovies about monsters that will not die. Ihad thoughtthat the percent in aspirin addition had been settledby studies like Dr. Fields', but using an analysis comparable to what we just heard, it was suggested that,although not statistically significant, there is a repeated trend toward better results when dipyridamole isadded to aspirin than when aspirin is given alone.Moreover, as we all know, except in patients with artificial heart valves, no one has studied dipyridamolealone compared to placebo. I understand the European Stroke PreventionTrialIll isgoing to address thatquestion, comparing dipyridamole alone, aspirinalone, dipyridamole plus aspirin, and placebo.
Question number four concerns ticlopidlne. Inboth the TASS study involving mild stroke and TIAand the CATS study involving more severe stroke,tielopidine was shown to be superior to aspirin inreducing fatal and nonfatal stroke and death. Ticlopidine's side effects included reversible diarrhea,reversible rash, severe but reversible neutropenia,and hypercholesterolemia, the significance of whichis uncertain. Moreover, a Swedish study showed thataspirin is of no value when given to patients who havehad significant lasting occlusive strokes. Yet, theFederal Drug Administration (FDA) approved ticlopidine only as a second-line drug, for people whocannot take aspirin, and I wondered if maybe whilewe are passing resolutions we ought to ask the FDA torecommend that it be given, especially in patientswith fixed strokes, as a first-line drug. Are they per-
haps so cost-conscious that they want to keep us fromusing the much more expensive drug?
Question number 5 concerns artial fibrillation. TheBoston Atrial Fibrillation Trial showed no benefitfrom aspirin in preventing stroke in patients withatrial fibrillation. The SPAF Trial from San Antonioshowed there was a benefit. Phil Kistler of the BostonTrial thinks that the benefit that the Texas groupshowed was only for mild strokes or TIAs and, therefore, he would not recommend it. I wonder what thisgroup thinks about that.
So, those are five controversial questons, and Dr.Easton is now going to take 5 min to answer each ofthem definitively!
Dr.]. Donald Easton: I think what we might do is try todeal with each of these ifwe can. Perhaps Dr. Lowenthal can begin with the dipyridamole issue, and then Iwill try to give a response to the tielopidine part andmake a comment about atrial fibrillation.
Dr. Annan Lmuenihal: As you may know, we began astudy, "European Stroke Prevention Study 1" (ESPSI), in 1979 and finished in 1985. We began a secondone, "ESPS 2," in February 1989. This is still ongoing.
Our problem is knowing what should be done withour patient. What should we prescribe? How shouldwe try to find our way through what was said thismorning and what has been published many timesalready? When we try to find a way, the answer isalways, "Well,you cannot compare such things. Well,let us look at the results of the four main studiesESPS 1, UK-TIA Study, SALT,and the CATS Study.In ESPS I, the patients received 225 mg dipyridamoleand 990 mg aspirin a day. In the UK-TIAStudy, theyreceived 300 or 1,200 mg aspirin a day. In the SALTStudy, they received 75 mg aspirin a day, and in theCATS Study, they received 500 mg tielopidine perday.
I compare those studies because they are the onlyimportant studies that were done for secondary prevention of ischemic cerebral lesions with antiplateletdrugs. The results of these studies, as shown in Table1, prove very clearly that the association betweenaspirin and dipyridamole gives the best prevention
against stroke, myocardial infarction (MI), and vascular death.
From the audience: What were the doses of aspirinand dipyridamole in that last slide?
Dr. Lowenthal: For seven studies with aspirin, thedoses were from 75 mg to 1,500 mg. For the twoaspirin/dipyridamole studies, the same dosage wasused: 990 mg aspirin and 225 mg dipyridamole. Inthe ongoing ESPS 2, it is 50 mg aspirin and 400 mgdipyridamole for the association.
Dr. Easton: I would like to take the first couple ofslides to respond to the comments about Persantineand then I would like to make a couple of commentsabout the ticlopidine issue.
I am not anti-Persantine. I would like very much toknow if Persantine added to aspirin is really morebeneficial than aspirin alone because if it is, I wouldlike to start using it today. But I am interested in particularly looking at direct comparisons rather thanindirect comparisons, and what we have until Dr.Lowenthal's next study is done in which there is adirect comparison are these: the Fields' trial at whichwe are looking at 53 strokes or death using aspirinplus dipyridamole and 60 strokes or death using aspirin alone. The Bousser study from Paris in which, ifwe look at the three groups, placebo, aspirin, or aspirin + dipyridamole, you see 18 in the aspirin +dipyridamole and 17 in the aspirin alone. This isabout 200 patients, 200 patients, 200 patients for atotal of 604. Whereas, as we have just heard, the ESPS1 was a comparison of aspirin + dipyridamole versusplacebo. The risk reduction is substantial; it is 33%and the question of whether that is a meaningful difference from the other studies is moot.
Let me take one minute to look at the same indirectcomparisons that we just heard about. This is an oddsratio depiction that we wiIIall be seeing shortly; this isthe 2nd Cycle Antiplatelet Trialists meta-analysis thatis about to be published shortly. And this rather busyslide is looking at stroke, MI, and vascular death inthese various treatments. You can see three differentdoses of aspirin here giving an aggregate meta-analysis odds reduction for all aspirin doses, and then youcan look at aspirin + dipyridamole, aspirin + sulfapyrizon, and so forth. What I would simply point outis that you can decide for yourself about the importance of these differences in these indirect comparisons. But, obviously, what we are looking at here arehorizontal lines showing the 99% confidence intervals for these various doses of aspirin, and you can seethat there are lots of outcomes in some of these groupsand very, very few outcomes in others. I certainlyagree with others who have said that it is not thenumber of patients in the trial that counts, it is the
ANTIPLATELETAGENTS
number of outcomes. We do not care if it is 22,000male physicians; we are interested in how manyevents occurred in terms of calculating the eventrates. We are certainly very interested in how oftenthe event occurs and its prevalence in the populationfor other purposes.
What the antiplatelet trials concluded is that aspirinreduces these three events in an aggregate of patientstreated with aspirin by 22%. Ifyou look down here ataspirin + dipyridamole, itis a reduction of about 30%.Ifyou look at dipyridamole alone, it is about 14%, andif you look at ticlopidine, it is 34%. The issue of howvery different these are-is it really true that aspirin +dipyridamole reduces the odds by 30%, whereasaspirin alone only does so by 22%?-we do not knowin these indirect comparisons because the confidenceintervals do overlap. This confidence interval overlaps with this confidence interval and all the others.Here is ticlopidine and you can see that its confidenceinterval overlaps with that of aspirin + dipyridamole.So do I think ticlopidine is better than aspirin + dipyridamole? Not from these data; the trend looks thatway, but we will not know unless the two are testedhead to head. Ifyou look at the head-to-head comparisons now, you wiII see how few data we reallyhave. Here is high-dose aspirin versus one aspirin orless per day in head-to-head trials in terms of theirability to reduce stroke, MI,and vascular death. Whatyou see is about a 6% reduction favoring high-doseaspirin with wide confidence intervals that includeunity, which, therefore, are not conventionally statistically significant. Ifyou look at dipyridamole + aspirin compared to aspirin alone, anything to the left ofthis line would favor the combination; anything to theright of the line would favor the aspirin alone and youcan see 2% favoring aspirin + dipyridamole in thisdirect head-to-head meta-analysis. It does include allsorts of patients, no question about it. It does includethe aggregate outcome of stroke, MI, and vasculardeath. And I am very much looking forward to theESPS Trial, which is going to give us a direct head-tohead comparison of these two groups. And we hopethat the numbers are big enough that it wiIIbe able toprovide important results. I think it will with thenumbers that we are looking at and event rates that wehave seen before.
Again, if you look at the' direct comparison of ticlopidine versus aspirin in this head-to-head meta-analysis of 3 trials, you see this 10% reduction favoringticlopidine, but again, the confidence interval includes unity, so whether, when this becomes 10 trialsinstead of 3, those confidence intervals will collapsedown and allow everyone to say with confidence thatticlopidine is better than aspirin, time wiII tell. I must
say that I am impressed as I look at these analyses thatthe difference between the publication in 1988, whichincluded about 30,000 patients, and 1990, which included about 100,000 patients, is practically nil. Whathas happened is these squares have gotten bigger andbigger, and the confidence intervals have becomenarrower and narrower, but all in all, the numbershave not changed much. So whether that will be thecase with these other combinations and other agents,time will tell.
From tile audience: I would just like to discuss dipyridamole briefly and address a couple of comments thathave been made. First, I would like to ask ProfessorLowenthal: What are the doses that you are using fordipyridamole and aspirin in the new trial?
Dr.Lowenthal: The new trial (ESPS 2) has four arms:2 X 25 mg aspirin, 2 X 200 mg dipyridamole, the association of 2 X 25 mg aspirin with 2 X 200 mgdipyridamole, and a placebo.
From tile audience: Let us be crystal clear about itfirst. It is 50 mg of aspirin daily?
Dr. Lowenthal: Yes.From the audience: How many total milligrams of
aspirin per day? So, we have a total of 70 mg of aspirindaily versus 400? Fifty milligrams of aspirin daily?The only reason I ask is that ifour thesis is that a higherdose is more appropriate, then I would wonder whatkind of an answer you are going to derive from this,but I am prepared, as everyone else in this room I amsure is prepared, to wait until you have results. I amnot being critical of it. It just seems that a higher doseof aspirin might be more effective.
Let me just make mention of one thing, which perhaps is not as well-known as it ought to be. One ofthestudies using not aspirin but sodium salicylate, whichis sold in this country as Alka Seltzer, was done in theVeterans Administration and published about 10 yearsago, and it had to do with unstable angina. It showed aremarkable reduction in myocardial infarction in patients treated with Alka Seltzer as compared withthose treated with placebo. Now, some of the issuesthat are raised about bleeding and gastrointestinaldiscomfort-here we have sodium salicylate compared with acetylsalicylic acid and the effect on platelet function is identical. Yet, nobody seems to knowanything about Alka Seltzer in this context. I speak ofthis with some knowledge because I was a consultantto Miles Laboratories with their proprietary drug division, and, for corporate reasons, they did not want topush this because they could sell a hell of a lot more
Alka Seltzer to relieve your indigestion than they canto take care of your TIAs or to prevent your strokes. Ithink it is worthwhile looking into this because someof the issues about side effects could very quickly bedismissed if we use a drug that is equally effective.Aspirin becomes sodium acetylsalicylic salicylatewhen it gets into your body. So, just face it, we mightas well take it that way and not have all the other complications.
Dr. Nancy Futrell: It is somewhat disconcerting thatwe have not heard any discussion of gender whenthere is some concern that aspirin may not be beneficial to women. So I suppose we could just give allwomen ticlopidine. The difficulty with that is not onlythe cost, but we are all finding a certain number ofunacceptable side effects of ticlopidine that are justnot as well-tolerated. I wonder if we are going to dosome work on finding out if there is a dose of aspirinthat is going to work in women. Women have different prostaglandin metabolism than men do, and itmay in fact be that there is a dose of aspirin that willwork if we look for it. The other possibility is thatwomen may respond differently to aspirin plus one ofthe other antiplatelet drugs such as Persantine, if welooked at that issue specifically in women.
From tile audience: I would respond by saying thatwithout getting into all the issues of meta-analysis, Ithink there is virtually no doubt that aspirin is as effective in women as it is in men for the prevention ofstrokes, MIs, and vascular death, but admittedly, it isall from cumulative data from a large number of trialsin which smaller numbers of women had to be addedtogether in order to be able to see the entire effect.But that is an opinion.
Dr. Brust: Two quick questions to discuss at lunchthen. The first: Is it really established that the gastrointestinal side effects of aspirin are related to acidity and local irritation as against the systemic cyclooxygenase actions?
Dr. Easton: Perhaps two-thirds of the effect is systemic .
Dr. Brust: So, buffering it should not make muchdifference. And the second question is for Dr. Easton.You are a co-author of the editorial reviewed forus, but you also wrote an editorial of your own notlong ago that recommended that aspirin be givenas a single pill a day. I wonder if you could explainthat?
