Preventing Heart Attacks and Strokes with Aspirin
By Marcus M. Reidenberg, MD, FACP
Weill Cornell CERT
The value of aspirin for preventing heart attacks and strokes in people who have already had one is proven (1). But the value of aspirin’s ability to prevent the first heart attack or stroke is not a clear from the clinical trials, and this unclear benefit is counterbalanced by the harm of aspirin’s ability to increase bleeding. Understanding more about aspirin may help clarify this topic.
Aspirin prevents heart attacks and strokes by permanently blocking one path to a platelet’s ability to become “activated” and cause a clump of platelets in a blood vessel. This clump blocks blood flow which causes the attack. Other pathways, not sensitive to aspirin, are in platelets so all attacks aren’t prevented, and we can form blood clots at sites of injury while taking aspirin so we don’t bleed to death. But we do bleed more when taking aspirin. Also, aspirin is irritating to the stomach, so it can cause ulcers which then bleed a lot since the platelets don’t clump as well to stop the bleeding. The goal of aspirin to prevent heart attacks and strokes is to prevent the clumping just enough to avoid undesired clumps in intact blood vessels, while permitting desired clumps in injured open vessels.
Learning how effective a medicine is in preventing something in a clinical trial depends on how likely the unwanted event is without the medicine. If the risk of getting a heart attack in the next 10 years is zero, then you need take nothing to prevent it since it won’t occur anyway. If you are a healthy 40 year old woman, your chance of a heart attack in the next 10 years is 1%. Since aspirin may prevent only some of these heart attacks, hundreds of women would have to take aspirin for 10 years to possibly prevent one heart attack. The risks of excessive bleeding after injury and stomach trouble from the aspirin are probably higher than the benefit of preventing that one heart attack in one out of so many women taking aspirin for so long. So the first question to answer is: Is my chance of a heart attack or stroke high enough to be worth the risk of bleeding or stomach trouble from the aspirin?
But the clinical trials seem to show that aspirin may not prevent first attacks anyway (2). If it does not prevent first attacks, then it makes no sense to take it to prevent them. Why is there such a difference between preventing second attacks but not preventing first attacks? Present medical science indicates that the underlying cause(s) of first and second attacks are the same. If the causes are the same, why does the effect of the same treatment differ?
There are two reasons for this apparent difference. The first is that it is easier to do a clinical trial to show efficacy if the likelihood of the disease is high in the people in the trial. This is because an effective medication will prevent more illnesses in the treated group, so it will be easier to show that it works. For example, a clinical trial to prevent strokes in people with a risk of stroke of 1% in 10 years, including 1,000 people in the treated group and another 1,000 in the control group, would show 10 strokes in the control group and 7 in the treated group after 10 years if the treatment prevented 1/3 of the strokes. This difference of 3 strokes out of so many people could easily be due to chance, so the trial would fail to prove efficacy even for an effective drug. On the other hand, if the risk were 10%, then the numbers would be 100 strokes in the control group and 70 in the treated group. Since it is so unlikely that this result would be due to chance, it would be accepted as proof that the drug worked.* Thus, because the risk of a second attack is so much greater than for the first one, a clinical trial would need to be much shorter and have fewer patients in it to test if the drug works to prevent the second attack than it would need to be to show efficacy in preventing a first attack.
The second reason is that aspirin is a tricky drug to understand. Its chemical name is acetylsalicylic acid. It is composed of two parts, the acetyl part and the salicylic part. When combined as acetylsalicylic acid, it can link the acetyl part to the enzyme in platelets that starts the clumping process. This inactivates the enzyme permanently. Tissues and blood contain enzymes that separate the two parts of aspirin. When the acetyl part is unlinked from the salicylic part, it can no longer link to the enzyme. In fact, these unlinking enzymes in the blood are so active that, on average, half of a dose of aspirin is unlinked in 20 minutes. This means that in an hour and a half, a dose of aspirin can no longer have a blocking effect on platelet clumping. Some people have faster unlinking and others have slower unlinking than the average (3). The pain relieving and fever lowering effect of aspirin is due to the salicylic part and this remains active after the unlinking of the two parts of aspirin. Platelets produced by the body two or more hours after a dose of aspirin are fully active for starting the clumping process. Most people replace about 1/7th of their platelets every day. Taking aspirin once a day is often enough to work on them adequately. Some people with some conditions replace their platelets more quickly so they need aspirin more frequently than once daily for continuous effect.
How much aspirin is needed to produce the platelet effect? Weksler, et al, did a nice dose response study and found that a single dose of 40 mg was modestly effective and 80 mg was sufficient to produce a substantial effect (4). This study is the basis for the 80 mg daily dose.
A major problem is the form in which the aspirin is taken. Ordinary uncoated aspirin exerts its platelet effect in everybody (5). But enteric coated or sustained release products impair the absorption of the linked acetylsalicylic aspirin while permitting the absorption of the unlinked salicylic part (6). Thus coated aspirin will relieve pain and fever but not consistently effect platelets. Combine this impaired absorption of coated aspirin with the lowest effective dose of 80 mg in the usual low dose tablets taken and it is not surprising that for many people a dose of an 80 mg coated tablet does not work. Many of the clinical trials of aspirin to prevent first attacks used coated or sustained release tablets. Six of 9 trials reviewed by Patrono (2) used these tablets. It is not surprising that they failed to give unequivocal evidence that the aspirin worked. Most of the trials to prevent a second attack were done with uncoated tablets and at higher aspirin doses. This is another reason why these trials may have shown efficacy while the trials to prevent first events did not.
We know that some people, such as those whose parent died of a heart attack at an age of less than 50 or 60, are at high risk of a cardiovascular event, while people whose parents lived to be over 80 have a low risk of having one. Thus, until we learn much more about the genetics of cardiovascular disease, we must use family history as our investigation of genetics in assessing a person’s risk, along with all the other risk factors known such as diabetes, hypertension, etc.
I conclude from this review that aspirin is likely to be beneficial in preventing strokes and heart attacks in people at relatively high risk for these events, and likely to be harmful by causing excessive bleeding in people at low risk for these events. There are various ways to estimate one’s risk and its a personal judgment of whether it is high or low. But I find too many questions about the trials of preventing first heart attacks to accept a conclusion that it does not prevent them.
* For readers interested in the statistics, a 2X2 Chi Square test gives a p value of 0.5 for the 1% example and 0.02 for the 10% example.
References
1. Hennekens CH, Dalen JE. Aspirin in the treatment and prevention of cardiovascular diseases. AM J Med 2013; 126: 373-383.
2. Patrono C. Low-dose aspirin in primary prevention, cardioprotection, chemoprevention, both, or neither? Europ Heart J 2013; 34: 3403-3411.
3. Zhou,G, et al., Aspirin hydrolysis in plasma is a variable function of .... JBC 2013; 288: 119440-11948.
4. Weksler BB, Pett SB, Alonzo D, et al. Differential inhibition by aspirin of vascualr and platelet prostaglandin synthesis in atherosclerotic patients. NEJM 1983; 308: 800-805.
5. Grosser T, Fries S, Lawson JA, et al., Drug resistance and psuedoresistance. An unintended consequence of enteric coated aspirin. Circulation 2013: 127: 377-385.
6. Brantmark B, Wahlin-Boll E, Melander A. Bioavailability of acetylsalicylic acid and salicyclic acid from rpid- and slow-release formulations.... Eur J /clin Pharmacol 1982; 22: 309-314.
Posted 2/21/2013
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