Aspirin

     There have been many articles written about the uses and benefits of aspirin, and I thought I would review them here. Without clouding the discussion, it is important to understand the distinction between primary and secondary benefits from taking a drug. If the drug has a primary benefit, then it prevents the disease or condition from occurring, and everyone might benefit from taking it. If the drug has a secondary benefit, then it is given to patients who already have had an attack of the disease, to prevent a second attack. It is always easier to demonstrate the existence or non-existence of a secondary effect, because the greatest risk factor for an attack of any disease (especially a heart attack) is having had a previous attack of the disease. One example of primary benefit would be in taking medicine as malaria prophylaxis when traveling to a malarious region of the world. Another example would be yellow fever vaccine. One example of a secondary benefit is giving all survivors of a heart attack a daily dose of a statin, which decreases the chance  of having a second heart attack.

     Aspirin, abbreviated ASA, is acetylsalicylic acid. Hippocrates knew that the bark of the willow plant could reduce fever, reduce pain, and reduce inflammation. The active ingredient was salicylic acid, which is an extreme irritant to the stomach. Most people are unaware that not only do we ingest salicylic acid in our diets, but that our bodies synthesize it from benzoic acid.  In 1897 a German chemist working for Bayer, (Felix Hoffman) was able to synthesize ASA by acetylizing salicylic acid, thereby making it much less injurious to the mucosal lining of the human stomach. Although he was not the first to create ASA in the lab, Bayer successfully patented ASA and initially made it available only through a doctor's prescription. Interestingly enough, about the same time Bayer chemists synthesized heroin which is diacetyl morphine, and it was sold  over-the-counter as a non-addictive(!) form of morphine.

     The precise mechanism of the action of aspirin in inhibiting the formation of prostaglandins  (by inhibiting the action of cyclo-oxygenase enzymes) and thromboxanes  is unimportant for the purposes of our discussion, except to note that the inhibition is irreversible and the effects of a single dose of aspirin on the bleeding time can last for 10 days, unlike the other Non-Steroidal Anti-Inflammatory Drugs (NSAID's) such as Advil whose effect is reversible. Since aspirin binds irreversibly to platelets, patients about to undergo surgery are advised to avoid all aspirin and aspirin-containing products for 10 days before surgery, since that is the length of time for which an extension of the bleeding time due to aspirin can be measured. The aspirin achieves this effect through its binding to platelets, which normally can clump together to form a clot and stop bleeding, and platelets bound to aspirin do not clump together.

     Let me list a few known facts. Aspirin is 99% cleared by metabolism in the liver, but if too large a dose is taken the hepatic clearance mechanism is saturated, renal clearance is needed, and the clearance kinetics shift from first order to zero order.  Thus the half-life of a 325 mg pill is 3 hrs, but a 2000 mg dose has a half-life of 9 hours.
In the United states, the basic strength of an adult ASA tablet is 325 mg, and that of a children's tablet 81mg. In Europe the strengths are 300mg and 75 mg respectively, but it makes no apparent clinical difference. Adding caffeine to an aspirin pill increases its pain-reducing strength, hence the popularity of APC's or Excedrin migraine compounds (aspirin, phenaciten or Tylenol, and caffeine). ASA in an effervescent solution is absorbed faster, hence the popularity of Alka-Seltzer. The bleeding effect of aspirin on the stomach can be reduced by taking ASA along with 500 mg of Vitamin C, or 500 mg of SAMe, or 350 mg of deglycyrrhizinated licorice. Many  people who take aspirin on a daily basis develop an iron-deficiency anemia from microscopic bleeding somewhere in the GI tract, and buffering the aspirin seems to make no difference. But buffered ASA is absorbed more slowly, and some recent studies suggest that this is the cause of apparent "aspirin resistance". I should mention here that aspirin given intravenously causes absolutely no GI irritation.

     There are studies showing that taking a daily aspirin (check with your doctor for the suggested dose) can lower the risk of a second heart attack, a stroke following a TIA, a cardiac embolus if you have atrial fibrillation, and cancer of the colon; the first two are examples of secondary prevention, and the last two of primary prevention. It is extremely dangerous to give aspirin to febrile children up to the age of 16  because ASA in a febrile child can trigger a sometimes fatal condition known as Reye's syndrome, which is swelling of the brain compounded by liver failure. A few people develop an acute allergic reaction to aspirin with angioedema. Aspirin exposed to water decomposes back into acetic acid (vinegar) and salicylic acid, hence the vinegary smell when you open a large bottle of aspirin that you  have had for some time.

     There are many drug interactions with ASA; for instance Diamox (acetazolamide) enhances the likelihood of salicylate poisoning, and alcohol increases the risk of gastric bleeding, as does taking Advil or any other NSAID along with aspirin. Because aspirin is  bound to protein in the blood, it can displace other drugs that are bound to protein, thereby raising their plasma concentration to dangerous levels. Some of these drugs are tolbutamide, methotrexate, Dilantin, valproic acid, and probenecid. Taking ASA can  raise the blood level of uric acid. Very rarely through a kidney-based mechanism, aspirin can cause elevated potassium in your blood; this is especially true for diabetics (hyporenin hypoaldosteronism).Aspirin can also inhibit the renal clearance of penicillin G if either drug is given in very high dose. And paradoxically, very high doses of aspirin can cause fever rather than alleviate it.  So whenever you get a prescription for any drug, it would be wise to ask your doctor about possible interactions with ASA.

     And please never forget that unless your doctor gives you permission, never take aspirin with any drug that can cause bleeding, such as Advil, Alleve, Coumadin, Xarelto, and, sometimes, alcohol.

 

   

Aspirin and Colon Cancer

There have been reports in the news lately about two different articles in medical journals: (1) whether daily aspirin use reduces the incidence of colon cancer, and (2) the expense and morbidity of robotic surgery as opposed to standard laparoscopic ("keyhole" or "mini") surgery. Since I am an internist and neither article will affect my practice or income, I feel  can comment on them without bias (outside my usual inquisitorial examination of the evidence presented in research papers, a habit than has only been intensified by my over 20 years of reviewing articles). This blog will discuss the possible aspirin-colon cancer reduction link, and the next will discuss robotic surgery.

Let us look at the aspirin-colon cancer article first. As some background, let me inform my non-medical readers that it appears that it takes 5 years from the time a polyp first develops in the colon until it becomes cancerous (and I am here excluding any familial cases). Since as the polyps enlarge they tend to put drops of blood into the stool, the first screening for colon cancer that was shown to reduce the death rate from colon cancer was the annual test for blood in the stool. When I started practice in the early 1980"s, it was known that  five year examinations of the distal 25 centimeters of the colon by a rigid proctoscope detected enough cancers to reduce the death rate from colon cancer, and this became a standard practice for me. One curious fact that was noted and unexplained was that even though only a minute part of the distal colon was examined, fatal cancers originating in the proximal colon were also reduced (although not by as much). The proctoscope, or rigid signoidoscopy was soon replaced by the flexible sigmoidoscope, which reached further into the distal colon. This examination, if given every 5 to 10 years, also reduced colon cancer deaths in the proximal as well as the distal colon, but, again the incidence of cancers in the distal colon were much more strongly affected, than that  of cancers in the proximal colon .

A few years ago, a 5 year retrospective study of 5,000 female American nurses was published. The study showed that the frequent use of NSAID's (usually Advil or Alleve) reduced the incidence of and death from colon cancer. (I might here mention that a parallel 5 year study of females placed on a low fat diet showed no reduction in the incidence of either colon or breast cancer, but people still seem to think, without any hard evidence, that animal fat is carcinogenic for humans.)  This study led to the Vioxx study, where Merck hoped that they could show that Vioxx, another NSAID, also reduced the incidence of colon cancer, so they could get FDA approval to market it as such. Unfortunately, the initial data showed an increase in cardiovascular events, so the study  was terminated, as was Vioxx. I leave it to the audience to search the published reports to see which NSAID is the safest and which is the most apt to produce cardiac events. The last time I reviewed the subject (and this may not be true now) prescription Celebrex was the safest anti-inflammatory , and OTC Alleve/Naprosyn had the highest incidence of cardiac events.

So now we come to the latest study, published in Lancet (Vol. 376, Nov. 20, 2010, pp1741-1750). The study found that a dose of 75 mg. of daily aspirin (a baby aspirin has 81 mg) reduced the incidence and mortality of colon cancer, and the benefit was highest for proximal cancers. A few caveats. This article was the result of pooling 5 different studies, and in none of the studies was colon cancer the endpoint. Furthermore, the pooling showed a much greater effect in men than in women.We also think we know that aspirin reduces the incidence of colon polyps by suppressing COX-2, and tumors in the distal colon seem to have greater interaction with COX-2 receptors than do proximal tumors. It also did not compare the use of daily aspirin with q. 5 year colonoscopes with regard to reduction in the incidence of colon cancer.

Now when my patients ask me about  how to apply the results of this study to their own medical lives, I will reply as follows: There is now some evidence that taking a daily 81 mg. (children's) aspirin will reduce your chance of getting colon cancer, but no one has compared the % reduction achieved with aspirin with that achieved by either an annual stool-for-blood test or q. 5-10 years colonoscopy, and daily aspirin use increases your risk of GI bleeding. We also have absolutely no idea if adding daily ASA to the suggested routine of colonoscopy plus stool-for-blood  will have a positive synergistic effect. On the other hand, it is evident that if aspirin does have a preventive effect, it is greater for proximal colon tumors than distal tumors, and proximal tumors are the ones least likely to be detected by either colonoscopy or stool-for-blood. I would also suggest that if they absolutely refuse to ever have a colonoscopy then a daily children's aspirin is probably a good idea.

Aspirin, Lipoprotein A, CRP, Anti-oxidants, Heart disease

There have been a number of articles published recently in Lancet, Journal of the AMA, and newspapers about primary prevention of heart disease. By primary prevention, we mean the reduction of risk of a heart attack in patients who have not had a heart attack. Since the greatest risk for having a heart attack is having had one, the number of patients in a study of primary prevention has to be larger and last for a longer time than a study of secondary prevention, where aspirin, beta-blockers, statins, etc., have been shown to be of help.

I should also mention that the over-riding problem in prevention of any disease is not lack of communication between doctors and patients,or lack of information on the part of patients, but the unwillingness of patients to change their behavior (and no, I am not blaming the victim). Most patients know that they should exercise, lose weight, and stop smoking to reduce their primary heart attack risk, but how many do, even if, as in NYC, the amount of calories per dish is published in the menu of every chain restaurant?

1) C-reactive protein, or CRP. Numerous studies have shown a correlation between elevated CRP and heart attacks. This correlation is about as strong as that between elevated homocysteine and heart attacks. However, just as pulling down on the metal elevator arrow in the lobby of a skyscraper does not bring the elevator down, lowering the homocysteine has not been shown to lower heart attack risk. Whether the CRP as a marker for inflammation means that inflammation is a primary risk factor remains to be seen. A recent published genetic analysis (similar to the Lp(A) analysis) seem to show that lowering CRP does NOT lower the risk for heart disease.

2) Aspirin. First we have to decide if we mean 81mg/day, 325 mg/day, or 325 mg twice a day. Since aspirin blocks platelet clumping for 7 days, it is not clear why the studies involved daily aspirin, rather than once or twice a week. In addition, none of the studies to date controlled for aspirin resistance, where aspirin at the suggested dose does not prevent platelet clumping. It has been a "consensus" that absent any other risk factors (smoking, diabetes,etc.) that aspirin prevention should start at age 45 for men and 55 for women. However, a recent article Lancet cast severe doubt on this recommendation, so your guess is as good as mine.

3) Lp(A), or lipoprotein A. A recent article used genetic analysis to suggest that elevated Lp(A) is an independent risk factor for heart attacks. However, no one has shown that lowering Lp(A), prevents heart attacks, nor do we have a good drug to lower Lp(A). The same could be said in reverse about low HDL, the "good" cholesterol.

4) Anti-oxidants. The prophylactic use of anti-oxidants should be approached with caution. Prospective studies have shown that extra daily Vitamin E increases the primary risk for heart attacks, and prophylactic beta carotene increases the risk for lung cancer in cigarette smokers. A recent study at Memorial Sloan-Kettering showed in vitro that vitamin C inhibited the killing effect of chemicals on cancer cells. Selenium and vitamin E have been shown to have no protective effect against prostate cancer.

The conceptual problem is, of course, that correlation does not imply causation. Just recall how coffee drinking was "shown" to be a risk factor for heart attacks until it was realized that more coffee drinkers than non-drinkers smoke cigarettes. We always have to beware of confounding factors, as well as a common cause that elevates both the risk of disease and the marker. Does anyone really understand why female Pima Indians of the American Southwest have such a high incidence of cholecystitis, or the female Parsees of India (Zoroastrians transplanted from the Mideast) have such a high incidence of breast cancer?