Thursday, August 13, 2009

The enemy of good evidence is better evidence: Aspirin, colorectal cancer, and knowing when enough is enough

An epidemiological study of the impact of aspirin (ASA) on outcomes from colorectal carcinoma (CRCA) in JAMA has made quite a splash which has extended to the lay press (see Chan et al: ; and ). I read this study, which normally would not have been of interest to me, because I knew that it was an epidemiological study and suspected that numerous methodological flaws would limit the conclusions that one could draw from it. And I admit that I was surprised that it has all the trappings of a methodologically superb study, complete in almost every way, including reporting of the Wald test for the assumption of proportional hazards, reporting of assessment for collinearity and overfitting of the model etc. It's all there, everything that one could want.

I should start by stating that there is biological plausibility of the hypothesis that ASA might influence the course of these cancers which express COX-2. I am no expert in this area, so I will take it as granted that the basic science evidence is sound enough to inflate the pre-test probability of an effect of ASA to a non-negligible level. Moreover, as pointed out by the authors, other smaller epidemiological investigations have suggested that ASA might improve outcomes from CRCA. The authors of the current investigation found a [marginally] statistically significant reduced hazards of death of approximately 0.3 in patients who took ASA after a diagnosis of CRCA, but not before.

Without delving into the details (knowing that one might find the devil there), I found the conclusions the authors made interesting, namely that additional investigations and randomized controlled trials will be needed before we can recommend ASA to patients diagnosed with CRCA. This caught me as a bit odd, depending upon what our goals are. If our goal is to further study the mechanisms of this disease in pursuit of the truth of the EFFICACY of ASA (see previous blog entry on vertebroplasty for the distinctions between efficacy and effectiveness research), then fine, we need a randomized controlled trial to eliminate all the potential confounding that is inherent in the current study, most notably the possibility that patients who took ASA are different from those who didn't in some important way that also influences outcome. But I'm prepared to accept that there is ample evidence that ASA benefits this condition and that if I had CRCA, the risks of not taking ASA far exceed the risks of taking it, and I would shun participation in any study in which I might be randomized to placebo. This may sound heretical, but allow me to explain my thinking.

I do worry that something that "makes sense" biologically and which is bolstered by epidemiological data might prove to be spurious, as happened in the decades-long saga of Premarin-prevention which came to a close with the Women's Health Initiative (WHI) study. But there are important differences here. Premarin had known side effects (clotting, increased risk of breast cancer) and it was being used long-term for the PREVENTION of remote diseases that would afflict women in the [distant] future. ASA has a proven safety profile spanning over a century, and patients with CRCA have a near-term risk of DEATH from it. So, even though both premarin and ASA might be used on the basis of fallible epidemiological data, there are important differences that we must consider. (I am also reminded of the ongoing debates and study of NAC for prevention of contrast nephropathy, which I think has gone on for far too long. There is ample evidence that it might help, and no evidence of adverse effects or excessive cost. When is enough enough?)

I just think we have become too beholden to certain mantras (like RCTs being the end-all-be-all or mortality being the only acceptable outcome measure), and we don't look at different situations with an independently critical eye. This is not low tidal volume ventilation where the critical care community needs unassailable evidence of efficacy to be convinced to administer it to patients who will have little say in the tidal volume their doctor uses to ventilate them. These are cognizant patients with cancer, this is a widely available over-the-counter drug, and this is a disease which makes people feel desperate, desperate enough to enroll in trials of experimental and toxic therapies. The minor side effects of ASA are the LEAST of their worries, especially considering that most of the patients in the cohort examined in this trial were using ASA for analgesia! If they are generally not concerned about side effects when it is used for arthritis, how can we justify withholding or not recommending it for patients with CANCER whose LIVES may be saved by it?

I were a patient with CRCA, I would take ASA (in fact I already take ASA!) and I would scoff at attempts to enroll me into a trial where I might receive placebo. The purists in pursuit of efficacy and mechanisms and the perfect trial be damned. I would much rather have a gastrointestinal hemorrhage than an early death from CRCA. That's just me. Others may appraise the risks and values of the various outcomes differently. And if they want to enroll in a trial, more power to them, so long as the investigators have adequately and accurately informed them of the existing data and the risks of both ASA and placebo, in the specific context of their specific disease and given the epidemiological data. Otherwise, their enrollment is probably ethically precarious, especially if they would go home and take an ASA for a more benign condition without another thought about it.


  1. Hello Scott, aren't you a little young to take ASA preventively: there is NO safe dose, it messes with ALL your prostaglandin pathways, it causes 1/4 million hospitalizations/year in the US, half of those for for congestive heart failure [for which you are too young] and half for bleeding [for which nobody is too young].

    The only 'healthy' use of ASA I believe is for [temporary] pain and in the case of an ongoing ischemic event [bring it on!].

    That ASA vs less colon cancer link is old and was reported about 12 years in NEJM and where one hypothesis explaining the benefit found was that those taking aspirin were MORE likely to bleed from the intestinal tract and thus uniquely receiving an early warning to be either diagnosed or treated.

  2. where is the data demonstrating that asa causes 1/8 million hospitalizations for chf?

  3. the watch trial suggested a link between asa and hospitalizations for chf but that's all i've seen.

  4. Here's from Archives Int. Med. .. 19% of hospitalizations for congestive heart failure ..

    I've seen this link elsewhere and am totally baffled as to why!

  5. Advocating a "personalized" approach to incorporation of medical evidence - rather than the delivery of medical care? how dare you, sir? What is next? A suggestion for different p levels based on the severity of disease, alternate treatments, etc?

  6. Jim and I speak the same language....

    Eddie - What's a GI hemorrhage? I scoff at them. I could probably insert my own Cordis and transfuse myself...

    I also take Niacin.... :-)

  7. Hospitalization for bleeding cannot be a happy thing, even if not life threatening and June 17 1999 NEJM figured aspirin kills as many Americans as does AIDS. is one reality check. In my reading of the data, the only benefit ever found from [daily preventive] aspirin was in NON-FATAL heart attacks [the U.S. physician health study] in men only and that was not replicated in any other study. The problem: they did not use pure aspirin but one with magnesium, an excellent antiarrhythmic and in which the average American does not reach RDI/DV amounts [oeps]. The devil is always in the confounders!

    BMJ editorial: Aspirin a poison

    Agree, niacin [+ a multivit to not raise homocysteine] is good prevention :)

  8. Eddie,
    In the Archives study they specifically excluded patients taking daily low-dose aspirin.

  9. Dear Anon, the BMJ editorial deals a bit with low dose, lovingly called 'baby aspirin' [not for babies!]. I don't think there is a safe dose, even 50 mg in daily prevention. However, if you MUST, I'd take 1/4 of a 500 mg pill and take that every second day. The idea is that the same platelet dysfunction will be obtained but that other functions of the at least 5 COX enzymes may not be totally affected, i.e. allowing normal and healthy expression of their fatty acid feedstock, ie creating eicosanoids. I'd take daily magnesium separately to reach RDA or slightly better, i.e. I'd make my own "Bufferin".
    I'd also take a 1 gram pill fish oil since its EPA is the mother of all pro-fluidity antiinflammatory prostaglandins / eicosanoids.

    My guess: if the makers of VIOXX had co packaged it with 1/2g EPA, that excellent pain killer might still be on the market; we'll never know!