Wednesday, March 21, 2012

Aspirin or bias?

Update 4PM Eastern, 3/21/12

Wanted to append a couple of thoughts I tweeted earlier about these studies, in case you don't follow me on Twitter or just missed them:

Around 2:30 PM Eastern:
And then closer to 3:00 PM Eastern: 


There is a fascinating review by Cancer Research UK of the new and old aspirin data with respect to its effects on cancer and cardiovascular complications in the context of a heightened risk for bleeding. The review is full of fabulous information about what we know and the uncertainties that remain, all with practical suggestions at the end, so go there and read it.

But here is what I wanted to highlight in the graph that I am reproducing from a screen shot:
There is something very interesting going on here. Just as the risk of bleeding begins to drop, so does the risk of developing cancer. This could be a complete coincidence, but perhaps not. An alternative explanation is that people who already have cancer, though it may not yet be diagnosed, may be at a higher risk for a bleeding complication. Those who develop a bleeding complication presumably are taken off aspirin. But remember, they may already be harboring a cancer that will rear its head in the near future. But what about those who do not bleed and therefore are able to tolerate aspirin for a longer time? They also seem to have a drop in their risk of incident cancer. But of course this may have nothing to do with aspirin's preventing cancer, so much as with its ability to unmask a cancer that is already present and essentially weed them out from the future risk pool for cancer development. And when you weed out those at a higher risk for clinical cancer, by definition you have a group with a lower than standard risk, creating the potential for a selection bias. Make sense?

Conversely, the risk of a cardiac event starts to increase roughly at the same time as the risks for cancer and bleeding begin to drop. This to me suggests confirmation that aspirin may prevent cardiovascular events early in the course of taking it. Furthermore, given my hypothesis above about aspirin's weeding out those with an early cancer, perhaps its cardiovascular impact is for some reason limited to those with an early cancer or with another reason for aspirin-induced bleeding.

All-in-all the data do not convince me to start taking aspirin -- I am still at odds with Dr. Agus on that. The selection bias that I described above may very well mean that aspirin's role is not as a cancer prevention, but more likely as a sort of a stress test for those with a subclinical cancer. So we are left again with the the chicken-and-egg question. But isn't that, after all, what makes science exciting?

Would love to know what others think -- does this make sense? Are there other possible explanations?      

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  1. Hi Marya,
    Aspirin's anti-cancer effects are generally attributed to the its anti-inflammatory properties. These effects, if real - as they likely are for some malignancies but not all, probably vary among tumors and may have a distinct influence on metastases as opposed to the primary tumor.

  2. Elaine, thank you so much for your comment. I totally agree that there is a plausible mechanism. Yet the three requirements for assigning causality (1. longitudinality, 2. correlation, and 3. no alternative explanation) are not all satisfied. So, I am just raising the possibility that there is another explanation. If indeed the RCTs that went into the meta-analysis were strictly ITT, and if the follow up was long enough, then I would have to believe that a selection bias is unlikely, and the mechanism I propose moved down as a possibility. And if that is the case, I would next have to interrogate the effect size, which I cannot do currently, as the Lancet paper is behind a paywall.

    Hope to continue this discussion, and once again, thanks.