Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377(9759):31-41. Epub 2010 Dec 6.
Analysis of individual patient data from 8 trials in which aspirin (doses ranged from 75–1,200 mg daily) was the interventional treatment used in cardiovascular risk reduction trials. None of the trials was designed to assess cancer incidence or deaths due to cancer. Trials were identified using public databases. All trials were randomized and had a mean scheduled treatment period of at least four years or more. Randomized allocation included aspirin versus no aspirin (no placebo given) or aspirin versus no aspirin in the presence of another antiplatelet or antithrombolytic agent (e.g., warfarin). Long-term (20-year) data was available for 3 trials using the United Kingdom’s national death certification and cancer registration systems.
Pooled analysis of 8 trials of aspirin showed a significant reduction in deaths due to cancer (674 deaths in 25,570 patients; OR 0.79, CI 0.68–0.92, P=0.003). Individual data available for 7 of the trials showed benefit was apparent only after 5 years’ follow-up (all cancers’ HR 0.66, CI 0.5–0.87; GI cancers HR=0.46, CI 0.27–0.77; P=0.003 for both sets of data). This latent effect was 5 years for esophageal, pancreatic, brain, and lung cancers. An even longer latency for measurable reduction in deaths was found for stomach, colorectal, and prostate cancers. The effect of aspirin was largely limited to adenocarcinomas. The benefit of aspirin was not related to the dose taken, gender, or smoking status. Benefit did appear to increase with age and duration of aspirin intervention used in the trial.
Many publications have suggested a protective role of aspirin intake on cancers of the colon, stomach, and esophagus.1,2,3,4 This is the first publication that shows a significant reduction of overall cancer deaths. In addition to the strong evidence for protective effects against gastrointestinal cancers, there is supportive evidence from several observation studies of a reduction in the incidence of prostate, ovarian, lung, and brain cancers as well.5,6 The above publication found that deaths due to cancers overall was reduced by 20% for those using aspirin long-term, and upwards of 35% for lower gastrointestinal cancers specifically. This is compelling outcome data on the use of an inexpensive, relatively safe intervention.
There are a few salient points in this study that are useful to keep in mind for clinicians. First, the benefit of aspirin did not correlate with the dosage used, so that a minimum dose of 75 mg is expected to be sufficient to confer benefit. Second, the benefit of aspirin was a latent effect, with reductions in deaths beginning after 5 years of follow up. Third, the reduction in deaths correlated with the duration of aspirin consumption, with longer aspirin intervention correlating with greater benefit. There was no benefit seen in those who took aspirin for less than 5 years. Last, reduction in deaths was found for individuals with adenocarcinoma specifically, not other histological types.
Not all studies have found a protective role for aspirin in cancer development. The Nurses’ Health Study, which used 100 mg every other day, did not show any reduction in the incidence of cancer.7 The Physician’s Health Study failed to show any difference in colon cancer or adenoma development in those that who aspirin, although this study only spanned 7 years.8 According to the cited study above, this may not be enough time as there was a 10-year latency period for a reduction in deaths from colon cancer. It appears that if there is a benefit for aspirin usage in lessening incidence of cancer or cancer deaths, its use should be daily and at a low dose for an extended period of time (greater than 5 years). This implies that those in their 40s or 50s may derive more benefit from a longer duration of intake. As the authors point out, there is no evidence of what to expect beyond 20 years.
There is a sufficient body of evidence implicating inflammatory mediators, including cyclooxygenase-2, in the carcinogenic, tumorigenic, and metastatic processes.9 Looking at this study from a broader physiological perspective, the question it may also be asking is, “Does lowering inflammation through cox-2 inhibition affect cancer death rates?” Granted, it is possible that aspirin’s effects are from another mechanism, but given the established role of inflammation in carcinogenesis, aspirin’s cox-2 inhibition is the putative mechanism to date. This is important conceptually, as there are many other means of affecting inflammation, many without any risk to the patient. These include whole-food diets, select herbs, fish oil, stress reduction, and proper sleep. To what extent is aspirin’s effect on lowering inflammation a convenient substitute for more meaningful changes in diet and lifestyle? This is a rhetorical question, as the number of confounding factors affecting inflammation would be nearly impossible to account for in any study design.
The widespread use of any drug should be considered with great caution. [PULLEDQUOTE]While low-dose aspirin has some risk of gastric irritation and bleeding, the data in the above publication is compelling in that this risk appears minimal compared to the benefits for most people. That said, each patient should be assessed for risk of bleeding—particularly gastrointestinal bleeds.
This data was culled from studies that originally were assessing aspirin as a primary or secondary intervention for cardiovascular disease/events. The trials were not designed to assess aspirin’s effects on cancer incidence or mortality. In addition, the data is only as good as the source, and death certificates may or may not accurately represent cancer as the cause of death. For example, a patient with cancer may die due to complications from the disease or treatment (e.g., infection, stroke), and this complication may be documented as the cause of actual death. Prospective trials are needed to support the conclusions from the above study.
Since all of the longer-term (20-year) data was derived from U.K. databases only, there is some dietary bias that may not be applicable to other populaces. The authors concede that “the benefits of aspirin may be less in populations with a high dietary intake of salicylates.” Assessment of salicylate intake at baseline and throughout may be helpful in the future.
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