On 2014 Nov 27, Mangesh Thorat commented:

Our systematic review of harms associated with aspirin use is now published (Thorat MA, 2015). Also recently published is our detailed response (Thorat MA, 2015) to Elwood P, 2015, who suggest that we have overestimated aspirin’s harms.

On 2014 Aug 22, Mangesh Thorat commented:

Response to Hilda Bastian’s recent comment:

Thank you for the continued discussion. Individual studies like PHS did report a 5-year follow-up, which is not uncommon. Rothwell’s recent overview (Rothwell PM, 2012) did look at studies with shorter follow-up, but the central question in this overview was aspirin’s effect on incidence. The effect on incidence starts to appear at 3 years, while that on mortality takes about 5 years. On the other hand, for example, the endpoint Seshasai SR, 2012 used was mortality and not incidence and therefore they could not observe a significant reduction. Sutcliffe P, 2013 looked at all these data and treated them as equal. Additionally, they did not have access to updated WHS results that showed a significant reduction in CRC. This resulted in their excessive perception of uncertainty; it is prominently reflected in their interpretation.

We believe that most experts agree that "the evidence supporting aspirin's benefits on cancer is now overwhelming.", the differences in opinion probably only exist for the magnitude and site-specific effects (e.g. 3 of our co-authors). This is the reason we provide several sensitivity analyses that use lower magnitude of benefits, higher magnitude of harms and also lack of effect on certain cancer sites. All these show a net benefit.

We agree that long-term harms should not be easily dismissed, but we believe that the severity of harms also needs to be considered in any assessment. In our assessments, we have erred on the side of caution and very likely over-estimated the harms. Individual circumstances differ, and therefore we believe that a careful assessment by and an informed discussion with a healthcare professional is necessary.

We also look forward to the new USPSTF review as we have been informed that on this occasion USPSTF will look at the overall picture by assessing impact on all diseases/conditions affected by aspirin and not just single disease/disease group.

Response to David Colquhoun’s comment:

Please note that the NHS Choices comment has been amended to delete the unsubstantiated statement about our study being ‘not reliable’. As stated in the paper this was a benefit-harm analysis based on very recent systematic overviews by some of our co-authors, so it was not necessary to repeat them.

On 2014 Aug 18, David Colquhoun commented:

NHS Choices does rather good assessments of medical headline news. I notice that they say of this study

"While the findings of this study show promise, it is not clear whether the methods used in compiling it were systematic, so the results may not be entirely reliable."

On 2014 Aug 16, Hilda Bastian commented:

Thanks for replying, Mangesh Thorat. I didn't review the primary studies, so hadn't picked up the error in Sutcliffe P, 2013 with respect to the Women's Health Study (Cook NR, 2013). The concern remains valid, as it applies to most of the evidence.

I disagree, though, that the Sutcliffe review has a "major flaw," considering all studies equal irrespective of follow-up. Their analyses for duration of follow-up are front and center. And they specifically report on, and discuss, 20-year analyses on colorectal cancer, in coming to their conclusions.

Nor are they the only group in this field to consider studies with shorter follow-up (see for example Rothwell PM, 2012). And the Physicians' Health Study (Steering Committee of the Physicians' Health Study Research Group., 1989) had 5-year follow-up.

Many people agree with your statement that "the evidence supporting aspirin's benefits on cancer is now overwhelming." But many do not. The National Cancer Institute's recent round-up (NCI, 2014) considers perspectives on the same body of evidence. NCI highlights "mixed opinions" and "reasons for caution."

While the potential for important net benefit from daily low-dose aspirin for more people is vitally important, I don't think the issue of harms of longterm use should be too easily dismissed. People who have common conditions that are potentially affected by taking aspirin daily (like asthma (Morales DR, 2014)), or at high risk of developing ARMD from mid-life, or whose concomitant medication use may be a relevant consideration (such as with arthritis (Colebatch AN, 2011)) might well want less uncertainty about what this means for them.

Given the differing interpretations of this body of evidence, the findings of the US Preventive Services Task Force review, expected this year, will be interesting (NCI, 2014).

On 2014 Aug 15, Mangesh Thorat commented:

We thank Hilda Bastian for her comment, our response to the points raised is given below:

Sutcliffe P, 2013's systematic review is not discussed in Cuzick J, 2015 because we believe that it has a major flaw; it considered all reviews to be equal irrespective of the length of follow-up. For example, the review by Seshasai SR, 2012 that failed to show any cancer benefit had a follow-up of only 6 years. As it takes 5 years for aspirin’s beneficial effects on mortality to appear, inclusion of such data by Sutcliffe P, 2013 resulted in underestimation of beneficial effects on cancer. The updated results of WHS (Cook NR, 2013), which showed 42% reduction in CRC incidence were published almost at the same time as Sutcliffe P, 2013, and therefore were not included in this review. Sutcliffe P, 2013 based their interpretation on earlier WHS results (Cook NR, 2005), which did not show any reduction in CRC.

Sutcliffe P, 2013 also were under wrong impression that all the primary studies and meta-analyses for benefit "assessed reduction in cancer incidence and mortality retrospectively through re-analysis of RCTs of aspirin for primary prevention of CVD." Cancer incidence and mortality is one of the primary endpoints in the WHS (Cook NR, 2013). The importance of WHS lies in the fact that it not only confirmed the benefit in cancer as a primary endpoint, even with alternate day low dose, but also confirmed that there is a long lead time and a prolonged carry-over benefit. This is where the recent WHS publication (Cook NR, 2013) differs from results published earlier (Cook NR, 2005).

We also disagree with the statement that “uncertainty around the cancer estimates remains high”, a very large body of evidence from observational studies (Bosetti C, 2012; Algra AM, 2012) is consistent with the findings from RCTs and should not be ignored as done in Sutcliffe P, 2013. The evidence supporting aspirin’s benefits on cancer is now overwhelming with over 200 published studies and those with adequate follow up showing very consistent evidence for a reduced incidence and mortality of three major digestive track cancers – colon, stomach and oesophagus.

It is clear from the evidence that the harms associated with aspirin (and the cardiovascular benefits) begin at the time of use and cease with stoppage of drug use. However, cancer benefits have a lead time before becoming apparent, but these continue for a long period after stopping drug use; a long carry-over effect as seen with other preventive drugs like tamoxifen. With this understanding, mere pooling of data from meta-analyses and trials with variable treatment durations and variable post-treatment follow-up to assess benefit and harms, as Sutcliffe P, 2013 have done is not a reliable method for assessing the impact of aspirin. This is primarily where our work and therefore the results differ.

In addition, we have modelled benefits and harms of aspirin for the average risk population using actual event rates in the general population to give estimates of the impact of aspirin specifically for this group, which is the major focus of our work.

We accept that the question of aspirin’s impact on ARMD is unresolved, but ARMD is uncommon (National Eye Institute) below 70 years of age, which again is the group on which we have focussed our attention.

On 2014 Aug 10, Hilda Bastian commented:

These authors (Cuzick J, 2015) come to a more positive conclusion about the state of the evidence on routine aspirin use and cancer prevention than do Sutcliffe P, 2013 (also reported at Sutcliffe P, 2013).

Sutcliffe P, 2013 undertook a thorough and well-reported systematic review of the evidence, based on previous systematic reviews, the primary studies in them, and the relevant RCTs published post-2008, re-analyzing the primary study data. They took into account the same individual patient data and other meta-analyses on which Cuzick J, 2015's interpretation of benefit rely. (Sutcliffe P, 2013's systematic review is not discussed in Cuzick J, 2015.)

The main data included in Cuzick J, 2015 but unavailable to Sutcliffe P, 2013 appear to be an analysis of harms (where insufficient detail on the sources or selection process have been published), and a long-term follow-up report from the Women's Health Study (Cook NR, 2013). However, as Cook NR, 2013 shows a broadly similar outcome to the <10 year results (no effect on total cancers, but an effect on colorectal cancer only), this does not appear to account for the difference in interpretation of the state of the evidence by these two groups.

The main data relied on in Sutcliffe P, 2013 that differ to those in key analyses of Cuzick J, 2015 are the Physicians' Health Study (Steering Committee of the Physicians' Health Study Research Group., 1989) and the Women's Health Study (Ridker PM, 2005). These are of long-term aspirin use on alternate days, rather than daily. These two studies include around 62,000 people, and Sutcliffe P, 2013's analyses show they dominate several calculations.

Sutcliffe P, 2013 point to a critical issue: all the primary studies and meta-analyses for benefit "assessed reduction in cancer incidence and mortality retrospectively through re-analysis of RCTs of aspirin for primary prevention of CVD." They conclude that the uncertainty around the cancer estimates remains high, and the "long term all-cause mortality data does not provide a compelling case for aspirin protection against CVD and cancer mortality."

With further trials underway, the picture may become clearer in the next few years. While previous trials and analyses address the major harms associated with long-term daily aspirin use (hemorrhagic stroke and gastrointestinal bleeding), many people considering this intervention may also be concerned about additional outcomes. For example, the still-unresolved question of any potential impact on neovascular age-related macular degeneration (Klein BE, 2012, Liew G, 2013, Christen WG, 2014).

On 2014 Aug 10, Hilda Bastian commented:

These authors (Cuzick J, 2015) come to a more positive conclusion about the state of the evidence on routine aspirin use and cancer prevention than do Sutcliffe P, 2013 (also reported at Sutcliffe P, 2013).

Sutcliffe P, 2013 undertook a thorough and well-reported systematic review of the evidence, based on previous systematic reviews, the primary studies in them, and the relevant RCTs published post-2008, re-analyzing the primary study data. They took into account the same individual patient data and other meta-analyses on which Cuzick J, 2015's interpretation of benefit rely. (Sutcliffe P, 2013's systematic review is not discussed in Cuzick J, 2015.)

The main data included in Cuzick J, 2015 but unavailable to Sutcliffe P, 2013 appear to be an analysis of harms (where insufficient detail on the sources or selection process have been published), and a long-term follow-up report from the Women's Health Study (Cook NR, 2013). However, as Cook NR, 2013 shows a broadly similar outcome to the <10 year results (no effect on total cancers, but an effect on colorectal cancer only), this does not appear to account for the difference in interpretation of the state of the evidence by these two groups.

The main data relied on in Sutcliffe P, 2013 that differ to those in key analyses of Cuzick J, 2015 are the Physicians' Health Study (Steering Committee of the Physicians' Health Study Research Group., 1989) and the Women's Health Study (Ridker PM, 2005). These are of long-term aspirin use on alternate days, rather than daily. These two studies include around 62,000 people, and Sutcliffe P, 2013's analyses show they dominate several calculations.

Sutcliffe P, 2013 point to a critical issue: all the primary studies and meta-analyses for benefit "assessed reduction in cancer incidence and mortality retrospectively through re-analysis of RCTs of aspirin for primary prevention of CVD." They conclude that the uncertainty around the cancer estimates remains high, and the "long term all-cause mortality data does not provide a compelling case for aspirin protection against CVD and cancer mortality."

With further trials underway, the picture may become clearer in the next few years. While previous trials and analyses address the major harms associated with long-term daily aspirin use (hemorrhagic stroke and gastrointestinal bleeding), many people considering this intervention may also be concerned about additional outcomes. For example, the still-unresolved question of any potential impact on neovascular age-related macular degeneration (Klein BE, 2012, Liew G, 2013, Christen WG, 2014).