Journal reference: Rothwell PM, Fowkes GR, Belch JFF, et al. 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 ^[1]

Link: http://dx.doi.org/10.1016/S0140-6736(10)62110-1

Published: 7 December 2010

Evidence cookie says...

Daily aspirin (≥ 75 mg) taken by participants in cardiovascular studies reduced the risk of cancer death. The risk of cancer death was: ↓ 34% after 5 years follow up ↓ 20% maintained at long-term 20 years follow up Aspirin specifically reduced the risk of death from oesophageal cancer, colorectal cancer, lung cancer, and adenocarcinomas. General practitioners could consider discussing the risks and benefits of daily aspirin with older patients. Note: this study does not provide evidence on the effect of long-term daily aspirin, nor the effect on cancer incidence. The effect on all-cause mortality was small.  The rate of major bleeding (not including haemorrhagic stroke) on daily aspirin is 0.1% (1 in 1000 people) per year [2].

More details:

Article details

Study design:

systematic review, meta-analysis of randomised controlled trials

Study aim:

to study deaths due to cancer during and after randomised trials of daily aspirin versus control (in trials originally performed for vascular events)

Methods summary:

Trial eligibility

• randomised allocation of aspirin (any dose) with aspirin versus no aspirin groups
• mean or median scheduled trial treatment period at least 4 years and a range extending beyond 5 years

Search:

• published data for all trials of antiplatelet agents from the Anti-Thrombotic Trialists’ (ATT) Collaboration (data up to 2002)
• searched for studies after 2002 in:
  • Cochrane Collaboration Database of Systematic Reviews
  • PubMed
  • Embase

Analysis:

• effects of allocation of aspirin on risk of death due to cancer and all-cause mortality were expressed as odds ratios (OR) with 95% confidence intervals (CI)
• pooled estimates with fixed-effects meta-analysis
• trials assessed for heterogeneity and then individual patient data pooled
• all analyses were by intention to treat
• in-trial deaths, stratified analyses:
  • gastrointestinal cancers vs other solid cancers vs haematological cancers
  • first 5 years after randomisation vs thereafter
  • common specific solid cancers (oesophagus, stomach, pancreas and biliary tract, colorectal, liver, lung, prostate, bladder and kidney, metastases with unknown primary)
• long-term risk of cancer death:
  • data from three UK trials with long-term follow up
  • heterogeneity as assessed
  • pooled individual patient data

Results summary:

In-trial deaths:

• 8 eligible trials of aspirin versus control
  • 674 cancer deaths among 25 570 patients
  • 2: primary prevention of vascular disease
  • 1: secondary prevention of recent vascular events
  • 5: prevention of vascular disease in groups with increased risk but without previous vascular events (diabetes, stable angina, low ankle brachial index)
• Individual patient data available for 7 trials
  • 657 cancer deaths among 23 535 patients
• Site of the primary cancer available in 6 trials:
  • 627 cancer deaths among 19 824 patients

Analysis of all trials, aspirin on the risk of death due to cancer:

• very little heterogeneity between trials
• overall: OR = 0.79, (95% CI 0.68-0.92), P =0.003
• aspirin 75-100 mg daily: OR = 0.81 (0.68-0.97), P = 0.03

Analysis of individual patient data, aspirin on the risk of death due to cancer:

• overall: HR = 0.82 (95% CI 0.70-0.95), P = 0.01
• after 5 years: HR = 0.66 (0.50-0.87), P = 0.003

Post-trial follow up:

• Long-term follow-up data (to 20 years) available in 3 trials
• 1634 cancer deaths among 12 659 patients

Analysis of risk of death due to cancer, 0-20 years:

• all cancers: HR = 0.78 (95% CI 0.70-0.87), P < 0.0001
• cancer types:
  • oesophagus: HR = 0.42 (0.25-0.71), P = 0.001
  • colorectal: HR = 0.60 (0.45-0.81), P = 0.0007
  • lung: HR = 0.71 (0.58-0.89), P = 0.002
  • adenocarcinoma: HR = 0.66 (0.56-0.77), P < 0.0001
• suggestive clinically relevant findings that did not reach statistical significance:
  • stomach: HR = 0.69 (0.43-1.10), P = 0.11
  • prostate: HR = 0.81 (0.61-1.06), P = 0.12
• non-significant findings:
  • pancreas
  • bladder and kidney
  • non-adenocarcinoma
  • haematological cancer

Study conclusion:

Daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention.

Participants:

• grouped data not given
• however, apart from two primary prevention studies, all participants were at risk at vascular events (either risks factors or secondary prevention)
• a variety of different study populations

Methodological weaknesses

• limitation due to the fact that the original studies were designed to examine vascular disease; effect from aspirin may be underestimated in this study
  • only three studies with long-term follow up data
  • aspirin intervention arms may have stopped aspirin at completion of trials
    • high drop out rates from aspirin even within trials (40% of the patients had stopped treatment by the end of the trial period in the three studies with long-term data)
• grouped participant characteristics not clearly described though appears to have been measured

Methodological strengths

• well conducted trial
• large number of study participants from double-blinded randomised trials
• ITT analyses to reduce bias
• heterogeneity measured
• pooled individual patient data
• consistent results between trials containing a number of different populations (though most had vascular risks); suggests generalisability of findings

Biases and conflicts of interests

• study declared as independent of any pharmaceutical company or other commercial interests
• the study authors have received various honoria, fees and subsidies from a number of different pharmaceutical companies, including those with an interest in antiplatelet drugs

Clinical relevance to primary health care

The role of aspirin in the primary prevention setting is unclear in general practice.  Although its utility is defined in the secondary prevention of cardiovascular disease, the evidence for primary prevention of cardiovascular disease is not ^[2], even in the presence of risk factors like diabetes ^[3].

This study demonstrated that daily aspirin (75 mg upwards) reduced the risk of cancer death by about 20% during cardiovascular trials, compared to no aspirin.  There was a 34% reduction of cancer deaths after 5 years.  Moreover, the protective effect was maintained in the longer term; at 20 years follow up, there was still a 20% relative risk reduction (7% absolute reduction at age 65 and older) in cancer mortality.  Aspirin was found to reduce the mortality of:

• oesophageal cancer: ↓ 58%
• colorectal cancer: ↓ 40%
• lung cancer: ↓ 29%
• adenocarcinomas: ↓ 34%

At 20-years, there were also suggestive reductions in the cancer deaths of stomach and prostate cancer but these results did not reach statistical significance.

It is likely that these results can be generalised outside of the study situation and it is possible (if not probable) that they are an underestimate.  Some caution is required in interpreting these results; the original studies were not designed to evaluate the effect of aspirin on cancer mortality. This study does not provide evidence on the effect of long-term daily aspirin and nor does it provide evidence of the effect of aspirin on cancer incidence.  Moreover, aspirin had only a small effect on all cause mortality at the limits of statistical significance: RR=0.93, (95% CI 0.87-1.00), P = 0.045.

Nevertheless, these are exciting findings that changes the balance of risks and benefits in the use of aspirin for primary prevention. General practitioners working in primary health care could consider discussing these finding with their older patients, particularly those with an interest in taking regular aspirin.

Note: the absolute rate of major haemorrhage (not including haemorrhagic stroke) on daily aspirin is 0.1% (1 in 1000 people) per year.  This is an absolute increase of 0.03% (1 in 3300 people) per year ^[2].

References

1. Rothwell PM, Fowkes GR, Belch JFF, et al. Eff ect 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
2. Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373(9678): 1849-60
3. De Berardis G, Sacco, M, Strippoli GFM, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ 2009; 339: b4531