Annals of Oncology
characterize the beneficial pharmacological effects of compounds acting on their converging pathways, is, therefore, now an urgent call for researchers working in the field of obesity and cancer prevention and treatment. M. Bifulco* Faculty of Pharmacy and Medicine, University of Salerno, Salerno, Italy (*E-mail: [email protected])
disclosure The author has declared no conflicts of interest.
1. Bhaskaran K, Douglas I, Forbes H et al. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults. Lancet 2014; pii: S0140-6736(14)60892-8. 2. Kaaks R, Kühn T. Epidemiology: Obesity and cancer-the evidence is fattening up. Nat Rev Endocrinol 2014; 10(11): 644–645. 3. Lapeire L, Hendrix A, Lambein K et al. Cancer-associated adipose tissue promotes breast cancer progression by paracrine Oncostatin M and Jak/STAT3 signaling. Cancer Res 2014; 74(23): 6806–6819. 4. McDonnell DP, Park S, Goulet MT et al. Obesity, cholesterol metabolism, and breast cancer pathogenesis. Cancer Res 2014; 74(18): 4976–4982. 5. Copson ER, Cutress RI, Maishman T et al. Obesity and the outcome of young breast cancer patients in the UK: the POSH study. Ann Oncol 2015; 26(1): 101–112. 6. Bifulco M, Pisanti S. “Adiponcosis”: a new term to name the obesity and cancer link. J Clin Endocr Metab 2013; 98(12): 4664–4665. 7. Bifulco M, Vitale M. Thyroid Adiponcosis: more than an hypothesis. Endocrine 2014 Sep 2 [epub ahead of print], doi: 10.1007/s12020-014-0379-7. 8. Ligibel JA, Alfano CM, Courneya KS et al. American Society of Clinical Oncology Position Statement on Obesity and Cancer. J Clin Oncol 2014; 32(31): 3568–3574.
doi: 10.1093/annonc/mdu545 Published online 18 November 2014
The harms of low-dose aspirin prophylaxis are overstated We commend the authors of this paper for their exacting evaluation of the benefits of long-term low-dose aspirin on incidence vascular disease and cancer [1]. In 2008, a paper we published a paper with the title: ‘Aspirin for everyone older than 50?’ [2]. This report by Cuzick et al. removes the need for a question mark! Nevertheless, we are alarmed by the estimates Cuzick et al. make of the number of fatal internal bleeding attributable to aspirin, leading the media in the UK to refer to aspirin prophylaxis as ‘a lottery’. Evidence from community-based studies and from randomised, controlled trials shows that the estimate by Cuzick et al. of two extra deaths in 1000 individuals aged 60 who took low-dose aspirin for 10 years, is a gross overestimate if not a serious misinterpretation of available evidence. With regard to gastrointestinal bleeding, the authors estimate that, under the age of 70 years, 5% of spontaneous gastrointestinal bleeds lead to death while, over the age of 70 years, they assume that 10% of spontaneous bleeds are fatal. The figure of 5% fatal bleeds is well supported by community-based studies,
Volume 26 | No. 2 | February 2015
both in the general community and in selected subjects taking low-dose aspirin. Thus, in two community-based studies, the mortality rate from GI complications, which were mostly upper GI bleeding, was 5.7% and 5.6% [3]. In 3000 patients admitted to hospital because of adverse drug reactions (ADRs) to aspirin [4], 162 subjects had been taking low-dose aspirin and 7 of these (4.3%) had died. In the UK, a ‘Yellow Card Scheme’ (https:// yellowcard,mhra.gov.uk.5) facilitates the reporting of ADRs by health care professionals and by members of the public. The degree of under-reporting in this scheme is unknown but is likely to be low for the most serious, life-threatening ADRs. Since 1963, 1572 gastrointestinal bleeds in patients taking low-dose aspirin have been reported, 60 (3.8%) of which were fatal [5]. The incidence of fatal GI bleeds reported in randomised trials is similar (5.2% and 4% [6–8] and the proportion of bleeds that are fatal is not increased in the subjects allotted to aspirin. Thus, in the Anti-Thrombosis Trialists’ overview [6], there were 9 fatal GI bleeds in subjects on aspirin and 20 in those on placebo, giving an odds ratio (OR) for a fatal bleed from aspirin of 0.48 (0.17, 1.34). Another report [7] states that deaths attributable to bleeding in subjects randomised to aspirin were 3.9 per 100 000 subjects per year and 5.1 per 100 000 per year in those on placebo, giving an OR of 0.79 [95% confidence interval (CI) 0.38–1.64]. In a long-term follow-up of 34 trials [8], 8 of 203 GI bleeds (4%) were fatal in subjects on aspirin, and 15 of 132 (11%) of those on placebo were fatal, an OR for aspirin of 0.32 (95% CI 0.12–0.83). In yet another review of 35 trials involving 87 000 subjects, the OR for a fatal bleed in patients randomised to aspirin was 0.94 (95% CI 0.47–1.87) [9]. Cerebral bleeding attributable to aspirin is rare and information on deaths is sparse. Hypertension is a major factor and in the antithrombosis trialists overview a rise of 20 mmHg in blood pressure was associated with a doubling of cerebral haemorrhage (risk ratio (RR) 2.18; 95% CI 1.65–2.87) [6]. The Hypertensive Optimal Treatment (HOT) trial [10], however, was based on patients with hypertensive disease, all of whom were optimally treated with antihypertensive drugs. There was no evidence of any extra cerebral bleeds in 10 000 patients randomised to aspirin (19 cerebral bleeds, 7 fatal) as in ten thousand on placebo (20 bleeds, 8 fatal). Cuzick et al. include peptic ulceration when referring to fatal internal bleeds. Whether or not low-dose aspirin is ever responsible for peptic ulceration is uncertain. Gastric and intestinal mucosal damage can be seen on endoscopic examination following shortterm aspirin administration, but this appears to improve rapidly during continued aspirin taking [11]. Although a ‘second wave’ of deeper mucosal injury has been described and can be responsible for blood loss, this too appears to heal with continued aspirin taking [12]. On balance therefore, it seems unlikely that aspirin is responsible for peptic ulceration let alone fatal ulceration [13]. Finally, estimates of bleeding attributable to aspirin should take account of a steady fall in risk over time. In an overview of 17 randomised studies, there was a fourfold risk of a bleed in subjects on aspirin during the first month (RR 4.4; 95% CI 3.2–6.1) and this then fell rapidly [14]. Data from the long-term follow-up of randomised trials take this further and while GI bleeding attributable to aspirin during the first 3 years of aspirin taking was almost double that, in subjects on placebo (OR 1.95; 95% CI 1.47–2.59), the risk reduced during the following 2 years and there was no significant excess in GI bleeding after 5 years on aspirin [15].
doi:10.1093/annonc/mdu538 |
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on March 8, 2015
references
letters to the editor
letters to the editor In summary therefore, long-term, low-dose prophylactic aspirin would seem to be remarkably safe, probably far safer than implied by Cuzick et al. with their estimate of 2 deaths caused by aspirin for every 17 vascular and cancer deaths prevented. Furthermore, if subjects are adequately screened for gastric pathology and for hypertension and appropriately treated if present, fatal internal bleeding attributable to aspirin is likely to be exceedingly rare. P. Elwood* & G. Morgan Cochrane Institute of Primary Care and Public Health, Cardiff University, Cardiff, UK (*E-mail: [email protected])
disclosure
references 1. Cuzick J, Thorat MA, Bosetti C et al. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Ann Oncol 2014; 26: 47–57. 2. Elwood P, Morgan G, Brown G, Pickering J. Aspirin for everyone over 50? BMJ 2005; 330: 1440–1441. 3. Lanas A, Perez-Aisa MA, Feu F et al. A nationwide study of mortality associated with hospital admission due to severe GI events and those associated with NSAID use. Am J Gastroenterol 2005; 100: 1685–1693. 4. Pirmohamed M, James S, Meakin S et al. Adverse drug reactions as a cause of admission to hospital: retrospective analysis of 18,820 patients. BMJ 2004; 329: 15–19.10. 5. MRHA Private communication on 28 January 2012 from the UK Medicines and Healthcare products Regulatory Agency. MRHA: e-mail [email protected]. 6. Antithrombotic Trialists’ Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849–1860. 7. Morgan G. Aspirin for the primary prevention of vascular events? Public Health 2009; 123: 787. 8. Rothwell PM, Price JF, Fowkes FGR et al. Short-term effects of daily aspirin on cancer incidence, mortality and non-vascular death: analysis of the time course of risks and benefits in 51 randomised trials. Lancet 2012; 379: 1602–1612. 9. Lanas A, Wu P, Medin J, Mills EJ. Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. Clin Gastroenterol Hepatol 2011; 9: 762–768. 10. Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) trial. HOT study group. Lancet 1998; 351: 1755–1762. 11. Graham DY, Smith JL, Dobbs SM. Gastric adaption occurs with aspirin administration in man. Dig Dis Sci 1983; 28: 1–6. 12. Yeomans ND. Aspirin: old drug, new uses and challenges. J Gastroenterol Heptal 2011; 26: 426–431. 13. Laine L, Maller ES, Yu C et al. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double blind trial. Gastroenterology 2004; 127: 385–402. 14. Garcia Rodriguez LA, Hermandez S, de Abajo J. Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. Br J Clin Pharmacol 2001; 52: 563–571. 15. Rothwell P, Wilson M, Elwin C-E et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010; 376: 1741–1750.
doi: 10.1093/annonc/mdu538 Published online 21 November 2014
| letters to the editor
Reply to the letter to the editor ‘The harms of low-dose aspirin prophylaxis are overstated’ by P. Elwood and G. Morgan We thank Elwood and Morgan [1] for drawing attention to estimation of harms in our paper [2]. As stated in our paper, we opted for conservative analyses, and this implied that we chose to err on the side of over-estimating harms. Therefore, as Elwood and Morgan [1] suggest, it is possible that the true harms of prophylactic aspirin are lower than we estimated. We also undertook an extensive assessment of harms and this is now published as a separate paper [3]. Here, we draw attention to some important findings in support of our approach for estimation of harms associated with aspirin use. The two extra deaths per 1000 persons reported in the media [4] comprise of deaths due stroke, GI bleeding or peptic ulcer. Stroke deaths account for approximately two thirds of these extra deaths. The ATT Collaborators’ meta-analysis [5] reported a 21% increase in stroke deaths with aspirin use in primary prevention trials. This excess was primarily driven by an increase in the number of fatal haemorrhagic strokes (73% increase, P = 0.02); the number of other fatal strokes were similar in users and non-users. We used this effect size to estimate excess stroke deaths as the ATT data are most relevant for prophylactic use in the general population [2, 3], even though the overall increase in fatal strokes was not statistically significant. Elwood and Morgan [1] suggest that 5% of GI bleeds are fatal. Our systematic search [3] identified studies reporting rates between 5% and 10.7%. We also noted that co-morbidities were associated with a higher death rate [6–8] and the risk of death also increased with increasing age [9, 10]. Therefore, we assumed fatality rates of 5% below age 70 years and 10% above that age in our analyses. However, we acknowledge that these fatality rates were derived from hospital-based studies, i.e. the denominator was major bleeding and, therefore, the fatality rates for all bleeding (major and minor) in general population are likely to be lower [3]. Indeed, we found that the rates of deaths attributable to GI bleeding or peptic ulcer reported by the Office of National Statistics (ONS) for the year 2008 were 50%–60% lower than our estimates [3], although the ONS rates could also be an under-estimate. Several systematic reviews [5, 11–13] have reported that the relative increase in aspirin-associated risk of fatal bleeding is lower (20%–30%) than the increase in the risk of bleeding overall [3]. We agree with Elwood and Morgan [1] that this suggests that bleeding associated with aspirin is less likely to be fatal. However, further evidence (and perhaps an improved mechanistic understanding) is necessary before such effect can be incorporated into benefit-harm models. We also agree with Elwood and Morgan that optimal control of hypertension should be an important consideration in mitigation of aspirin related harms as we have already discussed [2, 3]. Three primary prevention trials—the Women’s Health Study (WHS), the Physician’s Health Study (PHS) and the British Doctors’ Trial (BDT) have reported on peptic ulcers. All three show an aspirin-associated 20%–60% increase in the risk of peptic
Volume 26 | No. 2 | February 2015
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on March 8, 2015
PE is an occasional advisor to Bayer HealthCare. All remaining authors have declared no conflicts of interest.
Annals of Oncology
characterize the beneficial pharmacological effects of compounds acting on their converging pathways, is, therefore, now an urgent call for researchers working in the field of obesity and cancer prevention and treatment. M. Bifulco* Faculty of Pharmacy and Medicine, University of Salerno, Salerno, Italy (*E-mail: [email protected])
disclosure The author has declared no conflicts of interest.
1. Bhaskaran K, Douglas I, Forbes H et al. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults. Lancet 2014; pii: S0140-6736(14)60892-8. 2. Kaaks R, Kühn T. Epidemiology: Obesity and cancer-the evidence is fattening up. Nat Rev Endocrinol 2014; 10(11): 644–645. 3. Lapeire L, Hendrix A, Lambein K et al. Cancer-associated adipose tissue promotes breast cancer progression by paracrine Oncostatin M and Jak/STAT3 signaling. Cancer Res 2014; 74(23): 6806–6819. 4. McDonnell DP, Park S, Goulet MT et al. Obesity, cholesterol metabolism, and breast cancer pathogenesis. Cancer Res 2014; 74(18): 4976–4982. 5. Copson ER, Cutress RI, Maishman T et al. Obesity and the outcome of young breast cancer patients in the UK: the POSH study. Ann Oncol 2015; 26(1): 101–112. 6. Bifulco M, Pisanti S. “Adiponcosis”: a new term to name the obesity and cancer link. J Clin Endocr Metab 2013; 98(12): 4664–4665. 7. Bifulco M, Vitale M. Thyroid Adiponcosis: more than an hypothesis. Endocrine 2014 Sep 2 [epub ahead of print], doi: 10.1007/s12020-014-0379-7. 8. Ligibel JA, Alfano CM, Courneya KS et al. American Society of Clinical Oncology Position Statement on Obesity and Cancer. J Clin Oncol 2014; 32(31): 3568–3574.
doi: 10.1093/annonc/mdu545 Published online 18 November 2014
The harms of low-dose aspirin prophylaxis are overstated We commend the authors of this paper for their exacting evaluation of the benefits of long-term low-dose aspirin on incidence vascular disease and cancer [1]. In 2008, a paper we published a paper with the title: ‘Aspirin for everyone older than 50?’ [2]. This report by Cuzick et al. removes the need for a question mark! Nevertheless, we are alarmed by the estimates Cuzick et al. make of the number of fatal internal bleeding attributable to aspirin, leading the media in the UK to refer to aspirin prophylaxis as ‘a lottery’. Evidence from community-based studies and from randomised, controlled trials shows that the estimate by Cuzick et al. of two extra deaths in 1000 individuals aged 60 who took low-dose aspirin for 10 years, is a gross overestimate if not a serious misinterpretation of available evidence. With regard to gastrointestinal bleeding, the authors estimate that, under the age of 70 years, 5% of spontaneous gastrointestinal bleeds lead to death while, over the age of 70 years, they assume that 10% of spontaneous bleeds are fatal. The figure of 5% fatal bleeds is well supported by community-based studies,
Volume 26 | No. 2 | February 2015
both in the general community and in selected subjects taking low-dose aspirin. Thus, in two community-based studies, the mortality rate from GI complications, which were mostly upper GI bleeding, was 5.7% and 5.6% [3]. In 3000 patients admitted to hospital because of adverse drug reactions (ADRs) to aspirin [4], 162 subjects had been taking low-dose aspirin and 7 of these (4.3%) had died. In the UK, a ‘Yellow Card Scheme’ (https:// yellowcard,mhra.gov.uk.5) facilitates the reporting of ADRs by health care professionals and by members of the public. The degree of under-reporting in this scheme is unknown but is likely to be low for the most serious, life-threatening ADRs. Since 1963, 1572 gastrointestinal bleeds in patients taking low-dose aspirin have been reported, 60 (3.8%) of which were fatal [5]. The incidence of fatal GI bleeds reported in randomised trials is similar (5.2% and 4% [6–8] and the proportion of bleeds that are fatal is not increased in the subjects allotted to aspirin. Thus, in the Anti-Thrombosis Trialists’ overview [6], there were 9 fatal GI bleeds in subjects on aspirin and 20 in those on placebo, giving an odds ratio (OR) for a fatal bleed from aspirin of 0.48 (0.17, 1.34). Another report [7] states that deaths attributable to bleeding in subjects randomised to aspirin were 3.9 per 100 000 subjects per year and 5.1 per 100 000 per year in those on placebo, giving an OR of 0.79 [95% confidence interval (CI) 0.38–1.64]. In a long-term follow-up of 34 trials [8], 8 of 203 GI bleeds (4%) were fatal in subjects on aspirin, and 15 of 132 (11%) of those on placebo were fatal, an OR for aspirin of 0.32 (95% CI 0.12–0.83). In yet another review of 35 trials involving 87 000 subjects, the OR for a fatal bleed in patients randomised to aspirin was 0.94 (95% CI 0.47–1.87) [9]. Cerebral bleeding attributable to aspirin is rare and information on deaths is sparse. Hypertension is a major factor and in the antithrombosis trialists overview a rise of 20 mmHg in blood pressure was associated with a doubling of cerebral haemorrhage (risk ratio (RR) 2.18; 95% CI 1.65–2.87) [6]. The Hypertensive Optimal Treatment (HOT) trial [10], however, was based on patients with hypertensive disease, all of whom were optimally treated with antihypertensive drugs. There was no evidence of any extra cerebral bleeds in 10 000 patients randomised to aspirin (19 cerebral bleeds, 7 fatal) as in ten thousand on placebo (20 bleeds, 8 fatal). Cuzick et al. include peptic ulceration when referring to fatal internal bleeds. Whether or not low-dose aspirin is ever responsible for peptic ulceration is uncertain. Gastric and intestinal mucosal damage can be seen on endoscopic examination following shortterm aspirin administration, but this appears to improve rapidly during continued aspirin taking [11]. Although a ‘second wave’ of deeper mucosal injury has been described and can be responsible for blood loss, this too appears to heal with continued aspirin taking [12]. On balance therefore, it seems unlikely that aspirin is responsible for peptic ulceration let alone fatal ulceration [13]. Finally, estimates of bleeding attributable to aspirin should take account of a steady fall in risk over time. In an overview of 17 randomised studies, there was a fourfold risk of a bleed in subjects on aspirin during the first month (RR 4.4; 95% CI 3.2–6.1) and this then fell rapidly [14]. Data from the long-term follow-up of randomised trials take this further and while GI bleeding attributable to aspirin during the first 3 years of aspirin taking was almost double that, in subjects on placebo (OR 1.95; 95% CI 1.47–2.59), the risk reduced during the following 2 years and there was no significant excess in GI bleeding after 5 years on aspirin [15].
doi:10.1093/annonc/mdu538 |
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on March 8, 2015
references
letters to the editor
letters to the editor In summary therefore, long-term, low-dose prophylactic aspirin would seem to be remarkably safe, probably far safer than implied by Cuzick et al. with their estimate of 2 deaths caused by aspirin for every 17 vascular and cancer deaths prevented. Furthermore, if subjects are adequately screened for gastric pathology and for hypertension and appropriately treated if present, fatal internal bleeding attributable to aspirin is likely to be exceedingly rare. P. Elwood* & G. Morgan Cochrane Institute of Primary Care and Public Health, Cardiff University, Cardiff, UK (*E-mail: [email protected])
disclosure
references 1. Cuzick J, Thorat MA, Bosetti C et al. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Ann Oncol 2014; 26: 47–57. 2. Elwood P, Morgan G, Brown G, Pickering J. Aspirin for everyone over 50? BMJ 2005; 330: 1440–1441. 3. Lanas A, Perez-Aisa MA, Feu F et al. A nationwide study of mortality associated with hospital admission due to severe GI events and those associated with NSAID use. Am J Gastroenterol 2005; 100: 1685–1693. 4. Pirmohamed M, James S, Meakin S et al. Adverse drug reactions as a cause of admission to hospital: retrospective analysis of 18,820 patients. BMJ 2004; 329: 15–19.10. 5. MRHA Private communication on 28 January 2012 from the UK Medicines and Healthcare products Regulatory Agency. MRHA: e-mail [email protected]. 6. Antithrombotic Trialists’ Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849–1860. 7. Morgan G. Aspirin for the primary prevention of vascular events? Public Health 2009; 123: 787. 8. Rothwell PM, Price JF, Fowkes FGR et al. Short-term effects of daily aspirin on cancer incidence, mortality and non-vascular death: analysis of the time course of risks and benefits in 51 randomised trials. Lancet 2012; 379: 1602–1612. 9. Lanas A, Wu P, Medin J, Mills EJ. Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. Clin Gastroenterol Hepatol 2011; 9: 762–768. 10. Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) trial. HOT study group. Lancet 1998; 351: 1755–1762. 11. Graham DY, Smith JL, Dobbs SM. Gastric adaption occurs with aspirin administration in man. Dig Dis Sci 1983; 28: 1–6. 12. Yeomans ND. Aspirin: old drug, new uses and challenges. J Gastroenterol Heptal 2011; 26: 426–431. 13. Laine L, Maller ES, Yu C et al. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double blind trial. Gastroenterology 2004; 127: 385–402. 14. Garcia Rodriguez LA, Hermandez S, de Abajo J. Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. Br J Clin Pharmacol 2001; 52: 563–571. 15. Rothwell P, Wilson M, Elwin C-E et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010; 376: 1741–1750.
doi: 10.1093/annonc/mdu538 Published online 21 November 2014
| letters to the editor
Reply to the letter to the editor ‘The harms of low-dose aspirin prophylaxis are overstated’ by P. Elwood and G. Morgan We thank Elwood and Morgan [1] for drawing attention to estimation of harms in our paper [2]. As stated in our paper, we opted for conservative analyses, and this implied that we chose to err on the side of over-estimating harms. Therefore, as Elwood and Morgan [1] suggest, it is possible that the true harms of prophylactic aspirin are lower than we estimated. We also undertook an extensive assessment of harms and this is now published as a separate paper [3]. Here, we draw attention to some important findings in support of our approach for estimation of harms associated with aspirin use. The two extra deaths per 1000 persons reported in the media [4] comprise of deaths due stroke, GI bleeding or peptic ulcer. Stroke deaths account for approximately two thirds of these extra deaths. The ATT Collaborators’ meta-analysis [5] reported a 21% increase in stroke deaths with aspirin use in primary prevention trials. This excess was primarily driven by an increase in the number of fatal haemorrhagic strokes (73% increase, P = 0.02); the number of other fatal strokes were similar in users and non-users. We used this effect size to estimate excess stroke deaths as the ATT data are most relevant for prophylactic use in the general population [2, 3], even though the overall increase in fatal strokes was not statistically significant. Elwood and Morgan [1] suggest that 5% of GI bleeds are fatal. Our systematic search [3] identified studies reporting rates between 5% and 10.7%. We also noted that co-morbidities were associated with a higher death rate [6–8] and the risk of death also increased with increasing age [9, 10]. Therefore, we assumed fatality rates of 5% below age 70 years and 10% above that age in our analyses. However, we acknowledge that these fatality rates were derived from hospital-based studies, i.e. the denominator was major bleeding and, therefore, the fatality rates for all bleeding (major and minor) in general population are likely to be lower [3]. Indeed, we found that the rates of deaths attributable to GI bleeding or peptic ulcer reported by the Office of National Statistics (ONS) for the year 2008 were 50%–60% lower than our estimates [3], although the ONS rates could also be an under-estimate. Several systematic reviews [5, 11–13] have reported that the relative increase in aspirin-associated risk of fatal bleeding is lower (20%–30%) than the increase in the risk of bleeding overall [3]. We agree with Elwood and Morgan [1] that this suggests that bleeding associated with aspirin is less likely to be fatal. However, further evidence (and perhaps an improved mechanistic understanding) is necessary before such effect can be incorporated into benefit-harm models. We also agree with Elwood and Morgan that optimal control of hypertension should be an important consideration in mitigation of aspirin related harms as we have already discussed [2, 3]. Three primary prevention trials—the Women’s Health Study (WHS), the Physician’s Health Study (PHS) and the British Doctors’ Trial (BDT) have reported on peptic ulcers. All three show an aspirin-associated 20%–60% increase in the risk of peptic
Volume 26 | No. 2 | February 2015
Downloaded from http://annonc.oxfordjournals.org/ at KTH Royal Institute of Technology on March 8, 2015
PE is an occasional advisor to Bayer HealthCare. All remaining authors have declared no conflicts of interest.
Annals of Oncology
