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Requests for reprints should be addressed to Edward J. Mills, PhD, MSc, University of Ottawa, Faculty of Health Sciences, 43 Templeton Street, Ottawa, Ontario K1N 6X1, Canada
Low-dose aspirin is a common strategy for preventing cardiovascular disease and associated mortality. A recent individual patient data meta-analysis of 8 trials of low- and high-dose aspirin, with long-term follow-up, found important reductions in cancer mortality. We aimed to determine whether cancer mortality also is reduced by low-dose aspirin in the shorter term.
Methods
We conducted a comprehensive search of 10 electronic databases up to December 2011. We conducted a meta-analysis using data from all randomized clinical trials evaluating low-dose (75-325 mg) daily aspirin. We extracted data on non-cardiovascular disease mortality and cancer mortality. We pooled studies using a random-effects model and conducted a meta-regression. We supplemented this with a cumulative meta-analysis and trial sequential monitoring analysis.
Results
Twenty-three randomized studies reported on nonvascular death. There were 944 nonvascular deaths of 41,398 (2.28%) patients receiving low-dose aspirin and 1074 nonvascular deaths of 41,470 (2.58%) patients not receiving aspirin therapy. The relative risk of nonvascular death was 0.88 (95% confidence interval [CI], 0.81-0.96, I2 = 0%). Eleven trials included data evaluating cancer mortality involving 16,066 patients. There were 162 of 7998 (2.02%) and 210 of 8068 (2.60%) cancer deaths among low-dose aspirin users versus non-aspirin users, respectively, reported over an average follow-up of 2.8 years. The relative risk of cancer mortality was 0.77 (95% CI, 0.63-0.95, I2 = 0%). Studies demonstrated a significant treatment effect after approximately 4 years of follow-up. The optimal information size analysis showed that a sufficient number of patients had been randomized to provide convincing evidence of a preventive role of low-dose aspirin in nonvascular deaths.
Conclusion
Nonvascular deaths, including cancer deaths, are reduced with low-dose aspirin.
Aspirin (acetylsalicylic acid) is a mainstay of therapy for high-risk patients with cardiovascular disease for the prevention of cardiovascular events such as myocardial infarction.
Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
Randomized trials document that patients with prior cardiovascular disease have fewer cardiovascular events and deaths with the use of low-dose aspirin compared with patients who do not use low-dose aspirin.
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
Within primary prevention populations and elevated risk primary prevention populations, the role of low-dose aspirin for cardiovascular disease protection is less clear.
Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
Recent studies of high-dose aspirin demonstrate a cancer prevention role.
•
This meta-analysis shows conclusive evidence that low-dose aspirin offers cancer preventive effects that are clinically meaningful (relative risk, 0.77; 95% confidence interval, 0.63-0.95) and observed after approximately 4 years.
A recent randomized trial was reported that evaluated the preventive role of aspirin for cancer. In 2011, Burn et al
published a study examining 600 mg of aspirin per day among carriers of Lynch syndrome, the major form of hereditary colorectal cancer, and demonstrated a significant protective effect. This study provides compelling evidence that higher doses of aspirin have an important role to play in cancer protection. It is the only study currently completed that was designed to examine whether aspirin prevents cancer occurrence.
An individual patient data meta-analysis involving 8 randomized clinical trials demonstrated that aspirin reduced the long-term risk of cancer mortality (odds ratio [OR], 0.79; 95% CI, 0.68-0.92).
This effect was observed after only 5 years of treatment (OR, 0.66; 95% CI, 0.50-0.87) regardless of dose. This effect was consistent across all cancers, and the effect increased according to the duration of treatment, up to 20 years. Originally, the included trials were designed to examine cardiovascular disease prevention and ranged in doses from low dose (75 mg) to higher dose (500 mg). Although interest in aspirin for chemoprevention of cancers has existed for some time,
British Doctors Aspirin Trial and the UK-TIA Aspirin Trial Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies.
included trials with a minimum of 4 years of follow-up and included only 4 randomized clinical trials involving low-dose aspirin. We aimed to determine whether the cancer benefits of aspirin extend to low-dose aspirin by examining all published randomized clinical trials of low-dose aspirin regardless of duration.
Materials and Methods
Eligibility Criteria
Because most aspirin trials have been conducted to evaluate cardiovascular protection, we included any randomized clinical trial evaluating the therapeutic role of low-dose aspirin given on a daily basis in any population. We recognized that trials infrequently examined the outcome of cancer incidence and thus focused on non-cardiovascular disease and cancer mortality. Trials had to provide low-dose aspirin alone. Low-dose aspirin is defined as 75 to 325 mg daily.
ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.
We excluded nonrandomized trials, non-daily dosing, pharmacokinetic studies, and studies reporting only on surrogate markers of safety.
Search Strategy and Study Selection
Independently and in duplicate we searched the following databases from inception to December 2011: PubMed via MedLine, EMBASE, AMED, CinAHL, TOXNET, Cochrane CENTRAL, PsychINFO, and Web of Science, databases that included the full text of journals (ScienceDirect and Ingenta). In addition, the bibliographies of published systematic reviews were searched.
Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
We did not limit our search by language, patient status, or age. Search terms included the specific medication names and the truncated term “random*.”
Two investigators (EM, PW) working independently, in duplicate, scanned all abstracts and obtained the full text reports of records that indicated or suggested that the study was a randomized clinical trial evaluating low-dose aspirin. After obtaining full reports of the candidate trials, the same reviewers independently assessed eligibility from full text articles.
Data Abstraction and Analysis
The same 2 investigators conducted data extraction independently using a standardized pre-piloted form. We abstracted data independently, in duplicate, on the study populations. We defined the aspirin dosing, coadministered therapy, and control interventions. For the purpose of inferring study quality, we abstracted data on the reporting of sequence generation, allocation concealment, blinding status, use of intent-to-treat principal, and loss to follow-up of more than 20% considered important. However, we chose a priori not to use study quality as an inclusion criteria or bias estimate because reporting quality does not confer actual trial quality.
An observational study found that authors of randomized controlled trials frequently use concealment of randomization and blinding, despite the failure to report these methods.
We abstracted clinical data on the n completing the trial, all-cause mortality, non-cardiovascular disease mortality, and cancer mortality. We entered the data into an electronic database such that duplicate entries existed for each study; when the 2 entries did not match, we resolved differences through discussion and consensus.
Analysis
To assess inter-rater reliability on inclusion of articles, the Phi (ϕ) statistic was calculated. This provides a measure of interobserver agreement independent of chance.
For outcomes, we used relative risk as the primary effect measure. For studies that did not report intent to treat, we analyzed outcomes as all-patients randomized.
Users' guides to the medical literature: XX. Integrating research evidence with the care of the individual patient. Evidence-Based Medicine Working Group.
Our analysis assumes that all control interventions yield, more or less, a similar direction of treatment effect, an approach used by the Antithrombotic Trialists' Collaboration.
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
We applied the I2 statistic for each analysis as a measure of the proportion of the overall variation that is attributable to between-study heterogeneity.
We conducted a univariate random-effects meta-regression assessing the impact of duration and dose on effect sizes. To estimate the period with which treatment effects become significant between groups, we conducted a cumulative meta-analysis based on shortest to longest duration trials. Finally, we conducted a trial sequential analysis to determine the strength of information for our meta-analysis on the outcome of nonvascular mortality to determine the conservative number of patients required to provide an authoritative answer of therapeutic efficacy.
We applied a Lan-DeMets sequential monitoring boundary based on the event rates found in the studies, with heterogeneity-adjusted optimal information size. Analyses were conducted using Meta-analyst (Tufts University 2010) and Trial Sequential Analysis View (Copenhagen Trials Unit 2011, v 0.9).
Results
There was near-perfect agreement between reviewers on inclusion of the 23 studies (Phi = 0.85, Figure 1). The 23 publications included 41,398 patients receiving aspirin and 41,470 patients receiving control interventions for an average of 2.5 years. We included data on 25 trials reporting specifically on nonvascular deaths;
Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude Medical prosthesis: a clinical and transesophageal echocardiographic study.
Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.
Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial HOT Study Group.
Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation A randomized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane; FFAACS).
Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina Results of a Veterans Administration Cooperative Study.
Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Collaborative Group of the Primary Prevention Project.
The Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation The Copenhagen AFASAK study.
Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group.
Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke EAFT (European Atrial Fibrillation Trial) Study Group.
Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude Medical prosthesis: a clinical and transesophageal echocardiographic study.
Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation A randomized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane; FFAACS).
Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina Results of a Veterans Administration Cooperative Study.
The Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group.
Eleven trials, all secondary prevention of cardiovascular disease, reported specifically on cancer mortality, involving 7998 aspirin recipients and 8068 control patients, for an average follow-up of 33.6 months (range 1-80).
Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude Medical prosthesis: a clinical and transesophageal echocardiographic study.
Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation A randomized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane; FFAACS).
Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina Results of a Veterans Administration Cooperative Study.
The Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group.
Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude Medical prosthesis: a clinical and transesophageal echocardiographic study.
Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.
Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial HOT Study Group.
Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation A randomized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane; FFAACS).
Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina Results of a Veterans Administration Cooperative Study.
Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Collaborative Group of the Primary Prevention Project.
The Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation The Copenhagen AFASAK study.
Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group.
Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke EAFT (European Atrial Fibrillation Trial) Study Group.
Reports variably reported methodologic issues. Twenty of 23 reported sequence generation, 15 of 23 reported allocation concealment, 23 of 23 reported blinding status, 23 of 23 reported use of intent-to-treat principal, and 3 of 23 lost more than 20% to follow-up.
Non-cardiovascular Disease Mortality
Twenty-four trials in 23 publications reported on nonvascular deaths.
Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude Medical prosthesis: a clinical and transesophageal echocardiographic study.
Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.
Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial HOT Study Group.
Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation A randomized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane; FFAACS).
Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina Results of a Veterans Administration Cooperative Study.
Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice Collaborative Group of the Primary Prevention Project.
The Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation The Copenhagen AFASAK study.
Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group.
Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke EAFT (European Atrial Fibrillation Trial) Study Group.
There were 944 (2.28%) nonvascular deaths in the aspirin groups and 1074 (2.58%) deaths in the control groups. This results in a relative risk of 0.88 (95% CI, 0.81-0.96, P = .003, I2 = 0%). Figure 2 shows the pooled study findings.
Figure 2Nonvascular mortality. Forest plot displays the individual relative risk point estimates with 95% CI and the pooled overall relative risk estimate. UK-TIA = United Kingdom Transient Ischemic Attack; PHS = Physicians' Health Study; ECLAP = European Collaboration on Low-dose Aspirin in Polycythemia Vera; TPT = Thrombosis Prevention Trial; SPAF = Stroke Prevention in Atrial Fibrillation; CLIPS = Critical Leg Ischaemia Prevention Study; HOT = Hypertension Optimal Treatment; PEP = Pulmonary Embolism Prevention; FFAACS = Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane; SALT = Swedish Aspirin Low-Dose Trial; PPP = Primary Prevention Project; POPADAD = Prevention Of Progression of Arterial Disease And Diabetes; AFASAK = The Atrial Fibrillation, Aspirin and Anticoagulant Therapy Study; SAPAT = Swedish Angina Pectoris Aspirin Trial; EAFT = European Atrial Fibrillation Trial.
Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude Medical prosthesis: a clinical and transesophageal echocardiographic study.
Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation A randomized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane; FFAACS).
Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina Results of a Veterans Administration Cooperative Study.
The Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group.
There were a total of 162 cancer deaths (2.02%) in the aspirin group and 210 cancer deaths (2.60%) in the control groups. This resulted in a significant reduction in cancer mortality (relative risk, 0.77, 95% CI, 0.63-0.94, P = .019, I2 = 0%) in favor of a protective effect from low-dose aspirin treatment. Figure 3 shows the pooled study findings.
Figure 3Cancer mortality. Forest plot shows the individual relative risk point estimates with 95% CI and the pooled overall relative risk estimate. UK-TIA = United Kingdom Transient Ischemic Attack; TPT = Thrombosis Prevention Trial; CLIPS = Critical Leg Ischaemia Prevention Study; FFAACS = Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane; SALT = Swedish Aspirin Low-Dose Trial; POPADAD = Prevention Of Progression of Arterial Disease And Diabetes; SAPAT = Swedish Angina Pectoris Aspirin Trial.
We examined whether trials of a longer duration exhibited larger treatment effects, but this was not significant (coefficient−0.16, 95% CI,−0.67 to 0.34, P = .52). We also examined whether the dosage of aspirin (from 75 to 325 mg/d) affects the size of the effect, but a significant effect was not demonstrated (coefficient−0.12, 95% CI,−0.51 to 0.25, P = .51).
We conducted a cumulative meta-analysis examining trials from shortest to longest follow-up to determine when early significant effects were observed (Figure 4). The current analysis found that significant effects were observed after an average of 4 years of follow-up.
Figure 4Cumulative effects of aspirin on cancer mortality. Cumulative Forest plot shows the individual relative risk point estimates with 95% CI according to shortest to longest duration of trials reporting cancer mortality. FFAACS = Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane; CLIPS = Critical Leg Ischaemia Prevention Study; SALT = Swedish Aspirin Low-Dose Trial; TPT = Thrombosis Prevention Trial; UK-TIA = United Kingdom Transient Ischemic Attack; SAPAT = Swedish Angina Pectoris Aspirin Trial; POPADAD = Prevention Of Progression of Arterial Disease And Diabetes.
We conducted a trial sequential analysis and optimal information size. On the basis of the existing event rates of nonvascular deaths, the optimal information size of 33,586 was surpassed.
Discussion
In our analysis, we confirmed the findings of a previous individual patient data meta-analysis
that aspirin exhibits large cancer mortality protection. Additional knowledge based on this analysis includes the protective status of exclusively low-dose aspirin, the use of all published data, and the confirmation that aspirin protective elements seem to begin in the short term (∼4 years). These findings highlight the important role of aspirin in cancer protection and should be clinically useful for counseling both low- and high-risk patients with cardiovascular disease on the use of aspirin. Because any aspirin use is associated with increased risk of both gastrointestinal and nongastrointestinal bleeding, including cerebral bleeds, clinicians should be aware that the benefits of aspirin use must be balanced with bleeding risks.
There are both strengths and limitations to consider when interpreting our analysis. Strengths include our extensive searching of the literature for any randomized clinical trial of low-dose aspirin daily use. This provides greater inferences on the generalizability of aspirin therapy than the individual patient data analysis, although with less specificity. Our study examined both nonvascular deaths and cancer deaths. The individual patient data analysis did not examine nonvascular deaths and included 4 of the 11 cancer mortality trials that we included.
Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk The Medical Research Council's General Practice Research Framework.
The Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group.
However, these were some of the larger studies in our analysis and contributed some of the largest weight to the analysis. If we use only these 4 studies, the pooled relative risk is 0.77 (95% CI, 0.61-0.96, P = .02, I2 = 0%). Our analysis is limited by a lack of individual-level patient data in terms of allowing subgroup analysis, access to data on the incidence of cancers that did not result in deaths during the study periods, and long-term follow-up. It is likely that longer-term studies will identify the incidence of cancers more appropriately than short-term studies. Given that our studies were of a relatively short duration (average follow-up of 2.5 years), it is likely that we underestimate the effect of long-term treatment with aspirin on cancer deaths. The individual patient data analysis included trials with up to 20 years of follow-up and found a similar effect to ours.
There is likely reporting bias in terms of cancer mortality because studies were designed to evaluate cardiovascular disease outcomes. This confers 2 interesting issues: first, that cancer may be underreported (only 11 trials reported cancer mortality), and second, that publication bias is unlikely because study authors likely could not foresee that data would one day be used to evaluate cancer risks. Cancer can develop at any period of a patient's life. However, we included trials enrolling patients for cardiovascular disease protection that also reported on cancer mortality. We found that 12 trials reporting on nonvascular deaths failed to report on cancer deaths. It seems likely that the cardiovascular disease patient groups included in these trials may be at a different risk for cancer than higher-risk patients, although many had a history of risk factors for cancer, including diabetes and smoking.
Another recent individual patient data meta-analysis by the Antithrombotic Trialists' Collaboration
Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
focused on cardiovascular disease prevention with aspirin among primary prevention populations. The study found no significant cardiovascular disease protection but did find an increased risk of major bleeding. This creates a possible conundrum for clinicians. On the basis of our analysis and the individual patient data cancer analysis, the benefits of aspirin for cancer prevention are likely based on pleiotropic effects, perhaps anti-inflammatory, and other apoptotic effects, rather than only antithrombolytic effects.
Thus, many patients will request low-dose aspirin from clinicians or begin using it according to over-the-counter availability. However, even low-dose aspirin is associated with bleeding risks and certain populations increase the likelihood of bleeding events.
We previously demonstrated a risk of major bleeding from low-dose aspirin as an OR of 1.55 (95% CI, 1.27-1.90) compared with placebo and increasing in the presence of specific risks.
These include patients with long-term pharmacotherapy use, patients using combinations of low-dose aspirin with clopidogrel and warfarin, and patients with previous gastrointestinal ulcers or bleedings.
ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.
ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.
serious gastrointestinal bleeding and nongastrointestinal bleeding may be more difficult to prevent, especially among populations at a high-risk of bleeding. Proton-pump inhibitors seem to display a protective element for gastrointestinal bleeding even in aspirin-experienced and pharmacotherapy patients.
Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial.
Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial.
first hypothesized a polypill to reduce cardiovascular disease mortality based on the widespread use of simple and effective generic drugs for both poor and wealthy populations.
The polypill for cardiovascular disease combines generic and cheap drugs to reduce cholesterol, blood pressure, and thrombosis. It is now being evaluated in randomized trials.
Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial.
Perhaps a polypill for cancer prevention will exist in the future. Although it may be too early to speculate on combination formulations, it seems likely that aspirin will now be a backbone of cancer prevention strategies.
Conclusions
Our study demonstrates an important effect of low-dose aspirin for the prevention of nonvascular and cancer mortality that can be realized in the relative short term. The impact of widespread aspirin use on cancer mortality may have a large and important impact on public health. Public awareness of this may lead to widespread use of low-dose aspirin with or without clinician or pharmacist consultation. Clinicians and pharmacists should be prepared to discuss the broad benefits and risks of aspirin beyond their traditional use in cardiovascular disease. The emerging evidence on aspirin's cancer protection highlights an exciting time for cancer prevention through low-cost interventions.
References
Baigent C.
Blackwell L.
Collins R.
et al.
Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.
An observational study found that authors of randomized controlled trials frequently use concealment of randomization and blinding, despite the failure to report these methods.
Users' guides to the medical literature: XX. Integrating research evidence with the care of the individual patient. Evidence-Based Medicine Working Group.
Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude Medical prosthesis: a clinical and transesophageal echocardiographic study.
Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk.
Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.
Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
The Prevention Of Progression of Arterial Disease And Diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial.
Two important meta-analyses recently established the definitive additional benefit of long-term use of aspirin in the prevention of cancer development and risk of death.1,2 The extended use of aspirin has shown reductions in cancer incidence and mortality with its low case-fatality (decreasing metastases), which add to the case for daily aspirin as a potential chemopreventive agent against cancers.3,4
Mills et al1 demonstrated that the benefits of low-dose aspirin on cancer mortality protection seem to begin in the short term (∼4 years). The authors suggested that these benefits likely were based on pleiotropic effects, rather than only on antithrombotic action. Indeed, these data confirm a previous suggestion that an anticarcinogenic mechanism of prolonged aspirin use may be related to aspirin-induced chronic iron loss.2
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