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Aspirin in Elderly "Healthy" Men Over 65 - Not Effective, Caused Excessive Bleeding, Increased Cancer Rates
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Download the PDF here
Download the PDF here
Download the PDF here
from Jules: In the main study of 19,000 men aspirin (100mg) did not statistically prevent CVD in relatively healthy men over 65. They call them healthy. looking at Table 1 11% had diabetes, 65% lipidemia, 26% chronic kidney disease, 34$ stain use, Of more 34% were taking a statin so one could suggest if there was no statin use at all would they have found s CVD benefit, perhaps. But the 3 published studies also found greater risk for bleeding and a suggestion of increased cancer risk. One could say the 100mg dose might increase bleeding risk but in the face of this collective data the benefit of aspirin is at least very questionable as found in this study in older who are healthy. But there have other recent studies finding similarly but these studies were in persons at greater CVD risk, diabetes and Moderate" risk, similarly a relatively high percentage were also on statin:
- Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus [75% were on statin]..,.also is study looking at n-3 fatty acids in sub study, also in diabetics with 75% using a statin, adherence was 77% - (09/10/18)
- Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial - (09/07/18)
- ASCEND study results: Definitive data on the use of aspirin and omega-3 fatty acids in diabetic patients - (09/19/18)
- ASCEND: Aspirin Not Needed for Primary Prevention in Diabetes - (09/19/18)
(1) The rate of major adverse cardiovascular events was 7.8 events per 1000 person-years in the aspirin group and 8.8 events per 1000 person-years in the placebo group (hazard ratio, 0.89; 95% CI, 0.77 to 1.03) (Table 2, and Fig. S2 in the Supplementary Appendix). Individual rates of myocardial infarction, ischemic stroke, fatal cardiovascular disease, and hospitalization for heart failure were similar in the two groups (Table 2, and Figs. S3 and S4 in the Supplementary Appendix).
There was no evidence of a differential effect of aspirin on the risk of cardiovascular disease in any analyses of the prespecified subgroups or in post hoc analyses of subgroups of potential relevance to the risk of cardiovascular disease.
(2) The rate of major hemorrhage was 8.6 events per 1000 person-years in the aspirin group, as compared with 6.2 events per 1000 person-years in the placebo group (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). The progressive increase in the cumulative incidence of major hemorrhage across the trial follow-up period indicates that the risk of bleeding persisted throughout the course of therapy (Figure 2). The rate of fatal hemorrhage was less than 1 event per 1000 person-years in each group.
Gastrointestinal bleeding accounted for just less than half the major hemorrhagic events. The higher risk of upper gastrointestinal bleeding with aspirin than with placebo was particularly pronounced (hazard ratio, 1.87; 95% CI, 1.32 to 2.66) (Table 3). The risk of intracranial bleeding was also higher with aspirin than with placebo (hazard ratio, 1.50; 95% CI, 1.11 to 2.02) (Fig. S9 in the Supplementary Appendix), and this finding was reflected across all subtypes of intracranial bleeding (Table 3). There was no evidence of a differential effect of aspirin on the risk of bleeding in any subgroup analysis, except for the possibility of a less harmful effect with increasing age (Figs. S10 and S11 in the Supplementary Appendix).
Regarding bleeding here is what authors say: These two results - the absence of a large benefit on cardiovascular disease coupled with the higher risk of bleeding with the use of low-dose aspirin - are compatible with the results of a recent meta-analysis of eight primary prevention trials, predominantly involving adults younger than 70 years of age, which showed a 17% lower risk of nonfatal myocardial infarction and a 14% lower risk of stroke, coupled with a higher risk of serious bleeding, among participants who received aspirin than among those in control groups.33,40-47 As would be expected, the incidence of bleeding in this trial was substantially higher than the incidence in trials with younger participants.16,17,34 Because this trial enrolled healthy older persons from the general population, the results are likely to be broadly applicable to the healthy elderly, who are typically considered for primary prevention of cardiovascular disease. In contrast with most previous primary prevention trials, this trial did not enroll participants on the basis of elevated cardiovascular risk.
(3) Cancer risk HIGHER with aspirin: Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years. Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56).
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2nd publication reported:
"Effect of Aspirin on Disability-free Survival in the Healthy Elderly". In this trial involving community-dwelling older adults who were free from known cardiovascular disease, dementia, or major physical disability, the daily use of 100 mg of enteric-coated aspirin did not differ significantly from placebo in influencing the rates of disability-free survival at a median of 4.7 years......The rate of the composite of death, dementia, or persistent physical disability was 21.5 events per 1000 person-years in the aspirin group and 21.2 per 1000 person-years in the placebo group (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11; P=0.79). The rate of adherence to the assigned intervention was 62.1% in the aspirin group and 64.1% in the placebo group in the final year of trial participation. Differences between the aspirin group and the placebo group were not substantial with regard to the secondary individual end points of death from any cause (12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group), dementia, or persistent physical disability. The rate of major hemorrhage was higher in the aspirin group than in the placebo group (3.8% vs. 2.8%; hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001).
Conclusions
Aspirin use in healthy elderly persons did not prolong disability-free survival over a period of 5 years but led to a higher rate of major hemorrhage than placebo.
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3rd publication:
Effect of Aspirin on All-Cause Mortality in the Healthy Elderly.....cancer
Background
In the primary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, now published in the Journal, we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability-free survival among older adults. A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo.
Methods
From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. Deaths were classified according to the underlying cause by adjudicators who were unaware of trial-group assignments. Hazard ratios were calculated to compare mortality between the aspirin group and the placebo group, and post hoc exploratory analyses of specific causes of death were performed.
Results
Of the 19,114 persons who were enrolled, 9525 were assigned to receive aspirin and 9589 to receive placebo. A total of 1052 deaths occurred during a median of 4.7 years of follow-up. The risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (hazard ratio, 1.14; 95% confidence interval [CI], 1.01 to 1.29). Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years. Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56).
Among participants who received aspirin, the major contributor to the higher all-cause mortality was the higher risk of death for which the underlying cause was adjudicated to be cancer. The risk of cancer-related death was 6.7 events per 1000 person-years in the aspirin group and 5.1 events per 1000 person-years in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56) (Table S3 in the Supplementary Appendix). In a separate analysis that was based on a tabulation of the number of deaths in which cancer was recorded as a contributing cause on the death certificate, a similar pattern was observed, with 272 deaths (6.2 events per 1000 person-years) in the aspirin group and 206 deaths (4.6 events per 1000 person-years) in the placebo group. In curves showing the cumulative incidence of death according to each major cause, there is a progressive divergence beginning in the third year after randomization in the curves for death from any cause1 and for death related to cancer, as compared with the curves for death related to other major causes (Figure 1).
Table 2 shows cancer-related mortality according to the type of cancer. Despite the small number of deaths associated with each type of cancer, it is apparent that the higher cancer-related mortality in the aspirin group was not confined to specific tumor locations or pathologic types. A higher rate of death from gastrointestinal cancer (including colorectal cancer) in the aspirin group than in the placebo group contributed substantially to the overall excess mortality associated with aspirin. The excess cancer-related mortality among participants who received aspirin was seen both among those who entered the trial with a personal history of cancer (with cancer-related death occurring in 94 such participants in the aspirin group and in 88 in the placebo group) and among those in whom cancer was first diagnosed after randomization (with cancer-related death occurring in 198 and 138, respectively) (Table S3 in the Supplementary Appendix).
Conclusions
Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer-related death. In the context of previous studies, this result was unexpected and should be interpreted with caution.
AUTHORS SAID:
The biologic basis for either an early or a delayed effect of aspirin on cancer is unclear. Aspirin has been shown to influence various cellular and molecular pathways that are relevant to the initiation, progression, and spread of cancer.21 Questions may therefore arise about whether the biology of cancer differs among age groups with regard to the frequency of common molecular patterns, metastatic behavior, and treatment responses.
In the randomized, placebo-controlled ASPREE trial, the use of low-dose aspirin (100 mg per day for a median of 4.7 years) did not prolong disability-free survival among elderly participants, most of whom were 70 years of age or older at trial entry.1 Death from any cause, which was a component of the primary end point (disability-free survival) as well as a secondary end point, occurred in 558 participants in the aspirin group (at a rate of 12.7 events per 1000 person-years) and in 494 participants in the placebo group (at a rate of 11.1 events per 1000 person-years), with a hazard ratio of 1.14. The 95% confidence interval for the hazard ratio was 1.01 to 1.29. However, the calculation of the confidence interval did not account for the fact that multiple secondary end points were analyzed. Nevertheless, the results could not rule out an increase of 1 to 29% in all-cause mortality.
The apparent higher mortality in the aspirin group than in the placebo group was explained largely by higher cancer-related mortality in the aspirin group, with mortality related to major hemorrhage contributing only minimally. Cumulative incidence curves for death from any cause1 and cancer-related death were similar in the aspirin group and the placebo group during the first 3 years of the trial. Beyond that time, the curves for these end points in the aspirin group appeared to diverge progressively from the curves in the placebo group, whereas the curves for death related to other major causes were similar in the two groups. In an exploratory analysis, the hazard ratio for cancer-related death was 1.31 (95% CI, 1.10 to 1.56).
All-cause mortality and cancer-related mortality in the trial population were 32% and 49% of the rates in the general population, respectively. The lower rates in the trial population probably reflect the healthy nature of the trial volunteers and the exclusion of participants with previous cardiovascular or cerebrovascular disease, cognitive impairment, or a physician-estimated life expectancy of less than 5 years.
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Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly
NEJM Sept 16 2018
The use of low-dose aspirin as a primary prevention strategy in older adults resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo.....From 2010 through 2014, we enrolled community-dwelling men and women in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. The primary end point was a composite of death, dementia, or persistent physical disability; results for this end point are reported in another article in the Journal. Secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure).
Discussion
The ASPREE trial showed that, among elderly participants, the use of low-dose aspirin did not result in a significantly lower rate of the primary end point of disability-free survival (a composite that integrated the risks and benefits of aspirin) than placebo after a median follow-up of 4.7 years.19 On the basis of the results of previous trials, it was anticipated that benefits of aspirin treatment might arise from a reduction in the rate of cardiovascular events.28-35 However, in this trial, the rate of the prespecified secondary end point of cardiovascular disease (a composite that accounted for all cardiovascular events, including stroke due to intracranial hemorrhage and hospital admission for cardiac failure) was not significantly lower with low-dose aspirin than with placebo. The hazard ratio for this end point was 0.95 (95% CI, 0.83 to 1.08), which rules out the possibility of a major protective effect of aspirin but is compatible with a more modest lowering of risk of up to 17%. The rates of fatal cardiovascular disease and hospitalization for heart failure were similar in the two trial groups.
We also examined a nonprespecified end point of major adverse cardiovascular events, which was defined as a composite of fatal coronary heart disease, nonfatal myocardial infarction, or fatal or nonfatal ischemic stroke. This end point included the cardiovascular events that are most likely to be influenced favorably by aspirin. The rate of major adverse cardiovascular events did not differ significantly between the two groups. A similar conclusion was reached with regard to the individual rates of myocardial infarction and ischemic stroke.
Interpretation of these results should take into account the lower-than-expected rate of cardiovascular disease among the trial participants. In the trial protocol, the anticipated rate was 22.4 events per 1000 person-years. The observed rate was approximately half this estimate, most likely reflecting the relatively good health of the participant population at recruitment and the declining rate of cardiovascular disease in the two countries over time and across all age groups.36-39 Because of these factors, the absolute benefit that results from any proportionally lower rate of cardiovascular disease may be less than the benefit observed in studies from previous decades and is less likely than it had been to outweigh the risk of adverse events from aspirin.
This trial also showed that the risk of major hemorrhage was significantly higher with aspirin than with placebo. Major hemorrhagic events primarily involved upper gastrointestinal and intracranial bleeding. The relative effect of aspirin use, as compared with placebo, on the risk of major hemorrhage was constant over time, suggesting that persons who receive low-dose aspirin have a risk of bleeding that does not decline with continued use.
These two results - the absence of a large benefit on cardiovascular disease coupled with the higher risk of bleeding with the use of low-dose aspirin - are compatible with the results of a recent meta-analysis of eight primary prevention trials, predominantly involving adults younger than 70 years of age, which showed a 17% lower risk of nonfatal myocardial infarction and a 14% lower risk of stroke, coupled with a higher risk of serious bleeding, among participants who received aspirin than among those in control groups.33,40-47 As would be expected, the incidence of bleeding in this trial was substantially higher than the incidence in trials with younger participants.16,17,34
Because this trial enrolled healthy older persons from the general population, the results are likely to be broadly applicable to the healthy elderly, who are typically considered for primary prevention of cardiovascular disease. In contrast with most previous primary prevention trials, this trial did not enroll participants on the basis of elevated cardiovascular risk.
Current guidelines in the United States, Europe, and Australia have noted that there is limited evidence regarding the use of aspirin for primary prevention of cardiovascular disease in the elderly.48-50 Nevertheless, many millions of relatively healthy older persons in the United States and Australia take low-dose aspirin with the assumption that it will reduce the likelihood of future cardiovascular disease and stroke. Interpretation of the results of this trial should take into account the low percentage of participants (11%) who had been regularly taking low-dose aspirin before entering the trial. The trial did not directly address the question of whether healthy older persons who have been taking aspirin for primary prevention should continue its use.
This trial has some limitations. First, by the end of the trial, only approximately two thirds of the participants were still taking the assigned trial intervention, and this adherence rate may have led to an underestimation of any benefit of aspirin on cardiovascular outcomes. However, the adherence rate was sufficiently high for an increased bleeding risk to be identified, and the rate was probably similar to that seen in clinical practice.51,52 Second, the end point of major adverse cardiovascular events is commonly used in trials of antithrombotic therapy but was not prespecified in this trial. However, the results for this end point were similar to those for the prespecified end point that included hemorrhagic stroke and hospitalization for heart failure.
In conclusion, in this randomized trial involving healthy elderly persons who did not have known cardiovascular disease, the use of low-dose aspirin resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo.
Results
Participants and Follow-up
From March 2010 through December 2014, a total of 19,114 persons were enrolled in the trial and underwent randomization (9525 participants to the aspirin group and 9589 to the placebo group) (Fig. S1 in the Supplementary Appendix). The trial participants had a median age of 74 years at randomization, and 56% were women (Table 1). A total of 87% were Australian residents and 13% were U.S. residents. The two trial groups had similar cardiovascular risk profiles. At trial entry, one third of the participants reported use of statins and 14% reported regular use of NSAIDs.
The intervention phase ceased on June 12, 2017. All analyses were restricted to events that occurred through that date. The median follow-up was 4.7 years; 1.5% of the participants in the aspirin group and 1.6% of those in the placebo group had been lost to follow-up by the end of the trial, and 1.2% of the participants in each group had withdrawn consent (Fig. S1 in the Supplementary Appendix). In the final 12 months of the trial, 62% of the participants in the aspirin group and 64% of those in the placebo group were still taking the assigned trial intervention.
Cardiovascular Events
Rates of cardiovascular events are shown in Table 2 and Figure 1, and further details, including data on subclassification of the events, are provided in Table S3 in the Supplementary Appendix. The rate of the prespecified secondary end point of cardiovascular disease did not differ significantly between the aspirin group and the placebo group (10.7 events per 1000 person-years of follow-up and 11.3 events per 1000 person-years, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08).
The rate of major adverse cardiovascular events was 7.8 events per 1000 person-years in the aspirin group and 8.8 events per 1000 person-years in the placebo group (hazard ratio, 0.89; 95% CI, 0.77 to 1.03) (Table 2, and Fig. S2 in the Supplementary Appendix). Individual rates of myocardial infarction, ischemic stroke, fatal cardiovascular disease, and hospitalization for heart failure were similar in the two groups (Table 2, and Figs. S3 and S4 in the Supplementary Appendix).
There was no evidence of a differential effect of aspirin on the risk of cardiovascular disease in any analyses of the prespecified subgroups or in post hoc analyses of subgroups of potential relevance to the risk of cardiovascular disease (Figs. S5 and S6 in the Supplementary Appendix). There was also no evidence of an interaction between trial group and any of the subgroups with regard to the end point of major adverse cardiovascular events (Figs. S7 and S8 in the Supplementary Appendix).
Major Hemorrhagic Events
Rates of major hemorrhagic events are shown in Table 3, cumulative incidences are shown in Figure 2, and further details, including data on subclassification of the events, are provided in Table S4 in the Supplementary Appendix. The rate of major hemorrhage was 8.6 events per 1000 person-years in the aspirin group, as compared with 6.2 events per 1000 person-years in the placebo group (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). The progressive increase in the cumulative incidence of major hemorrhage across the trial follow-up period indicates that the risk of bleeding persisted throughout the course of therapy (Figure 2). The rate of fatal hemorrhage was less than 1 event per 1000 person-years in each group.
Gastrointestinal bleeding accounted for just less than half the major hemorrhagic events. The higher risk of upper gastrointestinal bleeding with aspirin than with placebo was particularly pronounced (hazard ratio, 1.87; 95% CI, 1.32 to 2.66) (Table 3). The risk of intracranial bleeding was also higher with aspirin than with placebo (hazard ratio, 1.50; 95% CI, 1.11 to 2.02) (Fig. S9 in the Supplementary Appendix), and this finding was reflected across all subtypes of intracranial bleeding (Table 3). There was no evidence of a differential effect of aspirin on the risk of bleeding in any subgroup analysis, except for the possibility of a less harmful effect with increasing age (Figs. S10 and S11 in the Supplementary Appendix)
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