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Across-the-board use of aspirin for primary prevention is “not justified” based on the results of ASPREE as well as the equivocal results from other recent primary prevention trials, according to Prakash C. Deedwania, MD, clinical professor of medicine and chief of the cardiology division at the Veterans Affairs Medical Center/University of California San Francisco Program in Fresno.
The importance of interpreting these studies lies in the recognition that while low-risk people don’t benefit, patients who are at mid to high cardiovascular (CV) risk clearly might. Aspirin’s role in secondary prevention after an initial CV event is clearly established, Dr. Deedwania added.
In ASPREE, a randomized, double-blind, placebo-controlled trial including nearly 20,000 participants, daily aspirin increased rates of major hemorrhage and did not significantly decrease risks of cardiovascular events, death, or other outcomes in healthy elderly individuals.
Aspirin did not prolong disability-free survival, a composite endpoint that included death, dementia, and permanent physical disability, according to one of three separate reports on ASPREE that were published in the New England Journal of Medicine.
Cardiovascular disease rates were likewise not significantly different between aspirin and placebo, with a hazard ratio that ruled out the possibility of a major protective effect, lead author John J. McNeil, MBBS, PhD, of Monash University, Melbourne, said in a second report on ASPREE.
All-cause mortality was actually higher in the aspirin arm versus the placebo arm, attributable largely to an excess of cancer-related deaths, Dr. McNeil and colleagues said in their third full report in the journal. However, that mortality finding needs to be interpreted with caution, they noted, given that previous investigations have shown a protective effect of aspirin on cancer-related death.
Potential harms of “innocuous” drug
The ASPREE (Aspirin in Reducing Events in the Elderly) study evaluated the use of aspirin as primary prevention in 19,114 healthy subjects, with a median age of 74 years, enrolled at 34 centers in Australia and the United States between 2010 and 2014.
The patients, who did not have cardiovascular disease, dementia, or disability at baseline, were randomized to daily 100-mg enteric-coated aspirin or placebo.
The rate of death, dementia, or disability was 21.5 events per 1,000 person-years in the aspirin group, and 21.2 events per 1,000 person-years in the placebo group, with a hazard ratio of 1.01 (95% confidence interval, 0.92-1.11; P = .79), Dr. McNeil and colleagues reported.
The rate of major hemorrhage was 8.6 events per 1,000 person-years for aspirin versus 6.2 events per 1,000 person years for placebo (HR, 1.38; 95% CI, 1.18-1.62; P less than .001), investigators found.
Cardiovascular outcomes: expectations vs. reality
Investigators said they thought they might see a significant cardiovascular benefit of aspirin in ASPREE based on earlier studies and meta-analyses that suggested a benefit in other populations. However, the rate of cardiovascular disease at 4.7 years of follow-up was 10.7 events per 1,000 person-years for aspirin, and 11.3 per 1,000 person years for placebo (HR, 0.95; 95% CI, 0.83-1.08).
That hazard ratio “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%,” Dr. McNeil and colleagues wrote.
The results are consistent with those of a recent meta-analysis including eight primary prevention trials, mainly in adults under 70 years of age. That analysis found a 17% reduction in nonfatal myocardial infarction risk, a 14% reduction in stroke risk, and a higher risk of serious bleeding for aspirin versus control groups.
Results of ASPREE have to be interpreted in light of event rates, which were much lower than the expected 22.4 events per 1,000 person-years, they added. The low event rate probably reflects both the relatively good health of the study subjects, and the declining rates of cardiovascular disease in recent years, they said.
“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,” investigators said in their report.
Current guidelines state that the evidence is limited for use of aspirin as primary prevention of cardiovascular disease in the elderly. “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,” study authors said in a discussion of the results.
Excess deaths explored
There were also no significant differences between arms for the endpoints of death, dementia, or disability evaluated separately. However, the rate of death by any cause was numerically higher in the aspirin group versus the placebo group, at 12.7 and 11.1 events per 1,000 person-years, respectively (HR, 1.14; 95% CI, 1.01-1.29).
Cancer was the major contributor to the imbalance in deaths, ASPREE results show, at 1.6 excess deaths per 1,000 person-years. A total of 3.1% of patients in the aspirin group had cancer-related deaths, compared with 2.3% in the placebo arm of the trial (HR, 1.31; 95% CI, 1.10-1.56).
Mortality related to major hemorrhage contributed “only minimally” to the excess in deaths, investigators added in their report.
The finding of excess deaths in the aspirin arm of ASPREE contrasts with meta-analyses of previous prevention trials. According to investigators, those studies show a protective effect of aspirin on cancer-related death that is apparent after 4-5 years of continuous treatment.
Various cellular and molecular pathways relevant to cancer development, progression, and spread are influenced by aspirin, previous studies show.
“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,” Dr. McNeil and coauthors wrote in their report.
Dr. McNeil reported nonfinancial support from Bayer received during the conduct of the study.
SOURCE: McNeil JJ et al. N Engl J Med. 2018 Sep 16.
Across-the-board use of aspirin for primary prevention is “not justified” based on the results of ASPREE as well as the equivocal results from other recent primary prevention trials, according to Prakash C. Deedwania, MD, clinical professor of medicine and chief of the cardiology division at the Veterans Affairs Medical Center/University of California San Francisco Program in Fresno.
The importance of interpreting these studies lies in the recognition that while low-risk people don’t benefit, patients who are at mid to high cardiovascular (CV) risk clearly might. Aspirin’s role in secondary prevention after an initial CV event is clearly established, Dr. Deedwania added.
In ASPREE, a randomized, double-blind, placebo-controlled trial including nearly 20,000 participants, daily aspirin increased rates of major hemorrhage and did not significantly decrease risks of cardiovascular events, death, or other outcomes in healthy elderly individuals.
Aspirin did not prolong disability-free survival, a composite endpoint that included death, dementia, and permanent physical disability, according to one of three separate reports on ASPREE that were published in the New England Journal of Medicine.
Cardiovascular disease rates were likewise not significantly different between aspirin and placebo, with a hazard ratio that ruled out the possibility of a major protective effect, lead author John J. McNeil, MBBS, PhD, of Monash University, Melbourne, said in a second report on ASPREE.
All-cause mortality was actually higher in the aspirin arm versus the placebo arm, attributable largely to an excess of cancer-related deaths, Dr. McNeil and colleagues said in their third full report in the journal. However, that mortality finding needs to be interpreted with caution, they noted, given that previous investigations have shown a protective effect of aspirin on cancer-related death.
Potential harms of “innocuous” drug
The ASPREE (Aspirin in Reducing Events in the Elderly) study evaluated the use of aspirin as primary prevention in 19,114 healthy subjects, with a median age of 74 years, enrolled at 34 centers in Australia and the United States between 2010 and 2014.
The patients, who did not have cardiovascular disease, dementia, or disability at baseline, were randomized to daily 100-mg enteric-coated aspirin or placebo.
The rate of death, dementia, or disability was 21.5 events per 1,000 person-years in the aspirin group, and 21.2 events per 1,000 person-years in the placebo group, with a hazard ratio of 1.01 (95% confidence interval, 0.92-1.11; P = .79), Dr. McNeil and colleagues reported.
The rate of major hemorrhage was 8.6 events per 1,000 person-years for aspirin versus 6.2 events per 1,000 person years for placebo (HR, 1.38; 95% CI, 1.18-1.62; P less than .001), investigators found.
Cardiovascular outcomes: expectations vs. reality
Investigators said they thought they might see a significant cardiovascular benefit of aspirin in ASPREE based on earlier studies and meta-analyses that suggested a benefit in other populations. However, the rate of cardiovascular disease at 4.7 years of follow-up was 10.7 events per 1,000 person-years for aspirin, and 11.3 per 1,000 person years for placebo (HR, 0.95; 95% CI, 0.83-1.08).
That hazard ratio “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%,” Dr. McNeil and colleagues wrote.
The results are consistent with those of a recent meta-analysis including eight primary prevention trials, mainly in adults under 70 years of age. That analysis found a 17% reduction in nonfatal myocardial infarction risk, a 14% reduction in stroke risk, and a higher risk of serious bleeding for aspirin versus control groups.
Results of ASPREE have to be interpreted in light of event rates, which were much lower than the expected 22.4 events per 1,000 person-years, they added. The low event rate probably reflects both the relatively good health of the study subjects, and the declining rates of cardiovascular disease in recent years, they said.
“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,” investigators said in their report.
Current guidelines state that the evidence is limited for use of aspirin as primary prevention of cardiovascular disease in the elderly. “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,” study authors said in a discussion of the results.
Excess deaths explored
There were also no significant differences between arms for the endpoints of death, dementia, or disability evaluated separately. However, the rate of death by any cause was numerically higher in the aspirin group versus the placebo group, at 12.7 and 11.1 events per 1,000 person-years, respectively (HR, 1.14; 95% CI, 1.01-1.29).
Cancer was the major contributor to the imbalance in deaths, ASPREE results show, at 1.6 excess deaths per 1,000 person-years. A total of 3.1% of patients in the aspirin group had cancer-related deaths, compared with 2.3% in the placebo arm of the trial (HR, 1.31; 95% CI, 1.10-1.56).
Mortality related to major hemorrhage contributed “only minimally” to the excess in deaths, investigators added in their report.
The finding of excess deaths in the aspirin arm of ASPREE contrasts with meta-analyses of previous prevention trials. According to investigators, those studies show a protective effect of aspirin on cancer-related death that is apparent after 4-5 years of continuous treatment.
Various cellular and molecular pathways relevant to cancer development, progression, and spread are influenced by aspirin, previous studies show.
“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,” Dr. McNeil and coauthors wrote in their report.
Dr. McNeil reported nonfinancial support from Bayer received during the conduct of the study.
SOURCE: McNeil JJ et al. N Engl J Med. 2018 Sep 16.
Across-the-board use of aspirin for primary prevention is “not justified” based on the results of ASPREE as well as the equivocal results from other recent primary prevention trials, according to Prakash C. Deedwania, MD, clinical professor of medicine and chief of the cardiology division at the Veterans Affairs Medical Center/University of California San Francisco Program in Fresno.
The importance of interpreting these studies lies in the recognition that while low-risk people don’t benefit, patients who are at mid to high cardiovascular (CV) risk clearly might. Aspirin’s role in secondary prevention after an initial CV event is clearly established, Dr. Deedwania added.
In ASPREE, a randomized, double-blind, placebo-controlled trial including nearly 20,000 participants, daily aspirin increased rates of major hemorrhage and did not significantly decrease risks of cardiovascular events, death, or other outcomes in healthy elderly individuals.
Aspirin did not prolong disability-free survival, a composite endpoint that included death, dementia, and permanent physical disability, according to one of three separate reports on ASPREE that were published in the New England Journal of Medicine.
Cardiovascular disease rates were likewise not significantly different between aspirin and placebo, with a hazard ratio that ruled out the possibility of a major protective effect, lead author John J. McNeil, MBBS, PhD, of Monash University, Melbourne, said in a second report on ASPREE.
All-cause mortality was actually higher in the aspirin arm versus the placebo arm, attributable largely to an excess of cancer-related deaths, Dr. McNeil and colleagues said in their third full report in the journal. However, that mortality finding needs to be interpreted with caution, they noted, given that previous investigations have shown a protective effect of aspirin on cancer-related death.
Potential harms of “innocuous” drug
The ASPREE (Aspirin in Reducing Events in the Elderly) study evaluated the use of aspirin as primary prevention in 19,114 healthy subjects, with a median age of 74 years, enrolled at 34 centers in Australia and the United States between 2010 and 2014.
The patients, who did not have cardiovascular disease, dementia, or disability at baseline, were randomized to daily 100-mg enteric-coated aspirin or placebo.
The rate of death, dementia, or disability was 21.5 events per 1,000 person-years in the aspirin group, and 21.2 events per 1,000 person-years in the placebo group, with a hazard ratio of 1.01 (95% confidence interval, 0.92-1.11; P = .79), Dr. McNeil and colleagues reported.
The rate of major hemorrhage was 8.6 events per 1,000 person-years for aspirin versus 6.2 events per 1,000 person years for placebo (HR, 1.38; 95% CI, 1.18-1.62; P less than .001), investigators found.
Cardiovascular outcomes: expectations vs. reality
Investigators said they thought they might see a significant cardiovascular benefit of aspirin in ASPREE based on earlier studies and meta-analyses that suggested a benefit in other populations. However, the rate of cardiovascular disease at 4.7 years of follow-up was 10.7 events per 1,000 person-years for aspirin, and 11.3 per 1,000 person years for placebo (HR, 0.95; 95% CI, 0.83-1.08).
That hazard ratio “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%,” Dr. McNeil and colleagues wrote.
The results are consistent with those of a recent meta-analysis including eight primary prevention trials, mainly in adults under 70 years of age. That analysis found a 17% reduction in nonfatal myocardial infarction risk, a 14% reduction in stroke risk, and a higher risk of serious bleeding for aspirin versus control groups.
Results of ASPREE have to be interpreted in light of event rates, which were much lower than the expected 22.4 events per 1,000 person-years, they added. The low event rate probably reflects both the relatively good health of the study subjects, and the declining rates of cardiovascular disease in recent years, they said.
“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,” investigators said in their report.
Current guidelines state that the evidence is limited for use of aspirin as primary prevention of cardiovascular disease in the elderly. “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,” study authors said in a discussion of the results.
Excess deaths explored
There were also no significant differences between arms for the endpoints of death, dementia, or disability evaluated separately. However, the rate of death by any cause was numerically higher in the aspirin group versus the placebo group, at 12.7 and 11.1 events per 1,000 person-years, respectively (HR, 1.14; 95% CI, 1.01-1.29).
Cancer was the major contributor to the imbalance in deaths, ASPREE results show, at 1.6 excess deaths per 1,000 person-years. A total of 3.1% of patients in the aspirin group had cancer-related deaths, compared with 2.3% in the placebo arm of the trial (HR, 1.31; 95% CI, 1.10-1.56).
Mortality related to major hemorrhage contributed “only minimally” to the excess in deaths, investigators added in their report.
The finding of excess deaths in the aspirin arm of ASPREE contrasts with meta-analyses of previous prevention trials. According to investigators, those studies show a protective effect of aspirin on cancer-related death that is apparent after 4-5 years of continuous treatment.
Various cellular and molecular pathways relevant to cancer development, progression, and spread are influenced by aspirin, previous studies show.
“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,” Dr. McNeil and coauthors wrote in their report.
Dr. McNeil reported nonfinancial support from Bayer received during the conduct of the study.
SOURCE: McNeil JJ et al. N Engl J Med. 2018 Sep 16.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE