John M. Boltri, MD

Evidence summary

A recent systematic review of obesity prevention studies found 9 RCTs demonstrating that dietary and physical activity interventions can prevent weight gain, but lacking sufficient evidence to recommend a specific type of program.¹

A systematic review of the effects of physical activity on weight reduction and maintenance analyzed 46 studies, including 8 RCTs that investigated interventions to reduce weight and 3 that examined measures to maintain it.² More than 80% of the studies showed a benefit from physical exercise. Prevention of weight gain appears to be dose-dependent. More exercise leads to less weight gain; a minimum of 1.5 hours per week of moderate exercise is needed to prevent weight gain.²

Less fat, more vegetables spur weight loss

The Women’s Health Initiative studied 46,808 postmenopausal women between 50 and 79 years of age who were randomly assigned to an intervention or control group.³ The intervention group received intensive group and individual counseling from dieticians aimed at reducing fat intake to 20%, increasing consumption of vegetables and fruits to 5 or more servings per day, and increasing consumption of grains to 6 or more servings per day. The control group received dietary education materials. Neither group had weight loss or calorie restriction goals or differences in physical activity.

The intervention group had a mean decrease in weight 1.9 kg greater than the controls at 1 year (P<.001) and 0.4 kg at 7.5 years (P<.01). Weight loss was greater in women who consumed more fruits and vegetables and greatest among women who decreased energy intake from fat.

A family-based intervention lowers BMI in females

A family-based trial of weight gain prevention randomized 82 families to a group that was encouraged to eat 2 servings of cereal a day and increase activity by 2000 steps a day, or to a control group.⁴ In the intervention group, body mass index (BMI) decreased by 0.4% in mothers (P=.027), and BMI percentage for age decreased by 2.6% in daughters (P<.01). Male family members showed no significant differences, however.

Family ties, self-weighing improve weight control

A systematic review of family-spouse involvement in weight control and weight loss found that involving spouses tended to improve the effectiveness of weight control.⁵

Two studies, 1 an RCT, found an association between self-weighing and preventing weight gain.^6,7 Patients who weighed themselves daily or weekly were less likely to gain weight than patients who weighed themselves monthly, yearly, or never.

Getting personal helps modify behavior

Three RCTs compared clinic-based, Web-based, and self-directed advice and counseling to prevent weight gain (2 studies) and maintain weight loss (1 study). In the first study, 67 patients were assigned to 4 months of clinic-based or home-based counseling to increase exercise and reduce fat intake, or to a control group.⁸ Weight change was–1.9 kg in the clinic-based group,–1.3 kg in the home-based group, and +0.22 kg in the control group (P=.007).

In the second study, 1032 overweight or obese adults with hypertension and/or dyslipidemia who completed a weight-loss program were randomly assigned to receive monthly personal contact, unlimited access to a Web-based intervention, or a self-directed control group.⁹ At 30 months, participants in the personal contact group had regained less weight than the Web-based or control groups (4.0, 5.1, and 5.5 kg, respectively; P<.01).

A third RCT randomized 284 healthy 25- to 44-year-old women with BMI <30 kg/m² to group meetings, lessons by mail, or a control group that received an information booklet. The study found no significant difference among the 3 groups in weight maintenance at a 3-year follow-up; 40% maintained weight, and 60% gained more than 2 pounds.¹⁰

Recommendations

Wide consensus supports screening by either BMI or height and weight. The US Preventive Services Task Force (USPSTF) recommends intensive counseling for everyone with a BMI ≥30 kg/m² coupled with behavioral modification to promote sustained weight loss.¹¹ The USPSTF found insufficient evidence to support less intensive counseling for obese patients or counseling of any intensity for overweight patients.

The Canadian Task Force on Preventive Health Care found insufficient evidence to recommend for or against BMI measurement during routine health evaluations of the general population.¹²

The American Diabetes Association¹³ and the American College of Preventive Medicine¹⁴ recommend counseling and behavior modification for all adults to prevent obesity.

Evidence summary

A recent systematic review of obesity prevention studies found 9 RCTs demonstrating that dietary and physical activity interventions can prevent weight gain, but lacking sufficient evidence to recommend a specific type of program.¹

A systematic review of the effects of physical activity on weight reduction and maintenance analyzed 46 studies, including 8 RCTs that investigated interventions to reduce weight and 3 that examined measures to maintain it.² More than 80% of the studies showed a benefit from physical exercise. Prevention of weight gain appears to be dose-dependent. More exercise leads to less weight gain; a minimum of 1.5 hours per week of moderate exercise is needed to prevent weight gain.²

Less fat, more vegetables spur weight loss

The Women’s Health Initiative studied 46,808 postmenopausal women between 50 and 79 years of age who were randomly assigned to an intervention or control group.³ The intervention group received intensive group and individual counseling from dieticians aimed at reducing fat intake to 20%, increasing consumption of vegetables and fruits to 5 or more servings per day, and increasing consumption of grains to 6 or more servings per day. The control group received dietary education materials. Neither group had weight loss or calorie restriction goals or differences in physical activity.

The intervention group had a mean decrease in weight 1.9 kg greater than the controls at 1 year (P<.001) and 0.4 kg at 7.5 years (P<.01). Weight loss was greater in women who consumed more fruits and vegetables and greatest among women who decreased energy intake from fat.

A family-based intervention lowers BMI in females

A family-based trial of weight gain prevention randomized 82 families to a group that was encouraged to eat 2 servings of cereal a day and increase activity by 2000 steps a day, or to a control group.⁴ In the intervention group, body mass index (BMI) decreased by 0.4% in mothers (P=.027), and BMI percentage for age decreased by 2.6% in daughters (P<.01). Male family members showed no significant differences, however.

Family ties, self-weighing improve weight control

A systematic review of family-spouse involvement in weight control and weight loss found that involving spouses tended to improve the effectiveness of weight control.⁵

Two studies, 1 an RCT, found an association between self-weighing and preventing weight gain.^6,7 Patients who weighed themselves daily or weekly were less likely to gain weight than patients who weighed themselves monthly, yearly, or never.

Getting personal helps modify behavior

Three RCTs compared clinic-based, Web-based, and self-directed advice and counseling to prevent weight gain (2 studies) and maintain weight loss (1 study). In the first study, 67 patients were assigned to 4 months of clinic-based or home-based counseling to increase exercise and reduce fat intake, or to a control group.⁸ Weight change was–1.9 kg in the clinic-based group,–1.3 kg in the home-based group, and +0.22 kg in the control group (P=.007).

In the second study, 1032 overweight or obese adults with hypertension and/or dyslipidemia who completed a weight-loss program were randomly assigned to receive monthly personal contact, unlimited access to a Web-based intervention, or a self-directed control group.⁹ At 30 months, participants in the personal contact group had regained less weight than the Web-based or control groups (4.0, 5.1, and 5.5 kg, respectively; P<.01).

A third RCT randomized 284 healthy 25- to 44-year-old women with BMI <30 kg/m² to group meetings, lessons by mail, or a control group that received an information booklet. The study found no significant difference among the 3 groups in weight maintenance at a 3-year follow-up; 40% maintained weight, and 60% gained more than 2 pounds.¹⁰

Recommendations

Wide consensus supports screening by either BMI or height and weight. The US Preventive Services Task Force (USPSTF) recommends intensive counseling for everyone with a BMI ≥30 kg/m² coupled with behavioral modification to promote sustained weight loss.¹¹ The USPSTF found insufficient evidence to support less intensive counseling for obese patients or counseling of any intensity for overweight patients.

The Canadian Task Force on Preventive Health Care found insufficient evidence to recommend for or against BMI measurement during routine health evaluations of the general population.¹²

The American Diabetes Association¹³ and the American College of Preventive Medicine¹⁴ recommend counseling and behavior modification for all adults to prevent obesity.

Evidence summary

A recent systematic review of obesity prevention studies found 9 RCTs demonstrating that dietary and physical activity interventions can prevent weight gain, but lacking sufficient evidence to recommend a specific type of program.¹

A systematic review of the effects of physical activity on weight reduction and maintenance analyzed 46 studies, including 8 RCTs that investigated interventions to reduce weight and 3 that examined measures to maintain it.² More than 80% of the studies showed a benefit from physical exercise. Prevention of weight gain appears to be dose-dependent. More exercise leads to less weight gain; a minimum of 1.5 hours per week of moderate exercise is needed to prevent weight gain.²

Less fat, more vegetables spur weight loss

The Women’s Health Initiative studied 46,808 postmenopausal women between 50 and 79 years of age who were randomly assigned to an intervention or control group.³ The intervention group received intensive group and individual counseling from dieticians aimed at reducing fat intake to 20%, increasing consumption of vegetables and fruits to 5 or more servings per day, and increasing consumption of grains to 6 or more servings per day. The control group received dietary education materials. Neither group had weight loss or calorie restriction goals or differences in physical activity.

The intervention group had a mean decrease in weight 1.9 kg greater than the controls at 1 year (P<.001) and 0.4 kg at 7.5 years (P<.01). Weight loss was greater in women who consumed more fruits and vegetables and greatest among women who decreased energy intake from fat.

A family-based intervention lowers BMI in females

A family-based trial of weight gain prevention randomized 82 families to a group that was encouraged to eat 2 servings of cereal a day and increase activity by 2000 steps a day, or to a control group.⁴ In the intervention group, body mass index (BMI) decreased by 0.4% in mothers (P=.027), and BMI percentage for age decreased by 2.6% in daughters (P<.01). Male family members showed no significant differences, however.

Family ties, self-weighing improve weight control

A systematic review of family-spouse involvement in weight control and weight loss found that involving spouses tended to improve the effectiveness of weight control.⁵

Two studies, 1 an RCT, found an association between self-weighing and preventing weight gain.^6,7 Patients who weighed themselves daily or weekly were less likely to gain weight than patients who weighed themselves monthly, yearly, or never.

Getting personal helps modify behavior

Three RCTs compared clinic-based, Web-based, and self-directed advice and counseling to prevent weight gain (2 studies) and maintain weight loss (1 study). In the first study, 67 patients were assigned to 4 months of clinic-based or home-based counseling to increase exercise and reduce fat intake, or to a control group.⁸ Weight change was–1.9 kg in the clinic-based group,–1.3 kg in the home-based group, and +0.22 kg in the control group (P=.007).

In the second study, 1032 overweight or obese adults with hypertension and/or dyslipidemia who completed a weight-loss program were randomly assigned to receive monthly personal contact, unlimited access to a Web-based intervention, or a self-directed control group.⁹ At 30 months, participants in the personal contact group had regained less weight than the Web-based or control groups (4.0, 5.1, and 5.5 kg, respectively; P<.01).

A third RCT randomized 284 healthy 25- to 44-year-old women with BMI <30 kg/m² to group meetings, lessons by mail, or a control group that received an information booklet. The study found no significant difference among the 3 groups in weight maintenance at a 3-year follow-up; 40% maintained weight, and 60% gained more than 2 pounds.¹⁰

Recommendations

Wide consensus supports screening by either BMI or height and weight. The US Preventive Services Task Force (USPSTF) recommends intensive counseling for everyone with a BMI ≥30 kg/m² coupled with behavioral modification to promote sustained weight loss.¹¹ The USPSTF found insufficient evidence to support less intensive counseling for obese patients or counseling of any intensity for overweight patients.

The Canadian Task Force on Preventive Health Care found insufficient evidence to recommend for or against BMI measurement during routine health evaluations of the general population.¹²

The American Diabetes Association¹³ and the American College of Preventive Medicine¹⁴ recommend counseling and behavior modification for all adults to prevent obesity.

Cardiovascular disease is the leading cause of death in the United States, and aspirin, a platelet aggregate inhibitor, is often recommended as prophylaxis for cardiovascular disease.^1-3Clinical studies have demonstrated the benefit of aspirin use for secondary prevention of cardiovascular disease and stroke.^1,4-10 In high-risk subjects, aspirin has been proven effective in primary prevention of major cardiovascular events and nonfatal ischemic heart disease.^11-13 Sanmuganathan and colleagues recently reported a meta-analysis of 4 randomized trials of aspirin for primary prevention. Although they determined that aspirin treatment is safe if the coronary event rate is at least 1.5% each year and unsafe if the rate is no higher than 0.5% each year, they did not address all-cause mortality, and 2 of the 4 trials did not include low-risk subjects.⁹

Many physicians and patients are prescribing aspirin with the expectation of reduced mortality in high-risk and low-risk individuals. Media advertisements and health programs may not clearly delineate the population for whom aspirin has clear benefits. A recent review suggested that aspirin is likely to be effective for primary prevention in yet to be defined groups.¹⁴ This review seeks to answer 2 questions. First, are there any primary prevention studies using aspirin that included only low-risk subjects? Second, should aspirin be prescribed routinely to persons at low risk for cardiovascular disease to decrease total mortality?

Methods

Search strategy

The MEDLINE database and the Cochrane Library were systematically searched using the terms aspirin or antiplatelet therapy and primary prevention or prevention and primary and mortality. An additional search was made with primary prevention and myocardial infarction or stroke. The Internet was searched (http://www.google.com) by using the same search terms. The studies were limited to human populations. Search results consisted of abstracts, complete reviews, and reference lists from articles. Morbidity associated with aspirin use also was reviewed.

Selection criteria: end points

Only those studies that investigated primary prevention of cardiovascular disease using aspirin, had low-risk subjects, and included a measure of total mortality were part of our analysis. We used the 2001 Adult Treatment Panel III Guidelines and the recent British Medical Journal clinical evidence guidelines on primary prevention of cardiovascular disorders to define the low-risk patient.^15,16 Those guidelines classified major risk factors for ischemic vascular disease as hypertension, low high-density lipoprotein cholesterol, high lowdensity lipoprotein cholesterol, family history of premature coronary heart disease, smoking, diabetes, and advancing age (men ≥ 45 years, women ≥ 55 years). We also classified those patients with past cerebrovascular events, myocardial infarction, and angina as high risk. We defined low risk as having no more than 1 of these risk factors.

Every trial was evaluated independently by each author according to the Jadad scale.¹⁷ Based on information in the original articles, we recalculated the odds ratios (ORs) for each study. The results of the 2 randomized trails were combined by means of the Mantel-Haenszel method for combining ORs, and StatXact 4 for Windows was used for the analysis.^18,19 The data were used to create a forest plot of mortal-ity.¹⁹ The decision to combine studies of like type was made a priority.

Results

MEDLINE search results for aspirin and primary prevention yielded 291 articles. Antiplatelet therapy and primary prevention yielded 64 articles. Myocardial infarction or stroke and primary prevention yielded 514 articles. Cross-referencing aspirin, prevention, and mortality yielded 690 articles. The Cochrane Library search of antiplatelet therapy and prevention and primary yielded 17 complete reviews and 6 abstracts of systematic reviews. No additional studies published or unpublished were identified through the Internet.

Five clinical trials and 1 cohort study that evaluated aspirin for primary prevention were identi-fied.^11,12,20-23 One of those, a pilot study, was excluded because it did not provide mortality data for the aspirin and placebo groups.²³ Two clinical trials, the Hypertension Optimal Treatment Trial and the Thrombosis Prevention Trial, did not include low-risk subjects.^11,12 Although no studies were identified that included only low-risk subjects, 3 studies met our inclusion criteria. Characteristics of those 3 studies are reported in Table 1.

The US Physicians Health Study (USPHS) randomized physicians into 4 treatment groups: aspirin plus beta-carotene, aspirin plus placebo, betacarotene plus placebo, and placebo plus placebo.²⁰ Both aspirin groups took 325 mg every other day. The mean age was 53.2 years.²⁴ Fifty percent of the participants were current or past smokers, and 9% had hypertension. Although the rate of myocardial infarction was significantly lower in the aspirin group, there was no reduction in total cardiovascular mortality. The results are reported in Table 2. More side effects were noted in the aspirin group, including gastric ulcers, gastrointestinal bleeding, hemorrhagic stroke, and other bleeding disorders.²⁰ No separate analysis of low-risk subjects’ risk was performed.

In the British Doctors Study (BDS), 66% of patients were randomized to take aspirin once daily and 33% were to avoid aspirin.²¹ More than half of the subjects were at least 60 years old. Physicians with stroke, myocardial infarction, ulcer disease, or currently taking any aspirin products were excluded. Six percent of the subjects had a history of heart disease other than myocardial infarction, 10% had hypertension, and 75% of participants were currently smoking or had a history of smoking. No significant differences were noted between groups for myocardial infarction or total mortality. By the end of the study, 44% of the aspirin group had discontinued aspirin secondary to side effects, the most common being dyspepsia. Of the control group, 2% per year started using aspirin because they developed risk factors such as vascular disease or for primary prevention. Low-risk individuals were not evaluated separately.

The Nurses Health Study (NHS) was a cohort study of women who were free of diagnosed coronary heart disease, stroke, and cancer at the start of the study. However, 29% of the women smoked and 15% had hypertension.²² The mean age was 46.0 years, and the follow-up was 96.7% of total potential person years. The study respondents were asked how many aspirin tablets they took per week: 0, 1 to 3, 4 to 6, 7 to 14, or 15+. Those who smoked or were overweight were more likely to take aspirin. No separate analysis of low-risk subjects was performed. Mortality from aspirin use was clearly dose dependent. For study participants taking 1 to 6 aspirin tablets each week, mortality was 0.84% (OR, 1.51; 95% confidence interval [CI], 1.26–1.82); for those taking 7 to 14 aspirin tablets, mortality was 0.99% (OR, 1.80; CI, 1.39–2.33); and for those taking 15+ aspirin tablets, mortality was 1.82% (OR, 3.32; CI, 2.62–4.21). Rates of myocardial infarction and stroke also were higher for all groups taking aspirin (see Table 2). When combined, the USPHS and the BDS demonstrated no significant difference in mortality between aspirin and placebo groups, whereas the NHS found increased mortality from aspirin (Figure).

TABLE 1

Characteristics of aspirin studies that included low-risk subjects

TABLE 2

Rates of myocardial infarction, stroke, total cardiovascular mortality, and total mortality in studies of aspirin vs no aspirin that included low-risk patients

FIGURE Forest plot of mortality in healthy patients on aspirin

Discussion

To date, there has been no study of aspirin for primary prevention that included a separate analysis of patients who were free of cardiovascular risk factors. Each of the 3 studies that included low-risk subjects grouped them with subjects at higher risk, those known to benefit from aspirin.^9,11,12 Even so, none of those studies demonstrated a statistically significant decrease in all-cause mortality. Even when combined, the BDS and the USPHS demonstrated no significant improvement in mortality. Mortality in the BDS was nearly 4 times greater than that in the USPHS. This finding is likely due to the higher baseline rate of smoking and other risk factors in the British doctors. In contrast to the BDS, the USPHS demonstrated significantly decreased rates for fatal and nonfatal myocardial infarction. Our analysis of the NHS associated aspirin with increased mortality, fatal myocardial infarction, and nonfatal myocardial infarction at any dose. The nurses on average had lower risk than the doctors, fewer smoked, and they were younger.

Many studies have clearly demonstrated the benefits of aspirin for primary prevention in high-risk subjects.^10-12,25 There may be other benefits to taking prophylactic aspirin. In the Cancer Prevention Study II, aspirin use was associated with decreased death rates from colon cancer.²⁶ Unfortunately, that study did not measure all-cause mortality.

There are a number of limitations to this study. There were no strictly low-risk studies of aspirin for primary prevention of cardiovascular mortality, and there was a paucity of studies that included low-risk subjects. Because the studies analyzed did not include only low-risk subjects, the results may not apply to all low-risk patients. The BDS did not include a placebo and was not blinded. Although not statistically significant, the ORs tended toward a protective effect for aspirin in the 2 randomized trials. The large difference in mortality between those 2 trials remains unexplained. The NHS was the only study to include women, and it was a cohort study, which is subject to selection and reporting biases. Therefore, aspirin users may have been at higher mortality risk due to smoking, obesity, or other illness, thus rendering the association between aspirin and higher mortality meaningless.

Many studies have shown significant side effects of aspirin, including epistaxis, peptic ulcer disease, gastrointestinal bleeds, and hemorrhagic stroke.^{15,20-22,27-32} In the BDS, 17% more subjects in the aspirin group developed peptic ulcer disease, and 19% stopped treatment during the first year secondary to gastrointestinal complaints.²¹

In conclusion, there is currently no evidence to recommend for or against the use of aspirin in low-risk individuals to decrease mortality. There may be other reasons to take aspirin prophylactically such as to reduce myocardial infarction or colon cancer. However, these benefits have not been established in a low-risk population. Health care providers should ask all patients whether they are taking aspirin and evaluate the risk-benefit ratio before recommending it.

Cardiovascular disease is the leading cause of death in the United States, and aspirin, a platelet aggregate inhibitor, is often recommended as prophylaxis for cardiovascular disease.^1-3Clinical studies have demonstrated the benefit of aspirin use for secondary prevention of cardiovascular disease and stroke.^1,4-10 In high-risk subjects, aspirin has been proven effective in primary prevention of major cardiovascular events and nonfatal ischemic heart disease.^11-13 Sanmuganathan and colleagues recently reported a meta-analysis of 4 randomized trials of aspirin for primary prevention. Although they determined that aspirin treatment is safe if the coronary event rate is at least 1.5% each year and unsafe if the rate is no higher than 0.5% each year, they did not address all-cause mortality, and 2 of the 4 trials did not include low-risk subjects.⁹

Many physicians and patients are prescribing aspirin with the expectation of reduced mortality in high-risk and low-risk individuals. Media advertisements and health programs may not clearly delineate the population for whom aspirin has clear benefits. A recent review suggested that aspirin is likely to be effective for primary prevention in yet to be defined groups.¹⁴ This review seeks to answer 2 questions. First, are there any primary prevention studies using aspirin that included only low-risk subjects? Second, should aspirin be prescribed routinely to persons at low risk for cardiovascular disease to decrease total mortality?

Methods

Search strategy

The MEDLINE database and the Cochrane Library were systematically searched using the terms aspirin or antiplatelet therapy and primary prevention or prevention and primary and mortality. An additional search was made with primary prevention and myocardial infarction or stroke. The Internet was searched (http://www.google.com) by using the same search terms. The studies were limited to human populations. Search results consisted of abstracts, complete reviews, and reference lists from articles. Morbidity associated with aspirin use also was reviewed.

Selection criteria: end points

Only those studies that investigated primary prevention of cardiovascular disease using aspirin, had low-risk subjects, and included a measure of total mortality were part of our analysis. We used the 2001 Adult Treatment Panel III Guidelines and the recent British Medical Journal clinical evidence guidelines on primary prevention of cardiovascular disorders to define the low-risk patient.^15,16 Those guidelines classified major risk factors for ischemic vascular disease as hypertension, low high-density lipoprotein cholesterol, high lowdensity lipoprotein cholesterol, family history of premature coronary heart disease, smoking, diabetes, and advancing age (men ≥ 45 years, women ≥ 55 years). We also classified those patients with past cerebrovascular events, myocardial infarction, and angina as high risk. We defined low risk as having no more than 1 of these risk factors.

Every trial was evaluated independently by each author according to the Jadad scale.¹⁷ Based on information in the original articles, we recalculated the odds ratios (ORs) for each study. The results of the 2 randomized trails were combined by means of the Mantel-Haenszel method for combining ORs, and StatXact 4 for Windows was used for the analysis.^18,19 The data were used to create a forest plot of mortal-ity.¹⁹ The decision to combine studies of like type was made a priority.

Results

MEDLINE search results for aspirin and primary prevention yielded 291 articles. Antiplatelet therapy and primary prevention yielded 64 articles. Myocardial infarction or stroke and primary prevention yielded 514 articles. Cross-referencing aspirin, prevention, and mortality yielded 690 articles. The Cochrane Library search of antiplatelet therapy and prevention and primary yielded 17 complete reviews and 6 abstracts of systematic reviews. No additional studies published or unpublished were identified through the Internet.

Five clinical trials and 1 cohort study that evaluated aspirin for primary prevention were identi-fied.^11,12,20-23 One of those, a pilot study, was excluded because it did not provide mortality data for the aspirin and placebo groups.²³ Two clinical trials, the Hypertension Optimal Treatment Trial and the Thrombosis Prevention Trial, did not include low-risk subjects.^11,12 Although no studies were identified that included only low-risk subjects, 3 studies met our inclusion criteria. Characteristics of those 3 studies are reported in Table 1.

The US Physicians Health Study (USPHS) randomized physicians into 4 treatment groups: aspirin plus beta-carotene, aspirin plus placebo, betacarotene plus placebo, and placebo plus placebo.²⁰ Both aspirin groups took 325 mg every other day. The mean age was 53.2 years.²⁴ Fifty percent of the participants were current or past smokers, and 9% had hypertension. Although the rate of myocardial infarction was significantly lower in the aspirin group, there was no reduction in total cardiovascular mortality. The results are reported in Table 2. More side effects were noted in the aspirin group, including gastric ulcers, gastrointestinal bleeding, hemorrhagic stroke, and other bleeding disorders.²⁰ No separate analysis of low-risk subjects’ risk was performed.

In the British Doctors Study (BDS), 66% of patients were randomized to take aspirin once daily and 33% were to avoid aspirin.²¹ More than half of the subjects were at least 60 years old. Physicians with stroke, myocardial infarction, ulcer disease, or currently taking any aspirin products were excluded. Six percent of the subjects had a history of heart disease other than myocardial infarction, 10% had hypertension, and 75% of participants were currently smoking or had a history of smoking. No significant differences were noted between groups for myocardial infarction or total mortality. By the end of the study, 44% of the aspirin group had discontinued aspirin secondary to side effects, the most common being dyspepsia. Of the control group, 2% per year started using aspirin because they developed risk factors such as vascular disease or for primary prevention. Low-risk individuals were not evaluated separately.

The Nurses Health Study (NHS) was a cohort study of women who were free of diagnosed coronary heart disease, stroke, and cancer at the start of the study. However, 29% of the women smoked and 15% had hypertension.²² The mean age was 46.0 years, and the follow-up was 96.7% of total potential person years. The study respondents were asked how many aspirin tablets they took per week: 0, 1 to 3, 4 to 6, 7 to 14, or 15+. Those who smoked or were overweight were more likely to take aspirin. No separate analysis of low-risk subjects was performed. Mortality from aspirin use was clearly dose dependent. For study participants taking 1 to 6 aspirin tablets each week, mortality was 0.84% (OR, 1.51; 95% confidence interval [CI], 1.26–1.82); for those taking 7 to 14 aspirin tablets, mortality was 0.99% (OR, 1.80; CI, 1.39–2.33); and for those taking 15+ aspirin tablets, mortality was 1.82% (OR, 3.32; CI, 2.62–4.21). Rates of myocardial infarction and stroke also were higher for all groups taking aspirin (see Table 2). When combined, the USPHS and the BDS demonstrated no significant difference in mortality between aspirin and placebo groups, whereas the NHS found increased mortality from aspirin (Figure).

TABLE 1

Characteristics of aspirin studies that included low-risk subjects

TABLE 2

Rates of myocardial infarction, stroke, total cardiovascular mortality, and total mortality in studies of aspirin vs no aspirin that included low-risk patients

FIGURE Forest plot of mortality in healthy patients on aspirin

Discussion

To date, there has been no study of aspirin for primary prevention that included a separate analysis of patients who were free of cardiovascular risk factors. Each of the 3 studies that included low-risk subjects grouped them with subjects at higher risk, those known to benefit from aspirin.^9,11,12 Even so, none of those studies demonstrated a statistically significant decrease in all-cause mortality. Even when combined, the BDS and the USPHS demonstrated no significant improvement in mortality. Mortality in the BDS was nearly 4 times greater than that in the USPHS. This finding is likely due to the higher baseline rate of smoking and other risk factors in the British doctors. In contrast to the BDS, the USPHS demonstrated significantly decreased rates for fatal and nonfatal myocardial infarction. Our analysis of the NHS associated aspirin with increased mortality, fatal myocardial infarction, and nonfatal myocardial infarction at any dose. The nurses on average had lower risk than the doctors, fewer smoked, and they were younger.

Many studies have clearly demonstrated the benefits of aspirin for primary prevention in high-risk subjects.^10-12,25 There may be other benefits to taking prophylactic aspirin. In the Cancer Prevention Study II, aspirin use was associated with decreased death rates from colon cancer.²⁶ Unfortunately, that study did not measure all-cause mortality.

There are a number of limitations to this study. There were no strictly low-risk studies of aspirin for primary prevention of cardiovascular mortality, and there was a paucity of studies that included low-risk subjects. Because the studies analyzed did not include only low-risk subjects, the results may not apply to all low-risk patients. The BDS did not include a placebo and was not blinded. Although not statistically significant, the ORs tended toward a protective effect for aspirin in the 2 randomized trials. The large difference in mortality between those 2 trials remains unexplained. The NHS was the only study to include women, and it was a cohort study, which is subject to selection and reporting biases. Therefore, aspirin users may have been at higher mortality risk due to smoking, obesity, or other illness, thus rendering the association between aspirin and higher mortality meaningless.

Many studies have shown significant side effects of aspirin, including epistaxis, peptic ulcer disease, gastrointestinal bleeds, and hemorrhagic stroke.^{15,20-22,27-32} In the BDS, 17% more subjects in the aspirin group developed peptic ulcer disease, and 19% stopped treatment during the first year secondary to gastrointestinal complaints.²¹

In conclusion, there is currently no evidence to recommend for or against the use of aspirin in low-risk individuals to decrease mortality. There may be other reasons to take aspirin prophylactically such as to reduce myocardial infarction or colon cancer. However, these benefits have not been established in a low-risk population. Health care providers should ask all patients whether they are taking aspirin and evaluate the risk-benefit ratio before recommending it.

Cardiovascular disease is the leading cause of death in the United States, and aspirin, a platelet aggregate inhibitor, is often recommended as prophylaxis for cardiovascular disease.^1-3Clinical studies have demonstrated the benefit of aspirin use for secondary prevention of cardiovascular disease and stroke.^1,4-10 In high-risk subjects, aspirin has been proven effective in primary prevention of major cardiovascular events and nonfatal ischemic heart disease.^11-13 Sanmuganathan and colleagues recently reported a meta-analysis of 4 randomized trials of aspirin for primary prevention. Although they determined that aspirin treatment is safe if the coronary event rate is at least 1.5% each year and unsafe if the rate is no higher than 0.5% each year, they did not address all-cause mortality, and 2 of the 4 trials did not include low-risk subjects.⁹

Many physicians and patients are prescribing aspirin with the expectation of reduced mortality in high-risk and low-risk individuals. Media advertisements and health programs may not clearly delineate the population for whom aspirin has clear benefits. A recent review suggested that aspirin is likely to be effective for primary prevention in yet to be defined groups.¹⁴ This review seeks to answer 2 questions. First, are there any primary prevention studies using aspirin that included only low-risk subjects? Second, should aspirin be prescribed routinely to persons at low risk for cardiovascular disease to decrease total mortality?

Methods

Search strategy

The MEDLINE database and the Cochrane Library were systematically searched using the terms aspirin or antiplatelet therapy and primary prevention or prevention and primary and mortality. An additional search was made with primary prevention and myocardial infarction or stroke. The Internet was searched (http://www.google.com) by using the same search terms. The studies were limited to human populations. Search results consisted of abstracts, complete reviews, and reference lists from articles. Morbidity associated with aspirin use also was reviewed.

Selection criteria: end points

Only those studies that investigated primary prevention of cardiovascular disease using aspirin, had low-risk subjects, and included a measure of total mortality were part of our analysis. We used the 2001 Adult Treatment Panel III Guidelines and the recent British Medical Journal clinical evidence guidelines on primary prevention of cardiovascular disorders to define the low-risk patient.^15,16 Those guidelines classified major risk factors for ischemic vascular disease as hypertension, low high-density lipoprotein cholesterol, high lowdensity lipoprotein cholesterol, family history of premature coronary heart disease, smoking, diabetes, and advancing age (men ≥ 45 years, women ≥ 55 years). We also classified those patients with past cerebrovascular events, myocardial infarction, and angina as high risk. We defined low risk as having no more than 1 of these risk factors.

Every trial was evaluated independently by each author according to the Jadad scale.¹⁷ Based on information in the original articles, we recalculated the odds ratios (ORs) for each study. The results of the 2 randomized trails were combined by means of the Mantel-Haenszel method for combining ORs, and StatXact 4 for Windows was used for the analysis.^18,19 The data were used to create a forest plot of mortal-ity.¹⁹ The decision to combine studies of like type was made a priority.

Results

MEDLINE search results for aspirin and primary prevention yielded 291 articles. Antiplatelet therapy and primary prevention yielded 64 articles. Myocardial infarction or stroke and primary prevention yielded 514 articles. Cross-referencing aspirin, prevention, and mortality yielded 690 articles. The Cochrane Library search of antiplatelet therapy and prevention and primary yielded 17 complete reviews and 6 abstracts of systematic reviews. No additional studies published or unpublished were identified through the Internet.

Five clinical trials and 1 cohort study that evaluated aspirin for primary prevention were identi-fied.^11,12,20-23 One of those, a pilot study, was excluded because it did not provide mortality data for the aspirin and placebo groups.²³ Two clinical trials, the Hypertension Optimal Treatment Trial and the Thrombosis Prevention Trial, did not include low-risk subjects.^11,12 Although no studies were identified that included only low-risk subjects, 3 studies met our inclusion criteria. Characteristics of those 3 studies are reported in Table 1.

The US Physicians Health Study (USPHS) randomized physicians into 4 treatment groups: aspirin plus beta-carotene, aspirin plus placebo, betacarotene plus placebo, and placebo plus placebo.²⁰ Both aspirin groups took 325 mg every other day. The mean age was 53.2 years.²⁴ Fifty percent of the participants were current or past smokers, and 9% had hypertension. Although the rate of myocardial infarction was significantly lower in the aspirin group, there was no reduction in total cardiovascular mortality. The results are reported in Table 2. More side effects were noted in the aspirin group, including gastric ulcers, gastrointestinal bleeding, hemorrhagic stroke, and other bleeding disorders.²⁰ No separate analysis of low-risk subjects’ risk was performed.

In the British Doctors Study (BDS), 66% of patients were randomized to take aspirin once daily and 33% were to avoid aspirin.²¹ More than half of the subjects were at least 60 years old. Physicians with stroke, myocardial infarction, ulcer disease, or currently taking any aspirin products were excluded. Six percent of the subjects had a history of heart disease other than myocardial infarction, 10% had hypertension, and 75% of participants were currently smoking or had a history of smoking. No significant differences were noted between groups for myocardial infarction or total mortality. By the end of the study, 44% of the aspirin group had discontinued aspirin secondary to side effects, the most common being dyspepsia. Of the control group, 2% per year started using aspirin because they developed risk factors such as vascular disease or for primary prevention. Low-risk individuals were not evaluated separately.

The Nurses Health Study (NHS) was a cohort study of women who were free of diagnosed coronary heart disease, stroke, and cancer at the start of the study. However, 29% of the women smoked and 15% had hypertension.²² The mean age was 46.0 years, and the follow-up was 96.7% of total potential person years. The study respondents were asked how many aspirin tablets they took per week: 0, 1 to 3, 4 to 6, 7 to 14, or 15+. Those who smoked or were overweight were more likely to take aspirin. No separate analysis of low-risk subjects was performed. Mortality from aspirin use was clearly dose dependent. For study participants taking 1 to 6 aspirin tablets each week, mortality was 0.84% (OR, 1.51; 95% confidence interval [CI], 1.26–1.82); for those taking 7 to 14 aspirin tablets, mortality was 0.99% (OR, 1.80; CI, 1.39–2.33); and for those taking 15+ aspirin tablets, mortality was 1.82% (OR, 3.32; CI, 2.62–4.21). Rates of myocardial infarction and stroke also were higher for all groups taking aspirin (see Table 2). When combined, the USPHS and the BDS demonstrated no significant difference in mortality between aspirin and placebo groups, whereas the NHS found increased mortality from aspirin (Figure).

TABLE 1

Characteristics of aspirin studies that included low-risk subjects

TABLE 2

Rates of myocardial infarction, stroke, total cardiovascular mortality, and total mortality in studies of aspirin vs no aspirin that included low-risk patients

FIGURE Forest plot of mortality in healthy patients on aspirin

Discussion

To date, there has been no study of aspirin for primary prevention that included a separate analysis of patients who were free of cardiovascular risk factors. Each of the 3 studies that included low-risk subjects grouped them with subjects at higher risk, those known to benefit from aspirin.^9,11,12 Even so, none of those studies demonstrated a statistically significant decrease in all-cause mortality. Even when combined, the BDS and the USPHS demonstrated no significant improvement in mortality. Mortality in the BDS was nearly 4 times greater than that in the USPHS. This finding is likely due to the higher baseline rate of smoking and other risk factors in the British doctors. In contrast to the BDS, the USPHS demonstrated significantly decreased rates for fatal and nonfatal myocardial infarction. Our analysis of the NHS associated aspirin with increased mortality, fatal myocardial infarction, and nonfatal myocardial infarction at any dose. The nurses on average had lower risk than the doctors, fewer smoked, and they were younger.

Many studies have clearly demonstrated the benefits of aspirin for primary prevention in high-risk subjects.^10-12,25 There may be other benefits to taking prophylactic aspirin. In the Cancer Prevention Study II, aspirin use was associated with decreased death rates from colon cancer.²⁶ Unfortunately, that study did not measure all-cause mortality.

There are a number of limitations to this study. There were no strictly low-risk studies of aspirin for primary prevention of cardiovascular mortality, and there was a paucity of studies that included low-risk subjects. Because the studies analyzed did not include only low-risk subjects, the results may not apply to all low-risk patients. The BDS did not include a placebo and was not blinded. Although not statistically significant, the ORs tended toward a protective effect for aspirin in the 2 randomized trials. The large difference in mortality between those 2 trials remains unexplained. The NHS was the only study to include women, and it was a cohort study, which is subject to selection and reporting biases. Therefore, aspirin users may have been at higher mortality risk due to smoking, obesity, or other illness, thus rendering the association between aspirin and higher mortality meaningless.

Many studies have shown significant side effects of aspirin, including epistaxis, peptic ulcer disease, gastrointestinal bleeds, and hemorrhagic stroke.^{15,20-22,27-32} In the BDS, 17% more subjects in the aspirin group developed peptic ulcer disease, and 19% stopped treatment during the first year secondary to gastrointestinal complaints.²¹

In conclusion, there is currently no evidence to recommend for or against the use of aspirin in low-risk individuals to decrease mortality. There may be other reasons to take aspirin prophylactically such as to reduce myocardial infarction or colon cancer. However, these benefits have not been established in a low-risk population. Health care providers should ask all patients whether they are taking aspirin and evaluate the risk-benefit ratio before recommending it.