Migraine with aura (MA) has been associated with increased risk of cardiovascular disease (CVD). The role of aspirin on this association remains unclear.
Post-hoc subgroup analyses of the Women’s Health Study, a randomized trial testing 100mg aspirin on alternate days in primary prevention of CVD among 39,876 women aged ≥45.
During 10 years, 998 major CVD events were confirmed in 39,757 women with complete migraine information. Aspirin reduced risk of ischemic stroke (RR=0.76; 95%CI=0.63–0.93) but not other CVD. Migraine or MA did not modify the effect of aspirin on CVD except for myocardial infarction (MI) (p-interaction=0.01). Women with MA on aspirin had increased risk of MI (RR=3.72, 95%CI=1.39–9.95). Further exploratory analyses indicate this is only apparent among women with MA on aspirin who ever smoked or had history of hypertension (p-interaction<0.01).
In post-hoc subgroup analyses, aspirin had similar protective effects on ischemic stroke for women with or without migraine. By contrast, our data suggest that women with MA on aspirin had increased risk of MI. The small number of outcome events in subgroups, the exploratory nature of our analyses, and lack of plausible mechanisms raise the possibility of a chance finding, which must caution the interpretation.
Aspirin reduces myocardial infarction but increases gastrointestinal bleeding. Proton pump inhibitors (PPIs) may reduce upper gastrointestinal bleed. We estimate the cost-utility of aspirin treatment with or without PPI for coronary heart disease (CHD) prevention among men at different risks for CHD and gastrointestinal bleed.
We updated a Markov model to compare costs and outcomes of low-dose aspirin+PPI (omeprazole 20-mg daily), low-dose aspirin alone, or no treatment for CHD prevention. We performed lifetime analyses in men with different risks for cardiovascular events and gastrointestinal bleed. Aspirin reduced nonfatal myocardial infarction by 30%, increased total stroke by 6%, and increased gastrointestinal bleed risk 2-fold. Adding PPI reduced upper gastrointestinal bleed by 80%. Annual aspirin cost was $13.99; generic PPI was $200.
In 45-year-old men with 10-year CHD risk of 10% and 0.8/1,000 annual gastrointestinal bleed risk, aspirin ($17,571 and 18.67 quality-adjusted life years [QALYs]) was more effective and less costly than no treatment ($18,483 and 18.44 QALYs). Compared with aspirin alone, aspirin+PPI ($21,037 and 18.68 QALYs) had an incremental cost/QALY of $447,077. Results were similar in 55- and 65-year-old men. The incremental cost/QALY of adding PPI was less than $50,000/QALY at annual gastrointestinal bleed probabilities greater than 4–6/1,000.
Aspirin for CHD prevention is less costly and more effective than no treatment in men over 45 with greater than 10-year, 10% CHD risks. Adding PPI is not cost-effective for men with average gastrointestinal bleed risk but may be cost-effective for selected men at increased risk for gastrointestinal bleed.
Objective To investigate the routine use of low dose aspirin in people aged ≥ 70 without overt cardiovascular disease.
Design Epidemiological modelling in a hypothetical population.
Setting Reference populations of men and women in the year 2000 from the state of Victoria, Australia.
Subjects 10 000 men and 10 000 women aged 70-74 with no cardiovascular disease.
Main outcome measures First ever myocardial infarction or unstable angina, ischaemic or haemorrhagic stroke, and major gastrointestinal haemorrhage. Health adjusted years of life lived.
Results The proportional benefit gained from the use of low dose aspirin by the prevention of myocardial infarctions (-389 in men, -321 in women) and ischaemic stroke (-19 in men and -35 in women) is offset by excess gastrointestinal (499 in men, 572 in women) and intracranial (76 in men, 54 in women) bleeding. The results in health adjusted years of life lived (which take into account length and quality of life) are equivocal for aspirin causing net harm or net benefit.
Conclusion Epidemiological modelling suggests that any benefits of low dose aspirin on risk of cardiovascular disease in people aged ≥ 70 are offset by adverse events. These findings are tempered by wide confidence intervals, indicating that the overall outcome could be beneficial or adverse.
Rationale: In an observational cohort study, women who self-selected for frequent aspirin use developed less newly diagnosed asthma than women who did not take aspirin.
Objective: To explore whether low-dose aspirin decreased the risk of newly diagnosed asthma in a randomized, double-blind, placebo-controlled trial.
Methods: The Physicians' Health Study randomized 22,071 apparently healthy male physicians, aged 40–84 yr at baseline and tolerant of aspirin, over an 18-wk run-in period, to 325 mg aspirin or placebo on alternate days. The aspirin component was terminated after 4.9 yr due principally to the emergence of a statistically extreme 44% reduction in risk of first myocardial infarction among those randomly assigned to aspirin.
Measurements: Physicians could self-report an asthma diagnosis on questionnaires at baseline, 6 mo, and annually thereafter. Asthma was not an a priori endpoint of the trial.
Results: Among 22,040 physicians without reported asthma at randomization, there were 113 new asthma diagnoses in the aspirin group and 145 in the placebo group. The hazard ratio was 0.78 (95% confidence interval, 0.61–1.00; p = 0.045). This apparent 22% lower risk of newly diagnosed asthma among those assigned to aspirin was not modified by baseline characteristics including smoking, body mass index, or age.
Conclusions: Aspirin reduced the risk of newly diagnosed adult-onset asthma in a large, randomized clinical trial of apparently healthy, aspirin-tolerant men. This result requires replication in randomized trials designed a priori to test this hypothesis; it does not imply that aspirin improves symptoms in patients with asthma.
asthma; aspirin; NSAIDs; analgesics; obstructive airways disease
Objectives To evaluate the risk of myocardial infarction and death from coronary heart disease after discontinuation of low dose aspirin in primary care patients with a history of cardiovascular events.
Design Nested case-control study.
Setting The Health Improvement Network (THIN) database in the United Kingdom.
Participants Individuals aged 50-84 with a first prescription for aspirin (75-300 mg/day) for secondary prevention of cardiovascular outcomes in 2000-7 (n=39 513).
Main outcome measures Individuals were followed up for a mean of 3.2 years to identify cases of non-fatal myocardial infarction or death from coronary heart disease. A nested case-control analysis assessed the risk of these events in those who had stopped taking low dose aspirin compared with those who had continued treatment.
Results There were 876 non-fatal myocardial infarctions and 346 deaths from coronary heart disease. Compared with current users, people who had recently stopped taking aspirin had a significantly increased risk of non-fatal myocardial infarction or death from coronary heart disease combined (rate ratio 1.43, 95% confidence interval 1.12 to 1.84) and non-fatal myocardial infarction alone (1.63, 1.23 to 2.14). There was no significant association between recently stopping low dose aspirin and the risk of death from coronary heart disease (1.07, 0.67 to 1.69). For every 1000 patients, over a period of one year there were about four more cases of non-fatal myocardial infarction among patients who discontinued treatment with low dose aspirin (recent discontinuers) compared with patients who continued treatment.
Conclusions Individuals with a history of cardiovascular events who stop taking low dose aspirin are at increased risk of non-fatal myocardial infarction compared with those who continue treatment.
Objective To evaluate the benefits and harms of low dose aspirin in people with diabetes and no cardiovascular disease.
Design Meta-analysis of randomised controlled trials.
Data sources Medline (1966-November 2008), the Cochrane central register of controlled trials (Cochrane Library 2008;issue 4), and reference lists of retrieved articles.
Review methods Randomised trials of aspirin compared with placebo or no aspirin in people with diabetes and no pre-existing cardiovascular disease were eligible for inclusion. Data on major cardiovascular events (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, and all cause mortality) were extracted and pooled with a random effect model. Results are reported as relative risks with 95% confidence intervals.
Results Of 157 studies in the literature searches, six were eligible (10 117 participants). When aspirin was compared with placebo there was no statistically significant reduction in the risk of major cardiovascular events (five studies, 9584 participants; relative risk 0.90, 95% confidence interval 0.81 to 1.00), cardiovascular mortality (four studies, n=8557, 0.94; 0.72 to 1.23), or all cause mortality (four studies, n=8557; 0.93, 0.82 to 1.05). Significant heterogeneity was found in the analysis for myocardial infarction (I2=62.2%; P=0.02) and stroke (I2=52.5%; P=0.08). Aspirin significantly reduced the risk of myocardial infarction in men (0.57, 0.34 to 0.94) but not in women (1.08, 0.71 to 1.65; P for interaction=0.056). Evidence relating to harms was inconsistent.
Conclusions A clear benefit of aspirin in the primary prevention of major cardiovascular events in people with diabetes remains unproved. Sex may be an important effect modifier. Toxicity is to be explored further.
Objectives To evaluate whether the association between migraine with aura and increased risk of cardiovascular disease is modified by vascular risk groups as measured by the Framingham risk score for coronary heart disease.
Design Prospective cohort study.
Setting Women’s health study, United States.
Participants 27 519 women who were free from cardiovascular disease at baseline with available information on the Framingham risk score and migraine status.
Main outcome measures Time to major cardiovascular disease event (non-fatal myocardial infarction, non-fatal ischaemic stroke, death from ischaemic cardiovascular disease), myocardial infarction, and ischaemic stroke.
Results At baseline, 3577 (13.0%) women reported active migraine, of whom 1418 (39.6%) reported migraine with aura. During 11.9 years of follow-up, there were 697 cardiovascular disease events. We stratified participants based on 10 year risk of coronary heart disease estimated from the Framingham risk score (≤1%, 2-4%, 5-9%, and ≥10%). Compared with women without migraine, the age adjusted hazard ratios in women with active migraine with aura were 1.93 (95% confidence interval 1.45 to 2.56) for major cardiovascular disease, 1.80 (1.16 to 2.79) for ischaemic stroke, and 1.94 (1.27 to 2.95) for myocardial infarction. When stratified by Framingham risk score, the association between migraine with aura and major cardiovascular disease was strongest in the lowest risk score group. There was a diametric association pattern for ischaemic stroke and myocardial infarction. Compared with women without migraine, the age adjusted hazard ratios in women who reported migraine with aura in the lowest Framingham risk score group were 3.88 (1.87 to 8.08) for ischaemic stroke and 1.29 (0.40 to 4.21) for myocardial infarction. Hazard ratios in women with migraine with aura in the highest Framingham risk score group were 1.00 (0.24 to 4.14) for ischaemic stroke and 3.34 (1.50 to 7.46) for myocardial infarction. Women with migraine without aura were not at increased risk of ischaemic stroke or myocardial infarction in any of the Framingham risk score groups.
Conclusion The association between migraine with aura and cardiovascular disease varies by vascular risk status. Information on history of migraine and vascular risk status might help to identify women at increased risk for specific future cardiovascular disease events.
Trial registration Clinical trials NCT00000479.
OBJECTIVE—To determine the cardiovascular and coronary risk thresholds at which aspirin for primary prevention of coronary heart disease is safe and worthwhile.
DESIGN—Meta-analysis of four randomised controlled trials of aspirin for primary prevention. The benefit and harm from aspirin treatment were examined to determine: (1) the cardiovascular and coronary risk threshold at which benefit in prevention of myocardial infarction exceeds harm from significant bleeding; and (2) the absolute benefit expressed as number needed to treat (NNT) for aspirin net of cerebral haemorrhage and other bleeding complications at different levels of coronary risk.
MAIN OUTCOME MEASURES—Benefit from aspirin, expressed as reduction in cardiovascular events, myocardial infarctions, strokes, and total mortality; harm caused by aspirin in relation to significant bleeds and major haemorrhages.
RESULTS—Aspirin for primary prevention significantly reduced all cardiovascular events by 15% (95% confidence interval (CI) 6% to 22%) and myocardial infarctions by 30% (95% CI 21% to 38%), and non-significantly reduced all deaths by 6% (95% CI −4% to 15%). Aspirin non-significantly increased strokes by 6% (95% CI −24% to 9%) and significantly increased bleeding complications by 69% (95% CI 38% to 107%). The risk of major bleeding balanced the reduction in cardiovascular events when cardiovascular event risk was 0.22%/year. The upper 95% CI for this estimate suggests that harm from aspirin is unlikely to outweigh benefit provided the cardiovascular event risk is 0.8%/year, equivalent to a coronary risk of 0.6%/year. At coronary event risk 1.5%/year, the five year NNT was 44 to prevent a myocardial infarction, and 77 to prevent a myocardial infarction net of any important bleeding complication. At coronary event risk 1%/year the NNT was 67 to prevent a myocardial infarction, and 182 to prevent a myocardial infarction net of important bleeding.
CONCLUSIONS—Aspirin treatment for primary prevention is safe and worthwhile at coronary event risk ⩾ 1.5%/year; safe but of limited value at coronary risk 1%/year; and unsafe at coronary event risk 0.5%/year. Advice on aspirin for primary prevention requires formal accurate estimation of absolute coronary event risk.
Keywords: aspirin; coronary heart disease; primary prevention; meta-analysis
OBJECTIVE—Subclinical inflammation is linked with the development of type 2 diabetes, and epidemiologic data suggest that this association may be stronger in women. Although small clinical studies have shown a prominent hypoglycemic effect of short-term high-dose aspirin, no randomized trials have directly evaluated the efficacy of aspirin in diabetes prevention at doses acceptable for use in routine clinical practice. We evaluated whether chronic low-dose aspirin prevents the development of clinical diabetes among initially healthy American women.
RESEARCH DESIGN AND METHODS—Subjects were enrolled in the Women's Health Study, a 10-year randomized double-blind, placebo-controlled trial of aspirin and vitamin E for primary prevention of cardiovascular disease and cancer. Between 1992 and 1995, 38,716 women aged ≥45 years and free of clinical diabetes were randomly assigned to either low-dose aspirin or placebo (median follow-up 10.2 years). Documented clinical type 2 diabetes was prospectively evaluated throughout the trial.
RESULTS—Among women randomly assigned to receive aspirin (n = 19,326) or placebo (n = 19,390), there was no statistically significant difference in the incidence of type 2 diabetes. There were 849 cases of diabetes in the aspirin group and 847 in the placebo group (rate ratio 1.01 [95% CI 0.91–1.11]). Stratification by diabetes risk factors including age, BMI, family history of diabetes, physical activity, A1C, and high-sensitivity C-reactive protein did not support a modulating effect of these variables. Analyses accounting for treatment duration and adherence similarly found no beneficial effects.
CONCLUSIONS—These data suggest that long-term low-dose aspirin does not prevent the development of clinical type 2 diabetes in initially healthy women.
Objective To evaluate the association of kidney function with cardiovascular disease and mortality among apparently healthy women.
Design Prospective cohort study.
Setting Women’s Health Study, United States.
Participants 27 939 female health professionals aged ≥45 who were free of cardiovascular disease and other major disease and who provided a blood sample at study entry.
Main outcome measures Time to cardiovascular disease (non-fatal stroke, non-fatal myocardial infarction, coronary revascularisation procedures, or death from cardiovascular cause), specific cardiovascular disease events, and all-cause mortality. End points were confirmed after review of medical records and death certificates.
Results Glomerular filtration rate (GFR) was estimated with the abbreviated Modification of Diet in Renal Disease Study equation. At baseline, 1315 (4.7%) women had GFR <60 ml/min/1.73 m2. During 12 years of follow-up, 1199 incident cardiovascular disease events and 856 deaths (179 from cardiovascular disease) occurred. Compared with women with GFR ≥90 ml/min/1.73 m2, the multivariable adjusted hazard ratios for any first cardiovascular disease were 0.95 (95% CI 0.83 to 1.08), 0.84 (0.70 to 1.00), and 1.00 (0.79 to 1.27) among women with GFR of 75-89.9, 60-74.9, and <60 ml/min/1.73 m2, respectively; the equivalent hazard ratios for all cause mortality were 0.93 (0.79 to 1.09), 1.03 (0.85 to 1.26), and 1.09 (0.83 to 1.45). Similar null findings were observed for myocardial infarction, stroke, coronary revascularisation, and non-cardiovascular death. However, an increased risk of death from cardiovascular disease was found among women with GFR <60 ml/min/1.73 m2 (hazard ratio 1.68 (1.02 to 2.79)).
Conclusions In this large cohort of women, a glomerular filtration rate <60 ml/min/1.73 m2 was associated with increased risk of cardiovascular disease death but not other cardiovascular disease events or non-cardiovascular disease mortality. We observed no increase in risk of any of the outcomes among women with less severe impairment of kidney function.
Constipation is common in Western societies, accounting for 2.5 million-physician visits/year in the US. Since many factors predisposing to constipation are also risk factors for cardiovascular disease, we hypothesized that constipation may be associated with increased risk of cardiovascular events.
We conducted a secondary analysis in 93,676 women enrolled in the observational arm of the Women’s Health Initiative. Constipation was evaluated at baseline by a self-administered questionnaire. Estimates of the risk of cardiovascular events (cumulative endpoint including mortality from coronary heart disease, myocardial infarction, angina, coronary revascularization, stroke and transient ischemic attack) were derived from Cox proportional hazards models adjusted for demographics, risk factors and other clinical variables (median follow-up: 6.9 years).
The analysis included 73,047 women. Constipation was associated with increased age, African American and Hispanic descent, smoking, diabetes, high cholesterol, family history of myocardial infarction, hypertension, obesity, lower physical activity levels, lower fiber intake, and depression. Women with moderate and severe constipation experienced more cardiovascular events (14.2 and 19.1 events/1000 person-years, respectively) compared to women with no constipation (9.6/1000 person-years). After adjustment for demographics, risk factors, dietary factors, medications, frailty and other psychological variables, constipation was no longer associated with an increased risk of cardiovascular events except for the severe constipation group, which had a 23% higher risk of cardiovascular events.
In postmenopausal women, constipation is a marker for cardiovascular risk factors and increased cardiovascular risk. Since constipation is easily assessed, it may be a helpful tool to identify women with increased cardiovascular risk.
cardiovascular disease; prevention; women’s health; risk factors
Aspirin is a cornerstone in prevention of cardiovascular events and modulates both platelet aggregation and fibrin clot formation. Some patients experience cardiovascular events whilst on aspirin, often termed aspirin treatment failure (ATF). This study evaluated both platelet aggregation and fibrin clot structure in patients with ATF.
We included 177 stable coronary artery disease patients on aspirin monotherapy. Among these, 116 (66%) had ATF defined as myocardial infarction (MI) whilst on aspirin. Platelet aggregation was assessed by Multiplate® aggregometry and VerifyNow®, whereas turbidimetric assays and scanning electron microscopy were employed to study fibrin clot characteristics.
Enhanced platelet aggregation was observed in patients with ATF compared with non-MI patients following stimulation with arachidonic acid 1.0 mM (median 161 (IQR 95; 222) vs. 97 (60; 1776) AU*min, p = 0.005) and collagen 1.0 µg/mL (293 (198; 427) vs. 220 (165; 370) AU*min, p = 0.03). Similarly, clot maximum absorbance, a measure of fibrin network density, was increased in patients with ATF (0.48 (0.41; 0.52) vs. 0.42 (0.38; 0.50), p = 0.02), and this was associated with thinner fibres (mean ± SD: 119.7±27.5 vs. 127.8±31.1 nm, p = 0.003) and prolonged lysis time (552 (498; 756) vs. 519 (468; 633) seconds; p = 0.02). Patients with ATF also had increased levels of C-reactive protein (CRP) (1.34 (0.48; 2.94) and 0.88 (0.32; 1.77) mg/L, p = 0.01) compared with the non-MI group. Clot maximum absorbance correlated with platelet aggregation (r = 0.31–0.35, p-values<0.001) and CRP levels (r = 0.60, p<0.001).
Patients with aspirin treatment failure showed increased platelet aggregation and altered clot structure with impaired fibrinolysis compared with stable CAD patients without previous MI. These findings suggest that an increased risk of aspirin treatment failure may be identified by measuring both platelet function and fibrin clot structure.
Objective To evaluate resting heart rate as an independent predictor of cardiovascular risk in women.
Design Prospective cohort study.
Setting The Women’s Health Initiative was undertaken at 40 research clinics in the United States.
Participants 129 135 postmenopausal women.
Main outcome measure Clinical cardiovascular events.
Results During a mean of 7.8 (SD 1.6) years of follow up, 2281 women were identified with myocardial infarction or coronary death and 1877 with stroke. We evaluated associations between resting heart rate and cardiovascular events in Cox regression models adjusted for multiple covariates. Higher resting heart rate was independently associated with coronary events (hazard ratio 1.26, 95% confidence interval 1.11 to 1.42 for highest [>76 beats per minute] v lowest quintile [≤62 beats per minute]; P=0.001), but not with stroke. The relation between heart rate and coronary events did not differ between white women and women from other ethnic groups (P for interaction=0.45) or between women with and without diabetes (P for interaction=0.31), but it was stronger in women aged 50-64 at baseline than in those aged 65-79 (P for interaction=0.009).
Conclusion Resting heart rate, a low tech and inexpensive measure of autonomic tone, independently predicts myocardial infarction or coronary death, but not stroke, in women.
Trial registration ClinicalTrials.gov NCT00000611.
Low-dose aspirin is an important therapeutic option in the secondary prevention of myocardial infarction (MI) and ischemic stroke, basedon its unique cost-effectiveness and widespread availability. In addition, based on the results of a number of large studies, aspirin is also widely used in the primary prevention of MI. This paper provides an update of the available data to offer greater clarity regarding the risks of aspirin with respect to hemorrhagic stroke. In the secondary prevention of cardiovascular, cerebrovascular, and ischemic events, the evidence supports that the benefits of aspirin treatment significantly outweigh the risk of a major hemorrhage. When considering whether aspirin is appropriate, the absolute therapeutic cardiovascular benefits of aspirin must be balanced with the possible risks associated with its use, being hemorrhagic stroke. Regarding these clinical facts, normal, COX 1 −/−, and COX 2 −/− mice were treated with a wide range of doses of aspirin and studied by induced hemorrhagic time. The results outlined three major conclusions: high doses of aspirin induce hemorrhage, while low doses of aspirin do not. In the absence of COX 1, ultra low doses of aspirin produce an antihemorrhagic effect not observed with intermediate doses. The absence of COX 2 induced a hemorrhagic effect that needs further research, probably originated in compensatory phenomena.
Aspirin has been recommended for the prevention of major adverse cardiovascular events (MACE, composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in diabetic patients without previous cardiovascular disease. However, recent meta-analyses have prompted re-evaluation of this practice. The study objective was to evaluate the relative and absolute benefits and harms of aspirin for the prevention of incident MACE in patients with diabetes.
We performed a systematic review and meta-analysis on seven studies (N = 11,618) reporting on the use of aspirin for the primary prevention of MACE in patients with diabetes. Two reviewers conducted a systematic search of electronic databases (MEDLINE, EMBASE, the Cochrane Library, and BIOSIS) and hand searched bibliographies and clinical trial registries. Reviewers extracted data in duplicate, evaluated the quality of the trials, and calculated pooled estimates.
A total of 11,618 participants were included in the analysis. The overall risk ratio (RR) for MACE was 0.91 (95% confidence intervals, CI, 0.82-1.00) with little heterogeneity among trials (I2 0.0%). Secondary outcomes of interest included myocardial infarction (RR, 0.85; 95% CI, 0.66-1.10), stroke (RR, 0.84; 95% CI, 0.64-1.11), cardiovascular death (RR, 0.95; 95% CI, 0.71-1.27), and all-cause mortality (RR, 0.95; 95% CI, 0.85-1.06). There were higher rates of hemorrhagic and gastrointestinal events. In absolute terms, these relative risks indicate that for every 10,000 diabetic patients treated with aspirin, 109 MACE may be prevented at the expense of 19 major bleeding events (with the caveat that the relative risk for the latter is not statistically significant).
The studies reviewed suggest that aspirin reduces the risk of MACE in patients with diabetes without cardiovascular disease, while also causing a trend toward higher rates of bleeding and gastrointestinal complications. These findings and our absolute benefit and risk calculations suggest that those with diabetes but without cardiovascular disease lie somewhere between primary and secondary prevention patients on the spectrum of benefit and risk. This underscores the importance of considering individual risk in clinical decision making regarding aspirin in those with diabetes.
OBJECTIVE: To examine the association between birth weight and non-fatal adult cardiovascular disease while controlling for potential confounders such as socioeconomic group and adult lifestyle. DESIGN: Retrospective self report of birth weight in an ongoing longitudinal cohort of nurses followed up by postal questionnaire every two years. SETTING: Nurses' health study, a cohort of 121700 women followed up since 1976. MAIN OUTCOME MEASURES: Non-fatal cardiovascular disease, including myocardial infarction, coronary revascularisation, and stroke. RESULTS: Among the 70297 women free of cardiovascular disease at baseline who reported birth weight in the 1992 questionnaire there were 1309 first cases of non-fatal cardiovascular disease. Increasing birth weight was associated with decreasing risk of non-fatal cardiovascular disease. There were 1216 first cases of non-fatal cardiovascular disease among women who were singletons and had been born full term; their relative risks adjusted for several cardiovascular risk factors were 1.49 (95% confidence interval 1.05 to 2.10) for birth weight < 2268 g (< 5 lb 0 oz); 1.25 (0.98 to 1.61) for birth weight 2268-2495 g (5 lb 0 oz to 5 lb 8 oz); 1.12 (0.98 to 1.27) for birth weight > 2495-3175 g (> 5 lb 8 oz to 7 lb 0 oz); 1.00 (referent) for birth weight > 3175-3856 g (> 7 lb 0 oz to 8 lb 8 oz); 0.96 (0.80 to 1.15) for birth weight > 3856-4536 g (> 8 lb 8 oz to 10 lb 0 oz); and 0.68 (0.46 to 1.00) for birth weight > 4536 g (> 10 lb 0 oz) (P value for trend = 0.0004). The inverse trend was apparent for both coronary heart disease and stroke. CONCLUSIONS: These data provide strong evidence of an association between birth weight and adult coronary heart disease and stroke.
Aspirin is effective for the prevention of cardiovascular events in patients with a history of vascular disease, as so-called secondary prevention. In general populations with no history of previous myocardial infarction or stroke, aspirin also seems useful for primary prevention of cardiovascular events, although the absolute benefits are smaller than those seen in patients with previous cardiovascular disease. Patients with diabetes mellitus are at an increased risk of cardiovascular events, but new trials have raised questions about the benefit of aspirin for primary prevention in patients with this disorder. This Review comprehensively examines the basic pharmacology of aspirin and provides an overview of the randomized, controlled trials of aspirin therapy that have included patients with diabetes mellitus. On the basis of currently available evidence from primary prevention trials, aspirin is estimated to reduce the relative risk of myocardial infarction and stroke by about 10% in patients with diabetes mellitus; however, aspirin also increases the risk of gastrointestinal bleeding. As such, low-dose aspirin therapy (75–162 mg) is reasonable for patients with diabetes mellitus and a 10-year risk of cardiovascular events >10%. Results from upcoming large trials will help clarify the effects of aspirin with greater precision, including whether the benefits differ between men and women.
To identify women who benefit from aspirin 100 mg on alternate days for primary prevention of vascular events by using treatment effect prediction based on individual patient characteristics.
Methods and results
Randomized controlled trial data from the Women's Health Study were used to predict treatment effects for individual women in terms of absolute risk reduction for major cardiovascular events (i.e. myocardial infarction, stroke, or cardiovascular death). Predictions were based on existing risk scores, i.e. Framingham (FRS), and Reynolds (RRS), and on a newly developed prediction model. The net benefit of different aspirin treatment-strategies was compared: (i) treat no one, (ii) treat everyone, (iii) treatment according to the current guidelines (i.e. selective treatment of women >65 years of age or having >10% FRS), and (iv) prediction-based treatment (i.e. selective treatment of patients whose predicted treatment effect exceeds a given decision threshold). The predicted reduction in 10-year absolute risk for major cardiovascular events was <1% in 97.8% of 27 939 study subjects when based on the refitted FRS, in 97.0% when based on the refitted RRS, and in 90.0% when based on the newly developed model. Of the treatment strategies considered, only prediction-based treatment using the newly developed model and selective treatment of women >65 years of age yielded more net benefit than treating no one, provided that the 10-year number-willing-to-treat (NWT) to prevent one cardiovascular event was above 50.
Aspirin was ineffective or even harmful in the majority of patients. Age was positively related to treatment effect, whereas current smoking and baseline risk for cardiovascular events were not. When the NWT is 50 or lower, the aspirin treatment strategy that is associated with optimal net benefit in primary prevention of vascular events in women is to treat none.
Trial registration information: Clinicaltrials.gov identifier number: NCT00000479.
Aspirin; Primary prevention; Treatment effect prediction; Net benefit
Evidence suggests that both selective cyclooxygenase (COX)‐2 inhibitors and non‐selective non‐steroidal anti‐inflammatory drugs (NSAIDs) increase the risk of cardiovascular events. However, evidence from prospective studies of currently available COX‐2 inhibitors and non‐selective NSAIDs is lacking in patients at high cardiovascular risk who are taking aspirin.
To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib.
The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18 325 patients with osteoarthritis comprised two parallel substudies, comparing lumiracoxib (COX‐2 inhibitor) with either ibuprofen or naproxen. A post hoc analysis by baseline cardiovascular risk, treatment assignment, and low‐dose aspirin use was performed. The primary composite end point was cardiovascular mortality, non‐fatal myocardial infarction, and stroke at 1 year; a secondary end point was the development of congestive heart failure (CHF).
In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899). High risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib (0% vs 1.57%, p = 0.027), but not for ibuprofen versus lumiracoxib (0.92% vs 0.80%, p = 0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs 0.14%; p = 0.031), whereas no difference existed between naproxen and lumiracoxib.
These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. The study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non‐aspirin users. This study is subject to inherent limitations, and therefore should be interpreted as a hypothesis‐generating study.
coronary disease; osteoarthritis; anti‐inflammatory agents, non‐steroidal anti‐inflammatory drugs; COX‐2 inhibitors; aspirin
Objectives To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.
Design Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies.
Data source WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36 282 community dwelling postmenopausal women.
Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data.
Results In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16 718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P=0.05 for clinical myocardial infarction or stroke, P=0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P=0.04), stroke (1.20 (1.00 to 1.43), P=0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), P=0.02). In meta-analyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28 072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P=0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P=0.009).
Conclusions Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.
The risk-benefit ratio of aspirin therapy in prevention of cardiovascular disease (CVD) remains contentious, especially in type 2 diabetes. This study examined the benefit and harm of low-dose aspirin (daily dose < 300 mg) in patients with type 2 diabetes.
This is a longitudinal observational study with primary and secondary prevention cohorts based on history of CVD at enrolment. We compared the occurrence of primary composite (non-fatal myocardial infarction or stroke and vascular death) and secondary endpoints (upper GI bleeding and haemorrhagic stroke) between aspirin users and non-users between January 1995 and July 2005.
Of the 6,454 patients (mean follow-up: median [IQR]: 4.7 [4.4] years), usage of aspirin was 18% (n = 1,034) in the primary prevention cohort (n = 5731) and 81% (n = 585) in the secondary prevention cohort (n = 723). After adjustment for covariates, in the primary prevention cohort, aspirin use was associated with a hazard-ratio of 2.07 (95% CI: 1.66, 2.59, p < 0.001) for primary endpoint. There was no difference in CVD event rate in the secondary prevention cohort. Overall, aspirin use was associated with a hazard-ratio of 2.2 (1.53, 3.15, p < 0.001) of GI bleeding and 1.71 (1.00, 2.95, p = 0.051) of haemorrhagic stroke. The absolute risk of aspirin-related GI bleeding was 10.7 events per 1,000 person-years of treatment.
In Chinese type 2 diabetic patients, low dose aspirin was associated with a paradoxical increase in CVD risk in primary prevention and did not confer benefits in secondary prevention. In addition, the risk of GI bleeding in aspirin users was rather high.
Patients with stable coronary artery disease on single-antiplatelet therapy with aspirin are still at risk for atherothrombotic events, and high on-aspirin residual platelet reactivity (RPR) has been suggested as a risk factor.
Methods and Results
In this randomized trial, the association between platelet function determined by the PFA100 platelet function analyzer system (Siemens Healthcare Diagnostics, Germany) and clinical outcome in 1001 patients, all on single-antiplatelet therapy with aspirin (160 mg/d) was studied. Patients were randomized to continue with aspirin 160 mg/d or change to clopidogrel 75 mg/d. A composite end point of death, myocardial infarction, ischemic stroke, and unstable angina was used. At 2-year follow-up, 106 primary end points were registered. The prevalence of high RPR was 25.9%. High on-aspirin RPR did not significantly influence the primary end point in the aspirin group (13.3% versus 9.9%, P=0.31). However, in post hoc analysis, patients with von Willebrand factor levels or platelet count below median values and high on-aspirin RPR had a statistically significant higher end point rate than that of patients with low RPR (20% versus 7.5%, P=0.014, and 18.2% versus 10.8%, P=0.039, respectively). The composite end point rate in patients with high on-aspirin RPR treated with clopidogrel was not different from that of patients treated with aspirin (7.6% versus 13.3%, P=0.16).
In stable, aspirin-treated patients with coronary artery disease, high on-aspirin RPR did not relate to clinical outcome and did not identify a group responsive to clopidogrel. Post hoc subgroup analysis raised the possibility that high on-aspirin RPR might be predictive in patients with low von Willebrand factor or platelet count, but these findings will require confirmation in future studies.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov Unique identifier: NCT00222261. (J Am Heart Assoc. 2012;1:e000703 doi: 10.1161/JAHA.112.000703.)
antiplatelet therapy; aspirin; clopidogrel; residual platelet reactivity; angina, stable
Systemic lupus erythematosus (SLE) has been associated with an increased risk of cardiovascular disease. However, prospective population-based data addressing this association have been lacking.
We conducted a prospective cohort study among 119,332 women participating in the Nurses’ Health Study who were free of cardiovascular disease and SLE at baseline in 1976. Incident SLE was confirmed by medical record review. Cardiovascular events included fatal and nonfatal myocardial infarction, stroke, coronary artery bypass grafting and angioplasty. The relative risk of cardiovascular events among participants with SLE as compared to those without was estimated using Cox proportional hazards models.
Over 28 years of follow-up (2.9 million person-years) 8,169 cardiovascular events occurred and 148 women developed incident SLE. Mean age at SLE diagnosis was 52.6 years, and 20 participants with SLE developed a subsequent cardiovascular event. After adjusting for potential confounding factors, including age, race, cardiovascular risk factors and medication use, the relative risk (RR) of a cardiovascular event in women with SLE compared with those without was 2.26 (95% CI 1.45–3.52). When endpoints were analyzed separately, the RR for coronary heart disease was 2.25; 95% CI 1.37–3.69, and the RR for stroke was 2.29; 95% CI 0.85–6.15.
In this prospective population-based study, we found a statistically significant over 2-fold increased risk of cardiovascular disease among participants with SLE. The risk was not as high as has been previously reported, which may be due to the relatively high age at diagnosis of SLE in this cohort.
cardiovascular diseases; epidemiology; immunology; systemic lupus erythematosus; women
Objective To compare cardiovascular risk among women with high normal blood pressure (130-9/85-9 mm Hg) against those with normal blood pressure (120-9/75-84 mm Hg) and those with baseline hypertension.
Design Prospective cohort study.
Setting Women's health study, United States.
Participants 39 322 initially healthy women classified into four categories according to self reported baseline blood pressure and followed for a median of 10.2 years.
Main outcome measures Time to cardiovascular death, myocardial infarction, or stroke (major cardiovascular event—primary end point); progression to hypertension.
Results 982 (2.5%) women developed a major cardiovascular event, and 8686 (30.1%) women without baseline hypertension progressed to hypertension. The age adjusted event rate for the primary end point was 1.6/1000 person years among women with normal blood pressure, 2.9/1000 person years among those with high normal blood pressure, and 4.3/1000 person years among those with baseline hypertension. Compared with women with high normal blood pressure (reference group), those with normal blood pressure had a lower risk of a major cardiovascular event (adjusted hazard ratio 0.61, 95% confidence interval 0.48 to 0.76) and of incident hypertension (0.42, 0.40 to 0.44). The hazard ratio for a major cardiovascular event in women with baseline hypertension was 1.30 (1.08 to 1.57). Women who progressed to hypertension (reference group) during the first 48 months of the study had a higher cardiovascular risk than those who remained normotensive (adjusted hazard ratio 0.64, 0.50 to 0.81). Women with high normal blood pressure at baseline who progressed to hypertension (reference group) had similar outcome rates to women with baseline hypertension (adjusted hazard ratio 1.17, 0.88 to 1.55).
Conclusion The cardiovascular risk of women with high normal blood pressure is higher than that of women with normal blood pressure. The cardiovascular risk of women who progress to hypertension is increased shortly after a diagnosis of hypertension has been made.
Trial registration Clinical trials NCT00000479.
Randomized evidence for aspirin in the primary prevention of cardiovascular disease (CVD) among women is limited and suggests at most a modest effect for total CVD. Lack of compliance, however, can null-bias estimated effects. We used marginal structural models (MSMs) to estimate the etiologic effect of continuous aspirin use on CVD events among 39,876 apparently healthy female health professionals aged 45 years and older in the Women’s Health Study, a randomized trial of 100 mg aspirin every other day versus placebo. As-treated analyses and MSMs controlled for time-varying determinants of aspirin use and CVD. Predictors of aspirin use differed by randomized group and prior use and included medical history, CVD risk factors, and intermediate CVD events. Previously reported intent-to-treat analyses found small non-significant effects of aspirin on total CVD (hazard ratio (HR) =0.91, 95% confidence interval (CI) =0.81–1.03) and CVD mortality (HR=0.95, 95% CI=0.74–1.22). As-treated analyses were similar for total CVD with a slight reduction in CVD mortality (HR=0.88, 95%CI=0.67–1.16). MSMs, which adjusted for non-compliance, were similar for total CVD (HR=0.93; 95% CI: 0.81, 1.07) but suggested lower CVD mortality with aspirin use (HR = 0.76; 95% CI: 0.54, 1.08). Adjusting for non-compliance had little impact on the estimated effect of aspirin on total CVD, but strengthened the effect on CVD mortality. These results support a limited effect of low-dose aspirin on total CVD in women, but potential benefit for CVD mortality.
Aspirin; cardiovascular disease; marginal structural model; myocardial infarction; stroke