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July 2006

A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.

BACKGROUND: Randomized trials have shown that low-dose aspirin decreases the risk of a first myocardial infarction in men, with little effect on the risk of ischemic stroke. There are few similar data in women. METHODS: We randomly assigned 39,876 initially healthy women 45 years of age or older to receive 100 mg of aspirin on alternate days or placebo and then monitored them for 10 years for a first major cardiovascular event (i.e., nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes). RESULTS: During follow-up, 477 major cardiovascular events were confirmed in the aspirin group, as compared with 522 in the placebo group, for a nonsignificant reduction in risk with aspirin of 9% (relative risk, 0.91; 95% confidence interval, 0.80 to 1.03; P=0.13). With regard to individual end points, there was a 17% reduction in the risk of stroke in the aspirin group, as compared with the placebo group (relative risk, 0.83; 95% confidence interval, 0.69 to 0.99; P=0.04), owing to a 24% reduction in the risk of ischemic stroke (relative risk, 0.76; 95% confidence interval, 0.63 to 0.93; P=0.009) and a nonsignificant increase in the risk of hemorrhagic stroke (relative risk, 1.24; 95% confidence interval, 0.82 to 1.87; P=0.31). As compared with placebo, aspirin had no significant effect on the risk of fatal or nonfatal myocardial infarction (relative risk, 1.02; 95% confidence interval, 0.84 to 1.25; P=0.83) or death from cardiovascular causes (relative risk, 0.95; 95% confidence interval, 0.74 to 1.22; P=0.68). Gastrointestinal bleeding requiring transfusion was more frequent in the aspirin group than in the placebo group (relative risk, 1.40; 95% confidence interval, 1.07 to 1.83; P=0.02). Subgroup analyses showed that aspirin significantly reduced the risk of major cardiovascular events, ischemic stroke, and myocardial infarction among women 65 years of age or older. CONCLUSIONS: In this large, primary-prevention trial among women, aspirin lowered the risk of stroke without affecting the risk of myocardial infarction or death from cardiovascular causes, leading to a nonsignificant finding with respect to the primary end point.

N Engl J Med. 2005 Mar 31;352(13):1293-304

Vascular dementia: distinguishing characteristics, treatment, and prevention.

Vascular dementia (VaD) is the second-most-common cause of dementia in the elderly, after Alzheimer’s disease (AD). VaD is defined as loss of cognitive function resulting from ischemic, hypoperfusive, or hemorrhagic brain lesions due to cerebrovascular disease or cardiovascular pathology. Diagnosis requires the following criteria: cognitive loss, often predominantly subcortical; vascular brain lesions demonstrated by imaging; a temporal link between stroke and dementia; and exclusion of other causes of dementia. Poststroke VaD may be caused by large-vessel disease with multiple strokes (multiinfarct dementia) or by a single stroke (strategic stroke VaD). A common form is subcortical ischemic VaD caused by small-vessel occlusions with multiple lacunas and by hypoperfusive lesions resulting from stenosis of medullary arterioles, as in Binswanger’s disease. Unlike with AD, in VaD, executive dysfunction is commonly seen, but memory impairment is mild or may not even be present. The cholinesterase inhibitors used for AD are also useful in VaD. Prevention strategies should focus on reduction of stroke and cardiovascular disease, with attention to control of risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, and hyperhomocysteinemia.

J Am Geriatr Soc. 2003 May;51(5 Suppl Dementia):S296-304

Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study.

BACKGROUND: Previous analyses from the Cache County (UT) Study showed inverse associations between the prevalence of AD and the use of nonsteroidal anti-inflammatory drugs (NSAID), aspirin compounds, or histamine H(2) receptor antagonists (H(2)RA). The authors re-examined these associations using data on incident AD. METHODS: In 1995 to 1996, elderly (aged 65+) county residents were assessed for dementia, with current and former use of NSAID, aspirin, and H(2)RA as well as three other “control” medication classes also noted. Three years later, interval medication histories were obtained and 104 participants with incident AD were identified among 3,227 living participants. Discrete time survival analyses estimated the risk of incident AD in relation to medication use. RESULTS: AD incidence was marginally reduced in those reporting NSAID use at any time. Increased duration of use was associated with greater risk reduction, and the estimated hazard ratio was 0.45 with >/=2 years of exposure. Users of NSAID at baseline showed little reduction in AD incidence, regardless of use thereafter. By contrast, former NSAID users showed substantially reduced incidence (estimated hazard ratio = 0.42), with a trend toward greatest risk reduction among those with extended exposure. Similar patterns appeared with aspirin but not with any other medicines examined. CONCLUSIONS: Long-term NSAID use may reduce the risk of AD, provided such use occurs well before the onset of dementia. More recent exposure seems to offer little protection. Recently initiated randomized trials of NSAID for primary prevention of AD are therefore unlikely to show effects with treatment until participants have been followed for several years.

Neurology. 2002 Sep 24;59(6):880-6

Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force.

BACKGROUND: The use of aspirin to prevent cardiovascular disease events in patients without a history of cardiovascular disease is controversial. PURPOSE: To examine the benefits and harms of aspirin chemoprevention. DATA SOURCES: MEDLINE (1966 to May 2001). STUDY SELECTION: 1) Randomized trials at least 1 year in duration that examined aspirin chemoprevention in patients without previously known cardiovascular disease and 2) systematic reviews, recent trials, and observational studies that examined rates of hemorrhagic strokes and gastrointestinal bleeding secondary to aspirin use. DATA EXTRACTION: One reviewer read and extracted data from each included article and constructed evidence tables. A second reviewer checked the accuracy of the data extraction. Discrepancies were resolved by consensus. DATA SYNTHESIS: Meta-analysis was performed, and the quantitative results of the review were then used to model the consequences of treating patients with different levels of baseline risk for coronary heart disease. Five trials examined the effect of aspirin on cardiovascular events in patients with no previous cardiovascular disease. For patients similar to those enrolled in the trials, aspirin reduces the risk for the combined end point of nonfatal myocardial infarction and fatal coronary heart disease (summary odds ratio, 0.72 [95% CI, 0.60 to 0.87]). Aspirin increased the risk for hemorrhagic strokes (summary odds ratio, 1.4 [CI, 0.9 to 2.0]) and major gastrointestinal bleeding (summary odds ratio, 1.7 [CI, 1.4 to 2.1]). All-cause mortality (summary odds ratio, 0.93 [CI, 0.84 to 1.02]) was not significantly affected. For 1,000 patients with a 5% risk for coronary heart disease events over 5 years, aspirin would prevent 6 to 20 myocardial infarctions but would cause 0 to 2 hemorrhagic strokes and 2 to 4 major gastrointestinal bleeding events. For patients with a risk of 1% over 5 years, aspirin would prevent 1 to 4 myocardial infarctions but would cause 0 to 2 hemorrhagic strokes and 2 to 4 major gastrointestinal bleeding events. CONCLUSIONS: The net benefit of aspirin increases with increasing cardiovascular risk. In the decision to use aspirin chemoprevention, the patient’s cardiovascular risk and relative utility for the different clinical outcomes prevented or caused by aspirin use must be considered.

Ann Intern Med. 2002 Jan 15;136(2):161-72

A randomized trial of aspirin to prevent colorectal adenomas

BACKGROUND: Laboratory and epidemiologic data suggest that aspirin has an antineoplastic effect in the large bowel. METHODS: We performed a randomized, double-blind trial of aspirin as a chemopreventive agent against colorectal adenomas. We randomly assigned 1,121 patients with a recent history of histologically documented adenomas to receive placebo (372 patients), 81 mg of aspirin (377 patients), or 325 mg of aspirin (372 patients) daily. According to the protocol, follow-up colonoscopy was to be performed approximately three years after the qualifying endoscopy. We compared the groups with respect to the risk of one or more neoplasms (adenomas or colorectal cancer) at least one year after randomization using generalized linear models to compute risk ratios and 95% confidence intervals. RESULTS: Reported adherence to study medications and avoidance of nonsteroidal antiinflammatory drugs were excellent. Follow-up colonoscopy was performed at least one year after randomization in 1,084 patients (97%). The incidence of one or more adenomas was 47% in the placebo group, 38% in the group given 81 mg of aspirin per day, and 45% in the group given 325 mg of aspirin per day (global P=0.04). Unadjusted relative risks of any adenoma (as compared with the placebo group) were 0.81 in the 81-mg group (95% confidence interval, 0.69 to 0.96) and 0.96 in the 325-mg group (95% confidence interval, 0.81 to 1.13). For advanced neoplasms (adenomas measuring at least 1 cm in diameter or with tubulovillous or villous features, severe dysplasia, or invasive cancer), the respective relative risks were 0.59 (95% confidence interval, 0.38 to 0.92) and 0.83 (95% confidence interval, 0.55 to 1.23). CONCLUSIONS: Low-dose aspirin has a moderate chemopreventive effect on adenomas in the large bowel. N Engl J Med. 2003 Mar 6;348(10):891-9 A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.BACKGROUND: Experimental studies in animals and observational studies in humans suggest that regular aspirin use may decrease the risk of colorectal adenomas, the precursors to most colorectal cancers. METHODS: We conducted a randomized, double-blind trial to determine the effect of aspirin on the incidence of colorectal adenomas. We randomly assigned 635 patients with previous colorectal cancer to receive either 325 mg of aspirin per day or placebo. We determined the proportion of patients with adenomas, the number of recurrent adenomas, and the time to the development of adenoma between randomization and subsequent colonoscopic examinations. Relative risks were adjusted for age, sex, cancer stage, the number of colonoscopic examinations, and the time to a first colonoscopy. The study was terminated early by an independent data and safety monitoring board when statistically significant results were reported during a planned interim analysis. RESULTS: A total of 517 randomized patients had at least one colonoscopic examination a median of 12.8 months after randomization. One or more adenomas were found in 17% of patients in the aspirin group and 27% of patients in the placebo group (P=0.004). The mean (+/-SD) number of adenomas was lower in the aspirin group than the placebo group (0.30+/-0.87 vs. 0.49+/-0.99, P=0.003 by the Wilcoxon test). The adjusted relative risk of any recurrent adenoma in the aspirin group, as compared with the placebo group, was 0.65 (95% confidence interval, 0.46 to 0.91). The time to the detection of a first adenoma was longer in the aspirin group than in the placebo group (hazard ratio for the detection of a new polyp, 0.64; 95% confidence interval, 0.43 to 0.94; P=0.022). CONCLUSIONS: Daily use of aspirin is associated with a significant reduction in the incidence of colorectal adenomas in patients with previous colorectal cancer.

N Engl J Med. 2003 Mar 6;348(10):883-90

Regional distribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer’s disease.

Cyclooxygenase-2 (COX-2), a key enzyme in prostanoid biosynthesis, may represent an important therapeutic target in Alzheimer’s disease (AD). In the present study, we explored the regulation of COX-2 in the hippocampal formation in sporadic AD. Using semiquantitative immunocytochemical techniques, we found that in AD cases (vs. age-matched controls) neurons of the CA1-CA4 subdivisions of the hippocampal pyramidal layer showed elevation of COX-2 signal; COX-2 levels correlated with amyloid plaque density. In contrast, the level of COX-2 immunostaining in the dentate gyrus granule neurons was not elevated in AD. No expression of COX-2 in cells with glial morphology was found in any case examined. In parallel, in vitro studies found that neurons derived from transgenic mice with neuronal overexpression of COX-2 are more susceptible to beta-amyloid (Abeta) toxicity, with potentiation of redox impairment. The results indicate elevated expression of neuronal COX-2 in subregions of the hippocampal formation in AD and that such elevation may potentiate Abeta-mediated oxidative stress.

J Neurosci Res. 1999 Aug 1;57(3):295-303

An update on aspirin in the primary prevention of cardiovascular disease.

BACKGROUND: In 1988, the aspirin component of the Physicians’ Health Study, a randomized, double-blind, placebo-controlled trial of 22,071 apparently healthy men was terminated early, due principally to a statistically extreme (P<.00001) 44% reduction in the risk of a first myocardial infarction (MI). The Cardio-Renal Drugs Advisory Committee recommended that the US Food and Drug Administration approve professional labeling of aspirin to prevent first MI. The agency did not act on this recommendation because the only other trial, the British Doctors’ Trial of 5,139 men, showed no significant benefits. Since that time, 3 additional randomized trials (which included men and women) of aspirin in the primary prevention of MI have been published. METHODS: A computerized search of the English literature from 1988 to the present revealed 5 published trials: the Physicians’ Health Study (22,071 participants), the British Doctors’ Trial (5,139), the Thrombosis Prevention Trial (5,085), the Hypertension Optimal Treatment Study (18,790), and the Primary Prevention Project (4495). RESULTS: Among the 55,580 randomized participants (11,466 women), aspirin was associated with a statistically significant 32% reduction in the risk of a first MI and a significant 15% reduction in the risk of all important vascular events, but had no significant effects on nonfatal stroke or vascular death. CONCLUSIONS: The current totality of evidence provides strong support for the initial finding from the Physicians’ Health Study that aspirin reduces the risk of a first MI. For apparently healthy individuals whose 10-year risk of a first coronary event is 10% or greater, according to the US Preventive Services Task Force and the American Heart Association, the benefits of long-term aspirin therapy are likely to outweigh any risks.

Arch Intern Med. 2003 Sep 22;163(17):2006-10

Inflammation and atherosclerosis.

Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.

Circulation. 2002 Mar 5;105(9):1135-43