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Background: Short-term aspirin therapy can lower the risk for venous thromboembolism (VTE) in high-risk patients, but whether the long-term use of low-dose aspirin reduces risk in healthy adults is uncertain.Objective: To test the efficacy of long-term aspirin therapy for preventing VTE.Design: Secondary analysis of a 10-year randomized, double-blind, placebo-controlled trial.Setting: U.S. female health care professionals in the Women's Health Study.Participants: 39,876 initially healthy women age 45 years or older (26,779 gave blood samples that were evaluated for factor V Leiden, G20210A prothrombin, and MTHFR 677C>T polymorphisms).Measurements: Documented VTE (deep venous thrombosis or pulmonary embolism) and unprovoked VTE (no recent surgery, trauma, or cancer diagnosis) were prospectively evaluated, secondary end points.Intervention: Aspirin, 100 mg, or placebo on alternate days.Results: Venous thromboembolism occurred in 482 women during follow-up, an incidence higher than that of myocardial infarction and nearly equal to that of stroke. The incidence of VTE (per 1000 person-years) was 1.18 among women randomly assigned to active aspirin, compared with 1.25 among women randomly assigned to placebo (relative hazard, 0.95 [95% CI, 0.79 to 1.13]; rate difference, -0.06 [CI, -0.28 to 0.16]). For unprovoked VTE, the relative hazard was 0.90 (CI, 0.70 to 1.16) and the rate difference was -0.06 (CI, -0.21 to 0.10). Relative hazards associated with aspirin use in higher-risk subgroups were 0.83 (CI, 0.50 to 1.39) among women with either factor V Leiden or the prothrombin mutation and 1.36 (CI, 0.77 to 2.41) among those with a history of VTE.Limitation: Venous thromboembolism was a secondary end point in the Women's Health Study.Conclusion: These data suggest that long-term, low-dose aspirin treatment has little effect on the prevention of VTE in initially healthy women. ClinicalTrials.gov registration number: NCT00000479. [ABSTRACT FROM AUTHOR]

Background: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in placebo-controlled trials of patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD)., Objective: To evaluate whether SGLT2 inhibitors and GLP-1 RAs are associated with differential cardiovascular benefit among T2D patients with and without CVD., Design: Population-based cohort study., Setting: Medicare and 2 U.S. commercial claims data sets (April 2013 to December 2017)., Participants: 1:1 propensity score-matched adult T2D patients with and without CVD (52 901 and 133 139 matched pairs) initiating SGLT2 inhibitor versus GLP-1 RA therapy., Measurements: Primary outcomes were myocardial infarction (MI) or stroke hospitalization and hospitalization for heart failure (HHF). Pooled hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, with 95% CIs, controlling for 138 preexposure covariates., Results: The initiation of SGLT2 inhibitor versus GLP-1 RA therapy was associated with a slightly lower risk for MI or stroke in patients with CVD (HR, 0.90 [95% CI, 0.82 to 0.98]; RD, -2.47 [CI, -4.45 to -0.50]) but similar risk in those without CVD (HR, 1.07 [CI, 0.97 to 1.18]; RD, 0.38 [CI, -0.30 to 1.07]). The initiation of SGLT2 inhibitor versus GLP-1 RA therapy was associated with reductions in HHF risk regardless of baseline CVD in patients with CVD (HR, 0.71 [CI, 0.64 to 0.79]; RD, -4.97 [CI, -6.55 to -3.39]) and in those without CVD (HR, 0.69 [CI, 0.56 to 0.85]; RD, -0.58 [CI, -0.91 to -0.25])., Limitation: Treatment selection was not randomized., Conclusion: Use of SGLT2 inhibitors versus GLP-1 RAs was associated with consistent reductions in HHF risk among T2D patients with and without CVD, although the absolute benefit was greater in patients with CVD. There were no large differences in risk for MI or stroke among T2D patients with and without CVD., Primary Funding Source: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School.

Background: The role of differing levels of frailty in the choice of oral anticoagulants for older adults with atrial fibrillation (AF) is unclear., Objective: To examine the outcomes of direct oral anticoagulants (DOACs) versus warfarin by frailty levels., Design: 1:1 propensity score-matched analysis of Medicare data, 2010 to 2017., Setting: Community., Patients: Medicare beneficiaries with AF who initiated use of dabigatran, rivaroxaban, apixaban, or warfarin., Measurements: Composite end point of death, ischemic stroke, or major bleeding by frailty levels, defined by a claims-based frailty index., Results: In the dabigatran-warfarin cohort ( n  = 158 730; median follow-up, 72 days), the event rate per 1000 person-years was 63.5 for dabigatran initiators and 65.6 for warfarin initiators (hazard ratio [HR], 0.98 [95% CI, 0.92 to 1.05]; rate difference [RD], -2.2 [CI, -6.5 to 2.1]). For nonfrail, prefrail, and frail persons, HRs were 0.81 (CI, 0.68 to 0.97), 0.98 (CI, 0.90 to 1.08), and 1.09 (CI, 0.96 to 1.23), respectively. In the rivaroxaban-warfarin cohort ( n  = 275 944; median follow-up, 82 days), the event rate per 1000 person-years was 77.8 for rivaroxaban initiators and 83.7 for warfarin initiators (HR, 0.98 [CI, 0.94 to 1.02]; RD, -5.9 [CI, -9.4 to -2.4]). For nonfrail, prefrail, and frail persons, HRs were 0.88 (CI, 0.77 to 0.99), 1.04 (CI, 0.98 to 1.10), and 0.96 (CI, 0.89 to 1.04), respectively. In the apixaban-warfarin cohort ( n  = 218 738; median follow-up, 84 days), the event rate per 1000 person-years was 60.1 for apixaban initiators and 92.3 for warfarin initiators (HR, 0.68 [CI, 0.65 to 0.72]; RD, -32.2 [CI, -36.1 to -28.3]). For nonfrail, prefrail, and frail persons, HRs were 0.61 (CI, 0.52 to 0.71), 0.66 (CI, 0.61 to 0.70), and 0.73 (CI, 0.67 to 0.80), respectively., Limitations: Residual confounding and lack of clinical frailty assessment., Conclusion: For older adults with AF, apixaban was associated with lower rates of adverse events across all frailty levels. Dabigatran and rivaroxaban were associated with lower event rates only among nonfrail patients., Primary Funding Source: National Institute on Aging.

Background: Inflammatory cytokines, such as interleukin (IL)-1β, alter iron homeostasis and erythropoiesis, resulting in anemia, but whether inhibition of IL-1β can reverse these effects is unclear., Objective: To determine whether IL-1β inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia., Design: Exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846)., Setting: Many clinical sites in 39 countries., Participants: 8683 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants without anemia at trial entry and 1303 with prevalent anemia at trial entry., Intervention: Random assignment to receive placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months., Measurements: Primary outcome was incident anemia (hemoglobin level <130 g/L in men or <120 g/L in women)., Results: Anemia incidence increased with rising baseline levels of high-sensitivity C-reactive protein (hsCRP), and both hsCRP and IL-6 decreased among participants receiving canakinumab compared with the placebo group. During a median follow-up of 3.7 years, participants without baseline anemia who received canakinumab at any dosage had significantly less incident anemia than those who received placebo (hazard ratio, 0.84 [95% CI, 0.77 to 0.93]; P < 0.001). Compared with placebo, the greatest benefits of IL-1β inhibition on incident anemia were observed among participants with the most robust anti-inflammatory response, an effect corroborated in formal mediation analyses. Among those with baseline anemia, canakinumab increased mean hemoglobin levels by 11.3 g/L (P < 0.001) compared with placebo after 2 years of treatment. Canakinumab increased the risk for infection and was associated with mild cases of thrombocytopenia and neutropenia, none of which was grade 3 or higher., Limitation: CANTOS was not designed to assess the cause of anemia in individual trial participants., Conclusion: These exploratory analyses of randomized trial data provide proof of principle that inflammation inhibition, at least through the IL-1β/IL-6 signaling pathway, reduces the incidence of anemia and improves hemoglobin levels in patients with anemia., Primary Funding Source: Novartis Pharmaceuticals.

Background: Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred., Objective: To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo., Design: Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333)., Setting: North America., Participants: Adults with known cardiovascular disease and diabetes or metabolic syndrome., Intervention: Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week., Measurements: Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication., Results: After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93])., Limitation: The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period., Conclusion: Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased., Primary Funding Source: National Institutes of Health.

Background: Although studies have shown that interleukin-1β (IL-1β) inhibitors can shorten gout attacks, whether they can prevent gout attacks is unclear., Objective: To examine the relationship among canakinumab, a monoclonal antibody targeting IL-1β; serum uric acid levels; and the incidence of gout attacks., Design: Secondary exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846)., Setting: Many clinical sites in 39 countries., Participants: 10 059 patients with a prior myocardial infarction and a high-sensitivity C-reactive protein (hsCRP) level of at least 19.1 nmol/L., Intervention: Random allocation to canakinumab (50 mg, 150 mg, or 300 mg) versus placebo, administered subcutaneously every 3 months., Measurements: Rates of gout attacks were compared across patients with different baseline concentrations of serum uric acid (≤404.5 µmol/L, 404.6 to 535.3 µmol/L, and ≥535.4 µmol/L) and in different intervention groups in Cox proportional hazards regression models., Results: The median baseline concentration of serum uric acid was 362.9 µmol/L (interquartile range, 309.3 to 428.3 µmol/L), and median follow-up was 3.7 years. Among participants receiving placebo, incidence rates of gout attacks for serum uric acid concentrations of 404.5 µmol/L or lower, 404.6 to 535.3 µmol/L, and 535.4 µmol/L or higher were 0.28, 1.36, and 5.94, respectively, per 100 person-years. Canakinumab did not affect serum uric acid levels over time yet significantly reduced rates of gout attacks at all baseline concentrations of serum uric acid: Hazard ratios were 0.40 (95% CI, 0.22 to 0.73) for concentrations of 404.5 µmol/L or lower, 0.48 (CI, 0.31 to 0.74) for those between 404.6 and 535.3 µmol/L, and 0.45 (CI, 0.28 to 0.72) for those of 535.4 µmol/L or higher., Limitation: No adjudication of gout attacks., Conclusion: Quarterly canakinumab administration was associated with significantly reduced risk for gout attacks without any change in serum uric acid levels. These data have relevance for the development of agents for gout that target the IL-1β pathway of innate immunity., Primary Funding Source: Novartis.

Background: Despite the widespread adoption of patient-centered medical homes into primary care practice, the evidence supporting their effect on health care outcomes has come primarily from geographically localized and well-integrated health systems., Objective: To assess the association between medication adherence and medical homes in a national patient and provider population, given the strong ties between adherence to chronic disease medications and health care quality and spending., Design: Retrospective cohort study., Setting: Claims from a large national health insurer., Patients: Patients initiating therapy with common medications for chronic diseases (diabetes, hypertension, and hyperlipidemia) between 2011 and 2013., Measurements: Medication adherence in the 12 months after treatment initiation was compared among patients cared for by providers practicing in National Committee for Quality Assurance-recognized patient-centered medical homes and propensity score-matched control practices in the same Primary Care Service Areas. Linear mixed models were used to examine the association between medical homes and adherence., Results: Of 313 765 patients meeting study criteria, 18 611 (5.9%) received care in patient-centered medical homes. Mean rates of adherence were 64% among medical home patients and 59% among control patients. Among 4660 matched control and medical home practices, medication adherence was significantly higher in medical homes (2.2% [95% CI, 1.5% to 2.9%]). The association between medical homes and better adherence did not differ significantly by disease state (diabetes, 3.0% [CI, 1.5% to 4.6%]; hypertension, 3.2% [CI, 2.2% to 4.2%]; hyperlipidemia, 1.5% [CI, 0.6% to 2.5%])., Limitation: Clinical outcomes related to medication adherence were not assessed., Conclusion: Receipt of care in a patient-centered medical home is associated with better adherence, a vital measure of health care quality, among patients initiating treatment with medications for common high-cost chronic diseases., Primary Funding Source: CVS Health.

Background: Despite widespread use of multivitamin supplements, their effect on cognitive health-a critical issue with aging-remains inconclusive. To date, no long-term clinical trials have studied multivitamin use and cognitive decline in older persons., Objective: To evaluate whether long-term multivitamin supplementation affects cognitive health in later life., Design: Randomized, double-blind, placebo-controlled trial of a multivitamin from 1997 to 1 June 2011. The cognitive function substudy began in 1998. Up to 4 repeated cognitive assessments by telephone interview were completed over 12 years. (ClinicalTrials.gov: NCT00270647) SETTING: The Physicians' Health Study II., Patients: 5947 male physicians aged 65 years or older., Intervention: Daily multivitamin or placebo., Measurements: A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary end point was a verbal memory score combining 4 tests of verbal memory, which is a strong predictor of Alzheimer disease., Results: No difference was found in mean cognitive change over time between the multivitamin and placebo groups or in the mean level of cognition at any of the 4 assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was -0.01 SU (95% CI, -0.04 to 0.02 SU) when treatment was compared with placebo. Similarly, cognitive performance did not differ between the multivitamin and placebo groups on the secondary outcome, verbal memory (mean difference in cognitive change over follow-up, -0.005 SU [CI, -0.04 to 0.03 SU])., Limitation: Doses of vitamins may be too low or the population may be too well-nourished to benefit from a multivitamin., Conclusion: In male physicians aged 65 years or older, long-term use of a daily multivitamin did not provide cognitive benefits., Primary Funding Source: National Institutes of Health, BASF, Pfizer, and DSM Nutritional Products.

Background: Randomized data on statins for primary prevention in older persons are limited, and the relative hazard of cardiovascular disease associated with an elevated cholesterol level weakens with advancing age., Objective: To assess the efficacy and safety of rosuvastatin in persons 70 years or older., Design: Secondary analysis of JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), a randomized, double-blind, placebo-controlled trial., Setting: 1315 sites in 26 countries randomly assigned participants in JUPITER., Participants: Among the 17 802 participants randomly assigned with low-density lipoprotein (LDL) cholesterol levels less than 3.37 mmol/L (<130 mg/dL) and high-sensitivity C-reactive protein levels of 2.0 mg/L or more without cardiovascular disease, 5695 were 70 years or older., Intervention: Participants were randomly assigned in a 1:1 ratio to receive 20 mg of rosuvastatin daily or placebo., Measurements: The primary end point was the occurrence of a first cardiovascular event (myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes)., Results: The 32% of trial participants 70 years or older accrued 49% (n = 194) of the 393 confirmed primary end points. The rates of the primary end point in this age group were 1.22 and 1.99 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio, 0.61 [95% CI, 0.46 to 0.82]; P < 0.001). Corresponding rates of all-cause mortality in this age group were 1.63 and 2.04 (hazard ratio, 0.80 [CI, 0.62 to 1.04]; P = 0.090). Although no significant heterogeneity was found in treatment effects by age, absolute reductions in event rates associated with rosuvastatin were greater in older persons. The relative rate of any serious adverse event among older persons in the rosuvastatin versus placebo group was 1.05 (CI, 0.93 to 1.17)., Limitation: Effect estimates from this exploratory analysis with age cut-point chosen after trial completion should be viewed in the context of the overall trial results., Conclusion: In apparently healthy older persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin reduces the incidence of major cardiovascular events., Primary Funding Source: AstraZeneca.

Background: Patients with reduced left ventricular function and ventricular enlargement after myocardial infarction are at significantly greater risk for congestive heart failure and death. Nevertheless, recovery of ventricular function occurs in a significant proportion of patients after myocardial infarction, and modern reperfusion strategies have been associated with increased recovery of function., Objective: To determine the extent and predictors of recovery of ventricular function after anterior Q-wave myocardial infarction in the reperfusion era., Design: Subgroup analysis of the Healing and Early Afterload Reducing Therapy study., Setting: 35 medical centers in the United States and Canada., Patients: 352 patients with Q-wave anterior myocardial infarction., Intervention: Placebo for 14 days, followed by full-dose (10 mg) ramipril until day 90; low-dose (0.625 mg) ramipril for 90 days; or full-dose ramipril for 90 days. All patients underwent reperfusion therapy., Measurements: Echocardiography was performed on day 1 (before randomization), day 14, and day 90 after myocardial infarction. Left ventricular volume and ejection fraction were measured and wall-motion analyses were performed at all three time points in 249 patients and at baseline in an additional 12 patients who died during follow-up. Echocardiographic and nonechocardiographic predictors of ventricular recovery were examined., Results: By day 90, 55 of 252 (22%) patients who had abnormal ejection fraction and wall-motion abnormalities on day 1 demonstrated complete recovery of function (ejection fraction in the normal range and infarct segment length of 0%), and an additional 36% (91 of 252 patients) demonstrated partial recovery of function. At 90 days, 53% (132 of 249) of patients had greater than 5% improvement in ejection fraction, whereas only 16% (39 of 249) had a decrease in ejection fraction of more than 5%. The majority of functional improvement occurred by day 14 after infarction. Of various clinical and echocardiographic measures obtained on day 1, peak creatine kinase level was the strongest independent predictor of subsequent recovery of ventricular function in multivariate analysis. Each 100-unit increase in peak creatine kinase was associated with a 4.3% decreased odds of recovery (P < 0.001) after adjustment for ejection fraction on day 1, extent of akinesis or dyskinesis, treatment regimen, Killip class, age, and sex., Conclusion: Significant myocardial stunning with subsequent improvement of ventricular function occurred in the majority of patients after Q-wave anterior myocardial infarction. A lower peak level of creatine kinase, an estimate of the extent of necrosis, is independently predictive of recovery of function. Early functional assessment (day 1 after acute myocardial infarction) had limited ability to predict recovery of ventricular function.

Background: In contrast to most observational studies, the randomized Physicians' Health Study found no association between aspirin use and colorectal cancer after 5 years., Objective: To determine the effect of randomly assigned aspirin treatment and self-selected aspirin use on the incidence of colorectal cancer after 12 years and to identify factors influencing the self-selection of regular aspirin use., Design: Randomized clinical trial and prospective cohort study., Setting: Male physicians throughout the United States., Patients: 22071 healthy male physicians who were 40 to 84 years of age in 1982., Intervention: 325 mg of aspirin every other day. In 1988, the aspirin arm of the randomized trial was stopped early. Participants then chose to receive either aspirin or placebo for the rest of the study., Measurements: Annual questionnaires asking about aspirin use and other variables, including occurrence of cancer., Results: Colorectal cancer was diagnosed in 341 patients during the study period. Over 12 years of follow-up, random assignment to aspirin was associated with a relative risk for colorectal cancer of 1.03 (95% CI, 0.83 to 1.28). Various gastrointestinal symptoms and diagnoses were strong predictors of less frequent aspirin use in 1988. The relative risk for colorectal cancer in persons who used aspirin frequently after 1988 was 1.07 (CI, 0.75 to 1.53)., Conclusions: In the Physicians' Health Study, both randomized and observational analyses indicate that there is no association between the use of aspirin and the incidence of colorectal cancer. The low dose of aspirin used and the short treatment period may account for the null findings. However, other characteristics associated with the use of aspirin in observational studies remain a plausible alternative explanation.

Background: The importance of total cholesterol level as a risk factor for coronary heart disease in older adults is controversial., Objective: To determine whether findings showing that total cholesterol level is not an important risk factor for coronary heart disease in older adults are the result of inadequate adjustment for co-occurring diseases and frailty., Design: Multicenter, longitudinal study with 5-year follow-up for death., Participants: 4066 men and women from East Boston, Massachusetts; Iowa and Washington counties, Iowa; and New Haven, Connecticut., Measurements: In 1988, participants were interviewed about their health status and had blood samples taken. Mortality follow-up was through 1992., Results: In analyses that included all fatal coronary heart disease events (252 deaths) and did not adjust for risk factors for coronary heart disease and measures of frailty, persons with the lowest total cholesterol levels (< or = 4.15 mmol/L [< or = 160 mg/dL]) had the highest rate of death from coronary heart disease, whereas those with elevated total cholesterol levels (> or = 6.20 mmol/L [> or = 240 mg/dL]) seemed to have a lower risk for death from coronary heart disease (P for trend = 0.04). After adjustment for established risk factors for coronary heart disease and markers of poor health (including chronic conditions, low serum iron and albumin levels) and exclusion of 44 deaths from coronary heart disease that occurred within the first year, elevated total cholesterol levels predicted increased risk for death from coronary heart disease, and the risk for death from coronary heart disease decreased as cholesterol levels decreased (P for trend = 0.005)., Conclusions: Elevated total cholesterol level is a risk factor for death from coronary heart disease in older adults, and the apparent adverse effects associated with low cholesterol levels are secondary to comorbidity and frailty. This suggests that excluding older persons from cholesterol screening is inappropriate, but interpretation of screening results in older persons requires clinical judgment. Results from controlled clinical trials are needed to clarify this issue.

Background: Previous reports suggest that younger carriers of the factor V Leiden mutation are at greater risk for venous thromboembolism than are older carriers. However, available data on thromboembolic risk are limited., Objective: To determine age-specific incidence rates of venous thromboembolism associated with the factor V Leiden mutation., Design: Prospective cohort study., Patients: 14,916 initially healthy men participating in the Physicians' Health Study who were followed from 1982 to August 1994 for the occurrence of deep venous thrombosis or pulmonary embolism., Measurements: Polymerase chain reaction was used to determine factor V Leiden mutation status in 156 study participants who developed venous thromboembolism during follow-up and in 2406 study participants who remained free of vascular disease., Results: Risks for venous thromboembolism in heterozygous carriers of factor V Leiden mutation increased with age at a rate significantly greater than that in noncarriers. Whereas incidence rates of venous thromboembolism were similar in men with and men without the factor V Leiden mutation who were younger than 50 years of age, incidence rate differences (per 1000 person-years of observation) between affected and unaffected men increased significantly from 1.23 (95% CI, -0.4 to 2.9) for those aged 50 to 59 years to 1.61 (CI, -0.5 to 3.7) for those aged 60 to 69 years of age to 5.97 (CI, 0.6 to 11.3) for those aged 70 years or older (P for trend = 0.008). For idiopathic venous thromboembolism, age-specific incidence rate differences between men with and without the factor V Leiden mutation increased significantly with age (P = 0.017). However, no significant relation was found for secondary events (P > 0.2)., Conclusions: The findings support the hypothesis that the pathogenesis of venous thromboembolism involves acquired as well as genetic risk factors and indicate that determination of factor V Leiden mutation status should not be limited to young patients.

Background: Although previous studies have found that moderate alcohol intake decreases the risk for myocardial infarction, many clinicians question the validity of this finding. Furthermore, the relation of moderate drinking to the risk for other events, such as angina pectoris, is not known., Objective: To determine whether moderate alcohol intake decreases the risk for angina pectoris or myocardial infarction in apparently healthy men., Design: Prospective cohort study., Setting: United States., Participants: 22,071 apparently healthy male physicians who were 40 to 84 years of age between 1981 and 1984., Measurements: Responses to annual questionnaires., Results: Through 1994, 1368 cases of new-onset angina and 690 cases of myocardial infarction had been documented. In multivariate analyses that controlled for several potential confounders, alcohol intake was strongly and inversely associated with the risk for each event (P for trend < 0.001). Compared with men who consumed less than one drink per week, those who consumed one drink per day had relative risks of 0.69 (95% CI, 0.59 to 0.81) for angina and 0.65 (CI, 0.52 to 0.81) for myocardial infarction. These associations were seen when either nondrinkers or occasional drinkers were used as the reference group., Conclusions: Moderate drinking decreases the risk for angina pectoris and myocardial infarction in apparently healthy men.

Objective: To quantify the risk for the occurrence of hyperglycemia requiring initiation of therapy among patients taking various antihypertensive regimens., Design: Case-control study., Setting: New Jersey Medicaid program., Patients: The study included New Jersey Medicaid enrollees 35 years of age or older. The 11,855 case patients were newly started on a hypoglycemic agent (oral agent or insulin) between 1981 and 1990. The 11,855 controls were selected randomly from among other Medicaid enrollees., Measurements and Main Results: The frequency of initiation of hypoglycemic therapy was increased for users of virtually all antihypertensive agents relative to nonusers after adjustment for age, gender, race, nursing home residency, number of days hospitalized, total number of prescriptions, and selected medication exposures. The estimated relative risk for initiation of hypoglycemic therapy was 1.40 for patients receiving thiazide diuretics (95% CI, 1.26 to 1.58) and ranged from 1.56 to 1.77 for patients receiving other antihypertensive medications, depending on the medication category. A higher risk was associated with multiple-agent regimens, whether they excluded a thiazide diuretic (odds ratio, 1.76; CI, 1.49 to 2.07) or included one (odds ratio, 1.93; CI, 1.75 to 2.13). When the analysis was restricted to users of antihypertensive agents (n = 8005), the risk associated with other single-agent antihypertensive regimens was not significantly different from that associated with thiazide diuretics. However, patients receiving multiple-agent regimens continued to be at increased risk for hyperglycemia requiring hypoglycemic therapy relative to those who used thiazide diuretic therapy alone., Conclusion: The association between antihypertensive therapy and the initiation of treatment for diabetes mellitus is more closely related to the intensity of therapy than to the individual agent used. Our data do not support the hypothesis that thiazide diuretics are more strongly associated with the initiation of hypoglycemic therapy than are other antihypertensive agents.