Comparative cardiovascular safety of glucagon-like peptide-1 receptor agonists versus other antidiabetic drugs in routine care: a cohort study.

AIMS: To evaluate the comparative cardiovascular disease (CVD) safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in head-to-head comparisons with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulphonylureas or insulin, when added to metformin, as used in 'real-world' patients with type 2 diabetes mellitus (T2DM). METHODS: Within a large US commercial health plan database linked to laboratory test results, we identified three pairwise 1 : 1 propensity-score-matched cohorts of patients with T2DM aged ≥18 years treated with metformin who initiated a GLP-1 RA or a comparator, i.e. DPP-4 inhibitor (n = 35 534), second-generation sulphonylureas (n = 28 138) or insulin (n = 47 068), between 2005 and 2013. We examined the association between drug initiation and a composite CVD endpoint, comprising hospitalizations for acute myocardial infarction, unstable angina, stroke or coronary revascularization. RESULTS: During the course of 1 year, there were 13.9 and 13.7 CVD events per 1000 person-years among propensity-score-matched initiators of GLP-1 RAs versus DPP-4 inhibitors [hazard ratio (HR) 1.02; 95% confidence interval (CI) 0.84-1.24]; and 12.1 versus 14.0 events among initiators of GLP-1 RAs versus sulphonylureas (HR 0.86; 95% CI 0.69-1.08). The effect estimates for GLP-1 RAs versus insulin were sensitive to the adjustment for glycated haemoglobin, after which the HR was 1.01 (95% CI 0.73-1.41). Results were robust across several sensitivity analyses, including an as-treated analysis considering up to 8.7 years of follow-up. CONCLUSIONS: This large study, performing head-to-head comparisons of GLP-1 RAs with other antidiabetic agents in real-world patients, provides estimates of relative safety precise enough to exclude large differences in CVD risk and adds further understanding to results from recent clinical trials.

Is grand-parental smoking associated with adolescent obesity? A three-generational study.

BACKGROUND/OBJECTIVES: Data from previous studies consistently suggest that maternal smoking is positively associated with obesity later in life. Whether this association persists across generations is unknown. We examined whether grand-parental smoking was positively associated with overweight status in adolescence. SUBJECT/METHODS: Participants were grandmother-mother-child triads in the Nurses' Health Study II (NHS II), the Nurses Mothers' Cohort Study and the Growing up Today Study (GUTS). Grandmothers provided information on their and their partner's smoking during pregnancy with the child's mother. Information on child's weight and height at ages 12 (N=3094) and 17 (N=3433) was obtained from annual or biennial GUTS questionnaires. We used logistic regression to estimate the odds ratios (ORs) of being overweight or obese, relative to normal weight. RESULTS: Grand-maternal smoking during pregnancy was not associated with overweight status in adolescence. After adjusting for covariates, the OR of being overweight or obese relative to normal weight at age 12 years in girls whose grandmothers smoked 15+ cigarettes daily during pregnancy was 1.21 (95% confidence interval (CI) 0.74-1.98; P(trend)=0.31) and 1.07 (0.65-1.77; P(trend)=0.41) in boys. Grand-paternal smoking during pregnancy was associated with being overweight or obese at age 12 in girls only, but not at age 17 for either sex: the OR for being overweight or obese at age 12 was 1.38 (95% CI 1.01-1.89; P(trend)=0.03) in girls and 1.31 (95% CI 0.97-1.76; P(trend)=0.07) in boys. Among children of non-smoking mothers, the OR for granddaughter obesity for grand-paternal smoking was attenuated and no longer significant (OR 1.28 (95% CI 0.87-1.89; P(trend)=0.18)). CONCLUSIONS: Our findings suggest that the association between maternal smoking and offspring obesity may not persist beyond the first generation. However, grand-paternal smoking may affect the overweight status of the granddaughter, likely through the association between grand-paternal smoking and maternal smoking.

Propensity scores for confounder adjustment when assessing the effects of medical interventions using nonexperimental study designs.

Treatment effects, especially when comparing two or more therapeutic alternatives as in comparative effectiveness research, are likely to be heterogeneous across age, gender, co-morbidities and co-medications. Propensity scores (PSs), an alternative to multivariable outcome models to control for measured confounding, have specific advantages in the presence of heterogeneous treatment effects. Implementing PSs using matching or weighting allows us to estimate different overall treatment effects in differently defined populations. Heterogeneous treatment effects can also be due to unmeasured confounding concentrated in those treated contrary to prediction. Sensitivity analyses based on PSs can help to assess such unmeasured confounding. PSs should be considered a primary or secondary analytic strategy in nonexperimental medical research, including pharmacoepidemiology and nonexperimental comparative effectiveness research.

Active safety monitoring of newly marketed medications in a distributed data network: application of a semi-automated monitoring system.

We developed a semi-automated active monitoring system that uses sequential matched-cohort analyses to assess drug safety across a distributed network of longitudinal electronic health-care data. In a retrospective analysis, we show that the system would have identified cerivastatin-induced rhabdomyolysis. In this study, we evaluated whether the system would generate alerts for three drug-outcome pairs: rosuvastatin and rhabdomyolysis (known null association), rosuvastatin and diabetes mellitus, and telithromycin and hepatotoxicity (two examples for which alerting would be questionable). Over >5 years of monitoring, rate differences (RDs) in comparisons of rosuvastatin with atorvastatin were -0.1 cases of rhabdomyolysis per 1,000 person-years (95% confidence interval (CI): -0.4, 0.1) and -2.2 diabetes cases per 1,000 person-years (95% CI: -6.0, 1.6). The RD for hepatotoxicity comparing telithromycin with azithromycin was 0.3 cases per 1,000 person-years (95% CI: -0.5, 1.0). In a setting in which false positivity is a major concern, the system did not generate alerts for the three drug-outcome pairs.

Comparison of associations of adherence to a Dietary Approaches to Stop Hypertension (DASH)-style diet with risks of cardiovascular disease and venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) and cardiovascular disease (CVD) share some risk factors, including obesity, but it is unclear how dietary patterns associated with reduced risk of CVD relate to risk of VTE. OBJECTIVE: To compare the relationships of adherence to a Dietary Approaches to Stop Hypertension (DASH)-style diet with the risks of CVD and VTE. PATIENTS/METHODS: We confirmed by medical record review 1094 incident cases of CVD and 675 incident VTEs during a mean follow-up of 14.6 years in 34 827 initially healthy participants in the Women's Health Study who completed at baseline a 133-item food frequency questionnaire scored for adherence to a DASH diet. We compared estimated associations of dietary patterns with CVD and VTE from proportional hazards models in a competing risk framework. RESULTS: Initial analyses adjusted for age, energy intake and randomized treatments showed 36-41% reduced hazards of CVD among women in the top two quintiles of DASH score relative to those in the bottom quintile (P(trend) < 0.001). In multivariate analysis, women in the top two quintiles had 12-23% reduced hazards of CVD relative to women in the bottom quintile (P(trend) = 0.04). Analyses restricted to coronary events showed more variable 10-33% reduced hazards in the top two quintiles (P(trend) = 0.09). In contrast, higher DASH scores were unrelated to risk of VTE, with a 1% reduced hazard for the top vs. bottom quintile (P(trend) = 0.95). CONCLUSION: An apparently strong association of adherence to the DASH diet with incidence of CVD was attenuated upon control for confounding variables. Adherence to the DASH diet was not associated with risk of VTE in women.

Assessing the comparative effectiveness of newly marketed medications: methodological challenges and implications for drug development.

Comparative-effectiveness research (CER) aims to produce actionable evidence regarding the effectiveness and safety of medical products and interventions as they are used outside of controlled research settings. Although CER evidence regarding medications is particularly needed shortly after market approval, key methodological challenges include (i) potential bias due to channeling of patients to the newly marketed medication because of various patient-, physician-, and system-related factors; (ii) rapid changes in the characteristics of the user population during the early phase of marketing; and (iii) lack of timely data and the often small number of users in the first few months of marketing. We propose a mix of approaches to generate comparative-effectiveness data in the early marketing period, including sequential cohort monitoring with secondary health-care data and propensity score (PS) balancing, as well as extended follow-up of phase III and phase IV trials, indirect comparisons of placebo-controlled trials, and modeling and simulation of virtual trials.

Non-steroidal anti-inflammatory drug use and risk of venous thromboembolism.

BACKGROUND: The association between the use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2-selective inhibitors (COX2Is) and the risk of venous thromboembolism (VTE) remains unclear. OBJECTIVES: To examine this association. PATIENTS/METHODS: We conducted a population-based case-control study in northern Denmark (population of 1.7 million). Using the National Patient Registry, we identified patients with a first hospital VTE diagnosis during 1999-2006 (n = 8368) and their comorbidities. For each case, we selected 10 controls (n = 82, 218) matched by age and sex. From the prescription database, we ascertained the use of NSAIDs at the time of diagnosis (current use) or before (recent use), and comedications. Current use was further classified as new use (first-ever prescription redemption within 60 days before diagnosis date) or long-term use. We used odds ratios from a logistic regression model to estimate incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: As compared with no use, the adjusted IRR associating current non-selective NSAID use with VTE was 2.51 (95% CI 2.29-2.76), and that for current COX2I use was 2.19 (95% CI 1.99-2.41). Recent users had substantially smaller increases than current users. The adjusted IRRs among long-term users were 2.06 for non-selective NSAIDs (95% CI 1.85-2.29) and 1.92 for COX2Is (95% CI 1.72-2.15). Similarly increased risks were found for unprovoked VTE (occurrence in the absence of pregnancy, cancer, major trauma, fracture or surgery within 3 months preceding the VTE), deep vein thrombosis, pulmonary embolism, and individual NSAIDs. CONCLUSIONS: The use of non-selective NSAIDs or COX2Is was associated with a two-fold or more increased risk of VTE.

Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy.

BACKGROUND: CYP2C9 and VKORC1 genotypes predict therapeutic warfarin dose at initiation of therapy; however, the predictive ability of genetic information after a week or longer is unknown. Experts have hypothesized that genotype becomes irrelevant once international normalized ratio (INR) values are available because INR response reflects warfarin sensitivity. METHODS: We genotyped the participants in the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, who had idiopathic venous thromboemboli and began low-intensity warfarin (therapeutic INR 1.5-2.0) using a standard dosing protocol. To develop pharmacogenetic models, we quantified the effect of genotypes, clinical factors, previous doses and INR on therapeutic warfarin dose in the 223 PREVENT participants who were randomized to warfarin and achieved stable therapeutic INRs. RESULTS: A pharmacogenetic model using data from day 0 (before therapy initiation) explained 54% of the variability in therapeutic dose (R(2)). The R(2) increased to 68% at day 7, 75% at day 14, and 77% at day 21, because of increasing contributions from prior doses and INR response. Although CYP2C9 and VKORC1 genotypes were significant independent predictors of therapeutic dose at each weekly interval, the magnitude of their predictive ability diminished over time: partial R(2) of genotype was 43% at day 0, 12% at day 7, 4% at day 14, and 1% at day 21. CONCLUSION: Over the first weeks of warfarin therapy, INR and prior dose become increasingly predictive of therapeutic dose, and genotype becomes less relevant. However, at day 7, genotype remains clinically relevant, accounting for 12% of therapeutic dose variability.

Lipid biomarkers, hormone therapy and the risk of venous thromboembolism in women.

BACKGROUND: Published reports of a relationship between lipids and incident venous thromboembolism (VTE) are conflicting. OBJECTIVES: To clarify the relationship between lipids and VTE risk in healthy women, including potential effect modification by hormone therapy (HT). PATIENTS/METHODS: Among 27 081 initially healthy women followed prospectively for incident VTE, we measured a full panel of lipid biomarkers, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides and apolipoproteins A-I (apo A-I) and B(100). RESULTS: During a median follow-up of 11.4 years, VTE occurred in 355 women. We observed no relationship between any of the lipids and VTE risk. However, when unprovoked VTE was considered separately (n=161), both HDL-C and apo A-I were positively associated with risk. Fully adjusted hazard ratios (HR) and 95% confidence intervals (CI) for extreme tertiles of HDL-C and apo A-I were 1.75 (1.13-2.73) and 1.70 (1.10-2.62), respectively. After stratifying by HT use, this relationship was present only among HT users; the HRs for unprovoked VTE for extreme tertiles of HDL-C and apo A-I were 3.58 (1.69-7.58) and 2.88 (1.29-6.42) among users, but only 0.79 (0.39-1.62) and 0.89 (0.50-1.57) among non-users. The interactions were statistically significant (each Pinteraction<0.05). CONCLUSIONS: We observed little evidence that lipid levels predict risk of incident VTE among non-users of HT. High levels of HDL-C and apo A-I associate with unprovoked VTE risk among HT users. This observation likely reflects prothrombotic effects of HT that are concomitant with HDL-C and apo A-I levels, rather than direct effects of those lipids.

Power and sample size estimation for the Wilcoxon rank sum test with application to comparisons of C statistics from alternative prediction models.

The Wilcoxon Mann-Whitney (WMW) U test is commonly used in nonparametric two-group comparisons when the normality of the underlying distribution is questionable. There has been some previous work on estimating power based on this procedure (Lehmann, 1998, Nonparametrics). In this article, we present an approach for estimating type II error, which is applicable to any continuous distribution, and also extend the approach to handle grouped continuous data allowing for ties. We apply these results to obtaining standard errors of the area under the receiver operating characteristic curve (AUROC) for risk-prediction rules under H(1) and for comparing AUROC between competing risk prediction rules applied to the same data set. These results are based on SAS-callable functions to evaluate the bivariate normal integral and are thus easily implemented with standard software.

Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.

Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.

Renin-angiotensin and endothelial nitric oxide synthase gene polymorphisms are not associated with the risk of incident type 2 diabetes mellitus: a prospective cohort study.

OBJECTIVE: The renin-angiotensin system and endothelial function have both been implicated in the pathogenesis of type 2 diabetes. The aim of this study was to assess the relationship between a set of well-characterized genetic variants of the renin-angiotensin system and the endothelial nitric oxide synthase (NOS3) gene and the incidence of type 2 diabetes. DESIGN: Prospective cohort study. SETTING: Women's Health Study, United States. SUBJECTS: A total of 24,309 Caucasian women free of diabetes at baseline. MAIN OUTCOME MEASURES: Six previously characterized single nucleotide polymorphisms (NOS3 rs1800779, NOS3 rs3918226, NOS3 rs1799983, ACE rs1799752, AGT rs699 and AGTR rs5186) were genotyped. Cox proportional-hazards models were constructed to compare the incidence of type 2 diabetes according to the different genotypes. RESULTS: During a median follow-up of 10.2 years (interquartile range 9.6-10.6 years), 999 women developed type 2 diabetes. The age-adjusted incidence rates across the six genotypes were very similar, and ranged from 3.7 to 4.8 cases/1000 person-years of follow-up. The multivariable adjusted hazard ratios (95% confidence intervals) for rs1800779, rs3918226, rs1799983, rs1799752, rs699, and rs5186 were 1.01 (0.92-1.10), 1.09 (0.93-1.27), 0.95 (0.86-1.05), 1.04 (0.95-1.14), 1.08 (0.98-1.18), 1.01 (0.91-1.11), confirming the lack of association between the genotypes and incident type 2 diabetes. Stratification by body mass index revealed essentially unchanged results. Finally, there was no association between NOS3-haplotypes and incident type 2 diabetes. CONCLUSION: We did not find an association between six well-characterized genetic polymorphisms of the renin-angiotensin system or the NOS3 gene and the occurrence of type 2 diabetes.

Effect of valsartan compared with valsartan/hydrochlorothiazide on plasma levels of cellular adhesion molecules: the Val-MARC trial.

BACKGROUND: The Val-MARC trial showed that the angiotensin receptor blocker valsartan reduces high-sensitivity C reactive protein (hsCRP) levels, an effect that is independent of blood pressure, and seems to be neutralised by the addition of hydrochlorothiazide. OBJECTIVE: To evaluate whether valsartan influences soluble intercellular adhesion molecule 1 (sICAM-1) or vascular cell adhesion molecule 1 (sVCAM-1). DESIGN: Post-hoc analysis from a randomised trial. SETTING: Val-MARC trial. PATIENTS: 1188 patients with stage 2 hypertension. INTERVENTION: Random allocation to either valsartan 320 mg (n = 607) or combination therapy with valsartan/hydrochlorothiazide 320 mg/12.5 mg (n = 581) for 6 weeks. MAIN OUTCOME MEASURE: Change in sICAM-1 and sVCAM-1 from baseline to 6 weeks of follow-up RESULTS: After treatment, median (interquartile range) sICAM-1 levels were reduced by both valsartan alone (-4 (-25 to 16) ng/ml, p = 0.005) and valsartan/hydrochlorothiazide (-4 (-22 to 17) ng/ml, p = 0.028), such that the between-group difference was not significant (p = 0.7). The median percentage change from baseline was small in both groups (-1.6% and -1.3%). Median (interquartile range) sVCAM-1 levels were reduced by both valsartan alone (-13 (-70 to 42) ng/ml, p = 0.001) and valsartan/hydrochlorothiazide (-26 (-88 to 38), p<0.001); the between-group difference was of borderline significance (p = 0.051). The median percentage change from baseline was small (-2.1% and -4.4%). The reduction of sICAM-1 and sVCAM-1 was independent of blood pressure reduction (rs = 0.03 and rs = 0.06 for the relationship of change in systolic blood pressure with change in sICAM-1 and sVCAM-1, respectively). CONCLUSION: In contrast to hsCRP, both valsartan and valsartan/hydrochlorothiazide induced reductions of sICAM-1 and sVCAM-1 in the Val-MARC trial. These effects, although statistically significant, were small and independent of changes in blood pressure.

Hormonal factors and risk of recurrent venous thrombosis: the prevention of recurrent venous thromboembolism trial.

BACKGROUND: In some but not all studies, men with venous thrombosis had a higher risk of recurrence than women. Information on women with initial hormone-related thrombosis is scant. OBJECTIVE: We assessed the incidence of recurrent thrombosis by gender, and among women using exogenous hormones or pregnant/postpartum at the time of index thrombosis. PATIENTS/METHODS: A total of 508 men and women with one or more previous venous thrombosis episodes were observed while participating in a randomized trial of low-intensity warfarin or placebo for 2.1 years. Index thrombosis events during treatment with postmenopausal hormones, oral contraceptives, or during pregnancy, or the puerperium were considered to be hormone-related events. RESULTS: Among 268 men the 3-year probability of recurrent thrombosis was 18.4% (95% confidence intervals; CI 12.3-24.4). Among 109 women without hormone-related thrombosis, the rate was 15.0% (95% CI 6.3-23.8). Among 129 women with hormone-related thrombosis, the rate was 5.0% (95% CI 1.1-8.9). Adjusting for other risk factors and treatment assignment, women had a 39% lower thrombosis recurrence risk than men: hazard ratio (HR) 0.61 (95% CI 0.34-1.08). Women with hormone-related thrombosis had a 58% lower risk than men: HR 0.42 (95% CI 0.19-0.97); and a 46% lower recurrence risk than other women; HR 0.54 (95% CI 0.19-1.54). Women without hormone-related index events had a recurrence rate similar to men; HR 0.83 (95% CI 0.42-1.66). CONCLUSIONS: In this trial population, women had a lower risk of recurrent venous thrombosis than men. This difference was explained by a low risk of recurrence among women with hormone-related index thrombosis.

D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism.

BACKGROUND: Elevated plasma D-dimer and factor VIII coagulant activity (FVIIIc) may be associated with the risk of recurrent venous thromboembolism (VTE). OBJECTIVES: To evaluate D-dimer and FVIIIc as risk factors for recurrent VTE and assess the efficacy of extended low-intensity warfarin (target International Normalized Ratio 1.5-2.0) in preventing recurrence by biomarker level. PATIENTS AND METHODS: In the Prevention of Recurrent Venous Thromboembolism trial, 508 idiopathic VTE patients treated for > or = 3 months with full-intensity warfarin, and who had stopped warfarin for 7 weeks on average, were randomized to low-intensity warfarin or placebo and followed for 2.1 years for recurrent VTE. Prerandomization blood samples were analysed for D-dimer and FVIIIc. RESULTS: One-third of participants had elevated baseline D-dimer (> or = 500 ng mL(-1)) and one-fourth, elevated FVIIIc (> or = 150 IU dL(-1)). Adjusting for other risk factors, the hazard ratios (HRs) for recurrent VTE with elevated D-dimer or FVIIIc were 2.0 [95% confidence interval (CI) 1.2-3.4] and 1.5 (95% CI 0.8-2.8), respectively. The association of elevated D-dimer with recurrence was larger among patients with one prior VTE (HR 3.2, 95% CI 1.3-8.0) than in patients with more than one event (HR 1.4, 95% CI 0.7-2.2). For patients with one prior VTE on placebo, the annual recurrence incidence was 10.9% with elevated D-dimer and 2.9% with normal values. Low-intensity warfarin was equally effective in recurrence risk reduction in those with normal or elevated biomarkers. CONCLUSIONS: Among patients with idiopathic VTE, measurement of D-dimer, but not FVIIIc, might be useful for risk stratification. The efficacy of extended low-intensity warfarin therapy did not vary by biomarker level.

Determinants of delayed nephrologist referral in patients with chronic kidney disease.

Late referral to nephrologists of patients with chronic kidney disease (CKD) is a major public health problem because it is prevalent and associated with increased morbidity, mortality, and greater healthcare costs. To identify factors associated with delayed nephrologist referral (first nephrologist visit < 90 days before the onset of renal replacement therapy), we identified a cohort of patients with preexisting CKD that progressed to end-stage renal failure. We developed a logistic regression model to measure the association of specific demographic and clinical covariates with delayed nephrologist referral. Delayed referral was highly associated with older age (P < 0.001), race other than white or black (P = 0.002), and the absence of certain comorbidities: hypertension (P < 0.001), coronary artery disease (P < 0.001), malignancy (P = 0.005), and diabetes (P = 0.02). Associations of late referral with male sex (P = 0.07) and lower socioeconomic status (P = 0.09) were of borderline significance. Patients who were predominantly cared for by a general internist were more likely to be referred late to a nephrologist compared with those cared for by a family or primary care practitioner (P = 0.002) or another subspecialist (P = 0.019). These findings suggest that several factors increase the risk that patients with CKD will have the first nephrologist consultation excessively late in the course of their disease. Although timely access to nephrologist services is important for all patients with advanced CKD, this is of particular concern in older patients, those in certain minority populations, and those in whom the absence of comorbidity may provide a false sense of true risk status.

Paradoxical relations of drug treatment with mortality in older persons.

Medication use patterns provide popular surrogate measures of disease, yet selective under-use of drugs by elderly patients with potentially unmeasured comorbidity may lead to artifactual "protective" associations between use of specific drugs and mortality. We examined the relation between use of 20 common classes of drugs and mortality among the 129,111 residents of New Jersey 65-99 years of age who had at least one hospitalization during the years 1991-1994 and filled prescriptions through either Medicaid or that state's Pharmacy Assistance for the Aged and Disabled program. Each study drug class was used by more than 5,000 subjects during the 120 days before hospitalization; 41,930 subjects died in the hospital or during the year after discharge. Users of drugs from each of seven therapeutic classes had reduced age- and sex-adjusted rates of death relative to non-users: lipid-lowering agents, nonsteroidal anti-inflammatory agents, beta blockers, thiazides, glaucoma drugs, calcium channel blockers, and anti-anxiety drugs. Adjustment for comorbidity and polypharmacy had little effect on these results. We found similar results in a separate nonhospitalized cohort of 132,071 elderly persons. Much of this observed association appears to be nonetiologic. These findings raise concerns about using observational studies in high-risk populations to infer associations between drug use and outcomes.

Association of incident Alzheimer disease and blood pressure measured from 13 years before to 2 years after diagnosis in a large community study.

BACKGROUND: It is uncertain whether high blood pressure increases the risk of developing Alzheimer disease (AD). OBJECTIVE: To examine the association between incident AD and blood pressure measured up to 13 years before diagnosis. DESIGN: Longitudinal cohort study conducted from 1982 to 1988, with blood pressure measured every 3 years in home interviews, and in 1973 for a portion (60%) of the sample. SETTING: Community of East Boston, Mass. PARTICIPANTS: Six hundred thirty-four subjects 65 years or older and without AD were selected as a stratified random sample of participants of the East Boston Established Populations for Epidemiologic Studies of the Elderly. MAIN OUTCOME MEASURE: Alzheimer disease was diagnosed by a neurologist using a structured clinical evaluation. RESULTS: High blood pressure was not associated with an increased risk of AD in logistic regression models adjusted for age, sex, and level of education. There was no association with systolic pressure measured 13 years before diagnosis (odds ratio = 1.03/10 mm Hg; 95% confidence interval, 0.80-1.32) and an inverse association with systolic pressure measured 4 years before diagnosis (odds ratio = 0.82/10 mm Hg; 95% confidence interval, 0.72-0.95). Associations for diastolic pressure were in the same direction as those for systolic pressure except with wider confidence intervals. The odds ratios were not materially different with further adjustment for cardiovascular risk factors and diseases. CONCLUSION: In this large community study, high blood pressure was not associated with an increased risk of AD.

Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data.

Comorbidity is an important confounder in epidemiologic studies. The authors compared the predictive performance of comorbidity scores for use in epidemiologic research with administrative databases. Study participants were British Columbia, Canada, residents aged >or=65 years who received angiotensin-converting enzyme inhibitors or calcium channel blockers at least once during the observation period. Six scores were computed for all 141,161 participants during the baseline year (1995-1996). Endpoints were death and health care utilization during a 12-month follow-up (1996-1997). Performance was measured by using the c statistic ranging from 0.5 for chance prediction of outcome to 1.0 for perfect prediction. In logistic regression models controlling for age and gender, four scores based on the International Classification of Diseases, Ninth Revision (ICD-9) generally performed better at predicting 1-year mortality (c = 0.771, c = 0.768, c = 0.745, c = 0.745) than medication-based Chronic Disease Score (CDS)-1 and CDS-2 (c = 0.738, c = 0.718). Number of distinct medications used was the best predictor of future physician visits (R(2) = 0.121) and expenditures (R(2) = 0.128) and a good predictor of mortality (c = 0.745). Combining ICD-9 and medication-based scores improved the c statistics (1.7% and 6.2%, respectively) for predicting mortality. Generalizability of results may be limited to an elderly, predominantly White population with equal access to state-funded health care.