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1.  Rosuvastatin for primary prevention in older individuals with high C-reactive protein and low LDL levels: exploratory analysis of a randomized trial 
Annals of internal medicine  2010;152(8):488-W174.
There are limited randomized data on statins for primary prevention in older people, and the relative hazard of cardiovascular disease associated with elevated cholesterol weakens with advancing age.
To assess the efficacy and safety of rosuvastatin in individuals 70 years of age or older.
Secondary analysis of the JUPITER trial, a randomized, double-blind, placebo-controlled trial.
1315 sites in 26 countries randomized subjects in JUPITER.
Among the 17802 randomized participants with low-density lipoprotein cholesterol (LDL) levels of less than 130 mg/dL and high-sensitivity C-reactive protein levels of 2.0 mg/L or higher, and without cardiovascular disease, 5695 were 70 years of age or older.
Participants were randomly assigned in a 1:1 ratio to receive 20 mg rosuvastatin daily or placebo.
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).
The 32% of trial participants aged 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; [95% CI, 0.62 to 1.04]; P=0.090). While there was no significant heterogeneity in treatment effects by age, absolute reductions in event rates associated with rosuvastatin were greater in older individuals. The relative rate of any serious adverse event among older people in the rosuvastatin group versus placebo was 1.05 (95% CI: 0.93–1.17).
Effect estimates from this exploratory analysis with age cutpoint chosen after trial completion should be viewed in the context of the overall trial results.
In apparently healthy older people without hyperlipidemia but with elevated high-sensitivity C-reactive protein, rosuvastatin reduces the incidence of major cardiovascular events.
Primary Funding Source
PMCID: PMC2946369  PMID: 20404379
2.  Risk factors for incident atrial fibrillation with and without left atrial enlargement in women 
International journal of cardiology  2013;168(3):1894-1899.
Left atrial (LA) enlargement facilitates induction and/or maintenance of atrial fibrillation (AF). However, little is known about risk factors for AF with normal LA size.
We prospectively followed 34713 initially healthy women for incident AF. Information on echocardiographic LA size at first AF diagnosis was abstracted from medical charts during AF confirmation. LA enlargement was defined as LA diameter >40mm. Using a competing risk approach, we constructed Cox proportional-hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) of risk factors for incident AF with and without LA enlargement, respectively.
Among 796 women with incident AF and available LA size, 328 (41%) had LA enlargement. In multivariable competing risk models, the relationship between age and incident AF was stronger in those with (HR 1.12, 95% CI 1.10–1.14) versus without (HR 1.08, 95% CI 1.06–1.09) LA enlargement (p for difference <0.0001). Body weight was associated with AF only in the presence of LA enlargement (HR per 10kg 1.34, 95% CI 1.26–1.43; versus 1.07, 95% CI 0.998–1.14, p for difference<0.0001). Hypertension and height were significantly associated with AF both in the presence (HR 1.99, 95% CI 1.49–2.65; and HR per 10cm 1.36, 95% CI 1.13–1.63) and absence (1.55, 1.25–1.92 and 1.29, 1.10–1.50) of LA enlargement (p for difference 0.17 and 0.66, respectively).
These data suggest that LA enlargement explains much of the increased AF risk associated with obesity and age. In contrast, height and hypertension appear to also influence AF risk through other mechanisms besides LA enlargement.
PMCID: PMC3643987  PMID: 23333369
Atrial fibrillation; left atrium; women; obesity; hypertension
3.  HDL cholesterol, size, particle number, and residual vascular risk after potent statin therapy 
Circulation  2013;128(11):10.1161/CIRCULATIONAHA.113.002671.
Chemically-measured high-density lipoprotein cholesterol (HDL-C) may not be the best clinical measure of HDL. Little is known about alternative HDL meassures such as HDL size or particle number (HDL-P) as determinants of residual risk after potent statin therapy.
Methods and Results
In JUPITER, HDL size and HDL-P were measured by nuclear magnetic resonance spectroscopy, and HDL-C and apolipoprotein A-I (apoA-I) were chemically assayed in 10,886 participants without cardiovascular disease (CVD) before and after random allocation to rosuvastatin 20 mg/day or placebo. Levels were examined with first CVD (N=234). HDL-P correlated better with apoA-I (Spearman r=0.69, p<0.0001) than with HDL-C (r=0.55, p<0.0001). Rosuvastatin lowered LDL cholesterol (49%) and raised HDL-C (6.1%), apoA-I (2.1%), HDL-P (3.8%) and HDL size (1.2%); all p<0.0001. Among placebo-allocated individuals, on-treatment HDL-C, apoA-I, and HDL-P had similar inverse associations with CVD (risk factor-adjusted hazard ratio and 95% CI per 1-SD: 0.79 [0.63–0.98], 0.75 [0.62–0.92], and 0.81 [0.67–0.97], respectively). Among rosuvastatin-allocated individuals, on-treatment HDL-P had a statistically significant and somewhat stronger association with CVD (0.73, 0.57–0.93, p=0.01) than HDL-C (0.82, 0.63–1.08, p=0.16) or apoA-I (0.86, 0.67–1.10, p=0.22). Among rosuvastatin-allocated individuals, on-treatment HDL-P remained significant (0.72, 0.53–0.97, p=0.03) after additionally adjusting for HDL-C. In risk factor-adjusted models, HDL size showed no significant association with CVD.
In the setting of potent statin therapy, HDL particle number may be a better marker of residual risk than chemically-measured HDL-C or apoA-I. This has potential implications for evaluating novel therapies targeting HDL.
Clinical Trial Registration; NCT00239681
PMCID: PMC3807967  PMID: 24002795
inflammation; lipids; lipoproteins; prevention; statins
4.  Calendar Time-Specific Propensity Scores and Comparative Effectiveness Research for Stage III Colon Cancer Chemotherapy 
Pharmacoepidemiology and drug safety  2013;22(8):10.1002/pds.3386.
Nonexperimental studies of treatment effectiveness provide an important complement to randomized trials by including heterogeneous populations. Propensity scores (PS) are common in these studies, but may not adequately capture changes in channeling experienced by innovative treatments. We use calendar time-specific (CTS) PSs to examine the effect of oxaliplatin during dissemination from off-label to widespread use.
Stage III colon cancer patients aged 65+ initiating chemotherapy between 2003–06 were examined using cancer registry data linked with Medicare claims. Two PS approaches for receipt of oxaliplatin vs. 5-flourouricil were constructed using logistic models with key components of age, sex, substage, grade, census level income, and comorbidities: 1) a conventional, year-adjusted PS and 2) a CTS PS constructed and matched separately within 1-year intervals, then combined. We compared PS-matched hazard ratios (HR) for mortality using Cox models.
Oxaliplatin use increased significantly; 8%(n=86) of patients received it in the first time period vs. 52%(n=386) in the last. Channeling by comorbidities, income, and age appeared to change over time. The CTS PS improved covariate balance within calendar time strata and yielded an attenuated estimated benefit of oxaliplatin (HR=0.75) compared with the conventional PS (HR=0.69).
In settings where prescribing patterns have changed and calendar time acts as a confounder, a CTS PS can characterize changes in treatment choices and estimating separate PSs within specific calendar time periods may result in enhanced confounding control. To increase validity of CER, researchers should carefully consider drug lifecycles and effects of innovative treatment dissemination over time.
PMCID: PMC3659185  PMID: 23296544
5.  Rationale and Design of the Cardiovascular Inflammation Reduction Trial (CIRT): A Test of the Inflammatory Hypothesis of Atherothrombosis 
American heart journal  2013;166(2):199-207.e15.
Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known.
The Cardiovascular Inflammation Reduction Trial (CIRT; NCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction and either type 2 diabetes or the metabolic syndrome to low dose methotrexate (target dose 15 to 20 mg per week) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis, lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant anti-atherothrombotic effects. The CIRT primary endpoint is a composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. Secondary endpoints are all-cause mortality, coronary revascularization plus the primary endpoint, hospitalization for congestive heart failure plus the primary endpoint, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary endpoint, incident type 2 diabetes, and net clinical benefit or harm. CIRT will employ standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants.
CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior myocardial infarction and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death. (Clinical Trial Registration Information -; Identifier: NCT01594333)
PMCID: PMC3888829  PMID: 23895801
6.  Breast Cancer Risk Prediction with Heterogeneous Risk Profiles According to Breast Cancer Tumor Markers 
American Journal of Epidemiology  2013;178(2):296-308.
Relationships between some risk factors and breast cancer incidence are known to vary by tumor subtype. However, breast tumors can be classified according to a number of markers, which may be correlated, making it difficult to identify heterogeneity of risk factors with specific tumor markers when using standard competing-risk survival analysis. In this paper, we propose a constrained competing-risk survival model that allows for assessment of heterogeneity of risk factor associations according to specific tumor markers while controlling for other markers. These methods are applied to Nurses’ Health Study data from 1980–2006, during which 3,398 incident invasive breast cancers occurred over 1.4 million person-years of follow-up. Results suggested that when estrogen receptor (ER) and progesterone receptor (PR) status are mutually considered, some risk factors thought to be characteristic of “estrogen-positive tumors,” such as high body mass index during postmenopause and increased height, are actually significantly associated with PR-positive tumors but not ER-positive tumors, while other risk factors thought to be characteristic of “estrogen-negative tumors,” such as late age at first birth, are actually significantly associated with PR-negative rather than ER-negative breast cancer. This approach provides a strategy for evaluating heterogeneity of risk factor associations by tumor marker levels while controlling for additional tumor markers.
PMCID: PMC3816337  PMID: 23645624
breast cancer; competing risks; proportional hazards model
7.  Predisposing Factors Associated With Development of Persistent Compared With Paroxysmal Atrial Fibrillation 
Once atrial fibrillation (AF) progresses to sustained forms, adverse outcomes increase and treatment success rates decrease. Therefore, identification of risk factors predisposing to persistence of AF may have a significant impact on AF morbidity.
Methods and Results
We prospectively examined the differential associations between traditional, lifestyle, and biomarker AF risk factors and development of paroxysmal versus nonparoxysmal AF (persistent/permanent) among 34 720 women enrolled in the Women's Health Study who were free of cardiovascular disease and AF at baseline. AF patterns were defined based on current guidelines and classified according to the most sustained form of AF within 2 years of diagnosis. During a median follow‐up of 16.4 years, 690 women developed paroxysmal AF and 349 women developed nonparoxysmal AF. In multivariable time‐varying competing risk models, increasing age (hazard ratio [HR] 1.11, 95% CI 1.10 to 1.13, versus HR 1.08, 1.07 to 1.09, per year), body mass index (HR 1.07, 1.05 to 1.09, versus HR 1.03, 1.02 to 1.05, per kg/m2), and weight (HR 1.30, 1.22 to 1.39, versus HR 1.14, 1.08 to 1.20, per 10 kg) were more strongly associated with the development of nonparoxysmal AF compared with paroxysmal AF. Hemoglobin A1c levels at baseline were directly related to the development of nonparoxysmal AF but inversely associated with paroxysmal AF in multivariable competing risk models (P for nonequal association=0.01).
In women without AF or CVD at baseline, increasing age, adiposity, and higher hemoglobin A1c levels were preferentially associated with the early development of nonparoxysmal AF. These data raise the hypothesis that efforts aimed at weight reduction or glycemic control may affect the proportion of the population with sustained AF.
PMCID: PMC4309092  PMID: 24786144
atrial fibrillation; HbA1c; obesity; risk factors
8.  Impact of drug interactions, dosage, and duration of therapy on the risk of hip fracture associated with benzodiazepine use in older adults 
Pharmacoepidemiology and drug safety  2010;19(12):1248-1255.
To determine how concomitant use of potentially interacting drugs, drug dosage, and duration of therapy modify the risk of hip fracture associated with use of benzodiazepines and related drugs (BDZ) in older adults.
A nested case-control study was conducted in Medicare patients 65 years or older, enrolled in the Pennsylvania drug assistance program (PACE) between 1994 and 2005. We included 17,198 patients with a hip fracture leading to hospitalization and 85,990 controls matched on hospitalization (index date). BDZ and interacting drug use within two weeks preceding the index date was determined using information on date of drug dispensing, days supplied, quantity dispensed, and strength. Date of the first BDZ prescription within the year preceding the index date was used as surrogate for duration of therapy.
While the adjusted relative risk (RR) for overall BDZ use and hip fracture was 1.2 (95% confidence interval 1.1, 1.2), the RRs for concomitant use of alprazolam, lorazepam, and zolpidem and their interacting drugs were 1.5 (1.3, 1.7), 1.9 (1.7, 2.2), and 1.7 (1.4, 2.0), and 2.1 (1.5, 2.8) for BDZ use initiated within 14 days preceding the index date. RR increased with increasing BDZ dose and was highest for defined daily BDZ doses >1 (RR: 1.3 (1.2, 1.5)).
BDZ associated hip fracture risk increases with concomitant use of interacting drugs, higher doses, and is highest at initiation. Clinicians should avoid concomitant use of BDZ and interacting drugs, because their impact on hip fracture risk is at least additive.
PMCID: PMC4018736  PMID: 20931664
Aged; benzodiazepines; case-control studies; drug interactions; hip fractures; zolpidem
9.  C-Reactive Protein and the Incidence of Macular Degeneration – Pooled Analysis of 5 Cohorts 
JAMA ophthalmology  2013;131(4):507-513.
To investigate the relationship between high-sensitivity C-reactive protein (hsCRP) and future risk of age-related macular degeneration (AMD) in US men and women.
We measured hsCRP in baseline blood samples from participants in five ongoing cohort studies. Patients were initially free of AMD. We prospectively identified 647 incident cases of AMD and selected age- and sex-matched controls for each AMD case (2 controls for each case with dry AMD, or 3 controls for each case of neovascular AMD). We used conditional logistic regression models to examine the relationship between hsCRP and AMD, and pooled findings using meta-analytic techniques.
After adjusting for cigarette smoking status, participants with high (> 3 mg/L) compared with low (< 1 mg/L) hsCRP levels, had cohort-specific odds ratios (OR) for incident AMD ranging from 0.94 (95% CI 0.58-1.51) in the Physicians’ Health Study to 2.59 (95% CI 0.58-11.67) in the Women’s Antioxidant and Folic Acid Cardiovascular Study. After testing for heterogeneity between studies (Q=5.61, p=0.23), we pooled findings across cohorts, and observed a significantly increased risk of incident AMD for high versus low hsCRP levels (OR=1.49, 95% CI 1.06-2.08). Risk of neovascular AMD was also increased among those with high hsCRP levels (OR=1.84, 95% CI 1.14-2.98).
Overall these pooled findings from 5 prospective cohorts add further evidence that elevated levels of hsCRP predict greater future risk of AMD. This information might shed light on underlying mechanisms, and could be of clinical utility in the identification of persons at high risk of AMD who may benefit from increased adherence to lifestyle recommendations, eye examination schedules, and therapeutic protocols.
PMCID: PMC3625501  PMID: 23392454
10.  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 healthcare data. In a retrospective analysis, we showed 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). During >5 years of monitoring, rate differences (RDs) comparing rosuvastatin to atorvastatin were -0.1 cases of rhabdomyolysis per 1,000 person-years (95% 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 to 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 three drug-outcome pairs.
PMCID: PMC3947906  PMID: 22588606
11.  Vascular risk factors, cardiovascular disease and restless legs syndrome in men 
The American journal of medicine  2013;126(3):228-235.e2.
Prevalences of vascular risk factors, cardiovascular disease and restless legs syndrome increase with age. Prior studies analyzing the associations between vascular risk factors, cardiovascular disease, and restless legs syndrome found controversial results. We therefore aim to evaluate the association between prevalent vascular risk factors, prevalent cardiovascular disease and restless legs syndrome.
We conducted a cross-sectional study among 22,786 participants of the US Physicians’ Health Studies I and II. Restless legs syndrome was classified according to the four minimal diagnostic criteria. Vascular risk factors and restless legs syndrome symptoms were self-reported. Prevalent cardiovascular disease events including major cardiovascular disease, stroke and myocardial infarction were confirmed by medical record review. Age- and multivariable-adjusted logistic regression models were used to evaluate the association between vascular risk factors, prevalent cardiovascular disease events and restless legs syndrome.
The mean age of the cohort 67.8 years. Restless legs syndrome prevalence was 7.5% and increased significantly with age. Diabetes significantly increased the odds (OR: 1.41, 95%CI: 1.21–1.65), while frequent exercise (OR: 0.78, 95%CI: 0.67–0.91) and alcohol consumption of one or more drinks per day (OR: 0.80, 95%CI: 0.69–0.92) significantly reduced the odds of restless legs syndrome in multivariable-adjusted models. Prevalent stroke showed an increased multivariable-adjusted OR of 1.40 (1.05–1.86) while men with prevalent myocardial infarction had a decreased OR of 0.73 (0.55–0.97) for restless legs syndrome.
The restless legs syndrome prevalence among US male physicians is similar to men of the same age group in other western countries. A history of diabetes is the most consistent risk factor associated with restless legs syndrome. Prevalent stroke and myocardial infarction are related to restless legs syndrome prevalence.
PMCID: PMC3574273  PMID: 23410563
Vascular risk factors; cardiovascular disease; Restless legs syndrome; cohort study
12.  Vascular risk factors, cardiovascular disease and restless legs syndrome in women 
The American journal of medicine  2013;126(3):220-227.e2.
Previous studies evaluating the association between cardiovascular disease and vascular risk factors with restless legs syndrome showed inconsistent results, especially for the potential relation between various vascular risk factors and restless legs syndrome. We therefore aimed to analyze the relationship between vascular risk factors, prevalent cardiovascular disease and restless legs syndrome.
This is a cross-sectional study of 30,262 female health professionals participating in the Women's Health Study (WHS). Restless legs syndrome was defined according to diagnostic criteria of the International Restless Legs Study Group. Information on vascular risk factors (diabetes, hypertension, hypercholesterolemia, body mass index, alcohol, smoking, exercise, family history of myocardial infarction) was self-reported. Cardiovascular disease events (coronary revascularization, myocardial infarction, stroke) were confirmed by medical record review. Prevalent major cardiovascular disease was defined as non-fatal stroke or non-fatal myocardial infarction. Logistic regression models were used to evaluate the association between vascular risk factors, prevalent cardiovascular disease and restless legs syndrome.
Of the 30,262 participants (mean age: 63.6 years), 3,624 (12.0%) reported restless legs syndrome. In multivariable-adjusted models, body mass index (OR for BMI ≥35kg/m2: 1.35, 95% CI: 1.17–1.56), diabetes (OR: 1.19, 95%CI: 1.04–1.35), hypercholesterolemia (OR: 1.17, 95% CI: 1.09–1.26), smoking status (OR for ≥15 cigarettes/day: 1.41, 95%CI: 1.19–1.66) and exercise (OR for exercise ≥ 4 times/week: 0.84, 95%CI: 0.74–0.95) were associated with restless legs syndrome prevalence. We found no association between prevalent cardiovascular disease (major cardiovascular disease, myocardial infarction, stroke) and restless legs syndrome prevalence. Women who underwent coronary revascularization had a multivariable-adjusted OR of 1.39 (1.10–1.77) for restless legs syndrome.
In this large cohort of female health professionals, various vascular risk factors are associated with restless legs syndrome prevalence. We could not confirm results of previous reports indicating an association between prevalent cardiovascular disease and restless legs syndrome.
PMCID: PMC3574635  PMID: 23410562
Vascular risk factors; cardiovascular disease; Restless legs syndrome; cohort study
13.  Algorithms to estimate the beginning of pregnancy in administrative databases 
The role of administrative databases for research on drug safety during pregnancy can be limited by their inaccurate assessment of the timing of exposure, as the gestational age at birth is typically unavailable. Therefore, we sought to develop and validate algorithms to estimate the gestational age at birth using information available in these databases.
Using a population-based cohort of 286,432 mother-child pairs in British Columbia (1998–2007), we validated an ICD-9/10-based preterm-status indicator, and developed algorithms to estimate the gestational age at birth based on this indicator, maternal age, singleton/multiple status, and claims for routine prenatal care tests. We assessed the accuracy of the algorithm-based estimates relative to the gold standard of the clinical gestational age at birth recorded in the delivery discharge record.
The preterm-status indicator had specificity and sensitivity of 98% and 91%. Estimates from an algorithm that assigned 35 weeks of gestational age at birth to deliveries with the preterm-status indicator and 39 weeks to those without them were within 2 weeks of the clinical gestational age at birth in 75% of preterm and 99% of term deliveries.
Subtracting 35 weeks (245 days) from the date of birth in deliveries with codes for preterm birth and 39 weeks (273 days) in those without them provided the optimal estimate of the beginning of pregnancy among the algorithms studied.
PMCID: PMC3437228  PMID: 22550030
Pregnancy; Premature birth; Term Birth; Duration of pregnancy; Claims databases; Last menstrual period
15.  Multivitamins in the Prevention of Cancer in Men: The Physicians’ Health Study II Randomized Controlled Trial 
Multivitamin preparations are the most common dietary supplement, taken by at least one-third of all US adults. Limited observational studies have not provided evidence regarding associations of multivitamin use with total and site-specific cancer incidence or mortality.
To determine whether long-term multivitamin supplementation decreases the risk of total and site-specific cancer events among men.
The Physicians’ Health Study II is a randomized, double-blind, placebo-controlled trial of a common multivitamin that began in 1997 with treatment and follow-up through June 1, 2011.
Setting and Participants
A total of 14,641 male U.S. physicians initially aged ≥50 years (mean [± SD] age; 64.3 [± 9.2] years), including 1,312 men with a history of cancer at randomization, were enrolled.
Daily multivitamin, as Centrum Silver.
Main Outcome Measures
A primary outcome was total cancer (excluding non-melanoma skin cancer), with prostate, colorectal, and other site-specific cancers among secondary endpoints included in this report.
During a median (interquartile range) follow-up of 11.2 (10.7 to 13.3) years, there were 2,669 men with confirmed cancer, including 1,373 cases of prostate cancer and 210 cases of colorectal cancer. Compared with placebo, men taking a daily multivitamin had a statistically significant reduction in the incidence of total cancer (active and placebo multivitamin groups, 17.0 and 18.3 events, respectively, per 1,000 person-years; hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.86–0.998; P=0.044). There was no significant effect of a daily multivitamin on prostate cancer (HR, 0.98; 95% CI, 0.88–1.09; P=0.76), colorectal cancer (HR, 0.89; 95% CI, 0.68–1.17; P=0.39), or other site-specific cancers There was a lower risk of cancer mortality that did not reach statistical significance (HR, 0.88; 95% CI, 0.77–1.01; P=0.07). Daily multivitamin use was associated with a reduction in total cancer among 1,312 men with a baseline history of cancer (HR, 0.73; 95% CI, 0.56–0.96; P=0.022), but this did not differ significantly from that among 13,329 men initially free of cancer (HR, 0.94; 95% CI, 0.87–1.02; P=0.15) (P, interaction = 0.07).
In this large prevention trial of male physicians, daily multivitamin supplementation modestly but significantly reduced the risk of total cancer.
PMCID: PMC3517179  PMID: 23162860
multivitamin; total cancer; prostate cancer; randomized clinical trial; men
16.  Multivitamins in the Prevention of Cardiovascular Disease in Men: The Physicians' Health Study II Randomized Controlled Trial 
Though multivitamins aim to prevent vitamin and mineral deficiency, there is a perception that multivitamins may prevent cardiovascular disease (CVD). Observational studies examining regular multivitamin use have been inconsistently associated with CVD, with no long-term clinical trials of multivitamin use.
To determine whether long-term multivitamin supplementation decreases the risk of major cardiovascular events among men.
The Physicians' Health Study II is a randomized, double-blind, placebo-controlled trial of a common daily multivitamin, that began in 1997 with continued treatment and follow-up through June 1, 2011.
Setting and Participants
A total of 14,641 male U.S. physicians initially aged ≥50 years (mean [± SD] age; 64.3 [± 9.2] years), including 754 men with a history of CVD at randomization, were enrolled.
Daily multivitamin, as Centrum Silver.
Main Outcome Measures
The primary cardiovascular outcome was a composite endpoint of major cardiovascular events, including nonfatal myocardial infarction (MI), nonfatal stroke, and fatal CVD. Secondary outcomes included MI and stroke individually.
During a median (interquartile range) follow-up of 11.2 (10.7 to 13.3) years, there were 1,732 confirmed major cardiovascular events. Compared with placebo, there was no significant effect of a daily multivitamin on major cardiovascular events (active and placebo multivitamin groups, 11.0 and 10.8 events per 1,000 person-years; hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.91–1.10; P=0.91). Further, a daily multivitamin had no effect on total MI (active and placebo multivitamin groups, 3.9 and 4.2 events per 1,000 person-years; HR, 0.93; 95% CI, 0.80–1.09; P=0.39), total stroke (active and placebo multivitamin groups, 4.1 and 3.9 events per 1,000 person-years; HR, 1.06; 95% CI, 0.91–1.23; P=0.48), or cardiovascular mortality (active and placebo multivitamin groups, 5.0 and 5.1 events per 1,000 person-years; HR, 0.95; 95% CI, 0.83–1.09; P=0.47). A daily multivitamin was also not significantly associated with total mortality (HR, 0.94; 95% CI, 0.88–1.02; P=0.13). The effect of a daily multivitamin on major cardiovascular events did not differ between men with or without a baseline history of CVD (P, interaction = 0.62).
A daily multivitamin did not reduce major cardiovascular events, MI, stroke, and CVD mortality after more than a decade of treatment and follow-up.
PMCID: PMC3501249  PMID: 23117775
multivitamin; cardiovascular disease; myocardial infarction; stroke; randomized clinical trial; men
17.  Use of topiramate in pregnancy and risk of oral clefts 
To evaluate the association between monotherapy topiramate use in pregnancy and cleft lip with or without cleft palate (CL/P) in the offspring.
Study design
Data from the Slone Epidemiology Center Birth Defects Study (BDS) from 1997–2009 and the National Birth Defects Prevention Study (NBDPS) from 1997–2007 were analyzed. Conditional logistic regression was used to compare first-trimester use of topiramate monotherapy to no antiepileptic drug use during the periconceptional period between mothers of infants with CL/P and mothers of controls for each study separately, and in pooled data.
BDS contained 785 CL/P cases and 6,986 controls; NBDPS contained 2,283 CL/P cases and 8,494 controls. The odds ratios (exact 95% confidence intervals) for the association between topiramate use and CL/P were 10.1 (1.1; 129.2) in BDS, 3.6 (0.7; 20.0) in NBDPS, and 5.4 (1.5; 20.1) in pooled data.
First-trimester use of topiramate may be associated with CL/P.
PMCID: PMC3484193  PMID: 22917484
Antiepileptic drugs; Birth defects; Cleft lip; Oral clefts; Topiramate
18.  Cardiovascular Benefits and Diabetes Risks of Statin Therapy in Primary Prevention 
Lancet  2012;380(9841):565-571.
As statin therapy increases risks of diabetes, the balance of benefit and risk in primary prevention for these agents has become controversial. We undertook an analysis of participants from the JUPITER trial to address the balance of vascular benefits and diabetes hazard of statin use.
In the randomized, double-blind JUPITER trial, 17,603 men and women without prior cardiovascular disease or diabetes were randomly allocated to rosuvastatin 20 mg or placebo and followed for up to 5 years for the trial primary endpoint (myocardial infarction, stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death) and the protocol pre-specified secondary endpoints of venous thromboembolism (VTE), all-cause mortality, and incident diabetes. To address balance of vascular benefits and diabetes hazard, participants were stratified on the basis of having none or at least one of the following major risk factors for developing diabetes: metabolic syndrome, impaired fasting glucose, body mass index >30 kg/m2, or HbA1c > 6 percent.
Trial participants with one or more major diabetes risk factor (N=11,508) were at higher risk of developing diabetes; for such individuals, statin allocation was associated with a 39 percent reduction in the primary endpoint (P=0.0001), a 36 percent reduction in VTE (P=0.08), a 17 percent reduction in total mortality (P=0.15) and a 28 percent increase in diabetes (P=0.01). Thus, for those with diabetes risk factors, 93 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. For trial participants with no major diabetes risk factor (N=6,095), statin allocation was associated with a 52 percent reduction in the primary endpoint (P=0.0001), a 53 percent reduction in VTE (P=0.05), a 22 percent reduction in total mortality (P=0.08) and no increase in diabetes (HR 0.99, P= 0.99). For such individuals, a total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed. In analysis limited to the 486 participants who developed diabetes during follow-up (270 on rosuvastatin vs. 216 on placebo group, P=0.01), the point estimate of cardiovascular risk reduction associated with statin therapy (hazard ratio 0.63) was consistent with that observed for the trial as a whole (hazard ratio 0.56). As compared to placebo, statin allocation accelerated the average time to diagnosis of diabetes by 5.4 weeks.
In the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including among those at higher risk for developing diabetes
PMCID: PMC3774022  PMID: 22883507
19.  Bias in comparative effectiveness studies due to regional variation in medical practice intensity: A legitimate concern or much ado about nothing? 
PMCID: PMC3519359  PMID: 22991351
Acute myocardial infarction; Epidemiology; Health policy and outcome research; Primary prevention; Secondary prevention; Resource utilization
20.  Association Between the Part D Coverage Gap and Adverse Health Outcomes 
Part D coverage gap entry is associated with a two-fold increased rate of drug discontinuation among beneficiaries now fully responsible for drug costs. Reduced adherence to drugs has been associated with adverse outcomes. We evaluated whether coverage gap entry is associated with risk of death or hospitalization for cardiovascular outcomes.
Prospective cohort study. Beneficiaries entered the study upon reaching the coverage gap spending threshold and were observed until an event, reaching the threshold for catastrophic coverage, or year’s end. Exposed patients were responsible for drug costs in the gap; unexposed patients received financial assistance. We matched 9,436 exposed patients to 9,436 unexposed patients based on propensity score (PS) or high-dimensional propensity score (hdPS).
Medicare Part D drug insurance.
303,978 Medicare beneficiaries aged 65+ in 2006 and 2007 with linked prescription and medical claims who enrolled in stand-alone Part D or retiree drug plans and reached the gap spending threshold.
Rates of death and hospitalization for any of 5 cardiovascular outcomes, including acute coronary syndrome+revascularization (ACS), after reaching the coverage gap spending threshold were compared using Cox proportional hazards models.
In PS-matched analyses, exposed beneficiaries had elevated but non-significant hazards of death (HR=1.25; 95% CI 0.98–1.59) and ACS (HR=1.16; 0.83–1.62) compared with unexposed patients. hdPS-matched analyses minimized residual confounding and confirmed results: death (HR=0.99; 0.78–1.24); ACS (HR=1.07; 0.81–1.41). Exposed beneficiaries were no more or less likely to experience other outcomes than were the unexposed.
During the short-term coverage gap period, having no financial assistance to pay for drugs was not associated with an increased risk of death or hospitalization for cardiovascular causes. However, long-term health consequences remain unclear.
PMCID: PMC3419279  PMID: 22788544
Medicare Part D; coverage gap; adverse health outcomes; cardiovascular disease; drug discontinuation
21.  Vitamins E and C and Medical Record-Confirmed Age-related Macular Degeneration in a Randomized Trial of Male Physicians 
Ophthalmology  2012;119(8):1642-1649.
To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of the diagnosis of age-related macular degeneration (AMD) in a large-scale randomized trial of male physicians.
Randomized, double-masked, placebo-controlled trial.
We included 14 236 apparently healthy United States male physicians aged ≥50 years who did not report a diagnosis of AMD at baseline.
Participants were randomly assigned to receive 400 international units (IU) of vitamin E or placebo on alternate days, and 500 mg of vitamin C or placebo daily. Participants reported new diagnoses of AMD on annual questionnaires and medical record data were collected to confirm the reports.
Main Outcome Measures
Incident diagnosis of AMD responsible for a reduction in best-corrected visual acuity to ≤20/30.
After 8 years of treatment and follow-up, a total of 193 incident cases of visually significant AMD were documented. There were 96 cases in the vitamin E group and 97 in the placebo group (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.78–1.37). For vitamin C, there were 97 cases in the active group and 96 in the placebo group (HR, 0.99; 95% CI, 0.75–1.31).
In a large-scale, randomized trial of United States male physicians, alternate-day use of 400 IU of vitamin E and/or daily use of 500 mg of vitamin C for 8 years had no appreciable beneficial or harmful effect on risk of incident diagnosis of AMD.
PMCID: PMC3535014  PMID: 22503302
22.  Risk of Ischemic Cerebrovascular and Coronary Events in Adult Users of Anticonvulsant Medications in Routine Care Settings 
Older‐generation anticonvulsants that highly induce cytochrome P450 enzyme system activity produce metabolic abnormalities that may increase cardiovascular risk. The objective of this study was to evaluate the risk of ischemic cerebrovascular and coronary events in adult new users of anticonvulsants that highly induce cytochrome P450 activity compared with other anticonvulsant agents, as observed in a routine care setting.
Methods and Results
This was a cohort study of patients 40 to 64 years old from the HealthCore Integrated Research Database who had initiated an anticonvulsant medication between 2001 and 2006 and had no recorded major coronary or cerebrovascular condition in the 6 months before treatment initiation. Propensity score (PS) matching was used to evaluate ischemic cerebrovascular and coronary risk among anticonvulsant new users. High‐dimensional propensity score (hdPS)–matched analyses were used to confirm adjusted findings. The study identified 913 events in 166 031 unmatched new treatment episodes with anticonvulsant drugs. In a PS‐matched population of 22 864 treatment episodes, the rate ratio (RR) for ischemic coronary or cerebrovascular events associated with highly inducing agents versus other agents was 1.22 (95% CI, 0.90‐1.65). The RR moved to 0.99 (95% CI, 0.73‐1.33) with adjustment for hdPS matching (RR, 1.47; 95% CI, 0.95‐2.28 for cerebrovascular events; RR, 0.70; 95% CI, 0.47‐1.05 for coronary events).
In this exploratory analysis, there was no evidence of a consistent and statistically significant effect of initiating anticonvulsants that highly induce cytochrome P450 activity on ischemic coronary or cerebrovascular outcomes compared with other agents, given routine care utilization patterns.
PMCID: PMC3828795  PMID: 23900213
anticonvulsant drugs; claims data; cohort study; myocardial infarction; stroke
23.  Ability of VKORC1 and CYP2C9 to Predict Therapeutic Warfarin Dose During the Initial Weeks of Therapy 
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.
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.
A pharmacogenetic model using data from day 0 (before therapy initiation) explained 54% of the variability in therapeutic dose (R2). The R2 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 R2 of genotype was 43% at day 0, 12% at day 7, 4% at day 14, and 1% at day 21.
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.
PMCID: PMC3718044  PMID: 19874474
24.  Applying propensity scores estimated in a full cohort to adjust for confounding in subgroup analyses 
A correctly-specified propensity score (PS) estimated in a cohort (“cohort PS”) should in expectation remain valid in a subgroup population. We sought to determine whether using a cohort PS can be validly applied to subgroup analyses and thus add efficiency to studies with many subgroups or restricted data. In each of 3 cohort studies we estimated a cohort PS, defined 5 subgroups, and then estimated subgroup-specific PSs. We compared difference in treatment effect estimates for subgroup analyses adjusted by cohort PSs versus subgroup-specific PSs. Then, 10M times, we simulated a population with known characteristics of confounding, subgroup size, treatment interactions, and treatment effect, and again assessed difference in point estimates. We observed that point estimates in most subgroups were substantially similar with the two methods of adjustment. In simulations, the effect estimates differed by a median of 3.4% (interquartile [IQ] range 1.3% to 10.0%). The IQ range exceeded 10% only in cases where the subgroup had <1000 patients or few outcome events. Our empirical and simulation results indicated that using a cohort PS in subgroup analyses was a feasible approach, particularly in larger subgroups.
PMCID: PMC3383902  PMID: 22162077
Propensity Scores; Confounding Factors (Epidemiology); Multicenter Study [Publication Type]; Epidemiologic Methods; Effect Modifiers (Epidemiology); Comparative Effectiveness Research
25.  Propensity Score Calibration in the Absence of Surrogacy 
American Journal of Epidemiology  2012;175(12):1294-1302.
Propensity score calibration (PSC) can be used to adjust for unmeasured confounders using a cross-sectional validation study that lacks information on the disease outcome (Y), under a strong surrogacy assumption. Using directed acyclic graphs and path analysis, the authors developed a formula to predict the presence and magnitude of the bias of PSC in the simplest setting of a binary exposure (T) and 1 confounder (X) that are observed in the main study and 1 confounder (C) that is observed in the validation study only. PSC bias is predicted on the basis of parameters that can be estimated from the data and a single unidentifiable parameter, the relative risk (RR) associated with C (RRCY). The authors simulated 1,000 cohort studies each with a Poisson-distributed outcome Y, varying parameter values over a wide range. When using the true parameter for RRCY, the formula predicts PSC bias almost perfectly in this simple setting (correlation with observed bias over 24 scenarios assessed: r = 0.998). The authors conclude that the bias from PSC observed in certain scenarios can be estimated from the imbalance in C between treated and untreated persons, after adjustment for X, in the validation study and assuming a range of plausible values for the unidentifiable RRCY.
PMCID: PMC3491974  PMID: 22688682
bias (epidemiology); confounding factors (epidemiology); epidemiologic methods; path analysis; propensity score; propensity score calibration; research design

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