Background:

There is an increased risk of venous thromboembolism among women taking oral contraceptives. However, whether there is an additional risk among women with polycystic ovary syndrome (PCOS) is unknown.

Methods:

We developed a population-based cohort from the IMS LifeLink Health Plan Claims Database, which includes managed care organizations in the United States. Women aged 18–46 years taking combined oral contraceptives and who had a claim for PCOS (n = 43 506) were matched, based on a propensity score, to control women (n = 43 506) taking oral contraceptives. Venous thromboembolism was defined using administrative coding and use of anticoagulation. We used Cox proportional hazards models to assess the relative risk (RR) of venous thromboembolism among users of combined oral contraceptives with and without PCOS.

Results:

The incidence of venous thromboembolism among women with PCOS was 23.7/10 000 person-years, while that for matched controls was 10.9/10 000 person-years. Women with PCOS taking combined oral contraceptives had an RR for venous thromboembolism of 2.14 (95% confidence interval [CI] 1.41–3.24) compared with other contraceptive users. The incidence of venous thromboembolism was 6.3/10 000 person-years among women with PCOS not taking oral contraceptives; the incidence was 4.1/10 000 person-years among matched controls. The RR of venous thromboembolism among women with PCOS not taking oral contraceptives was 1.55 (95% CI 1.10–2.19).

Interpretation:

We found a 2-fold increased risk of venous thromboembolism among women with PCOS who were taking combined oral contraceptives and a 1.5-fold increased risk among women with PCOS not taking oral contraceptives. Physicians should consider the increased risk of venous thromboembolism when prescribing contraceptive therapy to women with PCOS.

Purpose

Serotonin and the serotonin transporter have been implicated in the development of pulmonary hypertension (PH). Selective serotonin reuptake inhibitors (SSRIs) may have a role in PH treatment, but the effects of SSRI use on right ventricular (RV) structure and function are unknown. We hypothesized that SSRI use would be associated with RV morphology in a large cohort without cardiovascular disease (N = 4114).

Methods

SSRI use was determined by medication inventory during the Multi-Ethnic Study of Atherosclerosis baseline examination. RV measures were assessed via cardiac magnetic resonance imaging. The cross-sectional relationship between SSRI use and each RV measure was assessed using multivariable linear regression; analyses for RV mass and end-diastolic volume (RVEDV) were stratified by sex.

Results

After adjustment for multiple covariates including depression and left ventricular measures, SSRI use was associated with larger RV stroke volume (RVSV) (2.75 mL, 95% confidence interval [CI] 0.48–5.02 mL, p = 0.02). Among men only, SSRI use was associated with greater RV mass (1.08 g, 95% CI 0.19–1.97 g, p = 0.02) and larger RVEDV (7.71 mL, 95% 3.02–12.40 mL, p = 0.001). SSRI use may have been associated with larger RVEDV among women and larger RV end-systolic volume in both sexes.

Conclusions

SSRI use was associated with higher RVSV in cardiovascular disease-free individuals and, among men, greater RV mass and larger RVEDV. The effects of SSRI use in patients with (or at risk for) RV dysfunction and the role of sex in modifying this relationship warrant further study.

Background

Three types of non-steroidal anti-inflammatory drugs (NSAIDs) can be obtained both over the counter (OTC) and by prescription in the United States. OTC NSAID use is not recorded in prescription claims databases; this might lead to differential misclassification of NSAID exposure status in studies that use computerized pharmacy databases to study NSAID use.

Objective

To evaluate characteristics of OTC versus prescription NSAID users

Methods

This analysis is set within the Multi-Ethnic Study of Atherosclerosis (MESA) study; a prospective cohort study of 6,814 adults from 4 ethnic groups (European descent, Asian, African-American and Hispanic) with a mean age of 62 years. The cohort was restricted to those who initiated NSAID use (aspirin, ibuprofen or naproxen) during follow-up. We compared information about age, sex, ethnicity, body mass index, smoking, diabetes, medication use, education, income, health insurance status and exercisebetween groups.

Results

OTC NSAID use was prevalent at baseline (25% Aspirin, 9% Ibuprofen, 2% Naproxen). Compared to prescribed NSAID use, OTC NSAID use was lower for users of non-European descent for all classes: aspirin (p<0.0001), ibuprofen (p<0.0001) and naproxen (p=0.0094). For aspirin, differences were seen for male gender (Relative Risk (RR):0.92; 95%(Confidence interval) CI:0.86–0.98), use of lipid lowering drugs (RR:0.88; 95% CI: 0.80–0.96), low income (RR:0.89; 95%CI:0.81–0.97), and participants one standard deviation above average in intentional exercise (RR:1.03; 95%CI:1.01–1.05).

Conclusions

OTC NSAID use is prevalent in an older multi-ethnic population and OTC users differ from prescription NSAID users. Caution should be exercised when using prescribed NSAIDs as a proxy for NSAID use.

Background:

The evidence for the effectiveness of antihypertensive medication use for slowing decline in kidney function in older persons is sparse. We addressed this research question by the application of novel methods in a marginal structural model.

Methods:

Change in kidney function was measured by two or more measures of cystatin C in 1,576 hypertensive participants in the Cardiovascular Health Study over 7 years of follow-up (1989–1997 in four U.S. communities). The exposure of interest was antihypertensive medication use. We used a novel estimator in a marginal structural model to account for bias due to confounding and informative censoring.

Results:

The mean annual decline in eGFR was 2.41 ± 4.91 mL/min/1.73 m2. In unadjusted analysis, antihypertensive medication use was not associated with annual change in kidney function. Traditional multivariable regression did not substantially change these estimates. Based on a marginal structural analysis, persons on antihypertensives had slower declines in kidney function; participants had an estimated 0.88 (0.13, 1.63) ml/min/1.73 m2 per year slower decline in eGFR compared with persons on no treatment. In a model that also accounted for bias due to informative censoring, the estimate for the treatment effect was 2.23 (−0.13, 4.59) ml/min/1.73 m2 per year slower decline in eGFR.

Conclusion:

In summary, estimates from a marginal structural model suggested that antihypertensive therapy was associated with preserved kidney function in hypertensive elderly adults. Confirmatory studies may provide power to determine the strength and validity of the findings.

Objectives

To determine whether nitrogen-containing bisphosphonate (NCBP) therapy is associated with the prevalence of cardiovascular calcification.

Background

Cardiovascular calcification correlates with atherosclerotic disease burden. Experimental data suggest that NCBP may limit cardiovascular calcification, which has implications for disease prevention.

Methods

The relationship of NCBP use to the prevalence of aortic valve, aortic valve ring, mitral annulus, thoracic aorta, and coronary artery calcification (AVC, AVRC, MAC, TAC, and CAC, respectively) detected by computed tomography was assessed in 3,636 women within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling.

Results

Analyses were age-stratified because of a significant interaction between age and NCBP use (interaction p-values: AVC p<0.0001; AVRC p<0.0001; MAC p=0.002; TAC p<0.0001; CAC p=0.046). After adjusting for age, body mass index, demographics, diabetes, smoking, blood pressure, cholesterol levels, and statin, hormone replacement, and renin-angiotensin inhibitor therapy, NCBP use was associated with a lower prevalence of cardiovascular calcification in women ≥65 years old (prevalence ratio [95% confidence interval]: AVC 0.68 [0.41, 1.13]; AVRC 0.65 [0.51, 0.84]; MAC 0.54 [0.33, 0.93]; TAC 0.69 [0.54, 0.88]; CAC 0.89 [0.78, 1.02]), whereas calcification was more prevalent in NCBP users among the 2,181 women <65 years old (AVC 4.00 [2.33, 6.89]; AVRC 1.92 [1.42, 2.61]; MAC 2.35 [1.12, 4.84]; TAC 2.17 [1.49, 3.15]; CAC 1.23 [0.97, 1.57]).

Conclusions

Among women in the diverse MESA cohort, NCBPs were associated with decreased prevalence of cardiovascular calcification in older subjects, but more prevalent cardiovascular calcification in younger ones. Further study is warranted to clarify these age-dependent NCBP effects.

Systematic differences between readers or equipment in imaging studies are not uncommon; failure to account for such differences when using Carotid Ultrasonography may introduce bias into associations between carotid intima media thickness (cIMT) and outcomes. We demonstrate the impact of this source of systematic measurement error (SME) using data on 5,521 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and 661 participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Participants were between 37 and 78 years old. Two outcomes were considered: (1) the effect of HIV infection on cIMT (between study) and (2) the association of cIMT with cardiovascular events (within study). All estimates were adjusted for demographics (age, gender, and ethnicity) and for traditional cardiovascular disease risk factors (smoking, blood pressure, diabetes and cholesterol). When comparing the FRAM and MESA cohorts to estimate the association of HIV infection on common cIMT, accounting for machine and reader variability (between study variability) reduced the difference associated with HIV infection from +0.080 mm (95% Confidence Interval (CI):0.065–0.095) to +0.037 mm (95% CI:0.003 to 0.072) while internal cIMT declined from +0.254 mm (95% CI:0.205–0.303) to +0.192 mm (95% CI:0.076–0.308). Attenuation of the association between cIMT and cardiovascular endpoints occurred when within study reader variability was not accounted for. The effect of SME due to use of multiple readers or machines is most important when comparisons are made between two different study populations. Within-cohort measurement error dilutes the association with events.

Previous longitudinal cohort studies have suggested an association between baseline depressive symptoms and incident hypertension. We assessed this possible association using data from the Multi-ethnic Study of Atherosclerosis, a population-based prospective cohort study of 6,814 US adults from 4 different racial/ethnic groups. Baseline users of antihypertensive medications and participants lost to follow-up were excluded leaving 3914 participants. Patients with baseline depressive symptoms (n=622) were defined using a high score on the Center for Epidemiologic Studies Depression Scale (≥ 16) or the use of an antidepressant medication. Hypertension was defined as systolic blood pressure ≥ 140, diastolic blood pressure ≥90 or new use of antihypertensive medications plus physician diagnosis. Estimates were adjusted for known risk factors including: age, sex, baseline blood pressure, diabetes, and body mass index. Untreated blood pressure was estimated using an imputation approach. A total of 477 participants developed hypertension. Using relative risk regression, patients with baseline depressive symptoms did not have an increased risk of incident hypertension (Relative Risk = 1.02; 95% Confidence Interval (CI):0.99 to 1.05) although an association between tricyclic antidepressants and hypertension (Relative Risk 1.20; 95% CI:1.05 to 1.37) was observed in sub-group analysis. Depression, even after adjustment for covariates, was associated with small changes in systolic (+2.4 mmHG; 95% CI: 0.2 to 4.7) and diastolic (+0.8 mmHG; 95% CI: −0.6 to 2.3) blood pressure. Depressive symptoms may be associated with slight increases in blood pressure in this multi-ethnic cohort but it is premature to conclude much without longer studies in other populations.

To examine the associations of three understudied hemostatic factors – D-dimer, factor VIIIc, and antiplasmin (PAP) complex -- with incident CVD and all cause mortality in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Hemostatic factors were measured at baseline in 45–84 year olds (n =6,391) who were free of clinically recognized CVD. Over 4.6 years of follow-up, we identified 307 CVD events, 207 hard coronary heart disease (CHD) events, and 210 deaths. D-dimer, factor VIIIc, and PAP were not associated with CVD incidence after adjustment for other risk factors. In contrast, each factor was associated positively with total mortality, and D-dimer and factor VIIIc were associated positively with cancer mortality. When modeled as ordinal variables and adjusted for risk factors, total mortality was greater by 33% (95% CI = 15–54%) for each quartile increment of D-dimer, 26% (11–44%) for factor VIIIc, and 20% (4–38%) for PAP. This prospective cohort study did not find D-dimer, factor VIIIc, or PAP to be risk factors for CVD. Instead, elevated levels of these three hemostatic factors were associated independently with increased risk of death. Elevated D-dimer and factor VIIIc were associated with increased cancer death.

Background

Previous research has suggested that emerging evidence from randomized controlled trials (RCTs) is often not reflected in physician selection of medication class for first-line anti-hypertensive therapy.

Objectives

To evaluate the association of RCT evidence in December 2002 from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) on use of anti-hypertensive medications over time in a multi-ethnic cohort.

Methods

The Multi-Ethnic Study of Atherosclerosis study, a prospective cohort study of 6,814 adults from 4 ethnic groups, had four separate assessments of drug use. Users of anti-hypertensive medications at baseline were excluded. We evaluated temporal changes in the medication class reported by new users of antihypertensive medications.

Results

After the exclusion of antihypertensive drug users at baseline, 32% of new users of anti-hypertensive drugs seen at exam 2 were prescribed a diuretic. The publication of ALLHAT was associated with a subsequent increase in the proportion of new users taking diuretics at exam 3 compared with exam 2 (Relative Risk (RR):1.31; 95% Confidence Interval (CI):1.09–1.59). After the report from ALLHAT, the proportion of users of diuretics seen at exam 3 rose to 44% (starting in 2004) and 39% in exam 4 (starting in 2005). This increase in the proportion of diuretic use among new users of anti-hypertensive medications declined slightly but could still be detected at exam 4 as compared to exam 2 (RR:1.28; 95% CI:1.04–1.57).

Conclusions

The randomized trial evidence from the ALLHAT study was temporally associated with a moderate increase in diuretic use.

Introduction

There is evidence that the utilization of antidepressant medications (ADM) may vary between different ethnic groups in the United States population.

Methods

The Multi-Ethnic Study of Atherosclerosis is a population-based prospective cohort study of 6,814 US adults from 4 different ethnic groups. After excluding baseline users of ADM, we examined the relation between baseline depression and new use of ADM for 4 different ethnicities: African-Americans (n=1,822), Asians (n=784) Caucasians (n=2,300), and Hispanics (n=1,405). Estimates of the association of ethnicity and ADM use were adjusted for age, study site, gender, Center for Epidemiologic Studies Depression Scale (CES-D), alcohol use, smoking, blood pressure, diabetes, education, and exercise. Non-random loss to follow-up was present and estimates were adjusted using inverse probability of censoring weighting (IPCW).

Results

Of the four ethnicities, Caucasian participants had the highest rate of ADM use (12%) compared with African-American (4%), Asian (2%) and Hispanic (6%) participants. After adjustment, non-Caucasian ethnicity was associated with reduced ADM use: African-American (HR: 0.42; 95% Confidence Interval (CI):0.31– 0.58), Asian (HR: 0.14; 95%CI: 0.08–0.26) and Hispanic (HR: 0.47; 95%CI: 0.31–0.65). Applying IPCW to correct for non-random loss to follow-up among the study participants weakened but did not eliminate these associations: African-American (HR: 0.48; 95%CI: 0.30–0.57), Asian (HR: 0.23; 95% CI: 0.13–0.37) and Hispanic (HR: 0.58; 95%CI: 0.47–0.67).

Conclusion

Non-Caucasian ethnicity is associated with lower rates of new ADM use. After IPCW adjustment, the observed ethnicity differences in ADM use are smaller although still statistically significant.

Background

Previous research has demonstrated an increase in carotid intima–media thickness (cIMT) in HIV-infected individuals compared to controls. However, the reason for this increased level of subclinical vascular disease is unknown.

Objective

To identify HIV-related risk factors for increased cIMT.

Methods

We evaluated the relationship between HIV-related characteristics (including markers of HIV disease severity and use of antiretroviral therapy) and cIMT measurements in the internal/bulb and common carotid regions among 538 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). We used Bayesian model averaging to estimate the posterior probability of candidate HIV and non-HIV-related risk factors being true predictors of increased cIMT. Variables with a posterior probability of more than 50% were used to develop a selected regression model for each of the anatomic regions.

Results

For common cIMT, the Bayesian model selection process identified age, African-American race, and systolic and diastolic blood pressure with probability more than 95%, HDL cholesterol with probability 85% and Hispanic ethnicity with probability 51%. Among the HIV-related factors included in the analysis, only tenofovir use was selected (51% probability). In the selected model, duration of tenofovir use was associated with lower common cIMT (−0.0094 mm/year of use; 95% confidence interval: −0.0177 to −0.0010). For internal cIMT, no HIV-related risk factors were above the 50% posterior probability threshold.

Conclusion

We observed an inverse association between duration of tenofovir use and common carotid cIMT. Whether this association is causal or due to confounding by indication needs further investigation.

Background

Recent concerns have been raised about the risk of gallbladder disease associated with the use of drospirenone, a fourth-generation progestin used in oral contraceptives. We conducted a study to determine the magnitude of this risk compared with other formulations of oral contraceptives.

Methods

We conducted a retrospective cohort study using the IMS LifeLink Health Plan Claims Database. We included women who were using an oral contraceptive containing ethinyl estradiol combined with a progestin during 1997–2009. To be eligible, women had to have been taking the oral contraceptive continuously for at least six months. We computed adjusted rate ratios (RRs) for gallbladder disease using a Cox proportional hazards model. In the primary analysis, gallbladder disease was defined as cholecystectomy; in a secondary analysis, it was defined as hospital admission secondary to gallbladder disease.

Results

We included 2 721 014 women in the cohort, 27 087 of whom underwent surgical or laparoscopic cholecystectomy during the follow-up period. Compared with levonorgestrel, an older second-generation progestin, a small, statistically significant increase in the risk of gallbladder disease was associated with desogestrel (adjusted RR 1.05, 95% confidence interval [CI] 1.01–1.09), drospirenone (adjusted RR 1.20, 95% CI 1.16–1.26) and norethindrone (adjusted RR 1.10, 95% CI 1.06–1.14). No statistically significant increase in risk was associated with the other formulations of oral contraceptive (ethynodiol diacetate, norgestrel and norgestimate).

Interpretation

In a large cohort of women using oral contraceptives, we found a small, statistically significant increase in the risk of gallbladder disease associated with desogestrel, drospirenone and norethindrone compared with levonorgestrel. However, the small effect sizes compounded with the possibility of residual biases in this observational study make it unlikely that these differences are clinically significant.

Aims

Modern imaging technology allows us the visualization of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis. The prevalence, quantity, and risk factors for CAC were compared between two studies with similar imaging protocols but different source populations: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR).

Methods and results

The measured CAC in 2220 MESA participants were compared with those in 3126 HNR participants with the inclusion criteria such as age 45–75 years, Caucasian race, and free of baseline cardiovascular disease. Despite similar mean levels of CAC of 244.6 among participants in MESA and of 240.3 in HNR (P = 0.91), the prevalence of CAC > 0 was lower in MESA (52.6%) compared with HNR (67.0%) with a prevalence rate ratio of CAC > 0 of 0.78 [95% confidence interval (CI): 0.72–0.85] after adjustment for known risk factors. Consequently, among participants with CAC > 0, the participants in MESA tended to have higher levels of CAC than those in HNR (ratio of CAC levels: 1.39; 95% CI: 1.19–1.63), since many HNR participants have small (near zero) CAC values.

Conclusions

The CAC prevalence was lower in the United States (MESA) cohort than in the German (HNR) cohort, which may be explained by more favourable risk factor levels among the MESA participants. The predictors for increased levels of CAC were, however, similar in both cohorts with the exception that male gender, blood pressure, and body mass index were more strongly associated in the HNR cohort.

Objective To examine the association of myocardial infarction and stroke incidence with several commonly used two drug antihypertensive treatment regimens.

Design Population based case-control study.

Setting Group Health Cooperative, Seattle, WA, USA.

Participants Cases (n=353) were aged 30-79 years, had pharmacologically treated hypertension, and were diagnosed with a first fatal or non-fatal myocardial infarction or stroke between 1989 and 2005. Controls (n=952) were a random sample of Group Health members who had pharmacologically treated hypertension. We excluded individuals with heart failure, evidence of coronary heart disease, diabetes, or chronic kidney disease.

Exposures One of three common two drug combinations: diuretics plus β blockers; diuretics plus calcium channel blockers; and diuretics plus angiotensin converting enzyme inhibitors or angiotensin receptor blockers.

Main outcome measures Myocardial infarction or stroke.

Results Compared with users of diuretics plus β blockers, users of diuretics plus calcium channel blockers had an increased risk of myocardial infarction (adjusted odds ratio (OR) 1.98, 95% confidence interval 1.37 to 2.87) but not of stroke (OR 1.02, 95% CI 0.63 to 1.64). The risks of myocardial infarction and stroke in users of diuretics plus angiotensin converting enzyme inhibitors or angiotensin receptor blockers were slightly but not significantly lower than in users of diuretics plus β blockers (myocardial infarction: OR 0.76, 95% CI 0.52 to 1.11; stroke: OR 0.71, 95% CI 0.46 to 1.10).

Conclusions In patients with hypertension, diuretics plus calcium channel blockers were associated with a higher risk of myocardial infarction than other common two drug treatment regimens. A large trial of second line antihypertensive treatments in patients already on low dose diuretics is required to provide a solid basis for treatment recommendations.