Joseph A. Delaney

Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study

Background:Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors. Methods:Cross-sectional study of HIV-infected participants and controls without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Preclinical atherosclerosis was assessed by carotid intima-medial thickness (cIMT) measurements in the internal/bulb and common regions in HIV-infected participants and controls after adjusting for traditional CVD risk factors. Results:For internal carotid, mean IMT was 1.17 ± 0.50 mm for HIV-infected participants and 1.06 ± 0.58 mm for controls (P < 0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected participants vs. controls was 0.188 mm [95% confidence interval (CI) 0.113–0.263, P < 0.0001]. Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (0.148 mm, 95% CI 0.072–0.224, P = 0.0001). For the common carotid, HIV infection was independently associated with greater IMT (0.033 mm, 95% CI 0.010–0.056, P = 0.005). The association of HIV infection with IMT was similar to that of smoking, which was also associated with greater IMT (internal 0.173 mm, common 0.020 mm). Conclusion:Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared with the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.

Discontinuation of statin therapy following an acute myocardial infarction: a population-based study

AIMS Randomized clinical trials have shown that statins can reduce mortality after acute myocardial infarction (AMI). However, the impact of changes in patterns of statin use, particularly stopping statins, on survival post-AMI is unknown. Our objective was to estimate the extent to which different patterns of statin use are associated with post-AMI mortality. METHODS AND RESULTS Population-based, cohort study, from 2002 through 2004 in the United Kingdom General Practice Research Database (GPRD), involving patients surviving 90 days after their first AMI. Past statin use was defined as any statin prescription within 90 days before AMI; statin use post-AMI as any statin prescription within 90 days after AMI. Cohort entry was at day 90 post-AMI; subjects were followed for 1 year. Four groups were identified: (i) non-users (patients never on statins); (ii) users (on statins before and continued post-AMI); (iii) starters (started statins after the event); and (iv) stoppers (stopped statins after the event). Hazard ratios (HRs) were estimated using Cox proportional hazards model. The main outcome measure was 1-year all-cause mortality. The cohort included 9939 AMI survivors (mean age: 68.4 ± 12.8 years; 60.3% men), 22.7% of whom were not prescribed a statin post-AMI. When the non-user group (n = 2124) was considered as the reference, the adjusted HRs (95% confidence intervals) of death were 0.84 (0.66-1.09) for users (n = 2026), 0.72 (0.57-0.90) for starters (n = 5652), and 1.88 (1.13-3.07) for stoppers (n = 137). Stoppers of control medications (aspirin, β-blockers, and proton pump inhibitors) were not associated with increased mortality. CONCLUSION Discontinuation of statins in survivors of a first AMI was relatively rare in this cohort. However, statin discontinuation was associated with higher total mortality and this may represent a biological rebound or/and a risk-treatment mismatch phenomenon, where treatment is withdrawn from very ill patients. While awaiting further research, at present statin use should only be withdrawn under judicious clinical supervision.

Comparison of Coronary Artery Calcium Presence, Carotid Plaque Presence, and Carotid Intima-Media Thickness for Cardiovascular Disease Prediction in the Multi-Ethnic Study of Atherosclerosis

Background—Presence of coronary artery calcium (CAC), carotid plaque, and increased carotid intima-media thickness (IMT) may indicate elevated cardiovascular disease (CVD) risk; however, no large studies have compared them directly. This study compares predictive uses of CAC presence, carotid artery plaque presence, and high IMT for incident CVD events. Methods and Results—Participants were from the Multi-Ethnic Study of Atherosclerosis (MESA). Predictive values of carotid plaque, IMT, and CAC presence were compared using Cox proportional hazards models, c-statistics, and net reclassification indices. The 6779 participants were mean (SD) 62.2 (10.2) years old; 49.9% had CAC, and 46.7% had carotid plaque. The mean left and right IMT were 0.754 (0.210) mm and 0.751 (0.187) mm, respectively. After 9.5 years (mean), 538 CVD events, 388 coronary heart disease (CHD) events, and 196 stroke/transient ischemic attacks were observed. CAC presence was a stronger predictor of incident CVD and CHD than carotid ultrasound measures. Mean IMT ≥75th percentile (for age, sex, and race) alone did not predict events. Compared with traditional risk factors, c-statistics for CVD (c=0.756) and CHD (c=0.752) increased the most by the addition of CAC presence (CVD, 0.776; CHD, 0.784; P<0.001) followed by carotid plaque presence (CVD, c=0.760; CHD, c=0.757; P<0.05). Compared with risk factors (c=0.782), carotid plaque presence (c=0.787; P=0.045) but not CAC (c=0.785; P=0.438) improved prediction of stroke/transient ischemic attacks. Conclusions—In adults without CVD, CAC presence improves prediction of CVD and CHD more than carotid plaque presence or high IMT. CAC and carotid ultrasound parameters performed similarly for stroke/transient ischemic attack event prediction.

Bisphosphonate Use and Prevalence of Valvular and Vascular Calcification in Women: MESA (The Multi-Ethnic Study of Atherosclerosis)

OBJECTIVES the aim of this study was 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 might 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 3,710 women within the MESA (Multi-Ethnic Study of Atherosclerosis) with 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; demographic data; 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 of age (prevalence ratio: AVC 0.68 [95% confidence interval (CI): 0.41 to 1.13]; AVRC 0.65 [95% CI: 0.51 to 0.84]; MAC 0.54 [95% CI: 0.33 to 0.93]; TAC 0.69 [95% CI: 0.54 to 0.88]; CAC 0.89 [95% CI: 0.78 to 1.02]), whereas calcification was more prevalent in NCBP users among the 2,181 women <65 years of age (AVC 4.00 [95% CI: 2.33 to 6.89]; AVRC 1.92 [95% CI: 1.42 to 2.61]; MAC 2.35 [95% CI: 1.12 to 4.84]; TAC 2.17 [95% CI: 1.49 to 3.15]; CAC 1.23 [95% CI: 0.97 to 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.

Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study

BACKGROUND Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes. OBJECTIVES We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n-9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and vaccenic acid (18:1n-7)] and estimated dietary SFAs and MUFAs. DESIGN In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively. RESULTS At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs or MUFAs were not significantly associated with incident diabetes. CONCLUSIONS In this large prospective cohort, circulating palmitic acid and stearic acid were associated with higher diabetes risk, and vaccenic acid was associated with lower diabetes risk. These results indicate a need for additional investigation of biological mechanisms linking specific fatty acids in the DNL pathway to the pathogenesis of diabetes.

Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis

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.

The case-crossover study design in pharmacoepidemiology.

In the study of the association of transient drug exposures with acute outcomes, the case-crossover design is an efficient alternative to the case-control approach. This design based exclusively on the case series uses within-subject comparisons of drug exposures over time to estimate the rate ratio of the outcome associated with the drug under study. This design inherently removes the biasing effects of unmeasured, time-invariant confounding factors from the estimated rate ratio, but is sensitive to several assumptions. We illustrated the case-crossover design and explored its sensitivity using data from 4028 cases of gastrointestinal bleeding from the General Practice Research Database in assessing the effects of the drug warfarin. We compared the use of different time window lengths to assess exposure and considered the use of a case-time-control design to account for exposure time trends. The case-crossover approach found no excess risk of bleeding with warfarin exposure [rate ratio 0.98; 95% confidence interval (CI): 0.74—1.28] using a 1-month time window. When we restricted the analysis to subjects with truly transient drug exposure, defined by 1 to 3 prescriptions in the previous year, the rate ratio was 2.59 (95% CI: 1.42—4.74). To consider the longer 1-year exposure time window, the case-time-control approach was used and resulted in a rate ratio of 1.72 (95% CI: 1.08—2.43). In conclusion, the case-crossover design is potentially a powerful approach to assess the risk of drugs. This design is, however, highly sensitive to assumptions about intermittency of drug use and the length of the exposure time window, as demonstrated with the example of bleeding associated with warfarin use.

Associations of factor VIIIC, D-dimer, and plasmin-antiplasmin with incident cardiovascular disease and all-cause mortality

To examine the associations of three understudied hemostatic factors—D‐dimer, factor VIIIc, and plasmin‐antiplasmin (PAP) complex—with incident cardiovascular disease (CVD) and all cause mortality in the Multiethnic Study of Atherosclerosis cohort. Hemostatic factors were measured at baseline in 45–84‐year‐old patients (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 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. Am. J. Hematol., 2009.

Isotretinoin and Risk for Inflammatory Bowel Disease: A Nested Case-Control Study and Meta-analysis of Published and Unpublished Data

OBJECTIVE To examine the association between isotretinoin and the risk for inflammatory bowel disease (IBD) among women of reproductive age. DESIGN Nested case-control study and meta-analysis. SETTING A US health claims database. PARTICIPANTS We formed a cohort of women aged 18 to 46 years who had received at least 1 oral contraceptive prescription from May 1, 2001, through December 31, 2009. The IBD cases were required to have 3 health care contacts with documentation of IBD or a single health care contact followed by use of a drug to treat IBD. Twenty controls were selected for each case using incidence-density sampling, matched on age and date of diagnosis. MAIN OUTCOME MEASURES Risk ratios (RRs) were formed for incident cases of IBD associated with the use of isotretinoin. A subgroup analysis examined the risk for IBD among those diagnosed as having Crohn disease (CD) and ulcerative colitis (UC). A meta-analysis of published and unpublished studies assessing isotretinoin and IBD used a random-effects model to estimate a pooled RR. RESULTS In the case-control study, we identified 2159 IBD cases (1056 with UC and 1103 with CD) and matched them with 43 180 controls. Only 10 cases (0.46%) and 191 controls (0.44%) were exposed to isotretinoin. The adjusted RR for IBD was 0.99 (95% CI, 0.52-1.90). The RRs for UC and CD were 1.10 (95% CI, 0.44-2.70) and 0.91 (0.37-2.25), respectively. For the meta-analysis, the pooled RR for IBD for the 5 studies was 0.94 (95% CI, 0.65-1.36). CONCLUSIONS The results of this study do not suggest an increase in the risk for IBD, including UC or CD, with use of isotretinoin. Because inflammatory acne in children and adolescents carries a high psychological burden, clinicians should not be discouraged from prescribing this drug owing to a putative association with IBD.

Baseline Depressive Symptoms Are Not Associated With Clinically Important Levels of Incident Hypertension During Two Years of Follow-Up. The Multi-Ethnic Study of Atherosclerosis

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 6814 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 Epidemiological Studies Depression Scale (≥16) or the use of an antidepressant medication. Hypertension was defined as systolic blood pressure of ≥140 mm Hg, diastolic blood pressure of ≥90 mm Hg 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 subgroup analysis. Depression, even after adjustment for covariates, was associated with small changes in systolic (+2.4 mm Hg; 95% CI: 0.2 to 4.7) and diastolic (+0.8 mm Hg; 95% CI: −0.6 to 2.3) blood pressures. Depressive symptoms may be associated with slight increases in blood pressure in this multiethnic cohort, but it is premature to conclude much without longer studies in other populations.