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author:("entner, Paul")
1.  Evaluating the Framingham Hypertension Risk Prediction Model in Young Adults: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Hypertension  2013;62(6):1015-1020.
A prediction model was developed in the Framingham Heart Study (FHS) to evaluate short-term risk of hypertension. Our goal was to determine the predictive ability of the FHS hypertension model in a cohort of young adults advancing into middle age and compare it with the predictive ability of prehypertension, and individual components of the FHS model. We studied 4,388 participants, age 18-30 years without hypertension at baseline, enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study who participated in 2 consecutive exams occurring 5 years apart between the baseline (1985-1986) and Year 25 examination (2010-2011). Weibull regression was used to assess the association of the FHS model overall, individual components of the FHS model, and prehypertension with incident hypertension. Over the 25 year follow-up period, 1179 participants developed incident hypertension. The FHS hypertension model (c-index=0.84, 95% CI=0.83, 0.85) performed well in discriminating those who did and did not develop hypertension and was better than prehypertension alone (c-index=0.71, 95% CI=0.70, 0.73). The predicted risk from the FHS hypertension model was systematically lower than the observed hypertension incidence initially (χ2= 249.4; p<0.001), but demonstrated a good fit after recalibration (χ2= 14.6; p=0.067). In summary, the FHS model performed better than prehypertension and may be a useful tool for identifying young adults with a high risk for developing hypertension.
PMCID: PMC4019674  PMID: 24041951
hypertension; prehypertension; epidemiology; risk
2.  Low correlation between visit-to-visit variability and 24-hour variability of blood pressure 
Visit-to-visit variability (VVV) of clinic systolic blood pressure (SBP) has been associated with cardiovascular disease risk. Given the need for obtaining blood pressure (BP) at multiple visits to calculate VVV, substituting BP variability from ambulatory blood pressure monitoring (ABPM) may be a practical alternative. We assessed the correlation between VVV of BP and BP variability from ABPM using data from 146 untreated, mostly normotensive participants (mean age 47.9 years) in a substudy of the ongoing Masked Hypertension Study. VVV of SBP and diastolic blood pressure (DBP) was estimated by the standard deviation (SDvvv) and average real variability (ARVvvv) from 6 study visits over a median of 216 days. ABPM data were used to calculate the day-night SD (SDdn) and the ARV of SBP and DBP over 24 hours (ARV24). For SBP, the mean SDvvv and SDdn were 6.3 (SD=2.5) and 8.8 (SD=1.8) mmHg, respectively, and mean ARVvvv and ARV24 were 7.2 (SD=3.2) and 8.4 (SD=2.1) mmHg, respectively. The Spearman correlation coefficient between SDvvv and SDdn of SBP was rs=0.25 and between ARVvvv and ARV24 was rs=0.17. Participants in the highest quartile of SDdn of SBP were 1.66 (95% CI: 0.93 – 2.75) times more likely to be in the highest quartile of SDvvv of SBP. The observed-to-expected ratio between the highest quartiles of ARVvvv and ARV24 of SBP was 0.89 (95% CI: 0.41 – 1.69). The correlations for SDvvv and SDdn and ARVvvv and ARV24 of DBP were minimal. These data suggest VVV and 24-hour variability are weakly correlated and not interchangeable.
PMCID: PMC3856234  PMID: 23784506
Blood pressure variability; reliability; ambulatory blood pressure monitoring; blood pressure measurement; methods
3.  Medication adherence and stroke/TIA risk in treated hypertensives: results from the REGARDS study 
Journal of the American Society of Hypertension : JASH  2013;7(5):10.1016/j.jash.2013.05.002.
The extent to which low medication adherence in hypertensive individuals contributes to disparities in stroke and transient ischemic attack (TIA) risk is poorly understood.
Investigators examined the relationship between self-reported medication adherence and blood pressure (BP) control (<140/90 mm Hg), Framingham Stroke Risk Score, and physician-adjudicated stroke/TIA incidence in treated hypertensive subjects (n = 15,071; 51% black; 57% in Stroke Belt) over 4.9 years in the national population-based REGARDS cohort study.
Mean systolic BP varied from 130.8 ± 16.2 mm Hg in those reporting high adherence to 137.8 ± 19.5 mm Hg in those reporting low adherence (P for trend < .0001). In logistic regression models, each level of worsening medication adherence was associated with significant and increasing odds of inadequately controlled BP (≥140/90 mm Hg; score = 1, odds ratio [95% confidence interval], 1.20 [1.09–1.30]; score = 2, 1.27 [1.08–1.49]; score = 3 or 4, 2.21 [1.75–2.78]). In hazard models using systolic BP as a mediator, those reporting low medication adherence had 1.08 (1.04–1.14) times greater risk of stroke and 1.08 (1.03–1.12) times greater risk of stroke or TIA.
Low medication adherence was associated with inadequate BP control and an increased risk of incident stroke or TIA.
PMCID: PMC3807818  PMID: 23910009
Medication adherence; blood pressure control; stroke; transient ischemic attack
4.  Awareness, Treatment, and Control of LDL Cholesterol Are Lower Among U.S. Adults With Undiagnosed Diabetes Versus Diagnosed Diabetes 
Diabetes Care  2013;36(9):2734-2740.
Diabetes is often undiagnosed, resulting in incorrect risk stratification for lipid-lowering therapy. We conducted a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) 2005–2010 to determine the prevalence, awareness, treatment, and control of elevated LDL cholesterol (LDL-C) among U.S. adults with undiagnosed diabetes.
Fasting NHANES participants 20 years of age or older who had 10-year Framingham coronary heart disease (CHD) risk scores <20% and were free of CHD or other CHD risk equivalents (n = 5,528) were categorized as having normal glucose, impaired fasting glucose, undiagnosed diabetes, or diagnosed diabetes. High LDL-C was defined by the 2004 Adult Treatment Panel (ATP) III guidelines.
The prevalence of diagnosed and of undiagnosed diabetes was 8 and 4%, respectively. Mean LDL-C was 102 ± 2 mg/dL among those with diagnosed diabetes and 117 ± 3 mg/dL for those with undiagnosed diabetes (P < 0.001). The prevalence of high LDL-C was similar among individuals with undiagnosed (81%) and diagnosed (77%) diabetes. Among individuals with undiagnosed diabetes and high LDL-C, 38% were aware, 27% were treated, and 16% met the ATP III LDL-C goal for diabetes. In contrast, among individuals with diagnosed diabetes and high LDL-C, 70% were aware, 61% were treated, and 36% met the ATP III goal. Subjects with undiagnosed diabetes remained less likely to have controlled LDL-C after multivariable adjustment (prevalence ratio, 0.42; 95% CI, 0.23–0.80).
Improved screening for diabetes and reducing the prevalence of undiagnosed diabetes may identify individuals requiring more intensive LDL-C reduction.
PMCID: PMC3747886  PMID: 23637349
5.  Trends in the Prevalence, Awareness, Treatment and Control of High Low Density Lipoprotein-Cholesterol among US Adults from 1999–2000 through 2009–2010 
The American journal of cardiology  2013;112(5):664-670.
Marked increases in the awareness, treatment and control of high LDL-cholesterol occurred among US adults between 1988–1994 and 1999–2004. An update to the ATP-III guidelines was published in 2004 and it is unknown if these improvements have continued following publication of these revised treatment recommendations. We determined trends in the awareness, treatment and control of high LDL-cholesterol among US adults from 1999– 2000 through 2009–2010 using nationally representative samples of US adults ≥ 20 years of age from six consecutive National Health and Nutrition Examination Surveys (NHANES) in 1999–2000 (n=1,659), 2001–2002 (n=1,897), 2003–2004 (n=1,698), 2005–2006 (n=1,692), 2007–2008 (n=2,044) and 2009–2010 (n=2,318). LDL-cholesterol was measured after an overnight fast and high LDL-cholesterol and controlled LDL-cholesterol were defined using the 2004 updated ATP-III guidelines. Awareness and treatment of high cholesterol were defined using self-report. Among US adults, the prevalence of high LDL-cholesterol did not change from 1999–2000 (37.2%) through 2009–2010 (37.8%). Awareness of high LDLcholesterol increased from 48.9% in 1999–2000 to 62.8% in 2003–2004 but did not increase further through 2009–2010 (61.5%). Among those aware of having high LDL-cholesterol, treatment increased from 41.3% in 1999–2000 to 72.6% in 2007–2008 and was 70.0% in 2009–2010. Among US adults receiving treatment for high LDL-cholesterol, the percentage with controlled LDL-cholesterolincreased from 45.0% in 1999–2000 to 65.3% in 2005–2006 and decreased slightly by 2009–2010 (63.6%). High LDL-cholesterol remains common among US adults. Additional efforts are needed to prevent high LDL-cholesterol and increase the awareness, treatment and control of high LDL-cholesterol among US adults.
PMCID: PMC3769104  PMID: 23726177
LDL-cholesterol; statins; treatment; awareness; risk factors
6.  Antihypertensive Medication Classes Used among Medicare Beneficiaries Initiating Treatment in 2007–2010 
PLoS ONE  2014;9(8):e105888.
After the 2003 publication of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines, there was a 5–10% increase in patients initiating antihypertensive medication with a thiazide-type diuretic, but most patients still did not initiate treatment with this class. There are few contemporary published data on antihypertensive medication classes filled by patients initiating treatment.
Methods and Findings
We used the 5% random Medicare sample to study the initiation of antihypertensive medication between 2007 and 2010. Initiation was defined by the first antihypertensive medication fill preceded by 365 days with no antihypertensive medication fills. We restricted our analysis to beneficiaries ≥65 years who had two or more outpatient visits with a hypertension diagnosis and full Medicare fee-for-service coverage for the 365 days prior to initiation of antihypertensive medication. Between 2007 and 2010, 32,142 beneficiaries in the 5% Medicare sample initiated antihypertensive medication. Initiation with a thiazide-type diuretic decreased from 19.2% in 2007 to 17.9% in 2010. No other changes in medication classes initiated occurred over this period. Among those initiating antihypertensive medication in 2010, 31.3% filled angiotensin-converting enzyme inhibitors (ACE-Is), 26.9% filled beta blockers, 17.2% filled calcium channel blockers, and 14.4% filled angiotensin receptor blockers (ARBs). Initiation with >1 antihypertensive medication class decreased from 25.6% in 2007 to 24.1% in 2010. Patients initiated >1 antihypertensive medication class most commonly with a thiazide-type diuretic and either an ACE-I or ARB.
These results suggest that JNC 7 had a limited long-term impact on the choice of antihypertensive medication class and provide baseline data prior to the publication of the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults from the Panel Members Appointed to the Eighth Joint National Committee (JNC 8).
PMCID: PMC4143342  PMID: 25153199
7.  Association between urinary albumin excretion and coronary heart disease in black versus white adults 
JAMA : the journal of the American Medical Association  2013;310(7):10.1001/jama.2013.8777.
Excess urinary albumin excretion is more common in black individuals than in white individuals and is more strongly associated with incident stroke risk in blacks than whites. Whether similar associations extend to coronary heart disease (CHD) is unclear.
To determine whether the association of urinary albumin excretion with CHD events differs by race.
Design, Setting and Participants
Within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a prospective cohort of black and white US adults ≥45 years of age enrolled between 2003 and 2007 with follow-up through December 31 2009, we examined race-stratified associations of urinary albumin to creatinine ratio (ACR) with (1) incident CHD among 23,273 participants free of CHD at baseline, and (2) first recurrent CHD event among 4,934 participants with CHD at baseline.
Main Outcome Measure
Expert-adjudicated incident and recurrent myocardial infarction (MI) and acute CHD death.
A total of 616 incident CHD events (421 non-fatal MIs and 195 CHD deaths) and 468 recurrent CHD events (279 non-fatal MIs and 189 CHD deaths) were observed over a mean 4.4 years of follow-up. Among those free of CHD at baseline, age- and sex-adjusted incidence rates of CHD per 1000 person-years of follow-up increased with increasing categories of ACR in blacks and whites, with rates being nearly 1.5-fold higher in the highest category of ACR (>300 mg/g) in blacks vs. whites (20.59, 95% confidence interval [14.36,29.51] in blacks vs. 13.60 [7.60,24.25] in whites). In proportional hazards models adjusted for traditional cardiovascular risk factors and medications, higher baseline urinary ACR was associated with higher risk of incident CHD among blacks (hazard ratio [HR] comparing ACR >300 vs. <10 mg/g, 3.21 [2.02,5.09]) but not whites (HR comparing ACR >300 vs. <10 mg/g, 1.49 [0.80,2.76]) (P-interaction=0.03). Among those with CHD at baseline, fully-adjusted associations of baseline urinary ACR with first recurrent CHD event were similar in blacks and whites (HR comparing ACR >300 vs. <10 mg/g, 2.21 [1.22,4.00] in blacks vs. 2.48 [1.61,3.78] in whites) (P-interaction=0.53).
Higher urinary ACR was associated with higher risk of incident but not recurrent CHD in blacks compared to whites.
PMCID: PMC3837520  PMID: 23989654
8.  Risk for recurrent coronary heart disease and all-cause mortality among individuals with chronic kidney disease compared with diabetes mellitus, metabolic syndrome, and cigarette smokers 
American heart journal  2013;166(2):373-380.e2.
Lipid-lowering guidelines endorse a low-density lipoprotein cholesterol goal of <100 mg/dL for people with coronary heart disease (CHD). A more stringent threshold of <70 mg/dL is recommended for those with CHD and “very high-risk” conditions such as diabetes mellitus, metabolic syndrome, or cigarette smoking. Whether chronic kidney disease (CKD) confers a similar risk for recurrent CHD events is unknown.
Methods and Results
We evaluated the risk for recurrent CHD events and all-cause mortality among 3,938 participants ≥45 years with CHD in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Chronic kidney disease was defined by estimated glomerular filtration rate <60 mL/min per 1.73 m2 or urinary albumin to creatinine ratio ≥30 mg/g. Participants were categorized by the presence or absence of CKD and any very high-risk condition. Over a median of 4.1 years, the crude incidence (95% CI) of recurrent CHD events were 12.1 (9.0–15.2), 18.9 (15.5–22.3), 35.0 (25.4–44.6), and 34.2 (28.2–40.3) among those without CKD or high-risk conditions; very high-risk conditions alone; and CKD alone and both CKD and very high-risk conditions. After multivariable adjustment, compared with those without CKD or very high-risk conditions, the hazard ratio (95% CI) for recurrent CHD events was 1.45 (1.02–2.05), 2.24 (1.50–3.34), and 2.10 (1.47–2.98) among those with very high-risk conditions alone, CKD alone, and both CKD and very high-risk conditions, respectively. Results were consistent for all-cause mortality.
Chronic kidney disease is associated with risk for recurrent CHD events that approximates or is larger than other established very high-risk conditions.
PMCID: PMC4139360  PMID: 23895822
9.  Lifestyle-Related Factors, Obesity, and Incident Microalbuminuria: The CARDIA (Coronary Artery Risk Development in Young Adults) Study 
Modifiable lifestyle-related factors are associated with risk of coronary heart disease and may also influence kidney disease risk.
Study Design
Community-based prospective cohort study.
Setting & Participants
2354 African-American and white participants ages 28–40 years, without baseline microalbuminuria or estimated glomerular filtration rate <60 ml/min/1.73 m2 recruited from four U.S. centers: Birmingham AL, Chicago IL, Minneapolis MN, and Oakland CA.
Current smoking, physical activity, fast food habits, obesity, and diet quality, which was based on 8 fundamental components of the Dietary Approaches to Stop Hypertension (DASH) diet, including increased intake of fruits, vegetables, low-fat dairy products, whole grains, nuts and legumes, and reduced intake of sodium, sugar sweetened beverages, and red and processed meats.
Outcomes & Measurements
Spot urine albumin-creatinine ratios (ACRs) were obtained at baseline (1995–96) and 3 5-year follow-up examinations (5, 10, and 15 years follow-up). Incident microalbuminuria was defined as presence of race and sex-adjusted ACR ≥25 mg/g at 2 or more of the successive follow-up examinations.
Over the 15-year follow-up period, 77 individuals (3.3%) developed incident microalbuminuria. After multivariable adjustment, poor diet quality (OR, 2.0; 95% CI, 1.1–3.4) and obesity (OR, 1.9; 95% CI, 1.1–3.3) were significantly associated with microalbuminuria; current smoking (OR, 1.6; 95% CI, 0.9–2.8) was associated with microalbuminuria although the CI crossed 1.0. Neither low physical activity (OR, 1.0; 95% CI, 0.5–1.8) nor fast food consumption (OR, 1.2; 95% CI, 0.7–2.3) were associated with microalbuminuria. Compared to individuals with no unhealthy lifestyle-related factors (poor diet quality, current smoking and obesity), adjusted odds of incident microalbuminuria were 131%, 273%, and 634% higher for presence of 1 (OR, 2.3; 95% CI, 1.3–4.3), 2 (OR, 3.7; 95% CI, 1.8–7.7), and 3 (OR, 7.3; 95% CI, 2.1–26.1) unhealthy lifestyle-related factors.
Self-reported dietary history and physical activity, low number of outcomes.
Consuming an unhealthy diet and obesity are associated with incident microalbuminuria.
PMCID: PMC3720776  PMID: 23601954
10.  Trajectories of Kidney Function Decline in Young Black and White Adults With Preserved GFR: Results From the Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Strong racial discrepancies in end-stage renal disease exist. Whether there are race differences in kidney function loss in younger, healthy persons is not well established.
Study Design
Setting & Participants
3348 Black and White adults with at least two measures of cystatin C-based estimated glomerular filtration rate (eGFRcys) at scheduled Coronary Artery Risk Development in Young Adults (CARDIA) examinations (Years 10, 15, 20).
Outcomes & Measurements
We used linear mixed models (LMM) to examine race differences in annualized rates of eGFRcys decline, adjusting for age, sex, lifetime exposure to systolic blood pressure above 120mmHg, diabetes, and albumin-creatinine ratio. We used Poisson regression to compare racial differences in rapid decline (eGFRcys decline >3% per year) by study period (10–15 years after baseline exam defining period 1 and >15–20 years after baseline exam defining period 2).
Mean age was 35 ± 3.6 (SD) years, mean eGFRcys was 110 ± 20 ml/min/1.73m2 for Blacks and 104 ± 17 ml/min/1.73m2 for Whites at baseline. For both Blacks and Whites, eGFRcys decline was minimal at younger ages (<35 years) and eGFRcys loss accelerated at older ages. However, acceleration of eGFRcys decline occurred at earlier ages for Blacks than Whites. Blacks had somewhat faster annualized rates of decline compared with whites, but differences were attenuated after adjustment in period 1 (0.13 ml/min/1.73m2 per year faster; p=0.2). In contrast, during period 2, Blacks had significantly faster annualized rates of decline, even after adjustment (0.32 ml/min/1.73m2 per year faster; p=0.003). Prevalence of rapid decline was significantly higher among Blacks vs. Whites with prevalence rate ratios of 1.31 (95% CI, 1.04–1.63) for period 1 and 1.24 (95% CI, 1.09–1.41) for period 2. Differences were attenuated after full adjustment: adjusted prevalence rate ratios were 1.20 (95% CI, 0.95–1.49) for period 1 and 1.10 (95% CI, 0.96–1.26) for period 2.
No measured GFR.
eGFRcys decline differs by race at early ages, with faster annualized rates of decline among blacks. Future studies are required to explain observed differences.
PMCID: PMC3714331  PMID: 23473985
11.  Development and Evaluation of a Self-Report Tool to Predict Low Pharmacy Refill Adherence in Elderly Patients with Uncontrolled Hypertension 
Pharmacotherapy  2013;33(8):798-811.
To develop and evaluate a short self-report tool to predict low pharmacy refill adherence by using pharmacy refill data in older patients with uncontrolled hypertension.
Cross-sectional analysis of survey and administrative data data from the Cohort Study of Medication Adherence among Older Adults (CoSMO).
Three hundred ninety-four adults with uncontrolled blood pressure; mean ± SD age was 76.6 ± 5.6 years, 33.0% were black, 66.0% were women, and 23.4% had a low medication possession ratio (MPR).
Measurements and Main Results
We considered 164 self-reported candidate items for development of a prediction rule for low (< 0.8) vs. high (≥ 0.8) MPR from pharmacy refill data. Risk prediction models were evaluated by using best subsets analyses, and the final model was chosen based on clinical relevance and model parsimony. Bootstrap simulations assessed internal validity. The performance of the final 4-item model was compared to the 8-item Morisky Medication Adherence Scale (MMAS-8) and the 9-item Hill-Bone Compliance Scale. The 4-item self-report tool for predicting pharmacy refill adherence showed moderate discrimination (C statistic 0.704, 95% CI 0.683–0.714) and good model fit (Hosmer-Lemeshow χ2 = 1.238, p=0.743). Sensitivity and specificity were 67.4% and 67.8%, respectively. The C statistics for MMAS-8 and the Hill-Bone Compliance Scale were lower at 0.665 (95% CI 0.632–0.683) and 0.660 (95% CI 0.622–0.674), respectively.
A 4-item self-report tool moderately discriminated low from high pharmacy refill adherers, and its test performance was comparable to existing 8- and 9-item adherence scales. Parsimonious self-report tools predicting low pharmacy refill in patients with uncontrolled blood pressure could facilitate hypertension management in the elderly.
PMCID: PMC3729884  PMID: 23649849
hypertension; medication adherence; pharmacy refill; uncontrolled blood pressure; risk prediction
12.  Atrial Fibrillation and the Risk of Myocardial Infarction 
JAMA internal medicine  2014;174(1):107-114.
Myocardial infarction (MI) is an established risk factor for atrial fibrillation (AF). However, the extent to which AF is a risk factor for MI has not been investigated.
To examine the risk of incident MI associated with AF.
A prospective cohort of 23 928 participants residing in the continental United States and without coronary heart disease at baseline were enrolled from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort between 2003 and 2007, with follow-up through December 2009.
Expert-adjudicated total MI events (fatal and nonfatal).
Over 6.9 years of follow-up (median 4.5 years), 648 incident MI events occurred. In a sociodemographic-adjusted model, AF was associated with about 2-fold increased risk of MI (hazard ratio [HR], 1.96 [95% CI, 1.52–2.52]). This association remained significant (HR, 1.70 [95% CI, 1.26–2.30]) after further adjustment for total cholesterol, high-density lipoprotein cholesterol, smoking status, systolic blood pressure, blood pressure–lowering drugs, body mass index, diabetes, warfarin use, aspirin use, statin use, history of stroke and vascular disease, estimated glomerular filtration rate, albumin to creatinine ratio, and C-reactive protein level. In subgroup analysis, the risk of MI associated with AF was significantly higher in women (HR, 2.16 [95% CI, 1.41–3.31]) than in men (HR, 1.39 [95% CI, 0.91–2.10]) and in blacks (HR, 2.53 [95% CI, 1.67–3.86]) than in whites (HR, 1.26 [95% CI, 0.83–1.93]); for interactions, P = .03 and P = .02, respectively. On the other hand, there were no significant differences in the risk of MI associated with AF in older (≥75 years) vs younger (<75 years) participants (HR, 2.00 [95% CI, 1.16–3.35] and HR, 1.60 [95% CI, 1.11–2.30], respectively); for interaction, P = .44.
AF is independently associated with an increased risk of incident MI, especially in women and blacks. These findings add to the growing concerns of the seriousness of AF as a public health burden: in addition to being a well-known risk factor for stroke, AF is also associated with increased risk of MI.
PMCID: PMC4115282  PMID: 24190540
13.  The Association of Chronic Kidney Disease Complications by Glomerular Filtration Rate and Albuminuria: A Cross-sectional Analysis 
Clinical nephrology  2013;80(1):29-39.
Albuminuria is strongly associated with future risk for cardiovascular and kidney outcomes, and has been proposed to be included in the classification of chronic kidney disease (CKD) along with glomerular filtration rate (GFR). Few data are available on whether albuminuria is associated with concurrent complications of CKD.
Study Design
Setting & Participants
The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and blood pressure control on the progression of kidney disease. This analysis includes 1665 participants screened for the MDRD Study.
Urine albumin-creatinine ratio (ACR) and measured GFR using urinary clearance of iothalamate.
Outcomes & Measurements
Associations between ACR categories and GFR categories with anemia, acidosis, hyperphosphatemia and hypertension were evaluated using log-binomial regression.
Mean GFR (±SD) was 39 ml/min/1.73m2 (± 21) and the median (25th–75th percentile) ACR was 161 (38–680) mg/g. In multivariable models adjusted for age, sex, race, kidney disease etiology and GFR, higher ACR levels were not associated with any complication. For example, comparing ACR > 300 mg/g versus < 30 mg/g, the prevalence ratio (95% CI) for anemia was 0.98 (0.81–1.20), acidosis 1.13 (0.86–1.48), hyperphosphatemia 1.69 (0.91–3.17) and hypertension 1.04 (0.97–1.12). Lower levels of GFR were associated with all complications. For example, GFR levels < 30 ml/min/1.73m2 versus GFR levels 60–89 ml/min/1.73m2 were associated with prevalence ratios (95% CI) of anemia 4.35 (3.18–5.96), acidosis 5.31 (3.41–8.29), hyperphosphatemia 23.8 (7.71–73.6) and hypertension 1.21 (1.10–1.32).
Limited generalizability; lack of data on other complications that may be related to CKD.
Albuminuria is not associated with complications after controlling for GFR and thus would not affect clinical action plans for decisions regarding evaluation and treatment of complications.
PMCID: PMC4108165  PMID: 23803596
Albuminuria; GFR; CKD; complications
14.  Associations of Aortic Distensibility and Arterial Elasticity With Long-Term Visit-to-Visit Blood Pressure Variability: The Multi-Ethnic Study of Atherosclerosis (MESA) 
American Journal of Hypertension  2013;26(7):896-902.
Although higher visit-to-visit variability (VVV) of blood pressure (BP) is associated with increased cardiovascular disease risk, the physiological basis for VVV of BP is incompletely understood.
We examined the associations of aortic distensibility (assessed by magnetic resonance imaging) and artery elasticity indices (determined by radial artery pulse contour analysis) with VVV of BP in 2,640 and 4,560 participants, respectively, from the Multi-Ethnic Study of Atherosclerosis. Arterial measures were obtained at exam 1. BP readings were taken at exam 1 and at 3 follow-up visits at 18-month intervals (exams 2, 3, and 4). VVV was defined as the SD about each participant’s mean systolic BP (SBP) across visits.
The mean SDs of SBP were inversely associated with aortic distensibility: 7.7, 9.9, 10.9, and 13.2mm Hg for quartiles 4, 3, 2, and 1 of aortic distensibility, respectively (P trend < 0.001). This association remained significant after adjustment for demographics, cardiovascular risk factors, mean SBP, and antihypertensive medication use (P trend < 0.01). In a fully adjusted model, lower quartiles of large artery and small artery elasticity (LAE and SAE) indices were also associated with higher mean SD of SBP (P trend = 0.02 for LAE; P trend < 0.001 for SAE).
In this multiethnic cohort, functional alterations of central and peripheral arteries were associated with greater long-term VVV of SBP.
PMCID: PMC3693480  PMID: 23537891
arteries; blood pressure; epidemiology; hypertension; vasculature.
Journal of human hypertension  2013;28(1):10.1038/jhh.2013.49.
Visit-to-visit blood pressure variation (VTV-BPV) is an independent risk factor for cardiovascular events and death in the general population. We sought to determine the association of VTV-BPV with outcomes in patients on hemodialysis, using data from a National Institutes of Health-sponsored randomized trial (the HEMO Study). We used the coefficient of variation (CV) and the average real variability (ARV) in systolic blood pressure (SBP) as metrics of VTV-BPV. 1844 of 1846 randomized subjects had at least three visits with SBP measurements and were included in the analysis. Median follow-up was 2.5 years (interquartile range [IQR] 1.3 to 4.3 years), during which time there were 869 deaths from any cause and 408 (adjudicated) cardiovascular deaths. The mean pre-dialysis SBP CV was 9.9% ± 4.6%. In unadjusted models, we found a 31% higher risk of death from any cause per 10% increase in VTV-BPV. This association was attenuated after multivariable adjustment but remained statistically significant. Similarly, we found a 28% higher risk of cardiovascular death per 10% increase in VTV-BPV, which was attenuated and no longer statistically significant in fully adjusted models. The associations among VTV-BPV, death and cardiovascular death were modified by baseline SBP. In a diverse, well-dialyzed cohort of patients on maintenance hemodialysis, VTV-BPV, assessed using metrics of variability in pre-dialysis SBP, was associated with a higher risk of all-cause mortality and a trend towards higher risk of cardiovascular mortality, particularly in patients with a lower baseline SBP.
PMCID: PMC3795854  PMID: 23803593
blood pressure variability; cardiovascular disease; hemodialysis; hypertension; end-stage renal disease
16.  Life’s Simple 7 and Risk of Incident Stroke: REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Stroke; a journal of cerebral circulation  2013;44(7):10.1161/STROKEAHA.111.000352.
Background and Purpose
The American Heart Association developed Life’s Simple 7 (LS7) as a metric defining cardiovascular health. We investigated the association between LS7 and incident stroke in black and white Americans.
REGARDS is a national population-based cohort of 30,239 blacks and whites, aged ≥45 years, sampled from the US population in 2003 – 2007. Data were collected by telephone, self-administered questionnaires and an in-home exam. Incident strokes were identified through bi-annual participant contact followed by adjudication of medical records. Levels of the LS7 components (blood pressure, cholesterol, glucose, body mass index, smoking, physical activity, and diet) were each coded as poor (0 point), intermediate (1 point) or ideal (2 points) health. An overall LS7 score was categorized as inadequate (0–4), average (5–9) or optimum (10–14) cardiovascular health.
Among 22,914 subjects with LS7 data and no previous cardiovascular disease, there were 432 incident strokes over 4.9 years of follow-up. After adjusting for demographics, socioeconomic status, and region of residence, each better health category of the LS7 score was associated with a 25% lower risk of stroke (HR=0.75, 95% CI = 0.63, 0.90). The association was similar for blacks and whites (interaction p-value = 0.55). A one point higher LS7 score was associated with an 8% lower risk of stroke (HR=0.92, 95% CI=0.88, 0.95).
In both blacks and whites better cardiovascular health, based on the LS7 score, is associated with lower risk of stroke, and a small difference in scores was an important stroke determinant.
PMCID: PMC3816734  PMID: 23743971
Stroke; Racial differences; Risk factors; Life’s Simple 7
17.  Increased Neovascularization in Advanced Lipid-Rich Atherosclerotic Lesions Detected by Gadofluorine-M–Enhanced MRI 
Inflammation and neovascularization may play a significant role in atherosclerotic plaque progression and rupture. We evaluated gadofluorine-M–enhanced MRI for detection of plaque inflammation and neovascularization in an animal model of atherosclerosis.
Methods and Results
Sixteen rabbits with aortic plaque and 6 normal control rabbits underwent gadofluorine-M–enhanced MRI. Eight rabbits had advanced atherosclerotic lesions, whereas the remaining 8 had early lesions. Magnetic resonance atherosclerotic plaque enhancement was meticulously compared with plaque inflammation and neovessel density as assessed by histopathology. Advanced plaques and early atheroma were enhanced after gadofluorine-M injection. Control animals displayed no enhancement. After accounting for the within-animal correlation of observations, mean contrast-to-noise ratio was significantly higher in advanced plaques than compared with early atheroma (4.29±0.21 versus 3.00±0.32; P=0.004). Macrophage density was higher in advanced plaques in comparison to early atheroma (geometric mean=0.50 [95% CI, 0.19 to 1.03] versus 0.25 [0.07 to 0.42]; P=0.05). Furthermore, higher neovessel density was observed in advanced plaques (1.83 [95% CI, 1.51 to 2.21] versus 1.29 [0.99 to 1.69]; P=0.05). The plaque accumulation of gadofluorine-M correlated with increased neovessel density as shown by linear regression analysis (r=0.67; P<0.001). Confocal and fluorescence microscopy revealed colocalization of gadofluorine-M with plaque areas containing a high density of neovessels.
Gadofluorine-M–enhanced MRI is effective for in vivo detection of atherosclerotic plaque inflammation and neovascularization in an animal model of atherosclerosis. These findings suggest that gadofluorine-M enhancement reflects the presence of high-risk plaque features believed to be associated with plaque rupture. Gadofluorine-M plaque enhancement may therefore provide functional assessment of atherosclerotic plaque in vivo.
PMCID: PMC4073689  PMID: 19808627
atherosclerosis; MRI; vulnerable plaque; contrast media; molecular imaging
18.  Generic Alendronate Use among Medicare Beneficiaries: Are Part D Data Complete? 
Generic alendronate was approved in the United States on February 6, 2008. Medicare beneficiaries might pay for generic alendronate out-of-pocket without having claims submitted, resulting in misclassification of generic alendronate use in Medicare data.
To estimate the completeness of generic alendronate use in 2008 Medicare Part D data; to identify factors associated with staying on branded alendronate versus switching to a generic product.
We identified Medicare beneficiaries highly adherent (medication possession ratio ≥80%) with branded alendronate during 1/1/06-2/6/07 (“2007 cohort”) and during 1/1/07-2/6/08 (“2008 cohort”). The outcome was medication status at the end of follow-up (12/31/2007 or 12/31/2008), classified as continued branded alendronate, switched to generic alendronate, switched to another bisphosphonate or presumed discontinued bisphosphonate therapy. Cox regression estimated the hazard ratio (HR) for discontinuation in 2008 compared to 2007. Multinomial logistic regression identified factors associated with medication status for the 2008 cohort.
Among 15,310 subjects using branded alendronate in the 2008 cohort, 81% switched to generic alendronate. The proportion presumably discontinuing bisphosphonate therapy was 8.9% in 2008 compared to 7.7% in the 2007 cohort (adjusted HR, 1.15; 95% confidence interval, 1.05, 1.26). Factors associated with staying on branded alendronate in 2008 were higher income, eligibility for a low income subsidy and use of Fosamax® plus vitamin D.
Evaluation of Medicare prescription drug data suggests that the amount of missing claims for generic alendronate in 2008 was not substantial, and misclassification of exposure in studies examining alendronate use post generic product availability should be minimal.
PMCID: PMC4052770  PMID: 23135758
Generic drugs; alendronate; Medicare Part D; medication adherence
19.  Low Hemoglobin and Recurrent Falls in U.S. Men and Women: Prospective findings from the REasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort 
There are few data available on low hemoglobin levels and incident falls in the general U.S. population.
Of 30,239 Black and white U.S. adults ≥ 45 years old in the population-based REasons for Geographic and Racial Differences in Stroke (REGARDS) study, 16,782 had hemoglobin measured at baseline and follow-up data on falls. Hemoglobin was categorized by 1.0 g/dL increments relative to the World Health Organization cut-point for anemia (13.0 g/dL for men, 12.0 g/dL for women). Recurrent falls, defined as ≥2 falls in the 6 months following baseline were assessed during a telephone interview.
Recurrent falls occurred in 3.9% of men and 4.8% of women. Compared to those with a hemoglobin 1 to 2 g/dL above the anemia cut-point the multivariable adjusted odds ratios (OR; 95% confidence interval [CI]) for recurrent falls associated with hemoglobin levels ≥ 3g/dL, 2 to <3 g/dL, and 0 to 1 g/dL above the cut-point, and 0 to <1 g/dL and ≥1 g/dL below the cut-point were 0.73 (0.45–1.19), 0.84 (0.57–1.24), 1.29 (0.88–1.90), 1.32 (0.0.80–1.2.18) and 2.12 (1.23–3.63), respectively, among men (linear trend p<0.001) and 1.59 (1.10–2.3), 1.24 (0.95–1.62), 1.42(1.11–1.81), 1.28 (0.91–1.80) and 1.76 (1.13–2.74), respectively, among women (linear trend p=0.45; quadratic trend p=0.016).
Among men, lower hemoglobin was associated with an increased risk for recurrent falls. While our findings suggest an increased risk for recurrent falls at both lower and higher hemoglobin levels among women, these findings should be confirmed in subsequent studies.
PMCID: PMC3640699  PMID: 23328832
falls; hemoglobin; gender
20.  Alterations in Diastolic Function in Masked Hypertension: Findings from the Masked Hypertension Study 
American Journal of Hypertension  2013;26(6):808-815.
In a prior study of patients with diabetes, diastolic function was similarly impaired in masked hypertension (MHT) and sustained hypertension (SHT). We evaluated whether MHT is associated with impaired diastolic function compared with SHT and sustained normotension (NT) in the general population.
From February 2005 to December 2010, 798 participants without a history of cardiovascular disease or treated hypertension, were enrolled in the Masked Hypertension Study. Participants underwent clinic blood pressure (CBP) and 24-hour ambulatory blood pressure (ABP) measurements. A 2-dimensional Doppler echocardiogram was performed to evaluate diastolic function,s cardiac structure, volume, and systolic function. The 9 CBPs obtained across 3 clinic visits and awake ABP measurements were averaged. Clinic hypertension was defined as systolic/diastolic blood pressure (SBP/DBP) ≥ 140/90 mmHg. Ambulatory hypertension was defined as awake SBP/DBP ≥ 135/85mm Hg. MHT was defined as having ambulatory but not clinic hypertension. White-coat hypertensives (n = 8) were excluded from the analysis.
Of the 790 participants, 116 (14.7%) participants had MHT, 37 (4.7%) participants had SHT, and 637 (80.6%) participants had NT. After age, sex, race/ethnicity, and body mass index adjustment, compared with NT, E’-velocities were significantly lower in MHT (P < 0.01) and SHT (P < 0.05), and E/E’ ratios were significantly higher MHT (P < 0.05) and SHT (P < 0.05). These associations were independent of left ventricular mass. Diastolic function parameters did not significantly differ between MHT and SHT.
Diastolic function was impaired in MHT compared with NT independent of changes in left ventricular mass.
PMCID: PMC3657486  PMID: 23446956
ambulatory blood pressure monitoring; blood pressure;  echocardiography; hypertension.
21.  High Blood Pressure: The Leading Global Burden of Disease Risk Factor and the Need for Worldwide Prevention Programs 
Current hypertension reports  2013;15(3):134-136.
PMCID: PMC3699411  PMID: 23536128
Hypertension; Blood pressure; Cardiovascular disease; Global Burden of Disease Study; Risk factor; Prevention; Treatment; Epidemiology
22.  A Pilot Study Identifying Statin Non-adherence With Visit-to-visit Variability of Low Density Lipoprotein-Cholesterol 
The American journal of cardiology  2013;111(10):1437-1442.
Non-adherence to cardiovascular medications such as statins is a common, important problem. Clinicians currently rely on intuition to identify medication non-adherence. The visit-to-visit variability (VVV) of LDL-C may represent an opportunity to identify statin non-adherence with greater accuracy. We examined the clinical and pharmacy data from 782 members of the Boston Medical Center (BMC) Health Plan, seen at either BMC or its affiliated Community Health Centers, who were taking statins and had at least 3 LDL-C measurements between 2008 and 2011. The LDL-C VVV (defined by the within-patient standard deviation) was categorized into quintiles. Multivariable logistic regression models were generated with statin non-adherence (defined by the standard 80% pharmacy refill based medication possession ratio threshold) as the dependent variable. The proportion of statin non-adherence increased across quintiles of LDL-C VVV (64.3%, 71.2%, 89.2%, 92.3%, 91.7%). Higher quintiles of LDL-C VVV had a strong positive association with statin non-adherence with an adjusted odds ratio of 3.4 (CI: 1.7–7.1) in the highest versus lowest quintile of LDL-C VVV. The age and gender adjusted model had poor discrimination [C-statistic 0.62 (CI: 0.57, 0.67)] while the final adjusted (age, gender, race, mean LDL-C) model demonstrated good discrimination [C-statistic 0.75 (CI: 0.71, 0.79)] between adherent and non-adherent patients. In conclusion, the VVV of LDL-C demonstrated a strong association with statin non-adherence in a clinic setting. Further, a VVV- of LDL-C based model has good discrimination characteristics for statin non-adherence. Research is needed to validate and generalize these findings to other populations and biomarkers.
PMCID: PMC3644321  PMID: 23433758
Visit-to-visit variability; statins; medication adherence
23.  The ‘Perfect Storm’ and Acute Coronary Syndrome Onset: Do Psychosocial Factors Play a Role? 
The revolution in cardiac care over the past two decades, characterized by emergent revascularization, drug eluting stents, anti-platelet medications, and advanced imaging has had little impact on overall ACS recurrence, or ACS prevention. The “Perfect Storm” refers to a confluence of events and processes, including atherosclerotic plaque, coronary flow dynamics, hemostatic and fibrinolytic function, metabolic and inflammatory conditions, neurohormonal dysregulation, and environmental events that give rise to, and result in an ACS event. In this article we illustrate the limits of the traditional main effect research model, giving a brief description of the current state of knowledge regarding the development of atherosclerotic plaque and the rupturing of these plaques that defines an ACS event. We then apply the Perfect Storm conceptualization to describe a program of research concerning a psychosocial vulnerability factor that contributes to increased risk of recurrent ACS and early mortality, and that has defied our efforts to identify underlying pathophysiology and successfully mount efforts to fully mitigate this risk.
PMCID: PMC3652628  PMID: 23621970
24.  Nondisease-Specific Problems and All-Cause Mortality in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Problems that cross multiple domains of health are frequently assessed in older adults. We evaluated the association between six of these nondisease-specific problems and mortality among middle-aged and older adults.
Prospective, observational cohort
U.S. population sample
Participants included 23,669 black and white US adults ≥ 45 years of age enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.
Nondisease-specific problems included cognitive impairment, depressive symptoms, falls, polypharmacy, impaired mobility and exhaustion. Age-stratified (<65, 65-74, and ≥ 75 years) hazard ratios for all-cause mortality were calculated for each problem individually and by number of problems.
Among participants < 65, 65-74, ≥ 75 years old, one or more nondisease-specific problems occurred in 40%, 45% and 55% of participants, respectively. Compared to those with none of these problems the multivariable adjusted hazard ratios and 95% confidence intervals for all-cause mortality associated with each additional nondisease-specific problem was 1.34 (1.23–1.46), 1.24 (1.15–1.35) and 1.30 (1.21–1.39), among participants < 65, 65 – 74 years, ≥ 75 years of age, respectively.
Nondisease-specific problems were associated with mortality across a wide age spectrum. Future studies should determine if treating these problems will improve survival and identify innovative healthcare models to address multiple nondisease-specific problems simultaneously.
PMCID: PMC3656135  PMID: 23617688
nondisease-specific problems; geriatrics; mortality
25.  Claims-based algorithms for identifying Medicare beneficiaries at high estimated risk for coronary heart disease events: a cross-sectional study 
Databases of medical claims can be valuable resources for cardiovascular research, such as comparative effectiveness and pharmacovigilance studies of cardiovascular medications. However, claims data do not include all of the factors used for risk stratification in clinical care. We sought to develop claims-based algorithms to identify individuals at high estimated risk for coronary heart disease (CHD) events, and to identify uncontrolled low-density lipoprotein (LDL) cholesterol among statin users at high risk for CHD events.
We conducted a cross-sectional analysis of 6,615 participants ≥66 years old using data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study baseline visit in 2003–2007 linked to Medicare claims data. Using REGARDS data we defined high risk for CHD events as having a history of CHD, at least 1 risk equivalent, or Framingham CHD risk score >20%. Among statin users at high risk for CHD events we defined uncontrolled LDL cholesterol as LDL cholesterol ≥100 mg/dL. Using Medicare claims-based variables for diagnoses, procedures, and healthcare utilization, we developed algorithms for high CHD event risk and uncontrolled LDL cholesterol.
REGARDS data indicated that 49% of participants were at high risk for CHD events. A claims-based algorithm identified high risk for CHD events with a positive predictive value of 87% (95% CI: 85%, 88%), sensitivity of 69% (95% CI: 67%, 70%), and specificity of 90% (95% CI: 89%, 91%). Among statin users at high risk for CHD events, 30% had LDL cholesterol ≥100 mg/dL. A claims-based algorithm identified LDL cholesterol ≥100 mg/dL with a positive predictive value of 43% (95% CI: 38%, 49%), sensitivity of 19% (95% CI: 15%, 22%), and specificity of 89% (95% CI: 86%, 90%).
Although the sensitivity was low, the high positive predictive value of our algorithm for high risk for CHD events supports the use of claims to identify Medicare beneficiaries at high risk for CHD events.
PMCID: PMC4101858  PMID: 24779477
High risk; Coronary heart disease; Risk stratification; Medicare claims

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