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We examined the association of orthostatic hypertension with all-cause mortality in the active treatment and placebo randomized groups of the Systolic Hypertension in the Elderly Program (SHEP). SHEP was a multicenter, randomized, double-blind, placebo-controlled clinical trial of the effect of chlorthalidone-based antihypertensive treatment on the rate of occurrence of stroke among older persons with isolated systolic hypertension (ISH). Men and women aged 60 years and above with ISH defined by a systolic blood pressure (SBP) of 160 mm Hg or higher and diastolic blood pressure lower than 90 mm Hg were randomized to chlorthalidone-based stepped care therapy or matching placebo. Among 4736 SHEP participants, 4073 had a normal orthostatic response, 203 had orthostatic hypertension, and 438 had orthostatic hypotension. Compared with normal response, orthostatic hypertension was associated with higher all-cause mortality at 4.5 and 17 years in analyses adjusted for age, gender, treatment, SBP, and pulse pressure (PP, HR 1.87, 95% CI 1.30-2.69, p = 0.0007; HR 1.40, 95% CI 1.17-1.68, p = 0.0003, respectively). These associations remained significant after additional adjustment for risk factors and comorbidities (HR 1.43, 95% CI 0.99-0.08, p = 0.0566 at 4.5 years, and HR 1.27, 95% CI 1.06-1.53, p = 0.0096 at 17 years). The increased risk of all-cause mortality associated with orthostatic hypertension was observed in both the active and placebo groups without significant interaction between randomization group and the effect on mortality. Orthostatic hypertension is associated with future mortality risk, is easily detected, and can be used in refining cardiovascular risk assessment.

BACKGROUND Impaired renal function is a risk factor for cardiovascular disease, end-stage renal disease (ESRD), and mortality. The impact of short-term renal function decline on outcomes is less well studied. The association of antihypertensive medications with the impact of short-term estimated glomerular filtration rate (eGFR) decline is not known. METHODS We examined 20,207 hypertensive participants with baseline and 2-year creatinine levels from which eGFR changes were estimated. The associations between eGFR change with incident coronary heart disease (CHD), stroke, heart failure (HF), all-cause mortality, and ESRD during 2.9 years of in-trial follow up, and with mortality during in-trial and post-trial follow-up (7.6 years), were studied. Results were assessed by primary hypertension (HTN) treatment (chlorthalidone, lisinopril, and amlodipine) and adjusted for baseline eGFR levels. RESULTS In the short run, an eGFR decline below the cohort median (−1.28 ml/minute/1.73 m2/2 years) vs. above the median, or a 5 ml/min/1.73 m2/year decline vs. no decline, was associated with significant hazard risk for CHD (1.06–1.28), HF (1.24–1.91), ESRD (2.84–6.01), and mortality (1.08–1.19), but not with stroke risk. In the long term, there was a significant association with mortality (1.11–1.34). Interaction terms for outcomes by antihypertensive treatments were not statistically significant except for ESRD between amlodipine vs. chlorthalidone (hazard ratio: 3.17 [2.59, 3.88] vs. 2.41 [1.98, 2.97]; P interaction = 0.005) for a 5 ml/min/1.73 m2/year eGFR decline. CONCLUSION Decline in eGFR over 2 years is associated with increased risk of clinical outcomes beyond the effects of baseline eGFR. These risks were the same irrespective of the primary medication used to treat HTN.

Background and Purpose— The visual analogue scale is a self-reported, validated tool to measure quality of life (QoL). Our purpose was to determine whether baseline QoL predicted strokes in the ALLHAT study (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial) and evaluate determinants of poststroke change in QoL. In the ALLHAT study, among the 33 357 patients randomized to treatment arms, 1525 experienced strokes; 1202 (79%) strokes were nonfatal. This study cohort includes 32 318 (97%) subjects who completed the baseline visual analogue scale QoL estimate. Methods— QoL was measured on a visual analogue scale and adjusted using a Torrance transformation (transformed QoL [TQoL]). Kaplan–Meier curves and adjusted proportional hazards analyses were used to estimate the effect of TQoL on the risk of stroke, on a continuous scale (0–1) and by quartiles (≤0.81, >0.81≤0.89, >0.89≤0.95, >0.95). We analyzed the change from baseline to first poststroke TQoL using adjusted linear regression. Results— After adjusting for multiple stroke risk factors, the hazard ratio for stroke events for baseline TQoL was 0.93 (95% confidence interval, 0.89–0.98) per 0.1 U increase. The lowest baseline TQoL quartile had a 20% increased stroke risk (hazard ratio=1.20 [95% confidence interval, 1.00–1.44]) compared with the reference highest quartile TQoL. Poststroke TQoL change was significant within all treatment groups ( P ≤0.001). Multivariate regression analysis revealed that baseline TQoL was the strongest predictor of poststroke TQoL with similar results for the untransformed QoL. Conclusions— The lowest baseline TQoL quartile had a 20% higher stroke risk than the highest quartile. Baseline TQoL was the only factor that predicted poststroke change in TQoL. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00000542.

Aims Although group-level effectiveness of lipid, blood pressure, glucose, and aspirin treatment for prevention of cardiovascular disease (CVD) has been proven by trials, important differences in absolute effectiveness exist between individuals. We aim to develop and validate a prediction tool for individualizing lifelong CVD prevention in people with Type 2 diabetes mellitus (T2DM) predicting life-years gained without myocardial infarction or stroke. Methods and results We developed and validated the Diabetes Lifetime-perspective prediction (DIAL) model, consisting of two complementary competing risk adjusted Cox proportional hazards functions using data from people with T2DM registered in the Swedish National Diabetes Registry (n = 389 366). Competing outcomes were (i) CVD events (vascular mortality, myocardial infarction, or stroke) and (ii) non-vascular mortality. Predictors were age, sex, smoking, systolic blood pressure, body mass index, haemoglobin A1c, estimated glomerular filtration rate, non- high-density lipoprotein cholesterol, albuminuria, T2DM duration, insulin treatment, and history of CVD. External validation was performed using data from the ADVANCE, ACCORD, ASCOT and ALLHAT-LLT-trials, the SMART and EPIC-NL cohorts, and the Scottish diabetes register (total n = 197 785). Predicted and observed CVD-free survival showed good agreement in all validation sets. C-statistics for prediction of CVD were 0.83 (95% confidence interval: 0.83–0.84) and 0.64–0.65 for internal and external validation, respectively. We provide an interactive calculator at www.U-Prevent.com that combines model predictions with relative treatment effects from trials to predict individual benefit from preventive treatment. Conclusion Cardiovascular disease-free life expectancy and effects of lifelong prevention in terms of CVD-free life-years gained can be estimated for people with T2DM using readily available clinical characteristics. Predictions of individual-level treatment effects facilitate translation of trial results to individual patients.

BACKGROUND Elevations of fasting glucose (FG) levels are frequently encountered in people treated with thiazide diuretics. The risk is lower in people treated with ACE inhibitors (ACEi). To determine if genetic factors play a role in FG elevation, we examined the interaction of a diabetes gene risk score (GRS) with the use of 3 different antihypertensive medications. METHODS We examined 376 nondiabetic hypertensive individuals with baseline FG RESULTS For every 1 allele increase in GRS, the adjusted odds ratios (ORs) were 1.06 (95% confidence interval (CI): 0.99, 1.14; P = 0.06) and 1.09 (95% CI: 0.99, 1.20; P = 0.08). When results were examined by randomized medications, participants randomized to amlodipine had statistically significant odds for either outcome (OR: 1.23; 95% CI: 1.03, 1.48; P = 0.01 and OR: 1.31; 95% CI: 1.06, 1.62; P = 0.01). No such risk increase was found in participants randomized to the other 2 medications. CONCLUSIONS A diabetes GRS predicts FG elevation in people treated with a CCB, but not with an ACEi or diuretic. These findings require confirmation. CLINICAL TRIALS REGISTRATION Trial number NCT00000542.

Summary Background For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. Methods TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4–16 years and had abnormal TCD flow velocities (≥200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. Findings Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140–146) in children who received standard transfusions and 138 cm/s (135–142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10–8·98). Non-inferiority (p=8·82 × 10 −16 ) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). Interpretation For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. Funding National Heart, Lung, and Blood Institute, National Institutes of Health.

Although hemoglobin SC (HbSC) disease is usually considered less severe than sickle cell anemia (SCA), which includes HbSS and HbS/β(0) -thalassemia genotypes, many patients with HbSC experience severe disease complications, including vaso-occlusive pain, acute chest syndrome, avascular necrosis, retinopathy, and poor quality of life. Fully 20 years after the clinical and laboratory efficacy of hydroxyurea was proven in adult SCA patients, the safety and utility of hydroxyurea treatment for HbSC patients remain unclear. Recent NHLBI evidence-based guidelines highlight this as a critical knowledge gap, noting HbSC accounts for ∼30% of sickle cell patients within the United States. To date, only 5 publications have reported short-term, incomplete, or conflicting laboratory and clinical outcomes of hydroxyurea treatment in a total of 71 adults and children with HbSC. We now report on a cohort of 133 adult and pediatric HbSC patients who received hydroxyurea, typically for recurrent vaso-occlusive pain. Hydroxyurea treatment was associated with a stable hemoglobin concentration; increased fetal hemoglobin (HbF) and mean corpuscular volume (MCV); and reduced white blood cell count (WBC), absolute neutrophil count (ANC), and absolute reticulocyte count (ARC). Reversible cytopenias occurred in 22% of patients, primarily neutropenia and thrombocytopenia. Painful events were reduced with hydroxyurea, more in patients >15 years old. These multicenter data support the safety and potentially salutary effects of hydroxyurea treatment for HbSC disease; however, a multicenter, placebo-controlled, Phase 3 clinical trial is needed to determine if hydroxyurea therapy has efficacy for patients with HbSC disease.

Thiazide-type diuretics have been recommended for initial treatment of hypertension in most patients, but should this recommendation differ for patients with and without coronary heart disease (CHD)? The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind hypertension treatment trial in 42,418 participants with high risk of combined cardiovascular disease (CVD) (25% with preexisting CHD). This post hoc analysis compares long-term major clinical outcomes in those assigned amlodipine (n = 9048) or lisinopril (n = 9,054) with those assigned chlorthalidone (n = 15,255), stratified by CHD status. After 4 to 8 years, randomized treatment was discontinued. Total follow-up (active treatment + passive surveillance using national databases for deaths and hospitalizations) was 8 to 13 years. For most CVD outcomes, end-stage renal disease, and total mortality, there were no differences across randomized treatment arms regardless of baseline CHD status. In-trial rates of CVD were significantly higher for lisinopril compared with chlorthalidone, and rates of heart failure were significantly higher for amlodipine compared with chlorthalidone in those with and without CHD (overall hazard ratios [HRs] 1.10, p

Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial is a randomized, open-label comparison of hydroxycarbamide (also termed hydroxyurea) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia (SCA) and abnormal TCD. Severity and location of iron overload is an important secondary outcome measure. We report the baseline findings of abdominal organ iron burden in 121 participants. At enrollment, patients were young (9·8 ± 2·9 years), predominantly female (60:40), and previously treated with transfusions (4·1 ± 2·4 years) and iron chelation (3·1 ± 2·1 years). Liver iron concentration (LIC; 9·0 ± 6·6 mg/g dry weight) and serum ferritin were moderately elevated (2696 ± 1678 μg/l), but transferrin was incompletely saturated (47·2 ± 23·6%). Spleen R2* was 509 ± 399 Hz (splenic iron ~13·9 mg/g) and correlated with LIC (r(2) = 0·14, P = 0·0008). Pancreas R2* was increased in 38·3% of patients but not to levels associated with endocrine toxicity. Kidney R2* was increased in 80·7% of patients; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin-creatinine ratios. Extra-hepatic iron deposition is common among children with SCA who receive chronic transfusions, and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin.

Noninvasive, quantitative, and accurate assessment of liver iron concentration (LIC) by MRI is useful for patients receiving transfusions, but R2 and R2* MRI techniques have not been systematically compared in sickle cell anemia (SCA). We report baseline LIC results from the TWiTCH trial, which compares hydroxyurea with blood transfusion treatment for primary stroke prophylaxis assessed by transcranial Doppler sonography in pediatric SCA patients. Liver R2 was collected and processed using a FDA-approved commercial process (FerriScan®), while liver R2* quality control and processing were performed by a Core Laboratory blinded to clinical site and patient data. Baseline LIC studies using both MRI techniques were available for 120 participants. LICR2* and LICR2 results were highly correlated (r2 = 0.93). A proportional bias of LIC(R2*)/LIC(R2), decreasing with average LIC, was observed. Systematic differences between LICR2* and LICR2 were also observed by MRI manufacturer. Importantly, LICR2* and LICR2 estimates had broad 95% limits of agreement with respect to each other. We recommend LICR2 and LICR2* not be used interchangeably in SCA patients to follow individual patient trends in iron burden.Am. J. Hematol. 90:806–810, 2015. © 2015 Wiley Periodicals, Inc.

Importance While statin therapy for primary cardiovascular prevention has been associated with reductions in cardiovascular morbidity, the effect on all-cause mortality has been variable. There is little evidence to guide the use of statins for primary prevention in adults 75 years and older. Objectives To examine statin treatment among adults aged 65 to 74 years and 75 years and older when used for primary prevention in the Lipid-Lowering Trial (LLT) component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). Design, Setting, and Participants Post hoc secondary data analyses were conducted of participants 65 years and older without evidence of atherosclerotic cardiovascular disease; 2867 ambulatory adults with hypertension and without baseline atherosclerotic cardiovascular disease were included. The ALLHAT-LLT was conducted from February 1994 to March 2002 at 513 clinical sites. Interventions Pravastatin sodium (40 mg/d) vs usual care (UC). Main Outcomes and Measures The primary outcome in the ALLHAT-LLT was all-cause mortality. Secondary outcomes included cause-specific mortality and nonfatal myocardial infarction or fatal coronary heart disease combined (coronary heart disease events). Results There were 1467 participants (mean [SD] age, 71.3 [5.2] years) in the pravastatin group (48.0% [n = 704] female) and 1400 participants (mean [SD] age, 71.2 [5.2] years) in the UC group (50.8% [n = 711] female). The baseline mean (SD) low-density lipoprotein cholesterol levels were 147.7 (19.8) mg/dL in the pravastatin group and 147.6 (19.4) mg/dL in the UC group; by year 6, the mean (SD) low-density lipoprotein cholesterol levels were 109.1 (35.4) mg/dL in the pravastatin group and 128.8 (27.5) mg/dL in the UC group. At year 6, of the participants assigned to pravastatin, 42 of 253 (16.6%) were not taking any statin; 71.0% in the UC group were not taking any statin. The hazard ratios for all-cause mortality in the pravastatin group vs the UC group were 1.18 (95% CI, 0.97-1.42; P = .09) for all adults 65 years and older, 1.08 (95% CI, 0.85-1.37; P = .55) for adults aged 65 to 74 years, and 1.34 (95% CI, 0.98-1.84; P = .07) for adults 75 years and older. Coronary heart disease event rates were not significantly different among the groups. In multivariable regression, the results remained nonsignificant, and there was no significant interaction between treatment group and age. Conclusions and Relevance No benefit was found when pravastatin was given for primary prevention to older adults with moderate hyperlipidemia and hypertension, and a nonsignificant direction toward increased all-cause mortality with pravastatin was observed among adults 75 years and older. Trial Registration clinicaltrials.gov Identifier:NCT00000542

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in 33,357 high-risk hypertensive participants. ALLHAT compared cardiovascular disease outcomes in participants initially treated with an angiotensin-converting enzyme inhibitor (lisinopril), a calcium channel blocker (amlodipine), or a thiazide-type diuretic (chlorthalidone). We report stroke outcomes in 1517 participants in-trial and 1596 additional participants during post-trial passive surveillance, for a total follow-up of 8-13 years. Stroke rates were higher with lisinopril (6-year rate/100 = 6.4) than with chlorthalidone (5.8) or amlodipine (5.5) in-trial but not including post-trial (10-year rates/100 = 13.2 [chlorthalidone], 13.1[amlodipine], and 13.7 [lisinopril]). In-trial differences were driven by race (race-by-lisinopril/chlorthalidone interaction P = .005, race-by-amlodipine/lisinopril interaction P = .012) and gender (gender-by-lisinopril/amlodipine interaction P = .041), separately. No treatment differences overall, or by race or gender, were detected over the 10-year period. No differences appeared among treatment groups in adjusted risk of all-cause mortality including post-trial for participants with nonfatal in-trial strokes. Among Blacks and women, lisinopril was less effective in preventing stroke in-trial than either chlorthalidone or amlodipine, even after adjusting for differences in systolic blood pressure. These differences abated by the end of the post-trial period.

Most studies of an association of visit-to-visit variability of blood pressure with increased risk of future adverse cardiovascular events are of short duration and rarely include a placebo group. Using data from the double-blind, placebo-controlled Systolic Hypertension in the Elderly Program, the authors examined mortality from cardiovascular causes up to 17 years of follow-up using the National Death Index. Visit-to-visit blood pressure variability was associated with cardiovascular death after adjustment for sex, age, serum creatinine, diabetes, body mass index, smoking status, left ventricular failure, and high-density lipoprotein cholesterol. The relationship was significantly stronger in the active treatment group compared with the placebo group. Although this could be the result of an effect of the medications used unrelated to visit-to-visit variability, the data are compatible with the hypothesis that inconsistent adherence leading to missing active medication doses may be an additional explanation for the relationship of visit-to-visit variability with cardiovascular death.

Background/Aims: The role of statins in preventing cardiovascular outcomes in patients with chronic kidney disease (CKD) is unclear. This paper compares cardiovascular outcomes with pravastatin vs. usual care, stratified by baseline estimated glomerular filtration rate (eGFR). Methods: Post-hoc analyses of a prospective randomized open-label clinical trial; 10,151 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (lipid-lowering component) were randomized to pravastatin 40 mg/day or usual care. Mean follow-up was 4.8 years. Results: Through Year 6, total cholesterol declined in pravastatin (–20.7%) and usual-care groups (–11.2%). Use of statin therapy in the pravastatin group was 89.8% (Year 2) and 87.0% (Year 6). Usual-care group statin use increased from 8.2% (Year 2) to 23.5% (Year 6). By primary intention-to-treat analyses, no significant differences were seen between groups for coronary heart disease (CHD), total mortality or combined cardiovascular disease; findings were consistent across eGFR strata. In exploratory “as-treated” analyses (patients actually using pravastatin vs. not using), pravastatin therapy was associated with lower mortality (HR = 0.76 (0.68 – 0.85), p < 0.001) and lower CHD (HR = 0.84 (0.73 – 0.97), p = 0.01), but not combined cardiovascular disease (HR = 0.95 (0.88 – 1.04), p = 0.30). Total cholesterol reduction of 10 mg/dl from baseline to Year 2 was associated with 5% lower CHD risk. Conclusions: In hypertensive patients with moderate dyslipidemia, pravastatin was not superior to usual care in preventing total mortality or CHD independent of baseline eGFR level. However, exploratory “as-treated” analyses suggest improved mortality and CHD risk in participants using pravastatin, and decreased CHD events associated with achieved reduction in total cholesterol. Potential benefit from statin therapy may depend on degree of reduction achieved in total and LDL-cholesterol and adherence to therapy.

Randomized trials of hypertension have seldom examined heterogeneity in response to treatments over time and the implications for cardiovascular outcomes. Understanding this heterogeneity, however, is a necessary step toward personalizing antihypertensive therapy. We applied trajectory-based modeling to data on 39 763 study participants of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) to identify distinct patterns of systolic blood pressure (SBP) response to randomized medications during the first 6 months of the trial. Two trajectory patterns were identified: immediate responders (85.5%), on average, had a decreasing SBP, whereas nonimmediate responders (14.5%), on average, had an initially increasing SBP followed by a decrease. Compared with those randomized to chlorthalidone, participants randomized to amlodipine (odds ratio, 1.20; 95% confidence interval [CI], 1.10–1.31), lisinopril (odds ratio, 1.88; 95% CI, 1.73–2.03), and doxazosin (odds ratio, 1.65; 95% CI, 1.52–1.78) had higher adjusted odds ratios associated with being a nonimmediate responder (versus immediate responder). After multivariable adjustment, nonimmediate responders had a higher hazard ratio of stroke (hazard ratio, 1.49; 95% CI, 1.21–1.84), combined cardiovascular disease (hazard ratio, 1.21; 95% CI, 1.11–1.31), and heart failure (hazard ratio, 1.48; 95% CI, 1.24–1.78) during follow-up between 6 months and 2 years. The SBP response trajectories provided superior discrimination for predicting downstream adverse cardiovascular events than classification based on difference in SBP between the first 2 measurements, SBP at 6 months, and average SBP during the first 6 months. Our findings demonstrate heterogeneity in response to antihypertensive therapies and show that chlorthalidone is associated with more favorable initial response than the other medications.

Although hypertension guidelines define treatment-resistant hypertension as blood pressure uncontrolled by ≥3 antihypertensive medications, including a diuretic, it is unknown whether patient prognosis differs when a diuretic is included.Participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) were randomly assigned to first-step therapy with chlorthalidone, amlodipine, or lisinopril. At a Year 2 follow-up visit, those with average blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic on ≥3 antihypertensive medications, or blood pressure140/90 mm Hg on ≥4 antihypertensive medications were identified as having apparent treatment-resistant hypertension. The prevalence of treatment-resistant hypertension and its association with ALLHAT primary (combined fatal coronary heart disease or nonfatal myocardial infarction) and secondary (all-cause mortality, stroke, heart failure, combined coronary heart disease, and combined cardiovascular disease) outcomes were identified for each treatment group.Of participants assigned to chlorthalidone, amlodipine, or lisinopril, 9.6%, 11.4%, and 19.7%, respectively, had treatment-resistant hypertension. During mean follow-up of 2.9 years, primary outcome incidence was similar for those assigned to chlorthalidone compared with amlodipine or lisinopril (amlodipine- vs chlorthalidone-adjusted hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.53-1.39; P = .53; lisinopril- vs chlorthalidone-adjusted HR = 1.06; 95% CI, 0.70-1.60; P = .78). Secondary outcome risks were similar for most comparisons except coronary revascularization, which was higher with amlodipine than with chlorthalidone (HR 1.86; 95% CI, 1.11-3.11; P = .02). An as-treated analysis based on diuretic use produced similar results.In this study, which titrated medications to a goal, participants assigned to chlorthalidone were less likely to develop treatment-resistant hypertension. However, prognoses in those with treatment-resistant hypertension were similar across treatment groups.

Observational studies suggest that thiazide-type diuretics reduce fracture risk compared to other antihypertensive medications. The effects of calcium channel blockers (CCB) and angiotensin converting-enzyme inhibitors (ACEi) on fracture risk have not been well studied. We examined the relationship of antihypertensive drug therapy and hip and pelvic fracture hospitalizations in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ). It included >33,000 participants randomized to the thiazide-type diuretic chlorthalidone (C), ACEi lisinopril (L), or CCB amlodipine (A) as first line hypertension (HTN) therapy. Mean follow up was 4.9 years during the randomized phase (in-trial), and 5 additional years after the conclusion of the trial (post-trial) using linkage to national data bases. Risks of hip and pelvic fractures for L and A relative to C were derived from Cox models. There were 341 hip and pelvic fractures in-trial. Participants assigned C had the lowest risk and those assigned L the highest ( Figure 1a). The adjusted risk for L compared to C was 1.33 (95% CI 1.02-1.73; p=.04). Participants assigned A had intermediate risk compared to C (HR 1.22, 95% CI 0.93-1.59). During the combined in-trial and post-trial periods ( Figure 1b ), there were 646 fractures; the results were similar to the in-trial results, although differences were not statistically significant. Participants randomized to C continued to have the lowest risk of fractures after in-trial period, suggesting a legacy effect from prior C use. These findings have public health importance given the high prevalence of HTN in older adults and the widespread use of A and L in older adults.

Background— Thiazide-type diuretics are associated with an increased incidence of diabetes compared with other antihypertensive medications. In this study, we determined the long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes compared with the effects of incident diabetes associated with calcium channel blocker and angiotensin-converting enzyme inhibitor use. Methods and Results— A total of 22 418 participants from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with baseline diabetes, incident diabetes (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril), or no diabetes at 2 years of in-trial follow-up were followed for a mean total of 6.9 years (2.9 years in-trial and 4 additional years posttrial) through the use of national databases. The primary outcome was CVD mortality (death from coronary heart disease [CHD], stroke, heart failure, or other CVD). Among other outcomes were all-cause mortality, non-CVD mortality, and CHD (nonfatal myocardial infarction or fatal CHD). Participants on chlorthalidone with incident diabetes versus no diabetes had consistently lower, nonsignificant risk for CVD mortality (hazard ratio [HR], 1.04; 95% CI, 0.74–1.47), all-cause mortality (HR, 1.04; 95% CI, 0.82–1.30), and non-CVD mortality (HR, 1.05; 95% CI, 0.77–1.42) than participants on amlodipine or lisinopril with incident diabetes (HR range, 1.22–1.53). Participants with incident diabetes had elevated CHD risk compared with those with no diabetes (HR, 1.46; 95% CI, 1.09–1.96), but those on chlorthalidone had significantly lower risk than those on lisinopril (HR, 1.18 versus 2.57; P =0.04 for interaction). Conclusions— The findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops while on other antihypertensive medications. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00000542.

A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and ≥ 1 other coronary heart disease risk factors to receive chlorthalidone (n=15,002), amlodipine (n=8898), or lisinopril (n=8904) for 4 to 8 years, when double-blinded therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up. Primary outcome was cardiovascular mortality and secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post-trial period, data are not available on medications or blood pressure levels. No significant differences (P

Background and Purpose— Epidemiologic studies have demonstrated that hypertension increases the risk of stroke, and clinical trials have shown that antihypertensive therapy reduces this risk. Incident stroke was significantly decreased by treatment in the Systolic Hypertension in Elderly Program (SHEP) Trial, but the reduction in fatal events was not statistically significant. Methods— Vital status was determined for 4736 SHEP participants by matching to the National Death Index. We assessed the impact of antihypertensive treatment, stroke, and transient ischemic attacks (TIAs) during SHEP on long-term (mean, 14.3 years) mortality. Results— Treatment with a chlorthalidone-based antihypertensive regimen significantly reduced the risk of cardiovascular death (adjusted relative risk [RR]=0.86; 95% CI, 0.76 to 0.98, P =0.026) in the SHEP cohort without a significant ( P =0.39) interaction with stroke status. Patients who sustained a stroke during SHEP had significantly higher all-cause mortality at the 14.3-year mean follow-up: 65.6% compared with 40.6% among those free of stroke or TIA (adjusted RR=1.97; 95% CI, 1.67 to 2.33). They also were at higher risk for cardiovascular death (RR=2.00; 95% CI, 1.58 to 2.53) and stroke death (RR=2.94; 95% CI, 1.87 to 4.64). TIA was not significantly associated with increased total mortality (RR=1.13; 95% CI, 0.88 to 1.44), cardiovascular death (RR=1.30; 95% CI, 0.94 to 1.81), or stroke death (RR=1.76; 95% CI, 0.95 to 3.26). Conclusions— In SHEP, chlorthalidone-based treatment reduced the risk of cardiovascular death after 14 years of extended follow-up. Nearly two thirds of elderly persons with isolated systolic hypertension who experienced stroke died within 14 years.

Background: Two types of relationships between risk factors and cardiovascular outcomes have been described: linear, as is the case with smoking where even one cigarette is worse than total abstinence, and U- or J-shaped as is the case for body mass index (BMI). Using data from the Antihypertensive

Introduction: Clinicians need to translate results from randomized clinical trials to individual patients with type 2 diabetes mellitus (T2DM). In this study we aim to develop and validate a model for the prediction of absolute risk reductions (ARR) for major cardiovascular events by usual-dose statin therapy for individuals with T2DM. Methods: Data from the ASCOT-LLA trial (atorvastatin 10 mg versus placebo) of 2,725 T2DM patients were used to predict 10-year individualized ARR on major cardiovascular events (myocardial infarction, stroke or cardiovascular death). Predictions were based on a newly developed model of 8 predictors: age, sex, current smoking, systolic blood pressure, non-HDL cholesterol, fasting glucose, history of cardiovascular events and treatment allocation (statin or placebo). External validation was performed in ALLHAT-LLT (3,878 T2DM patients) and CARDS (2,838 T2DM patients). Possible effect modification of statin therapy was evaluated for baseline cardiovascular risk and single interactions between predictors and treatment allocation. Results: The predicted 10-year ARR for cardiovascular events was low (50 (Figure 1). About 30% of the T2DM patients had an ARR of >4% (10-year NNT Conclusion: Absolute risk reductions by statin therapy can be estimated for individual patients with T2DM using a model based on trial data. There is a wide distribution in absolute risk reduction by statin therapy in T2DM patients due to a distribution in cardiovascular risk. Individualized treatment effects are more informative for patients and clinicians than relative average effects and can be used to guide clinical decision-making.

Apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled hypertension despite the use of ≥3 antihypertensive medication classes or controlled hypertension while treated with ≥4 antihypertensive medication classes. Although a high prevalence of aTRH has been reported, few data are available on its association with cardiovascular and renal outcomes. We analyzed data on 14 684 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants to determine the association between aTRH (n=1870) with coronary heart disease, stroke, all-cause mortality, heart failure, peripheral artery disease, and end-stage renal disease. We defined aTRH as blood pressure not at goal (systolic/diastolic blood pressure ≥140/90 mm Hg) while taking ≥3 classes of antihypertensive medication or taking ≥4 classes of antihypertensive medication with blood pressure at goal during the year 2 ALLHAT study visit (1996–2000). Use of a diuretic was not required to meet the definition of aTRH. Follow-up occurred through 2002. The multivariable adjusted hazard ratios (95% confidence intervals) comparing participants with versus without aTRH were as follows: coronary heart disease (1.44 [1.18–1.76]), stroke (1.57 [1.18–2.08]), all-cause mortality (1.30 [1.11–1.52]), heart failure (1.88 [1.52–2.34]), peripheral artery disease (1.23 [0.85–1.79]), and end-stage renal disease (1.95 [1.11–3.41]). aTRH was also associated with the pooled outcomes of combined coronary heart disease (hazard ratio, 1.47; 95% confidence interval, 1.26–1.71) and combined cardiovascular disease (hazard ratio, 1.46; 95% confidence interval, 1.29–1.64). These results demonstrate that aTRH increases the risk for cardiovascular disease and end-stage renal disease. Studies are needed to identify approaches to prevent aTRH and reduce risk for adverse outcomes among individuals with aTRH.

Epidemiologically, there is a strong relationship between BMI and blood pressure (BP) levels. We prospectively examined randomization to first-step chlorthalidone, a thiazide-type diuretic; amlodipine, a calcium-channel blocker; and lisinopril, an angiotensin-converting enzyme inhibitor, on BP control and cardiovascular outcomes in a hypertensive cohort stratified by baseline BMI [kg/m(2); normal weight (BMI25), overweight (BMI = 25-29.9), and obese (BMI30)].In a randomized, double-blind, practice-based Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, 33,357 hypertensive participants, aged at least 55 years, were followed for an average of 4.9 years, for a primary outcome of fatal coronary heart disease or nonfatal myocardial infarction, and secondary outcomes of stroke, heart failure, combined cardiovascular disease, mortality, and renal failure.Of participants, 37.9% were overweight and 42.1% were obese at randomization. For each medication, BP control (140/90 mmHg) was equivalent in each BMI stratum. At the fifth year, 66.1, 66.5, and 65.1% of normal-weight, overweight, and obese participants, respectively, were controlled. Those randomized to chlorthalidone had highest BP control (67.2, 68.3, and 68.4%, respectively) and to lisinopril the lowest (60.4, 63.2, and 59.6%, respectively) in each BMI stratum. A significant interaction (P = 0.004) suggests a lower coronary heart disease risk in the obese for lisinopril versus chlorthalidone (hazard ratio 0.85, 95% confidence interval 0.74-0.98) and a significant interaction (P = 0.011) suggests a higher risk of end-stage renal disease for amlodipine versus chlorthalidone in obese participants (hazard ratio 1.49, 95% confidence interval 1.06-2.08). However, these results were not consistent among other outcomes.BMI status does not modify the effects of antihypertensive medications on BP control or cardiovascular disease outcomes.

Background: Research on the association between antihypertensive drug treatment (HTDT) and cancer is equivocal. We tested the hypothesis that large, rapid decreases in blood pressure following HTDT are associated with higher cancer mortality. Methods: Data from the Systolic Hypertension in the Elderly Program (SHEP) with 15-year cause-specific follow-up for mortality were used. We used changes from baseline in seated and standing systolic blood pressure (SBP) measurements at 3, 6, 9, and 12 months after the initiation of HTDT. Hazard ratios adjusted for demographics, comorbidities, and competing risk of non–cancer-related deaths were estimated to determine the association between SBP change, as a continuous or time-dependent measure, and cancer-related death. Results: SHEP participants taking antihypertensive medication who exhibited a decrease in seated SBP of 29 mm Hg or more (50th percentile and above) at 3 months were at a 58% greater risk of cancer-related death during a 15-year follow-up compared with those with no decrease in SBP (P = 0.007, 42% increased risk P = 0.02 for standing SBP). Those participants whose maximal seated SBP change occurred in the first 3 months of treatment had 2.6-times greater risk of cancer mortality compared with those whose maximal seated SBP change occurred at 12 months (P = 0.004). Conclusions: Large SBP decreases early in HTDT were associated with an increased risk of cancer-related death during a 15-year follow-up. Further studies are needed to confirm and explore the potential mechanisms for this association. Impact: Rapid decreases in blood pressure following HTDT may be a risk factor for cancer. Cancer Epidemiol Biomarkers Prev; 23(8); 1589–97. ©2014 AACR.

Previous studies of blood pressure visit-to-visit variability (VVV) were of rather short duration and rarely included placebo. We investigated VVV of systolic blood pressure (SBP) in the active and placebo groups of Systolic Hypertension in the Elderly Program (SHEP). SHEP was a placebo-controlled

Background: TCD With Transfusions Changing to Hydroxyurea (TWiTCH, ClinicalTrials.gov NCT01425307), an NHLBI-sponsored Phase III multicenter trial, compared transfusions to hydroxyurea for maintaining TCD velocities in children with sickle cell anemia who previously received transfusions for abnormal TCD velocities. Iron overload was treated with serial phlebotomy in children randomized to hydroxyurea. At the first scheduled interim analysis, non-inferiority of hydroxyurea was demonstrated and the study was terminated prematurely. Methods: Participants randomized to hydroxyurea received decreasing volumes of monthly transfusions during hydroxyurea dose escalation to maximum tolerated dose (MTD), averaging 6-7 months. During this transfusion overlap period, no chelation therapy was given. After hydroxyurea MTD was reached, transfusions were discontinued and children started monthly phlebotomy if their entry liver iron concentration (LIC) by MRI-R2 (FerriScan®) was ≥2 mg Fe/g dry weight liver (DWL). The prescribed phlebotomy volume was 10 mL/kg (maximum 500 mL) with adjustments for anemia (5 mL/kg for Hb 8.0-8.5 g/dL and held if Hb Results: Sixty children (mean age 9.7±3.2 years; range 5.2-19.0 years; 48% male) were randomized to the Hydroxyurea Treatment Arm. The average duration of previous transfusions was 4.5±2.8 years. Almost all (51/60, 85%) had previously received chelation, primarily deferasirox, and 48 (80%) were on chelation therapy at study enrollment. Hydroxyurea MTD was achieved in 57 children (95%), and 54 commenced phlebotomy (two had low iron burden with LIC A total of 18 Adverse Events (17 Grade 2 and one Grade 3) occurred in 14 participants in association with phlebotomy (2.3% prevalence). The most common complication was light headedness/near-syncope (6) followed by anemia (4), hypotension (3), headache (3), and pain at the venous access site (1). One subject had a syncopal episode followed by transient weakness, which was centrally adjudicated as TIA. An average of 53.6±21.8 mL/kg blood was administered in the hydroxyurea-treated arm, which calculates to an average iron loading of 40.1±16.3 mg Fe/kg, while an average of 112 mL/kg of venous blood was removed by phlebotomy, which calculates to an average iron unloading of 36.1±15.7 mg Fe/kg. For the 54 children who received phlebotomy, the average LIC was 12.0± 9.7 mg/g at study entry, 13.4±10.3 at midpoint reflecting overlap transfusions without chelation, and 9.7±8.9 at study exit reflecting serial phlebotomy, for an average net LIC decrease of 2.3±4.1 mg/g. Average serum ferritin at study entry was 3105±741 ng/mL and 1392±1542 ng/mL at study exit. For 39 children who completed all 24 months of treatment before study closure, the overall average LIC decrease was 3.2±3.8 mg/gram DWL and 10 had final LIC measurements Conclusions: In the TWiTCH trial, phlebotomy was a feasible, safe, well-tolerated, and effective treatment for transfusional iron overload in children with sickle cell anemia. Although initial overlap transfusions without chelation limited the phlebotomy effects, in children who reached hydroxyurea MTD and discontinued chronic transfusions, monthly phlebotomy led to net iron unloading and lower LIC, and significantly reduced iron burden. Disclosures Rogers: Apopharma: Consultancy. Kalfa:Baxter/Baxalta/Shire: Research Funding. Kwiatkowski:Sideris Pharmaceuticals: Consultancy; Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Apopharma: Research Funding; Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shire Pharmaceuticals: Consultancy. Wood:World Care Clinical: Consultancy; Biomed Informatics: Consultancy; Biomed Informatics: Consultancy; Celgene: Consultancy; Celgene: Consultancy; AMAG: Consultancy; Apopharma: Consultancy; Apopharma: Consultancy; AMAG: Consultancy; World Care Clinical: Consultancy; Vifor: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy. Ware:Global Blood Therapeutics: Consultancy; Biomedomics: Research Funding; Bayer Pharmaceuticals: Consultancy; Addmedica: Research Funding; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding.

History and physical, target organ damage, and biomarkers are used to estimate risk in patients with hypertension. Orthostatic hypertension is a marker of elevated risk that can be identified during physical examination but is not usually appreciated by clinicians. Vital status and cause of death

A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and ≥ 1 other coronary heart disease risk factors to receive chlorthalidone (n=15,002), amlodipine (n=8898), or lisinopril (n=8904) for 4 to 8 years, when double-blinded therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up. Primary outcome was cardiovascular mortality and secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post-trial period, data are not available on medications or blood pressure levels. No significant differences (P.05) appeared in cardiovascular mortality for amlodipine (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.93-1.06) or lisinopril (HR, 0.97; CI, 0.90-1.03), each compared with chlorthalidone. The only significant differences in secondary outcomes were for heart failure, which was higher with amlodipine (HR, 1.12; CI, 1.02-1.22), and stroke mortality, which was higher with lisinopril (HR, 1.20; CI, 1.01-1.41), each compared with chlorthalidone. Similar to the previously reported in-trial result, there was a significant treatment-by-race interaction for cardiovascular disease for lisinopril vs chlorthalidone. Black participants had higher risk than non-black participants taking lisinopril compared with chlorthalidone. After accounting for multiple comparisons, none of these results were significant. These findings suggest that neither calcium channel blockers nor angiotensin-converting enzyme inhibitors are superior to diuretics for the long-term prevention of major cardiovascular complications of hypertension.

Context In the Systolic Hypertension in the Elderly Program (SHEP) trial, conducted between 1985 and 1990, antihypertensive therapy with chlorthalidone-based stepped-care therapy resulted in a lower rate of cardiovascular events than placebo but effects on mortality were not significant. Objective To study the gain in life expectancy of participants randomized to active therapy at the 22-year follow-up. Design, Setting, and Participants A National Death Index ascertainment of death in the long-term follow-up of a randomized, placebo-controlled, clinical trial (SHEP) of patients aged 60 years or older with isolated systolic hypertension. Recruitment was between March 1, 1985, and January 15, 1988. After the end of a 4.5-year randomized phase of the SHEP trial, all participants were advised to receive active therapy. The time interval between the beginning of recruitment and the ascertainment of death by National Death Index (December 31, 2006) was approximately 22 years (21 years 10 months). Main Outcome Measures Cardiovascular death and all-cause mortality. Results At the 22-year follow-up, life expectancy gain, expressed as the area between active (n = 2365) and placebo (n = 2371) survival curves, was 105 days (95% CI, −39 to 242; P = .07) for all-cause mortality and 158 days (95% CI, 36-287; P = .009) for cardiovascular death. Each month of active treatment was therefore associated with approximately 1 day extension in life expectancy. The active treatment group had higher survival free from cardiovascular death vs the placebo group (hazard ratio [HR], 0.89; 95% CI, 0.80-0.99; P = .03) but similar survival for all-cause mortality (HR, 0.97; 95% CI, 0.90-1.04; P = .42). There were 1416 deaths (59.9%) in the active treatment group and 1435 deaths (60.5%) in the placebo group (log-rank P = .38, Wilcoxon P = .24). Cardiovascular death was lower in the active treatment group (669 deaths [28.3%]) vs the placebo group (735 deaths [31.0%]; log-rank P = .03, Wilcoxon P = .02). Time to 70th percentile survival was 0.56 years (95% CI, −0.14 to 1.23) longer in the active treatment group vs the placebo group (11.53 vs 10.98 years; P = .03) for all-cause mortality and 1.41 years (95% CI, 0.34-2.61; 17.81 vs 16.39 years; P = .01) for survival free from cardiovascular death. Conclusion In the SHEP trial, treatment of isolated systolic hypertension with chlorthalidone stepped-care therapy for 4.5 years was associated with longer life expectancy at 22 years of follow-up.

Response: We read with interest the comments of Dr Bath and his associates related to our article. The focus of our report was the persistence of the effect of chlorthalidone-based therapy in significantly decreasing cardiovascular mortality up to 14.3 years after randomization in spite of the advice to all SHEP participants to receive …

Background Dyslipidemia is common in patients with chronic kidney disease. The role of statin therapy in the progression of kidney disease is unclear. Study Design Prospective randomized clinical trial, post hoc analyses. Setting & Participants 10,060 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (lipid-lowering component) stratified by baseline estimated glomerular filtration rate (eGFR): less than 60, 60 to 89, and 90 or greater mL/min/1.73 m 2 . Mean follow-up was 4.8 years. Intervention Randomized; pravastatin, 40 mg/d, or usual care. Outcomes & Measurements Total, high-density lipoprotein, and low-density lipoprotein cholesterol; end-stage renal disease (ESRD), eGFR. Results Through year 6, total cholesterol levels decreased in the pravastatin (−20.7%) and usual-care groups (−11.2%). No significant differences were seen between groups for rates of ESRD (1.36 v 1.45/100 patient-years; P = 0.9), composite end points of ESRD and 50% or 25% decrease in eGFR, or rate of change in eGFR. Findings were consistent across eGFR strata. In patients with eGFR of 90 mL/min/1.73 m 2 or greater, the pravastatin arm tended to have a higher eGFR. Limitations Proteinuria data unavailable, post hoc analyses, unconfirmed validity of the Modification of Diet in Renal Disease Study equation in normal eGFR range, statin drop-in rate in usual-care group with small cholesterol differential between groups. Conclusions In hypertensive patients with moderate dyslipidemia and decreased eGFR, pravastatin was not superior to usual care in preventing clinical renal outcomes. This was consistent across the strata of baseline eGFR. However, benefit from statin therapy may depend on the degree of the cholesterol level decrease achieved.

Transcranial Doppler (TCD) screening in children with sickle cell anemia (SCA) identifies abnormally elevated cerebral artery flow velocities that confer an elevated risk for primary stroke. Chronic transfusions offer effective stroke prophylaxis in this setting, but must be continued indefinitely and lead to transfusional iron overload. An alternative treatment strategy that offers similar effective protection against primary stroke, and provides control of iron overload, is needed. TCD With Transfusions Changing to Hydroxyurea (TWiTCH, NCT01425307) was an NHLBI-funded Phase III multicenter randomized clinical trial comparing 24-months of standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with SCA and abnormal TCD velocities. All eligible children had received at least 12 months of transfusions. TWiTCH had a non-inferiority trial design; the primary study endpoint was the 24-month TCD velocity obtained from a linear mixed model, controlling for baseline (enrollment) values, with a non-inferiority margin of 15 cm/sec. The transfusion arm maintained children at HbS 240 cm/sec. Exit brain MRI/MRA exams documented no new parenchymal abnormalities but one child (transfusion arm) developed new vasculopathy. Sickle cell related serious adverse events were more common in the hydroxyurea arm than the transfusion arm (23 to 15), but none was related to study treatment or study procedures. Iron overload improved more in the hydroxyurea arm than in the transfusion arm, with a greater average change in serum ferritin (-1085 compared to -38 ng/mL, p Disclosures Ware: Eli Lilly: Other: DSMB membership; Bayer Pharmaceuticals: Consultancy; Bristol Myers Squibb: Research Funding; Biomedomics: Research Funding. Off Label Use: Hydroxyurea for children with SCA. Owen:Novartis: Speakers Bureau. Rogers:BioRad Labs: Consultancy; Apopharma: Consultancy; Baxter: Consultancy; Glaxo Smith Kline: Consultancy. Kwiatkowski:Shire Pharmaceuticals and Sideris Pharmaceuticals: Consultancy; Sideris Pharmaceuticals: Consultancy; Novartis: Research Funding; ISIS: Membership on an entity's Board of Directors or advisory committees. Heeney:Sancillio: Consultancy; Eli Lilly: Research Funding. Nottage:Janssen Pharmaceuticals: Employment. Cohen:Novartis: Consultancy; ApoPharma: Other: DSMB member.

Introduction: Transcranial Doppler ultrasonography (TCD) is an established screening modality used to predict stroke in children with sickle cell anemia (SCA). Children with abnormal TCD velocities are at high risk for primary stroke. Based on STOP and STOP 2 data, indefinite chronic red cell transfusion therapy is recommended for children with SCA and abnormal TCD velocity, defined as a maximum time-averaged mean velocity (TAMV) ≥200 cm/sec. The aim of the current analysis was to evaluate the long term effects of transfusion therapy on TCD velocities, in a large cohort of children with SCA who received chronic red cell transfusion therapy for primary stroke prophylaxis. Methods: The TCD With Transfusions Changing to Hydroxyurea (TWiTCH) study is a phase III, randomized, controlled, multicenter non-inferiority trial comparing hydroxyurea to transfusions for primary stroke prevention in children with SCA and abnormal TCD velocities (ClinicalTrials.gov NCT01425307). Children with SCA and a history of abnormal TCD who received at least 12 months of transfusion therapy were eligible to participate. All subjects’ index TCD velocities (the TCD examination that prompted the start of chronic transfusion therapy) were reviewed centrally to confirm study eligibility. At enrollment, study TCD velocities were obtained using the SONARA/tek TCD Module by trained examiners and reviewed centrally. In addition, all children were evaluated with brain magnetic resonance angiography (MRA) scans, which were also reviewed centrally. Associations between demographic, clinical, radiological, and laboratory findings and index/enrollment TCD velocities were examined. Results: One hundred and thirty eight children with complete data were included in this analysis. Mean age for the entire cohort at enrollment was 9.8±2.8 years; 40% were male and 98.8% had HbSS. Mean age at the diagnosis of index TCD was 5.5±2 years. The mean duration of transfusion therapy was 4.3±2.4 years with 63% receiving simple transfusions, 30% receiving partial exchange transfusions, and 7% undergoing erythrocytapheresis. The mean pre-transfusion hemoglobin at study entry was 9.1±0.8 gm/dL and the mean pre-transfusion %HbS for the last 6 months prior to study entry was 29.5±8.3%. The average index TCD TAMV was 217±22 cm/sec (range 147-325). At study entry, the average TAMV was lower at 150±27cm/sec overall (142±27 cm/sec on the left and 140±29 cm/sec on the right). In 77% of the subjects, the TCD velocities had decreased to normal levels ( Conclusions: Most of the children with SCA at high risk for primary stroke enrolled in the TWiTCH study have normal TCD velocities at study entry, although 21% have conditional and 3% still have abnormal velocities. Longer duration of transfusion therapy was associated with lower TCD velocities, while the presence of severe vasculopathy on brain MRA and recent higher pre-transfusion %HbS values were associated with higher TCD velocities. The TWiTCH trial will serially perform TCD examinations to compare the effects of hydroxyurea versus transfusions. Disclosures Off Label Use: Use of hydroxyurea in children with sickle cell disease.

Introduction : Stroke is a major cause of morbidity and mortality in children with sickle cell anemia (SCA), and current efforts seek to prevent primary stroke in this high-risk population through transcranial Doppler (TCD) screening programs and prophylactic blood transfusions for children with abnormally high intracranial TCD velocities. During the SWITCH trial (ClinicalTrials.gov NCT00122980), a novel MRA vasculopathy grading (VOG) scale was developed, which documented baseline bilateral vessel stenosis and parenchymal injury in children receiving transfusions for secondary stroke prophylaxis, and provided a severity scale suitable for future clinical trials. We now describe the baseline brain magnetic resonance imaging/angiography (MRI/MRA) results and vasculopathy grading scores in children with SCA on primary stroke prophylaxis, and report correlations with intracranial TCD velocities and duration of transfusion. Methods: TCD With Transfusions Changing to Hydroxyurea (TWiTCH) is a Phase three randomized, controlled, multicenter clinical trial (ClinicalTrials.gov NCT01425307), comparing transfusions versus hydroxyurea for children with abnormal TCD velocities. Children were eligible for TWiTCH enrollment if they currently receive monthly transfusions for primary stroke prophylaxis, and had no known history of stroke, transient ischemic attack, or severe vasculopathy. All TWiTCH participants underwent baseline MRI/MRA examinations with central review after study enrollment. Baseline TCD examinations were also centrally reviewed and Time-Averaged Mean Velocities (TAMV) were recorded for the distal internal carotid artery (dICA), internal carotid bifurcation (BIF), first segment middle cerebral artery (MCA) = M1, mid MCA (MCA), and posterior cerebral artery (PCA). MRA vasculopathy grades were recorded bilaterally and compared to the TCD velocities and duration of transfusion. Results: Of 159 enrolled subjects, 143 had complete baseline MRI/MRA data. The mean age at study enrollment was 9.8 years, with a 2:3 male:female ratio, and mean age at the original abnormal (Index) TCD exam was 5.4 years. A total of 62 children had parenchymal abnormalities identified on baseline brain MRI, including 2 with infarcts, 54 with leukoencephalopathy, 5 with encephalomalacia, and 20 with lacunae lesions (not mutually exclusive). A total of 124 children had baseline MRA vasculopathy scores ≤3, while 19 had grades 4-6 (severe vasculopathy) that required removal from the study. There were significant positive associations between the baseline hemisphere vasculopathy grades and the corresponding TAMV velocities in the Left dICA (p=0.02), Left BIF (p˂.0001), Left MCA (p=.0002), Right BIF (p=.0003) and Right MCA (p=.0002). Likewise, when TCD velocities were categorized as low ( Conclusions: Since the TWiTCH study excluded the enrollment of children on chronic transfusion therapy for primary stroke prevention with a known history of stroke, TIA, or severe vasculopathy, the prevalence of baseline brain MRI and MRA abnormalities was relatively higher than expected and 19 participants failed screening due to unrecognized severe vessel stenosis. The recent published SWiTCH vasculopathy grading scale was validated in the TWiTCH population, with more severe stenosis found to be associated with higher ipsilateral TCD velocities. Exit brain MRI/MRA exams will be compared to entry studies, to provide longitudinal data including comparisons between the effects of continued transfusions and hydroxyurea. Disclosures No relevant conflicts of interest to declare.

Introduction Chronic transfusion therapy is the standard of care for children with sickle cell anemia (SCA) and abnormal transcranial Doppler velocities. Although effective, monthly transfusions are costly, inconvenient, and produce iron overload in the liver and extrahepatic organs. The TWiTCH study (ClinicalTrials.gov NCT01425307) is a randomized clinical trial to determine whether hydroxyurea therapy leads to comparable time averaged TCD velocities as conventional transfusion therapy, while reducing somatic iron stores. We report baseline data on iron burden in the spleen, pancreas, and kidneys from the TWiTCH cohort. Methods Pediatric patients from 22 centers underwent screening R2* assessment of the liver, spleen, pancreas, and kidneys. All sites used a 1.5 Tesla magnet, torso phased array coils, and a multiple echo gradient echo sequence with a minimum echo time ≤1.3 ms. Images were analyzed centrally at Children’s Hospital Los Angeles; core laboratory staff were blinded to patient, site, and visit data. Raw R2* values were used as iron surrogates for spleen, pancreas, and kidney. All statistics were performed by the TWiTCH Data Coordinating Center. Results A total of 113/159 enrolled patients (mean age 8.8 ± 6.3 years) successfully completed baseline abdominal R2* assessment (Table 1). Patients had received chronic transfusions for 4.2 ± 2.4 years and iron chelation for 3.2 ± 2.2 years. Serum ferritin values ranged from 191 to 10593 ng/ml (2655.6 ± 1668.1 ng/ml). All subjects had liver iron detectable by R2*, with 51.3% having liver iron concentration (LIC) >7 mg/g, and 13.3% >15 mg/g of dry weight. Splenic R2* could be assessed in 80/113 (71%) subjects, with the remainder having surgical splenectomy or autoinfarction. Splenic R2* revealed splenic tissue was comparable to liver tissue containing on average 13.1 mg Fe/g of dry weight. Pancreas R2* was greater than the upper limits of normal in 39.3% but no values exceeded 100 Hz (the level associated with pancreas dysfunction, pituitary iron accumulation, and cardiac iron deposition in thalassemia patients). LIC was the only significant predictor of pancreas R2* (r2 = 0.06, p=0.001). Kidney R2* was above the upper limits of normal in 79.5% of the patients and demonstrated preferential cortical distribution. Kidney R2* positively correlated with lactate dehydrogenase levels (p < 0.001), positive correlated with LIC R2* (p=0.005) and negatively correlated with hemoglobin level(p = 0.01) with a combined r2 of 0.29. No association was found with total bilirubin or reticulocyte count. Discussion This represents the first multicenter study documenting the prevalence and extent of extrahepatic iron deposition in children with SCA receiving chronic transfusions. Splenic iron deposition was common but uncorrelated with LIC,, suggesting different kinetics of iron loading transport. Clinically-significant pancreatic iron deposition was not observed. Renal R2* tracked with intravascular hemolysis markers, rather than LIC or ferritin, consistent with tubular uptake of filtered cell-free hemoglobin. Overall, chronically transfused children with SCA have greater splenic and renal iron deposition, but much milder pancreatic iron overload, than that observed in transfused thalassemia patients. Disclosures: Wood: Novartis: Honoraria; Apopharma: Honoraria, Patents & Royalties; Shire: Consultancy, Research Funding. Off Label Use: Hydroxyurea is FDA-approved for use in adults but not children. Thompson:Amgen: Research Funding; Eli Lilly: Research Funding; Glaxo Smith Kline: Research Funding; ApoPharma: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; bluebird bio: Research Funding.

Strategies are needed to improve the translation of clinical trial results into practice. We assessed the impact of the ALLHAT/JNC7 Dissemination Project's academic detailing component on thiazide-type diuretic prescribing (ALLHAT indicates Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; JNC7 indicates the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure).We used 2 national databases available from IMS Health: a physician survey of medications reported for hypertension and a pharmacy dispensing database on antihypertensive medications. At a county level, we correlated medication data with Dissemination Project intensity. Practices before the Dissemination Project in 2004 were compared with those after its completion in 2007. We also examined 2000-2008 national trends.Academic detailing reached 18 524 physicians in 1698 venues via 147 investigator-educators. We noted an association between ALLHAT/JNC7 academic detailing activities and increased prescribing of thiazide-type diuretics. Physician survey data showed that the percentage of hypertension visits where the physician recorded a thiazide-type diuretic increased the most in counties where academic detailing activity was the highest (an increase of 8.6%, from 37.9% to 46.5%) compared with counties where activity was moderate (an increase of 2%) or low (a decrease of 2%), or where there was none (an increase of 2%; P value for trend,.05). Pharmacy dispensing data showed that thiazide-type diuretic prescribing increased by 8.7% in counties with Dissemination Project activities compared with 3.9% in those without activities (P.001). Nationally, thiazide-type diuretic use did not increase between 2004 and 2008.The ALLHAT/JNC7 Dissemination Project was associated with a small effect on thiazide-type diuretic use consistent with its small dose and the potential of external factors to diminish its impact. Academic detailing may increase physicians' implementation of clinical trial results, thereby making prescribing more consistent with evidence.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is reevaluated considering information from new clinical trials, meta-analyses, and recent subgroup and explanatory analyses from ALLHAT, especially those regarding heart failure (HF) and the association of drug treatment with new-onset diabetes mellitus (DM) and its cardiovascular disease (CVD) consequences. Chlorthalidone was superior to (1) doxazosin mesylate in preventing combined CVD (CCVD) (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.13-1.27), especially HF (RR, 1.80; 95% CI, 1.40-2.22) and stroke (RR, 1.26; 95% CI, 1.10-1.46); (2) lisinopril in preventing CCVD (RR, 1.10; 95% CI, 1.05-1.16), including stroke (in black persons only) and HF (RR, 1.20; 95% CI, 1.09-1.34); and (3) amlodipine besylate in preventing HF, overall (by 28%) and in hospitalized or fatal cases (by 26%). Central independent blinded reassessment of HF hospitalizations confirmed each comparison. Results were consistent by age, sex, race (except for stroke and CCVD), DM status, metabolic syndrome status, and renal function level. Neither amlodipine nor lisinopril was superior to chlorthalidone in preventing end-stage renal disease overall, by DM status, or by renal function level. In the chlorthalidone arm, new-onset DM was not significantly associated with CCVD (RR, 0.96; 95% CI, 0.88-2.42). Evidence from subsequent analyses of ALLHAT and other clinical outcome trials confirm that neither alpha-blockers, angiotensin-converting enzyme inhibitors, nor calcium channel blockers surpass thiazide-type diuretics (at appropriate dosage) as initial therapy for reduction of cardiovascular or renal risk. Thiazides are superior in preventing HF, and new-onset DM associated with thiazides does not increase CVD outcomes.

Background: Antihypertensive drugs with favorable metabolic effects are advocated for first-line therapy in hypertensivepatientswithmetabolic/cardiometabolicsyndrome (MetS). We compared outcomes by race in hypertensiveindividualswithandwithoutMetStreatedwith athiazide-typediuretic(chlorthalidone),acalciumchannel blocker (amlodipine besylate), an -blocker (doxazosin mesylate), or an angiotensin-converting enzyme inhibitor (lisinopril). Methods: A subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind hypertension treatment trial of 42418 participants. We defined MetSashypertensionplusatleast2ofthefollowing:fasting serum glucose level of at least 100 mg/dL, body mass index(calculatedasweightinkilogramsdividedbyheight in meters squared) of at least 30, fasting triglyceride levels of at least 150 mg/dL, and high-density lipoprotein cholesterol levels of less than 40 mg/dL in men or less than 50 mg/dL in women. Results: Significantly higher rates of heart failure were consistentacrossalltreatmentcomparisonsinthosewith MetS.Relativerisks(RRs)were1.50(95%confidenceinterval, 1.18-1.90), 1.49 (1.17-1.90), and 1.88 (1.422.47) in black participants and 1.25 (1.06-1.47), 1.20 (1.01-1.41), and 1.82 (1.51-2.19) in nonblack participants for amlodipine, lisinopril, anddoxazosin comparisons with chlorthalidone, respectively. Higher rates for combined cardiovascular disease were observed with lisinopril-chlorthalidone (RRs, 1.24 [1.09-1.40] and 1.10 [1.02-1.19], respectively) and doxazosin-chlorthalidonecomparisons(RRs,1.37[1.19-1.58]and1.18[1.081.30], respectively) in black and nonblack participants with MetS. Higher rates of stroke were seen in black participants only (RR, 1.37 [1.07-1.76] for the lisinoprilchlorthalidonecomparison,andRR,1.49[1.09-2.03]for the doxazosin-chlorthalidone comparison). Black patients with MetS also had higher rates of end-stage renal disease (RR, 1.70 [1.13-2.55]) with lisinopril compared with chlorthalidone. Conclusions: The ALLHAT findings fail to support the preference for calcium channel blockers, -blockers, or angiotensin-convertingenzymeinhibitorscomparedwith thiazide-type diuretics in patients with the MetS, despite their more favorable metabolic profiles. This was particularly true for black participants. Trial Registration: clinicaltrials.gov Identifier: NCT00000542

Elevated blood glucose levels are reported with thiazide-type diuretic treatment of hypertension. The significance of this finding is uncertain. Our objectives were to compare the effect of first-step antihypertensive drug therapy with thiazide-type diuretic, calcium-channel blocker, or angiotensin-converting enzyme inhibitor on fasting glucose (FG) levels and to determine cardiovascular and renal disease risks associated with elevated FG levels and incident diabetes mellitus (DM) in 3 treatment groups.We performed post hoc subgroup analyses from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) among nondiabetic participants who were randomized to receive treatment with chlorthalidone (n = 8419), amlodipine (n = 4958), or lisinopril (n = 5034) and observed for a mean of 4.9 years.Mean FG levels increased during follow-up in all treatment groups. At year 2, those randomized to the chlorthalidone group had the greatest increase (+8.5 mg/dL [0.47 mmol/L] vs +5.5 mg/dL [0.31 mmol/L] for amlodipine and +3.5 mg/dL [0.19 mmol/L] for lisinopril). The odds ratios for developing DM with lisinopril (0.55 [95% confidence interval, 0.43-0.70]) or amlodipine (0.73 [95% confidence interval, 0.58-0.91]) vs chlorthalidone at 2 years were significantly lower than 1.0 (P.01). There was no significant association of FG level change at 2 years with subsequent coronary heart disease, stroke, cardiovascular disease, total mortality, or end-stage renal disease. There was no significant association of incident DM at 2 years with clinical outcomes, except for coronary heart disease (risk ratio, 1.64; P = .006), but the risk ratio was lower and nonsignificant in the chlorthalidone group (risk ratio, 1.46; P = .14).Fasting glucose levels increase in older adults with hypertension regardless of treatment type. For those taking chlorthalidone vs other medications, the risk of developing FG levels higher than 125 mg/dL (6.9 mmol/L) is modestly greater, but there is no conclusive or consistent evidence that this diuretic-associated increase in DM risk increases the risk of clinical events.

Background Optimal first-step antihypertensive drug therapy in type 2 diabetes mellitus (DM) or impaired fasting glucose levels (IFG) is uncertain. We wished to determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor decreases clinical complications compared with treatment with a thiazide-type diuretic in DM, IFG, and normoglycemia (NG). Methods Active-controlled trial in 31 512 adults, 55 years or older, with hypertension and at least 1 other risk factor for coronary heart disease, stratified into DM (n = 13 101), IFG (n = 1399), and NG (n = 17 012) groups on the basis of national guidelines. Participants were randomly assigned to double-blind first-step treatment with chlorthalidone, 12.5 to 25 mg/d, amlodipine besylate, 2.5 to 10 mg/d, or lisinopril, 10 to 40 mg/d. We conducted an intention-to-treat analysis of fatal coronary heart disease or nonfatal myocardial infarction (primary outcome), total mortality, and other clinical complications. Results There was no significant difference in relative risk (RR) for the primary outcome in DM or NG participants assigned to amlodipine or lisinopril vs chlorthalidone or in IFG participants assigned to lisinopril vs chlorthalidone. A significantly higher RR (95% confidence interval) was noted for the primary outcome in IFG participants assigned to amlodipine vs chlorthalidone (1.73 [1.10-2.72]). Stroke was more common in NG participants assigned to lisinopril vs chlorthalidone (1.31 [1.10-1.57]). Heart failure was more common in DM and NG participants assigned to amlodipine (1.39 [1.22-1.59] and 1.30 [1.12-1.51], respectively) or lisinopril (1.15 [1.00-1.32] and 1.19 [1.02-1.39], respectively) vs chlorthalidone. Conclusion Our results provide no evidence of superiority for treatment with calcium channel blockers or angiotensin-converting enzyme inhibitors compared with a thiazide-type diuretic during first-step antihypertensive therapy in DM, IFG, or NG.

Background: This study was performed to determine whether, in high-risk hypertensive patients with a reduced glomerular filtration rate (GFR), treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of renal disease outcomes compared with treatment with a diuretic. Methods: We conducted post hoc analyses of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertensive participants 55 years or older with at least 1 other coronary heart disease risk factor were randomized to receive chlorthalidone, amlodipine, or lisinopril for a mean of 4.9 years. Renal outcomes were incidence of end-stage renal disease (ESRD) and/or a decrement in GFR of 50% or more from baseline. Baseline GFR, estimated by the simplified Modification of Diet in Renal Disease equation, was stratified into normal or increased (90 mL /min per 1.73 m 2 , n=8126), mild reduction (60-89 mL/min per 1.73 m 2 , n=18 109), or moderate-severe reduction (60 mL/min per 1.73 m 2 , n=5662) in GFR. Each stratum was analyzed for effects of the treatments on outcomes. Results: In 448 participants, ESRD developed. Compared with patients taking chlorthalidone, no significant differences occurred in the incidence of ESRD in patients taking amlodipine in the mild (relative risk [RR], 1.47; 95% confidence interval [CI], 0.97-2.23) or moderate-severe (RR,0.92; 95% CI, 0.68-1.24) reduction in GFR groups. Compared with patients taking chlorthalidone, no significant differences occurred in the incidence of ESRD in patients taking lisinopril in the mild (RR, 1.34; 95% CI, 0.87-2.06) or moderate-severe (RR,0.98; 95% CI, 0.73-1.31) reduction in GFR groups. In patients with mild and moderate-severe reduction in GFR, the incidence of ESRD or 50% or greater decrement in GFR was not significantly different in patients treated with chlorthalidone compared with those treated with amlodipine (odds ratios, 0.96 [P = .74] and 0.85 [P=.23], respectively) and lisinopril (odds ratios, 1.13 [P=.31] and 1.00 [P=.98], respectively). No difference in treatment effects occurred for either end point for patients taking amlodipine or lisinopril compared with those taking chlorthalidone across the 3 GFR subgroups, either for the total group or for participants with diabetes at baseline. At 4 years of follow-up, estimated GFR was 3 to 6 mL/min per 1.73 m 2 higher in patients assigned to receive amlodipine compared with chlorthalidone, depending on baseline GFR stratum. Conclusions: In hypertensive patients with reduced GFR, neither amlodipine nor lisinopril was superior to chlorthalidone in reducing the rate of development of ESRD or a 50% or greater decrement in GFR. Participants assigned to receive amlodipine had a higher GFR than those assigned to receive chlorthalidone, but rates of development of ESRD were not different between the groups. Arch Intern Med. 2005;165:936-946

Background: The prevalence of reduced glomerular filtration rate (GFR) in older hypertensive patients and the relationship between level of GFR and cardiovascular disease (CVD) and its risk factors are not well known. Methods: We evaluated baseline renal function in 40514 hypertensive patients 55 years or older who were enrolled in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). We used the simplified Modification of Diet in Renal Disease study equation to estimate GFR and examined the prevalence of CVD in patients with different levels of GFR. Results: Fifty-seven percent of patients had mild (60-89 mL/min per 1.73 m 2 ), 17.2% had moderate (30-59 mL/ min per 1.73 m 2 ), and 0.6% had severe (29 mL/min per 1.73 m 2 ) reductions in GFR. Compared with patients with normal or mildly reduced GFR, patients with moderate or severe reductions in GFR were more likely to have had a prior myocardial infarction or stroke (19.2% and 23.4% vs 28.7% and 26.9%, respectively), have ischemic changes on electrocardiography (ECG) (16.0% and 18.9% vs 24.6% and 34.1%, respectively), and have left ventricular hypertrophy on ECG (ECG-LVH) (3.9% and 4.2% vs 6.0% and 11.2%, respectively). A decrease in GFR of 10 mL/min per 1.73 m 2 was independently associated with a 6% higher risk for CVD and 14% higher risk for ECG-LVH. The increase in risk was marked at a GFR of approximately 60 to 70 mL/min per 1.73 m 2 . Conclusions: The prevalence of reduced GFR is high in older hypertensive patients. Patients with moderate or severe reduction in GFR are more likely to have a history of CVD and ECG-LVH. Even modest reductions in GFR are independently associated with a higher prevalence of CVD and ECG-LVH. Arch Intern Med. 2004;164:969-976