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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.

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.

This review summarizes the impact of thiazide diuretics on fracture risk in older hypertensive individuals. We performed a post hoc evaluation of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, a randomized, prospective, double blind hypertension study comparing a thiazide-like diuretic, a calcium channel blocker (CCB), and an angiotensin converting enzyme inhibitor (ACEi). We examined the risk of hip and pelvic fractures during the in-trial period (n = 22,180 participants; mean 4.9-year follow-up) and during the post-trial period using national data bases (n = 16,622 participants) (mean total follow-up 7.8 years). During the trial, participants randomized to the thiazide diuretic versus the CCB or the ACEi had a lower risk of fracture on adjusted analyses (HR 0.79 [95% CI, 0.63, 0.98], p = 0.04). Risk of fracture was significantly lower in participants randomized to the diuretic as compared to those randomized to the ACEi (HR 0.75 [95% CI, 0.58, 0.98]; p = 0.04), but not significantly different compared to the CCB (HR 0.87 [95% CI, 0.71, 1.09]; p = 0.17). Over the entire trial and post-trial period of follow-up, the cumulative incidence of fractures was non-significantly lower in participants assigned to the diuretic vs assignment to the ACEi or the CCB (HR 0.87 [0.74–1.03], p = 0.10) and versus each medication separately. These findings establish a benefit for thiazide diuretic treatment for the prevention of fractures versus other commonly used antihypertensive medications using prospective, randomized data. The effects of the thiazide diuretic on bone appear to be long lasting.

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.

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.

BACKGROUND/OBJECTIVES Chronic kidney disease (CKD) and cancer are both common in older patients; whether CKD increases risk for cancer is unclear. This study evaluated CKD as a risk factor for cancer mortality in a large cohort of hypertensive patients. STUDY DESIGN We did post-hoc analyses of in-trial and post-trial data from participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). SETTING AND PARTICIPANTS Participants were ≥ 55 years old with hypertension and one other additional risk factor for coronary heart disease. PREDICTOR Baseline estimated glomerular filtration rate (eGFR). OUTCOMES Cancer mortality was ascertained by cancer-related deaths reported in national databases during and after the trial. Cox proportional hazard models were used to calculate hazard ratios (HRs) adjusted for possible confounders and were stratified by baseline GFR. RESULTS Participants' mean age was 66.9 years. After a mean follow-up of 8.9 years, there were 2,338 reported cancer-related deaths. Participants with GFR < 45 mL/min/1.73 m2 were at increased risk of cancer mortality compared to those with GFR ≥ 90 mL/min/1.73 m2 (adjusted HR 1.54 (1.22 - 1.94), p-value for trend 0.004). These findings were consistent across subgroups defined by race, gender, and diabetes. Participants with GFR < 45 mL/min/1.73 m2 were at higher risk for mortality related to colon cancer (p-value for trend 0.048, HR 2.28 (1.12 - 4.62)) and urinary tract cancer (p-value for trend 0.001, adjusted HR 2.95 (1.14 - 7.65)). LIMITATIONS This is a post hoc analysis of clinical trial data. CONCLUSIONS In a large cohort of hypertensive patients, GFR < 45 mL/min/1.73 m2 was associated with a higher risk of cancer-related mortality.

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.

Diuretic-based antihypertensive therapy is associated with the development of diabetes but with improved clinical outcomes. It has been proposed that the duration of clinical trials has been too short to detect the adverse effects of diabetes. We assessed the long-term mortality rate of subjects in the Systolic Hypertension in the Elderly Program (n = 4,732) who were randomized to stepped-care therapy with 12.5 to 25.0 mg/day of chlorthalidone or matching placebo. If blood pressure remained above the goal, atenolol or matching placebo was added. At a mean follow-up of 14.3 years, cardiovascular (CV) mortality rate was significantly lower in the chlorthalidone group (19%) than in the placebo group (22%; adjusted hazard ratio [HR] 0.854, 95% confidence interval [CI] 0.751 to 0.972). Diabetes at baseline (n = 799) was associated with increased CV mortality rate (adjusted HR 1.659, 95% CI 1.413 to 1.949) and total mortality rate (adjusted HR 1.510, 95% CI 1.347 to 1.693). Diabetes that developed during the trial among subjects on placebo (n = 169) was also associated with increased CV adverse outcome (adjusted HR 1.562, 95% CI 1.117 to 2.184) and total mortality rate (adjusted HR 1.348, 95% CI 1.051 to 1.727). However, diabetes that developed among subjects during diuretic therapy (n = 258) did not have significant associations with CV mortality rate (adjusted HR 1.043, 95% CI 0.745 to 1.459) or total mortality rate (adjusted HR 1.151, 95% CI 0.925 to 1.433). Diuretic treatment in subjects who had diabetes was strongly associated with lower long-term CV mortality rate (adjusted HR 0.688, 95% CI 0.526 to 0.848) and total mortality rate (adjusted HR 0.805, 95% CI 0.680 to 0.952). Thus, chlorthalidone-based treatment improved long-term outcomes, especially among subjects who had diabetes. Subjects who had diabetes associated with chlorthalidone had no significant increase in CV events and had a better prognosis than did those who had preexisting diabetes.

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.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized clinical outcome trial of antihypertensive and lipid-lowering therapy in a diverse population (including substantial numbers of women and minorities) of 42,419 high-risk hypertensives aged > or = 55 years with a planned mean follow-up of 6 years. In this paper, we describe our experience in the identification, recruitment, and selection of clinical centers for this large simple trial capable of meeting the recruitment goals outlined for ALLHAT, and we highlight factors associated with clinical center performance. Over 135,000 recruitment brochures were mailed to physicians. Requests for information and application packets were received from 9351 (6.8%) interested investigators. A total of 1053 completed applications were received and 909 sites (86%) were eventually approved to join the trial. Of the approved sites, 278 either later declined participation or were never activated, and 8 were closed within a year for lack of enrollment. The final 623 randomizing centers exceeded the trial's recruitment goal to enroll at least 40,000 participants into the trial, although the recruitment period was extended 1.5 years longer than planned. Fewer than a quarter of the sites (22.6%) were recruited from academic medical centers or Department of Veterans Affairs Medical Centers. More than half of the sites (54.7%) were private solo or group practices, which contributed 53% of randomized participants. Community health centers comprised about 8% of the ALLHAT sites and 2.9% were part of health maintenance organizations. More than 22% of the principal investigators reported that they had no previous clinical research experience. In summary, ALLHAT was successful in recruiting a diverse group of clinical centers to achieve its patient recruitment goals.

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, practice-based trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI). The double-blind, active-controlled component of ALLHAT was designed to determine whether the rate of the primary outcome-a composite of fatal coronary heart disease and nonfatal myocardial infarction-differs between diuretic (chlorthalidone) treatment and each of three other classes of antihypertensive drugs: a calcium antagonist (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin) in high-risk hypertensive persons ages 55 years and older. In addition, 10,377 ALLHAT participants with mild to moderate hypercholesterolemia were also enrolled in a randomized, open-label trial designed to determine whether lowering serum LDL cholesterol with an HMG CoA reductase inhibitor (pravastatin) will reduce all-cause mortality as compared to a control group receiving "usual care." In January 2000, an independent data review committee recommended discontinuing the doxazosin treatment arm. The NHLBI director promptly accepted the recommendation. This article discusses the steps involved in the orderly closeout of one arm of ALLHAT and the dissemination of trial results. These steps included provisional preparations; the actual decision process; establishing a timetable; forming a transition committee; preparing materials and instructions; informing 65 trial officers and coordinators, 628 active clinics and satellite locations, 313 institutional review boards, over 42,000 patients, and the general public; reporting detailed trial results; and monitoring the closeout process. Control Clin Trials 2001;22:29-41

OBJECTIVE: The purpose of this study was to determine older persons' reasons for joining a clinical trial, and to provide data that could be useful in planning and carrying out clinical trials in older and minority populations. DESIGN: A survey. PARTICIPANTS: The sample included 4281 men and women 60 years of age or older who were randomized to the Systolic Hypertension in the Elderly Program (SHEP). MEASUREMENTS: A 10-item satisfaction/attitude questionnaire was designed to evaluate (1) what personal benefits people expect from participation in this trial, (2) motivation for joining, and (3) satisfaction with clinic staff and operations. Each question had a response category asking for a measure of agreement, satisfaction, or importance. RESULTS: The most important reasons for joining the clinical trial were to contribute to science (96%), improve the health of others (96%), and improve their own health (93%). Free medical care and social aspects were less important reasons to join. There were no differences by treatment assignment, but differences in reasons for joining SHEP by age, race, gender, and education were observed. CONCLUSION: Older adults were enthusiastic about clinical trial participation. Recruitment, participant management strategies, and allocation of resources should consider the needs of specific patient groups. J Am Geriatr Soc 45:934–938, 1997.

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.

OBJECTIVE: To assess variability in the use of coronary artery bypass grafting (CABG) and percutaneous transluminal angioplasty (PTCA) in the Systolic Hypertension in the Elderly Program (SHEP) cohort with incident coronary heart disease (CHD) by age, sex, and race. DESIGN: Retrospective analysis of a multicenter prospective cohort study. PATIENTS: Among 4736 subjects initially enrolled in SHEP, there were 432 incident cases of CHD, excluding those patients who experienced rapid or sudden cardiac death. SETTING: Community-based ambulatory population in academic centers. MAIN OUTCOME MEASURE: Incident cases of CHD who underwent CABG or PTCA. RESULTS: Of those participants ≤ 60 and 75 years (P = 0.14). 15.4% of those lt75 underwent CABG surgery, compared with 7.8% of those 75 and older (P = 0.018). When both of these endpoints, CABG and PTCA, were combined, 22.4% of those lt75 underwent a procedure, while only 11.7% of the older cohort did (P = 0.005). Twenty-six percent of men underwent either CABG or PTCA, while only 9.1% of women did (P < 0.001). Of those

Ventricular ectopic activity was recorded at baseline in 5.6% of the 12-lead electrocardiograms and 8.2% of the 2-minute rhythm strips of 4674 subjects with isolated systolic hypertension (systolic blood pressure 160 to 219 mm Hg, diastolic blood pressure 10 VPB on the 2-minute rhythm strip. Correlates of VPB presence on the 12-lead ECG were older-age male sex, presence of Q/QS pattern and higher heart rate. Participants with serum potassium < 3.5 mmol/L had a higher prevalence of VPB. Similarly, the number of VPB on the 2-minute rhythm strip was associated with male sex, increasing age, with lower serum potassium, history of palpitations, and presence of Q/QS patterns.

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.

Purpose of review The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is re-evaluated considering information from recent subgroup and exploratory analyses, other new clinical trials, and meta-analyses. The ALLHAT analyses specifically emphasize heart failure findings, results in Black participants and those with chronic kidney disease, selection and doses of thiazide and similar diuretics, and the association of antihypertensive drug use with new-onset diabetes and its cardiovascular consequences. Recent findings The initial ALLHAT conclusion, that thiazide diuretics are superior to angiotensin-converting enzyme inhibitors (ACEIs), calcium antagonists (CCBs) and alpha-blockers in preventing one or more major clinical outcomes, including heart failure and stroke, and unsurpassed in significantly preventing any cardiovascular or renal outcome, has been further validated for patients with diabetes, renal disease, and/or metabolic syndrome. The evidence is even more compelling for Black patients. New-onset diabetes associated with thiazides did not increase cardiovascular outcomes. The diuretic was superior to all in preventing heart failure with preserved left-ventricular ejection fraction (LVEF) and similar to the ACEI in preventing heart failure with impaired LVEF. It was also unsurpassed in preventing atrial fibrillation. Summary The totality of evidence re-affirms the initial ALLHAT conclusion that thiazide and similar diuretics (at evidence-based doses) are the preferred first-step therapy in most patients with hypertension.

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.

Chronic kidney disease is common in older patients with hypertension.To compare rates of coronary heart disease (CHD) and end-stage renal disease (ESRD) events; to determine whether glomerular filtration rate (GFR) independently predicts risk for CHD; and to report the efficacy of first-step treatment with a calcium-channel blocker (amlodipine) or an angiotensin-converting enzyme inhibitor (lisinopril), each compared with a diuretic (chlorthalidone), in modifying cardiovascular disease (CVD) outcomes in high-risk patients with hypertension stratified by GFR.Post hoc subgroup analysis.Multicenter randomized, double-blind, controlled trial.Persons with hypertension who were 55 years of age or older with 1 or more risk factors for CHD and who were stratified into 3 baseline GFR groups: normal or increased (or = 90 mL/min per 1.73 m2; n = 8126 patients), mild reduction (60 to 89 mL/min per 1.73 m2; n = 18,109 patients), and moderate or severe reduction (60 mL/min per 1.73 m2; n = 5662 patients).Random assignment to chlorthalidone, amlodipine, or lisinopril.Rates of ESRD, CHD, stroke, and combined CVD (CHD, coronary revascularization, angina, stroke, heart failure, and peripheral arterial disease).In participants with a moderate to severe reduction in GFR, 6-year rates were higher for CHD than for ESRD (15.4% vs. 6.0%, respectively). A baseline GFR of less than 53 mL/min per 1.73 m2 (compared with104 mL/min per 1.73 m2) was independently associated with a 32% higher risk for CHD. Amlodipine was similar to chlorthalidone in reducing CHD (16.0% vs. 15.2%, respectively; hazard ratio, 1.06 [95% CI, 0.89 to 1.27]), stroke, and combined CVD (CHD, coronary revascularization, angina, stroke, heart failure, and peripheral arterial disease), but less effective in preventing heart failure. Lisinopril was similar to chlorthalidone in preventing CHD (15.1% vs. 15.2%, respectively; hazard ratio, 1.00 [CI, 0.84 to 1.20]), but was less effective in reducing stroke, combined CVD events, and heart failure.Proteinuria data were not available, and combination therapies were not tested.Older high-risk patients with hypertension and reduced GFR are more likely to develop CHD than to develop ESRD. A low GFR independently predicts increased risk for CHD. Neither amlodipine nor lisinopril is superior to chlorthalidone in preventing CHD, stroke, or combined CVD, and chlorthalidone is superior to both for preventing heart failure, independent of level of renal function.

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.

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.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a practice-based, randomized, multicenter clinical trial in 42,419 high-risk hypertensive patients aged 55 years and older; 10,356 of these patients are also in a lipid-lowering trial component. The purpose of the antihypertensive component is to determine whether the occurrence of fatal coronary heart disease and/or nonfatal myocardial infarction differs between patients randomized to diuretic (chlorthalidone) and those randomized to either calcium antagonist (amlodipine), angiotensin-converting enzyme inhibitor (lisinopril), or alpha-adrenergic blocker (doxazosin) therapy. (The doxazosin arm has been discontinued.) The purpose of the lipid-lowering component is to determine whether lowering low-density lipoprotein cholesterol with a 3-hydroxymethyl-glutaryl coenzyme A reductase inhibitor (pravastatin) in moderately hypercholesterolemic patients will reduce all-cause mortality compared to a control group receiving "usual care." ALLHAT recruited patients from a variety of practice settings from February 1994 through January 1998. Sites were paid for randomizations and are paid for completed follow-up visits and documented study events. Communication and monitoring were facilitated by nine regional coordinator teams. It was recognized from the outset that patient recruitment would be a very large task because of the number of participants (> 40,000) needed, the ambitious nature of the goal for recruitment of African-Americans (> 55%), and the knowledge that many investigators had limited experience recruiting participants for clinical trials. Multiple adjustments in the initial ALLHAT overall recruitment plan facilitated achievement of sample size goals for both components of the trial. The experience obtained from this large trial should be valuable for the planning and implementation of successful recruitment in future trials.

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.

The Systolic Hypertension in the Elderly Program (SHEP) was a randomized multicenter double-blind placebo-controlled trial designed to test the efficacy of antihypertensive drug treatment in persons 60 years of age or older who had isolated systolic hypertension (ISH). ISH was defined as a systolic blood pressure (SBP) (160–219 mmHg) and a diastolic blood pressure (DBP) (< 90 mmHg). Prior to the completion of SHEP, ISH remained the most important unresolved therapeutic problem involving hypertension; no definitive data were available on the possible benefits of treating this condition. Previous randomized controlled trials on efficacy of antihypertensive drug treatment, including the few that included older people in their samples, have focused primarily on the problem of elevated DBP (90 mmHg or higher) and used diastolic hypertension as the sole or main entry criterion.