Baseline Subgroups Research Articles

Dependence of the minimal clinically important improvement on the baseline value is a consequence of floor and ceiling effects and not different expectations by patients

ObjectiveEstimates of minimal clinically important improvements (MCIIs) are larger among patients with higher values at baseline, suggesting that these patients require larger changes to appreciate improvements. We examined if baseline dependency of MCIIs was associated with specific patients across three measures, or was owing to floor and ceiling effects. Study Design and SettingWe prospectively examined 250 outpatients with active rheumatoid arthritis (RA). We used an anchor-based approach to estimate MCIIs for three measures of RA activity (patient global assessment, swollen joint count, and walking time). We examined if the same patients constituted the baseline subgroups with high MCIIs across measures. ResultsThe MCIIs were greater for those with higher baseline values of all three measures. At the ceiling, there was little opportunity to improve, and judgments were unrelated to measured changes. At midrange, improvements were balanced by worsenings, including some judged as improvements. At the floor, improvements were not similarly balanced. Patients in subgroups with high MCII for patient global assessment were not also predominantly in subgroups with high MCII for the swollen joint count or walking time, and vice versa. ConclusionVariation in MCII by baseline values is because of floor and ceiling effects rather than expectations of particular patients.

Influence of baseline variables on changes in International Prostate Symptom Score after combined therapy with dutasteride plus tamsulosin or either monotherapy in patients with benign prostatic hyperplasia and lower urinary tract symptoms: 4‐year results of the CombAT study

To examine, using post hoc analysis, the influence of baseline variables on changes in international prostate symptom score (IPSS), maximum urinary flow rate (Qmax ) and IPSS quality of life (QoL) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with either the α-blocker tamsulosin or the dual 5-alpha reductase inhibitor dutasteride, alone or in combination, as part of the 4-year Combination of Avodart and Tamsulosin (CombAT) study. CombAT was a 4-year, multicentre, randomized, double-blind, parallel-group study in 4844 men ≥50 years of age with a clinical diagnosis of BPH by medical history and physical examination, an IPSS ≥12 points, prostate volume (PV) ≥30 mL, total serum PSA level ≥1.5 ng/mL, and Qmax >5 mL/s and ≤15 mL/s with a minimum voided volume ≥125 mL. Eligible subjects were randomized to receive oral daily tamsulosin, 0.4 mg; dutasteride, 0.5 mg; or a combination of both. Baseline variable subgroups analysed were as follows: PV (30 to <40; 40 to <60; 60 to <80; ≥80 mL), PSA level (1.5 to <2.5; 2.5 to <4; ≥4 ng/mL), age (median: <66, ≥66 years), IPSS (median: <16, ≥16; IPSS thresholds, <20, ≥20), IPSS QoL score (question 8, Q8) (median: <4, ≥4), Qmax (median: <10.4, ≥10.4 mL/s), BPH impact index (BII) (median: <5, ≥5) and body mass index (BMI, median: <26.8, ≥26.8 kg/m(2) ). Within each baseline variable subgroup, changes in IPSS, Qmax and IPSS QoL Q8 from baseline were evaluated using a generalized linear model with effects for baseline IPSS, Qmax or IPSS QoL Q8 and treatment group at each post-baseline assessment up to and including the month 48 visit using a last observation carried forward approach. The treatment comparisons of combination therapy vs dutasteride and combination therapy vs tamsulosin were performed from the general linear model with statistical significance defined as P ≤ 0.01. Combination therapy resulted in a significantly greater improvement from baseline IPSS at 48 months vs tamsulosin monotherapy across all baseline subgroups. The benefit of combination therapy over dutasteride was confined to groups with lower baseline PV (<60 mL) and PSA (<4 ng/mL). In groups with baseline PV ≥60 mL and PSA ≥4 ng/mL, dutasteride and combination therapy show similar improvements in symptoms. Combination therapy resulted in significantly improved Qmax compared with tamsulosin but not dutasteride monotherapy. Qmax improvement appeared to increase with PV and PSA level in combination therapy subjects. The proportion of subjects with an IPSS QoL ≤2 (at least mostly satisfied) at 48 months was significantly higher with combination therapy than with dutasteride for subgroups with PV 40-60 mL and PSA level <4 ng/mL and than with tamsulosin for all PSA subgroups and PV subgroups ≥40 mL. CombAT data support the use of long-term combination therapy with dutasteride and tamsulosin in patients considered at risk for progression of BPH, as determined by high PV (≥30 mL) and high PSA (≥1.5 ng/mL). Combination therapy, dutasteride monotherapy and tamsulosin monotherapy all improved Qmax , but to different extents (combination therapy > dutasteride >> tamsulosin), suggesting that dutasteride contributes most to the Qmax benefit in combination therapy. Combination therapy provided consistent improvement over tamsulosin in LUTS across all analysed baseline variables at 48 months. Compared with dutasteride, the superiority of combination therapy at 48 months was shown in patients with PV <60 mL or PSA <4 ng/mL.

Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data

TRACK-HD is a multinational prospective observational study of Huntington's disease (HD) that examines clinical and biological findings of disease progression in individuals with premanifest HD (preHD) and early-stage HD. We aimed to describe phenotypic changes in these participants over 36 months and identify baseline predictors of progression. Individuals without HD but carrying the mutant huntingtin gene (classed as preHD-A if ≥10·8 years and preHD-B if <10·8 years from predicted onset), participants with early HD (classed as HD1 if they had a total functional capacity score of 11-13 and HD2 if they had a score of 7-10), and healthy control individuals were assessed at four study sites in the Netherlands, the UK, France, and Canada. We measured 36-month change for 3T MRI, clinical, cognitive, quantitative motor, and neuropsychiatric assessments and examined their prognostic value. We also assessed the relation between disease progression and the combined effect of CAG repeat length and age. All participants were analysed according to their baseline subgroups. Longitudinal results were analysed using a combination of repeated-measure weighted least squares models and, when examining risk of new diagnosis, survival analysis. At baseline, 366 participants were enrolled between Jan 17, and Aug 26, 2008, and of these 298 completed 36-month follow-up: 97 controls, 58 participants with preHD-A, 46 with preHD-B, 66 with HD1, and 31 with HD2. In the preHD-B group, several quantitative motor and cognitive tasks showed significantly increased rates of decline at 36 months, compared with controls, whereas few had at 24 months. Of the cognitive measures, the symbol digit modality test was especially sensitive (adjusted mean loss 4·11 points [95% CI 1·49-6·73] greater than controls; p=0·003). Among psychiatric indicators, apathy ratings specifically showed significant increases (0·34 points [95% CI 0·02-0·66] greater than controls; p=0·038). There was little evidence of reliable change in non-imaging measures in the preHD-A group, with the exception of the speeded tapping inter-tap interval (0·01 s [95% CI 0·01-0·02] longer than controls; p=0·0001). Several baseline imaging, quantitative motor, and cognitive measures had prognostic value, independent of age and CAG repeat length, for predicting subsequent clinical diagnosis in preHD. Of these, grey-matter volume and inter-tap interval were particularly sensitive (p=0·013 and 0·002, respectively). Longitudinal change in these two measures was also greater in participants with preHD who received a diagnosis of HD during the study compared with those who did not, after controlling for CAG repeat length and age-related risk (p=0·006 and 0·0003, respectively). In early HD, imaging, quantitative motor, and cognitive measures were predictive of decline in total functional capacity and tracked longitudinal change; also, neuropsychiatric changes consistent with frontostriatal pathological abnormalities were associated with this loss of functional capacity (problem behaviours assessment composite behaviour score p<0·0001). Age and CAG repeat length explained variance in longitudinal change of multimodal measures, with the effect more prominent in preHD. We have shown changes in several outcome measures in individuals with preHD over 36 months. These findings further our understanding of HD progression and have implications for clinical trial design. CHDI Foundation.

SYNTAX scale estimates of coronary stenosis severity and outcomes of various revascularisation strategies in patients with ST segment elevation myocardial infarction and multi-vessel coronary pathology

Aim. To assess 30-day and long-term outcomes of various revascularisation strategies in patients with myocardial infarction and ST segment elevation (STEMI) and multi-vessel coronary pathology (MVCP), in regard to the severity of coronary stenosis, as assessed by the SYNTAX scale. Material and methods. The 30-day and long-term outcomes of various strategies of primary percutaneous coronary intervention (PCI) were assessed in 227 STEMI patients, in regard to the severity of their coronary stenosis (as assessed by the SYNTAX scale). Group 1 included 40 patients who underwent multi-vessel stenting (MVS) as a part of their primary PCI, while Group 2 included 187 patients with indications for staged revascularisation (SR). Results. At baseline, the MVS and SR subgroups with severe coronary stenosis (SYNTAX score

The Number of Regulatory T Cells Correlates with Hemodynamic Improvement in Patients with Inflammatory Dilated Cardiomyopathy After Immunoadsorption Therapy

Inflammatory DCM (iDCM) may be related to autoimmune processes. An immunoadsorption (IA) has been reported to improve cardiac hemodynamics. The benefit of IA is probably related to the removal of autoantibodies. A recent study suggests additional effects of IA on the T cell-mediated immune reactions, especially on regulatory T cells (Tregs). In this prospective study, the correlation between the level of Tregs and improvement of myocardial contractility in response to IA in patients with iDCM was investigated. Patients (n = 18) with iDCM, reduced left ventricular (LV) ejection fraction (<35%), were enrolled for IA. Before and 6 months after IA, LV systolic function was assessed by echocardiography, and blood levels of Tregs were quantified by FACS analysis. Patients (n = 12) with chronic ischaemic heart failure and comparable reduced LV-EF served as controls. IA improved LV-EF in 12 of 18 patients at 6-month follow-up. These patients were classified as 'IA responder'. In 6 patients, LV-EF remained unchanged. At baseline, IA responder and non-responder subgroups showed similar values for C-reactive protein, white blood cells, lymphocytes and T helper cells, but they differ for the number of circulating Tregs (responder: 2.32 ± 1.38% versus non-responder: 4.86 ± 0.28%; P < 0.01). Tregs increased significantly in the IA responders, but remained unchanged in the IA non-responders. In patients with ischaemic cardiomyopathy, none of these values changed over time. A low level of Tregs in patients with chronic iDCM may characterize a subset of patients who do best respond to IA therapy.

Post Hoc Subgroup Analysis of the HEART2D Trial Demonstrates Lower Cardiovascular Risk in Older Patients Targeting Postprandial Versus Fasting/Premeal Glycemia

OBJECTIVETo identify the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) trial subgroups with treatment difference.RESEARCH DESIGN AND METHODSIn 1,115 type 2 diabetic patients who had suffered from an acute myocardial infarction (AMI), the HEART2D trial compared two insulin strategies targeting postprandial or fasting/premeal glycemia on time until first cardiovascular event (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for acute coronary syndrome). The HEART2D trial ended prematurely for futility. We used the classification and regression tree (CART) to identify baseline subgroups with potential treatment differences.RESULTSCART estimated the age of >65.7 years to best predict the difference in time to first event. In the subgroup aged >65.7 years (prandial, n = 189; basal, n = 210), prandial patients had a significantly longer time to first event and a lower proportion experienced a first event (n = 56 [29.6%] vs. n = 85 [40.5%]; hazard ratio 0.69 [95% CI 0.49–0.96]; P = 0.029), despite similar A1C levels.CONCLUSIONSOlder type 2 diabetic AMI survivors may have a lower risk for a subsequent cardiovascular event with insulin targeting postprandial versus fasting/premeal glycemia.

Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4‐year results from the randomized, double‐blind Combination of Avodart and Tamsulosin (CombAT) trial

• To investigate the influence of baseline variables on the 4-year incidence of acute urinary retention (AUR), benign prostatic hyperplasia (BPH)-related surgery and overall clinical progression in men treated with tamsulosin, dutasteride, or a combination of both. • The 4-year Combination of Avodart® and Tamsulosin (CombAT) study was a multicenter, randomized, double-blind, parallel-group study of clinical outcomes in men aged ≥ 50 years with symptomatic (International Prostate Symptom Score [IPSS]≥ 12) BPH, with prostate-specific antigen (PSA) levels of ≥ 1.5 ng/mL and ≤ 10 ng/mL, and a prostate volume (PV) of ≥ 30 mL. • Eligible patients received tamsulosin 0.4 mg, dutasteride 0.5 mg, or a combination of both. • The primary endpoint was time to first AUR or BPH-related surgery. Secondary endpoints included clinical progression of BPH and symptoms. Posthoc analyses of the influence of baseline variables (including age, IPSS health-related quality of life [HRQL], PV, PSA, IPSS, peak urinary flow rate [Q(max) ] and body-mass index [BMI]) on the incidence of AUR or BPH-related surgery, clinical progression of BPH, and symptoms were performed. • There were 4844 men in the intent-to-treat population. Overall baseline characteristics were similar across all patient groups. • Regardless of baseline subgroup, the incidence of AUR or BPH-related surgery was higher in men treated with tamsulosin than in those treated with dutasteride or combined therapy. • Combined therapy was statistically better than tamsulosin in reducing the risk of AUR or BPH-related surgery in subgroups of baseline PV > 42.0 mL, in all subgroups of baseline PSA level, and all other baseline subgroups (P ≤ 0.001). • Across treatment groups, the incidence of clinical progression was highest in men with a baseline IPSS of < 20 or IPSS HRQL score of < 4. The incidence of clinical progression was also higher in men receiving tamsulosin than dutasteride or combined therapy in all baseline subgroups, except for men with a baseline PV of < 40 mL. Combined therapy reduced the relative risk (RR) of clinical progression compared with tamsulosin across all baseline subgroups and compared with dutasteride across most baseline subgroups. • Symptom deterioration was the most common progression event in each treatment group regardless of baseline subgroup, except in those men with an IPSS of ≥ 20 at baseline. Combined therapy reduced the RR of symptom deterioration compared with tamsulosin across all but one baseline subgroup (the reduction was not significant for men with a baseline PV of < 40 mL) and compared with dutasteride in most subgroups. • Men with a baseline PV of ≥ 40 mL and any baseline PSA level of ≥1.5 ng/mL had greater reductions in the RR of AUR or BPH-related surgery and greater reductions in the RR of clinical progression and symptom deterioration on combined therapy or dutasteride monotherapy than on tamsulosin monotherapy. • These analyses support the long-term use of combined therapy with dutasteride plus tamsulosin in men with moderate-to-severe BPH symptoms and a slightly enlarged prostate.

Influence of Hemoglobin Level on Clinical Findings In Infants with Sickle Cell Anemia: Data From BABY HUG

AbstractAbstract 1631 Introduction:Infants with sickle cell anemia (SCA) are at risk for organ damage and clinical events. Risk may vary depending on steady state hemoglobin level. BABY HUG (ClinicalTrials.org, NCT00006400), a NHLBI-NICHD supported phase III randomized placebo-controlled trial, examined the ability of hydroxyurea (HU) to reduce end organ damage to the kidneys and spleen and attenuate other complications of SCA in infants. In this secondary study, we investigated whether placebo-treated subgroups defined by extremes of baseline hemoglobin level differed from one another in frequency of sickle cell-related complications and other laboratory findings, and then compared these data to the entire group of infants treated with HU. Methods:BABY HUG subjects randomized at ages 9 – 18 mo were treated with hydroxyurea (20 mg/kg/d) (N=96) or with placebo (N=97) for 2 years. Those randomized to placebo were classified according to their age-adjusted baseline hemoglobin level and subgroups in the lowest (n=24) and highest (n=24) quartiles compared. (Demarcating Hb values were: age 9 to <12 mo, <8.0 vs. >10.2gm/dL; age12 – 18 mo, <8.1 vs. >9.9gm/dL.) Results:BABY HUG primary endpoints of spleen (splenic uptake of 99mTc sulfur colloid on liver-spleen scan) and kidney (GFR by DTPA clearance) function did not differ in placebo group subjects who were in the lowest and highest quartile hemoglobin levels. However, those in the lowest hemoglobin quartile had a higher incidence of acute chest syndrome (ACS) than those in the highest quartile (0.31 vs. 0.02 events/person-year, RR 14.4, p=0.01) and this difference was significantly attenuated by HU (0.05 events/person-year). The relative risk for developing a pain crisis did not differ between the two placebo subgroups (2.2 vs. 2.1 events/person-year), but HU significantly reduced pain frequency compared to either subgroup (0.94 events/person-year, p<0.001). Subjects in the lowest hemoglobin quartile had higher baseline mean TCD velocities than those in the highest quartile (126.2 vs. 112.4 cm/sec, p=0.008). These differences persisted over the two-year period of study, with exit values of 164.9 and 139.6 cm/sec, respectively (p=0.003). By comparison mean TCD velocity in the HU-treated group was 124.5 cm/sec at baseline and 145.6 at exit. Results of neurocognitive testing were not statistically different between groups; however, a trend toward a lower performance developmental index (PDI, p=0.07), but not a lower mental development index (MDI, p=0.15), was observed in subjects with the lowest hemoglobin levels. Subjects in the lowest quartile also had a higher mean WBC (18.0 vs. 11.4 × 109/L, p<0.001), absolute neutrophil count (5.3 vs. 3.6 × 109/L, p=0.001), and platelet count (416 vs. 315 × 109/L, p=0.0001) compared to those with the highest hemoglobin. The laboratory findings of patients receiving HU also were significantly lower than those of subjects in the lowest hemoglobin group and similar to those in the highest hemoglobin group. Conclusions:Severe anemia in very young patients with SCA was associated with elevated WBC and platelet counts and higher TCD velocities. Interestingly, severe anemia also was associated with increased frequency of ACS, in contrast to the association of ACS with higher hemoglobin levels in older patients. Future studies will need to confirm this relationship and clarify to what extent associated findings (e.g., hyposplenia, elevated WBC or platelet count) contribute to this susceptibility. Severe anemia in young SCA patients is a negative prognostic factor that is significantly impacted by early hydroxyurea therapy. Disclosures:Off Label Use: Hydroxyurea is not approved by FDA for infants with sickle cell disease. Miller:NIH/NHLBI; Emmaus Med Inc, Novartis Pharmaceutical; St Jude Childrens Hospital: Research Funding.

Effect of Intensive Compared With Standard Glycemia Treatment Strategies on Mortality by Baseline Subgroup Characteristics

OBJECTIVETo determine if baseline subgroups in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial can be identified for whom intensive compared with standard glycemia treatment had different effects on all-cause mortality.RESEARCH DESIGN AND METHODSExploratory post hoc intention-to-treat comparisons were made between intensive and standard glycemia groups on all-cause mortality by subgroups defined by baseline characteristics.RESULTSThere were few significant interactions between baseline characteristics and effects of intensive versus standard glycemia treatment on mortality: self-reported history of neuropathy (hazard ratio [HR] 1.95, 95% CI 1.41–2.69) versus no history of neuropathy (0.99, 0.79–1.26; P value for interaction 0.0008), higher A1C (A1C >8.5%: HR 1.64, 95% CI 1.22–2.22; A1C 7.5–8.4%: 1.00, 0.75–1.34; A1C <7.5%: 1.00, 0.67–1.50; P value for interaction 0.04), and aspirin use (HR 1.45, 95% CI 1.13–1.85, compared with 0.96, 0.72–1.27, in nonusers; P value for interaction 0.03).CONCLUSIONSWe found a remarkable similarity of effect from intensive compared with standard glycemia treatment on mortality across most baseline subgroups. No differential effect was found in subgroups defined by variables anticipated to have an interaction: age, duration of diabetes, and previous history of cardiovascular disease. The three baseline characteristics that defined subgroups for which there was a differential effect on mortality may help identify patients with type 2 diabetes at higher risk of mortality from intensive regimens for glycemic control. Further research is warranted.

The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study

Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels...

The Influence of Baseline Parameters on Changes in International Prostate Symptom Score with Dutasteride, Tamsulosin, and Combination Therapy among Men with Symptomatic Benign Prostatic Hyperplasia and an Enlarged Prostate: 2-Year Data from the CombAT Study

BackgroundKnowledge of baseline factors that influence outcomes for men with benign prostatic hyperplasia (BPH) receiving medical therapy may help to improve outcomes and cost effectiveness. ObjectivesTo examine the influence of baseline parameters on changes in International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Qmax) in men with BPH receiving dutasteride, tamsulosin, or a combination of the two using 2-yr Combination of Avodart and Tamsulosin (CombAT) study data. Design, setting, and participantsCombAT is an ongoing, 4-yr, multicentre, randomised, double-blind study in 4844 men aged ≥50 yr with clinical diagnosis of BPH, IPSS ≥12, prostate volume ≥30cm3, prostate-specific antigen (PSA) 1.5–10ng/ml, and Qmax >5 and ≤15ml/s with minimum voided volume ≥125ml. InterventionDaily tamsulosin 0.4mg, dutasteride 0.5mg, or the combination. MeasurementsPost hoc analyses of mean IPSS and Qmax changes from baseline by treatment group and by baseline prostate volume, PSA, age, body mass index (BMI), IPSS, IPSS quality of life (QoL) score, BPH Impact Index score, Qmax, and previous BPH medical therapy. Results and limitationsCombination therapy was more effective than either monotherapy after 24 mo in improving IPSS in all baseline subgroups, with benefit onset varying by baseline prostate volume. Combination therapy was also more effective in improving Qmax versus tamsulosin in all subgroups and versus dutasteride in 10 of 18 subgroups. At 24 mo, dutasteride monotherapy resulted in significantly greater IPSS improvements versus tamsulosin in men with lower age, worse symptoms, worse QoL, less bother, higher BMI, greater Qmax, higher prostate volume, and higher PSA at baseline. Post hoc analyses, the lack of placebo control, and the exclusion of men with unsuccessful medical BPH treatment are study limitations. ConclusionsCombination therapy with tamsulosin and dutasteride affords the greatest and the most rapid symptomatic benefit among men with higher baseline prostate volume and is effective regardless of previous BPH medical therapy. Dutasteride monotherapy is more effective than tamsulosin in men with higher baseline prostate volume or PSA and worse symptoms.

Effect of Baseline Viral Susceptibility on Response to Darunavir/Ritonavir versus Control Protease Inhibitors in Treatment-Experienced HIV Type 1-Infected Patients: POWER 1 and 2

Data from two Phase IIb trials, POWER 1 and 2 (TMC114-C213 and C202), were pooled to examine the effect of baseline viral susceptibility on response to control protease inhibitors [CPI(s)] compared with response to darunavir (TMC114) given with low-dose ritonavir (darunavir/r) in treatment-experienced HIV patients. POWER 1 and 2 were randomized, controlled Phase IIb trials with a similar design. Patients with one or more primary PI mutations and HIV-1 RNA >1000 copies/ml were randomized to receive an optimized background regimen plus darunavir/r or CPI(s). POWER 1 and 2 week 24 efficacy (intent-to-treat using time-to-loss of virologic response algorithm) data were pooled and analyzed according to baseline subgroups of susceptibility to the CPI regimen, fold-change (FC) in EC(50) to darunavir, and number of darunavir resistance-associated mutations (RAMs). In total, 131 patients received darunavir/r 600/100 mg twice daily; 124 received CPI(s) [lopinavir/r, 20%; saquinavir/r, 19%; (fos)-amprenavir/r, 24%; atazanavir/r, 11%; and 23% used dual-boosted CPI(s)]. At baseline, 72% of patients were resistant (defined as FC) to their investigator-selected CPIs. At week 24, darunavir/r 600/100 mg twice daily provided greater efficacy benefits over CPI(s), even when the virus was predicted to be fully susceptible to the CPI. The response to darunavir decreased when FC to darunavir at baseline was >40 or when three or more darunavir RAMs (in addition to other PI mutations) were present at baseline. Darunavir/r 600/100 mg twice daily showed efficacy benefits over CPI use regardless of viral susceptibility at baseline, FC to darunavir or boosting type in a population of treatment-experienced HIV-infected patients.

Effect of Calcium and Vitamin D Supplementation on Blood Pressure

Experimental and epidemiological studies suggest that calcium and vitamin D supplements may lower blood pressure. We examined the effect of calcium plus vitamin D supplementation on blood pressure and the incidence of hypertension in postmenopausal women. The Women's Health Initiative Calcium/Vitamin D Trial randomly assigned 36 282 postmenopausal women to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily or placebo in a double-blind fashion. Change in blood pressure and the incidence of hypertension were ascertained. Over a median follow-up time of 7 years, there was no significant difference in the mean change over time in systolic blood pressure (0.22 mm Hg; 95% CI: -0.05 to 0.49 mm Hg) and diastolic blood pressure (0.11 mm Hg; 95% CI: -0.04 to 0.27 mm Hg) between the active and placebo treatment groups. This null result was robust in analyses accounting for nonadherence to study pills and in baseline subgroups of interest, including black subjects and women with hypertension or high levels of blood pressure, with low intakes of calcium and vitamin D or low serum levels of vitamin D. In 17 122 nonhypertensive participants at baseline, the hazard ratio for incident hypertension associated with calcium/vitamin D treatment was 1.01 (95% CI: 0.96 to 1.06.) In postmenopausal women, calcium plus vitamin D3 supplementation did not reduce either blood pressure or the risk of developing hypertension over 7 years of follow-up.

Comparison of Warfarin versus Aspirin for the Prevention of Recurrent Stroke or Death: Subgroup Analyses from the Warfarin-Aspirin Recurrent Stroke Study

Background and Purpose: We performed a combination of prespecified and exploratory subgroup analyses to detect any treatment differences among various baseline subgroups in the Warfarin-Aspirin Recurrent Stroke Study (WARSS) cohort. Methods: The WARSS compared the efficacy of adjusted-dose warfarin (INR 1.4–2.8) to aspirin (325 mg/day) for recurrent ischemic stroke or death within 2 years. The effect of warfarin and aspirin was compared among prespecified and exploratory subgroups with respect to sociodemographic and vascular risk factors, stroke subtype, arterial territory, and infarct topography. Hazard ratios and 95% confidence intervals comparing warfarin to aspirin were calculated using Cox proportional hazards models. Differences in hazard ratios were tested using interaction terms. Results: No treatment differences between warfarin and aspirin were found across multiple prespecified subgroups. In a multivariate model, warfarin was associated with greater hazard among patients with moderate stroke severity (HR 1.63, 95% CI 1.005–2.64, p = 0.047) and a greater benefit among those with posterior circulation location without brainstem infarction (HR 0.54, 95% CI 0.33–0.88, p = 0.013). In post-hoc analyses of the cryptogenic subgroup, warfarin was associated with worse outcomes among patients with moderate stroke severity and better outcomes among those without baseline hypertension or with posterior circulation infarcts sparing the brainstem. Conclusions: In the WARSS, the majority of subgroup analyses showed no benefit of warfarin over aspirin. Warfarin benefit was limited to brainstem-sparing posterior circulation infarcts and select cryptogenic stroke subgroups. Pending future clinical trial evidence to the contrary, antiplatelets are recommended for survivors of noncardioembolic stroke.

A systemic-wholistic approach to differential aging: Longitudinal findings from the Berlin Aging Study.

Wholistic perspectives on differential change focus on multiple-indicator information at a person level. They supplement the modeling of average trajectories at a variable level. The authors extended cross-sectional work in the Berlin Aging Study (J. Smith & P. B. Baltes, 1997) to 6-year longitudinal cluster analyses (n = 132). At baseline, 3 subgroups were identified with distinct within-person psychological profiles across cognitive, personality, and social integration constructs. Over time, highly similar subgroup profiles were found, and about two thirds of the participants could be classified as remaining in the same subgroups. Baseline subgroups differed in level and slope of change and in 2 outcomes, well-being and mortality. Independent of subgroup membership, subgroup-to-subgroup change was associated with greater decline and predicted poststudy mortality. These findings demonstrate the usefulness of a wholistic approach for long-term prediction of outcomes and within-person systemic variability.

509 The efficacy of entecavir is similar regardless of disease-related baseline subgroups in treatment of nucleo side-naive, HBeAg(+) and HBeAg(−) patients with chronic hepatitis B

509 The efficacy of entecavir is similar regardless of disease-related baseline subgroups in treatment of nucleo side-naive, HBeAg(+) and HBeAg(−) patients with chronic hepatitis B

First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome (MDS).

MDS is a disease of the elderly marked by dysplasia of hematopoetic cell lines resulting in cytopenias and AML progression. There is currently no treatment approved to alter the natural history of the disease. Aberrant methylation associated with cancer is a potential target for pharmacologic therapy, and DacogenTM (decitabine) for injection (SuperGen, Inc.), a cytosine analogue, indirectly depletes methylcytosine after incorporation into DNA with subsequent inactivation of DNA methyltransferases. We report the results of a Phase III trial of decitabine (DAC) vs. supportive care (Supp.Care) in adult MDS patients with IPSS Intermediate (Int)-1 (31%), Int-2 (44%) and high risk disease (26%). Secondary MDS (14%) and previously treated (27%) MDS patients were not excluded. Bone marrows were assessed by a blinded, independent pathologist. 170 patients (accrued from July 2001 through April 2003 at 23 centers) were randomized 1:1 to either Supp.Care or DAC (a 3 hr infusion of 15mg/m2/hr every 8 hrs on 3 consecutive days every 6 wks for up to 10 cycles. The groups were comparable for numerous risk factors, including time from diagnosis (median 29 weeks for DAC and 35 weeks for Supp.Care). Kaplan Meier (KM) curves for time to AML progression or death showed early and clinically meaningful separation (consistent with clinical benefit) in favor of DAC in all patients (intent to treat; ITT), Int-2/High Risk, and High Risk patients. Using the Cox proportional hazards model for the ITT population, the probability of progression to AML or death was 1.68-fold greater for Sup.Care than for DAC (p=0.023).Median Time to AML or Death (Days)MDS group (n)DACSupp.Carep-valuen=89n=81Wilcoxon1,2Log rank1All Patients (170)3382630.0460.204Int-2/High Risk (118)3341890.0050.040High Risk (44)260790.0010.006Treatment naïve (124)3541890.0050.0341Protocol specified test. 2Preferred test for analysis of early separation of KM curves. [Display omitted] Investigator reported response rate by International Working Group criteria was 25% (10% CR, 15% PR) for DAC vs. 0% for Supp.Care (p< 0.001), with responses equally distributed across baseline subgroups. Time to response was 100 days and median duration was estimated at >9 months. Responders (CR and PR) vs. non-responders had a median survival of 678 days vs. 406 days (p= 0.038 Wilcoxon). There were no treatment related deaths. As expected, grade 3–4 toxicity (including hematologic toxicity, febrile neutropenia) occurred in more DAC patients than in Supp.Care patients. Most patients tolerated treatment well. DAC appears a promising therapy for MDS with manageable toxicity. Final results of independently reviewed response rates and clinical benefit (transfusion independence; Quality of Life) will be presented.

Use of ramipril in preventing stroke: double blind randomised trial

Objective: To determine the effect of the angiotensin converting enzyme inhibitor ramipril on the secondary prevention of stroke.Design: Randomised controlled trial with 2×2 factorial design.Setting: 267 hospitals in 19 countries.Participants:...