The doubly labeled water method produces highly reproducible longitudinal results in nutrition studies.

The doubly labeled water (DLW) method is considered the reference method for the measurement of energy expenditure under free-living conditions. However, the reproducibility of the DLW method in longitudinal studies is not well documented. This study was designed to evaluate the longitudinal reproducibility of the DLW method using 2 protocols developed and implemented in a multicenter clinical trial-the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE). To document the longitudinal reproducibility of the DLW method, 2 protocols, 1 based on repeated analysis of dose dilutions over the course of the clinical trial (dose-dilution protocol) and 1 based on repeated but blinded analysis of randomly selected DLW studies (test-retest protocol), were carried out. The dose-dilution protocol showed that the theoretical fractional turnover rates for (2)H and (18)O and the difference between the 2 fractional turnover rates were reproducible to within 1% and 5%, respectively, over 4.5 y. The Bland-Altman pair-wise comparisons of the results generated from 50 test-retest DLW studies showed that the fractional turnover rates and isotope dilution spaces for (2)H and (18)O, and total energy expenditure, were highly reproducible over 2.4 y. Our results show that the DLW method is reproducible in longitudinal studies and confirm the validity of this method to measure energy expenditure, define energy intake prescriptions, and monitor adherence and body composition changes over the period of 2.5-4.4 y. The 2 protocols can be adopted by other laboratories to document the longitudinal reproducibility of their measurements to ensure the long-term outcomes of interest are meaningful biologically. This trial was registered at clinicaltrials.gov as NCT00427193.

Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: a 1-y randomized controlled trial.

BACKGROUND: There remains no consensus about the optimal dietary composition for sustained weight loss. OBJECTIVE: The objective was to examine the effects of 2 dietary macronutrient patterns with different glycemic loads on adherence to a prescribed regimen of calorie restriction (CR), weight and fat loss, and related variables. DESIGN: A randomized controlled trial (RCT) of diets with a high glycemic load (HG) or a low glycemic load (LG) at 30% CR was conducted in 34 healthy overweight adults with a mean (+/-SD) age of 35 +/- 6 y and body mass index (kg/m(2)) of 27.6 +/- 1.4. All food was provided for 6 mo in diets controlled for confounding variables, and subjects self-administered the plans for 6 additional months. Primary and secondary outcomes included energy intake measured by doubly labeled water, body weight and fatness, hunger, satiety, and resting metabolic rate. RESULTS: All groups consumed significantly less energy during CR than at baseline (P < 0.01), but changes in energy intake, body weight, body fat, and resting metabolic rate did not differ significantly between groups. Both groups ate more energy than provided (eg, 21% and 28% CR at 3 mo and 16% and 17% CR at 6 mo with HG and LG, respectively). Percentage weight change at 12 mo was -8.04 +/- 4.1% in the HG group and -7.81 +/- 5.0% in the LG group. There was no effect of dietary composition on changes in hunger, satiety, or satisfaction with the amount and type of provided food during CR. CONCLUSIONS: These findings provide more detailed evidence to suggest that diets differing substantially in glycemic load induce comparable long-term weight loss.

Racial differences in nocturnal dipping status in diabetic kidney disease: Results from the STOP-DKD (Simultaneous Risk Factor Control Using Telehealth to Slow Progression of Diabetic Kidney Disease) study.

While racial variation in ambulatory blood pressure (BP) is known, patterns of diurnal dipping in the context of diabetic kidney disease have not been well defined. The authors sought to determine the association of race with nocturnal dipping status among participants with diabetic kidney disease enrolled in the STOP-DKD (Simultaneous Risk Factor Control Using Telehealth to Slow Progression of Diabetic Kidney Disease) trial. The primary outcome was nocturnal dipping-percent decrease in average systolic BP from wake to sleep-with categories defined as reverse dippers (decrease <0%), nondippers (0%-<10%), and dippers (≥10%). Twenty-four-hour ambulatory BP monitoring was completed by 108 participants (54% were nondippers, 24% were dippers, and 22% were reverse dippers). In adjusted models, the common odds of reverse dippers vs nondippers/dippers and reverse dippers/nondippers vs dippers was 2.6 (95% confidence interval, 1.2-5.8) times higher in blacks than in whites. Without ambulatory BP monitoring data, interventions that target BP in black patients may be unable to improve outcomes in this high-risk group.

Body-composition changes in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)-2 study: a 2-y randomized controlled trial of calorie restriction in nonobese humans.

Background: Calorie restriction (CR) retards aging and increases longevity in many animal models. However, it is unclear whether CR can be implemented in humans without adverse effects on body composition.Objective: We evaluated the effect of a 2-y CR regimen on body composition including the influence of sex and body mass index (BMI; in kg/m2) among participants enrolled in CALERIE-2 (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), a multicenter, randomized controlled trial.Design: Participants were 218 nonobese (BMI: 21.9-28.0) adults aged 21-51 y who were randomly assigned to 25% CR (CR, n = 143) or ad libitum control (AL, n = 75) in a 2:1 ratio. Measures at baseline and 12 and 24 mo included body weight, waist circumference, fat mass (FM), fat-free mass (FFM), and appendicular mass by dual-energy X-ray absorptiometry; activity-related energy expenditure (AREE) by doubly labeled water; and dietary protein intake by self-report. Values are expressed as means ± SDs.Results: The CR group achieved 11.9% ± 0.7% CR over 2-y and had significant decreases in weight (-7.6 ± 0.3 compared with 0.4 ± 0.5 kg), waist circumference (-6.2 ± 0.4 compared with 0.9 ± 0.5 cm), FM (-5.4 ± 0.3 compared with 0.5 ± 0.4 kg), and FFM (-2.0 ± 0.2 compared with -0.0 ± 0.2 kg) at 24 mo relative to the AL group (all between-group P < 0.001). Moreover, FFM as a percentage of body weight at 24 mo was higher, and percentage of FM was lower in the CR group than in the AL. AREE, but not protein intake, predicted preservation of FFM during CR (P < 0.01). Men in the CR group lost significantly more trunk fat (P = 0.03) and FFM expressed as a percentage of weight loss (P < 0.001) than women in the CR group.Conclusions: Two years of CR had broadly favorable effects on both whole-body and regional adiposity that could facilitate health span in humans. The decrements in FFM were commensurate with the reduced body mass; although men in the CR group lost more FFM than the women did, the percentage of FFM in the men in the CR group was higher than at baseline. CALERIE was registered at clinicaltrials.gov as NCT00427193.

Elevated body mass index and intermediate-term clinical outcomes after acute coronary syndromes.

PURPOSE: Obesity is a coronary disease risk factor, but its independent effect on clinical outcomes following acute coronary syndromes has not been quantified. We evaluated the relationship between elevated body mass index (BMI) and 30-day, 90-day, and 1-year clinical outcomes postacute coronary syndromes. SUBJECTS AND METHODS: Using 15 071 patients (normal weight [BMI = 18.5-24.9 kg/m(2)], overweight [BMI = 25-29.9 kg/m(2)], obese [BMI = 30-34.9 kg/m(2)] or very obese [BMI > or =35 kg/m(2)]) randomized from 1997-1999 in the SYMPHONY (Sibrafiban vs aspirin to Yield Maximum Protection from ischemic Heart events postacute cOroNary sYndromes) and 2nd SYMPHONY trials, we evaluated the relationships between BMI and 30-day, 90-day, and 1-year mortality and 30-day and 90-day death or myocardial infarction. RESULTS: Increasing BMI was associated with younger age, multiple comorbidities, and greater cardiac medication and procedure use; however, systolic function and coronary disease extent were similar for all BMI categories. Unadjusted Kaplan-Meier mortality estimates were higher for normal-weight patients than for all other BMI groups. After multivariable adjustment, the 30-day mortality hazard ratios (95% confidence interval [CI]) were: overweight, 0.66 (95% CI: 0.47 to 0.94); obese, 0.61 (95% CI: 0.39 to 0.97); very obese, 0.89 (95% CI: 0.48 to 1.64). Adjusted hazard ratios were similar for 90-day and 1-year mortality. There were no statistically significant differences among BMI groups in 30-day and 90-day death or myocardial infarction (unadjusted or adjusted). CONCLUSION: Overweight and obese BMI classifications were associated with better intermediate-term survival after acute coronary syndromes than normal weight and very obese, but death or myocardial infarction rates were similar. Further study is required to understand the apparent association of overweight and moderate obesity with better intermediate-term outcomes.

Prevalence and management of hypertension in acute coronary syndrome patients varies by sex: observations from the Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events postacute cOroNary sYndromes (SYMPHONY) randomized clinical trials.

BACKGROUND: Hypertension affects 1 billion individuals worldwide and is an independent risk factor for death after acute coronary syndromes (ACS). METHODS: We examined the prevalence and medical treatment of hypertension among 15,904 ACS patients randomized in the SYMPHONY and 2nd SYMPHONY trials. Analyses were performed overall and according to sex for the United States and across international practice. Multivariable models identified factors associated with use of antihypertensive medication classes and examined the association of hypertension and sex with mortality. RESULTS: In the United States, hypertension was more prevalent in women than in men, overall (63% vs 50%) and within every decile of age. Hypertensive women more often received calcium-channel blockers (35% vs 30%) and diuretics (33% vs 19%) and less often received beta-blockers (51% vs 57%). Angiotensin-converting enzyme inhibitor use was similar (35% vs 34%). Women received multiple agents more frequently than did men: 2 agents, 35% vs 30%; > or = 3 agents, 16% vs 13%. Female sex independently predicted drug-class use only for diuretics. Mortality was higher in hypertensive women than in hypertensive men; after multivariable adjustment, mortality was similar without evidence of a differential association between hypertension and mortality according to sex. Although there was international variation in the use of individual classes of agents, the overall findings by sex were similar across regions. CONCLUSION: Hypertension is more prevalent in women than in men with ACS, and its medical management varies by sex, but its association with mortality is similar. Opportunities exist to improve medical therapy and outcomes in women with hypertension.

Association of diabetes mellitus and glycemic control strategies with clinical outcomes after acute coronary syndromes.

BACKGROUND: Diabetes is associated with an increased risk for coronary artery disease (CAD) and its complications. The relative effect of glucose-lowering strategies of "insulin provision" versus "insulin sensitization" among patients with CAD remains unclear. METHODS: To evaluate the associations of diabetes and hypoglycemic strategies with clinical outcomes after acute coronary syndromes, we analyzed data from 15,800 patients enrolled in the SYMPHONY and 2nd SYMPHONY trials. RESULTS: Compared with nondiabetic patients, patients with diabetes (n = 3101; 19.6%) were older, more often female, more often had prior CAD, hypertension, and hyperlipidemia, and less often were current smokers. The diabetic cohort had higher 90-day unadjusted risk of the composite of death/myocardial infarction (MI)/severe recurrent ischemia (SRI), death/MI, and death alone, as well as a near doubling of 1-year mortality rates. At 1 year, diabetes was associated with significantly higher adjusted risks of death/MI/SRI (OR, 1.3 [95% confidence interval, 1.1, 1.5]) and death/MI (OR, 1.2 [1.0, 1.4]). Hypoglycemic therapy including only insulin and/or sulfonylurea (insulin-providing; n = 1473) was associated with higher 90-day death/MI/SRI compared with therapy that included only biguanide and/or thiazolidinedione therapy (insulin-sensitizing; n = 100) (12.0% vs 5.0%); (adjusted OR, 2.1 [1.2, 3.7]). CONCLUSIONS: Diabetic patients with acute coronary syndromes had worse clinical outcomes. Although the findings regarding the influence of glycemic-control strategies should be interpreted with caution because of the exploratory nature of the analyses and the relatively small sample size of the insulin-sensitizing group, the improved risk-adjusted outcomes associated with insulin-sensitizing therapy underscore the need to further evaluate treatment strategies for patients with diabetes and CAD.

Association of race with complications and prognosis following acute coronary syndromes.

The baseline characteristics, complications, and survival of 489 black and 6,890 non-black patients with acute coronary syndromes were studied. Important racial differences were observed in demographic features, atherosclerosis risk factors, and treatment strategies; however, despite these differences, no independent difference was observed in clinical outcomes according to race. The 1-year mortality rate was 2.9% for black patients and 2.5% for non-black patients (p = 0.93).

Frequency of stent thrombosis after acute coronary syndromes (from the SYMPHONY and 2nd SYMPHONY trials).

We studied stent thrombosis in 4,607 patients with acute coronary syndromes who received a coronary stent as part of routine care during 2 trials of aspirin versus sibrafiban for secondary prevention. In these patients, stent thrombosis occurred more often than in previous patients who underwent elective percutaneous coronary intervention. These patients and their outcomes may be more representative of patients with typical acute coronary syndromes undergoing stenting in clinical practice.

Postmenopausal hormone use in women with acute coronary syndromes.

BACKGROUND: Recent trials reveal no benefit and possible harm from chronic hormone replacement therapy (HRT). Less is known about intermediate-term outcomes associated with HRT use in the setting of acute coronary syndromes (ACS). METHODS: To examine the prevalence of HRT use and relationships with intermediate-term outcomes among women with ACS, we classified as HRT users or nonusers 4029 postmenopausal women (age > 50 years or postmenopausal by case report form) randomized in the Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-Acute Coronary Syndromes (SYMPHONY) and 2nd SYMPHONY trials. Outcomes included 90-day and 1-year death and 90-day stroke, death, or myocardial infarction (MI); death, MI, or stroke; and death, MI, or severe recurrent ischemia (SRI). RESULTS: HRT use was 13% overall and varied by region (Asia, 0%; Eastern Europe, 0.2%; Latin America, 0.8%; Western Europe, 4%; Australia/New Zealand, 12%; Canada, 14%; United States, 24%); estrogen-only regimens were most common (90%). HRT users were younger, had higher estimated creatinine clearance, more frequently were smokers and had prior revascularization, but less frequently had diabetes, prior angina, or heart failure. Unadjusted 90-day and 1-year mortality rates were lower among HRT users (hazard ratios [95% CI] 0.48 [0.23-0.98] and 0.35 [0.18-0.68], respectively) but after multivariable adjustment, were not significantly different. Ninety-day stroke and composite end points did not differ between HRT users and nonusers. CONCLUSIONS: HRT use (predominantly estrogen-only) was low among patients with ACS but varied by region and was not associated with improved intermediate-term outcomes. These results are consistent with the absence of benefit from HRT use (combination or estrogen only) in previous studies in more stable populations.

Low or moderate dietary energy restriction for long-term weight loss: what works best?

Theoretical calculations suggest that small daily reductions in energy intake can cumulatively lead to substantial weight loss, but experimental data to support these calculations are lacking. We conducted a 1-year randomized controlled pilot study of low (10%) or moderate (30%) energy restriction (ER) with diets differing in glycemic load in 38 overweight adults (mean +/- s.d., age 35 +/- 6 years; BMI 27.6 +/- 1.4 kg/m(2)). Food was provided for 6 months and self-selected for 6 additional months. Measurements included body weight, resting metabolic rate (RMR), adherence to the ER prescription assessed using (2)H(2)(18)O, satiety, and eating behavior variables. The 10%ER group consumed significantly less energy (by (2)H(2)(18)O) than prescribed over 12 months (18.1 +/- 9.8%ER, P = 0.04), while the 30%ER group consumed significantly more (23.1 +/- 8.7%ER, P < 0.001). Changes in body weight, satiety, and other variables were not significantly different between groups. However, during self-selected eating (6-12 months) variability in % weight change was significantly greater in the 10%ER group (P < 0.001) and poorer weight outcome on 10%ER was predicted by higher baseline BMI and greater disinhibition (P < 0.0001; adj R(2) = 0.71). Weight loss at 12 months was not significantly different between groups prescribed 10 or 30%ER, supporting the efficacy of low ER recommendations. However, long-term weight change was more variable on 10%ER and weight change in this group was predicted by body size and eating behavior. These preliminary results indicate beneficial effects of low-level ER for some but not all individuals in a weight control program, and suggest testable approaches for optimizing dieting success based on individualizing prescribed level of ER.

Renal function, concomitant medication use and outcomes following acute coronary syndromes.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent in patients with cardiovascular disease. We explored the associations of CKD with outcomes using combined data from two large acute coronary syndrome (ACS) trials. We also explored the associations of CKD with prescription patterns for common cardiovascular medications and the association of these prescription patterns with clinical outcomes. METHODS: Patients were stratified by CKD stage using creatinine clearance (CrCl, ml/min) estimated by the modified MDRD equation using baseline core laboratory creatinine measures. Serum creatinine > or =1.5 mg/dl was an exclusion criterion for the SYMPHONY trials. Baseline characteristics and outcomes across CKD categories were compared and Cox proportional hazards regression was used to assess the relationship of renal insufficiency with clinical outcomes after adjusting for previously identified outcome predictors. Interactions between the use of specific medications and calculated CrCl were tested in the final Cox proportional hazards model predicting time to mortality. RESULTS: Of 13 707 patients analysed, 6840 had CKD stage I (CrCl > or =90 ml/min), 5909 stage II (CrCl 60-89 ml/min), 955 stage III (CrCl 30-59 ml/min) and three stage IV (CrCl <30 ml/min). Patients with more advanced CKD (III) were older, more often female, non-smokers and more likely to have co-morbid diseases including diabetes mellitus, hypertension and congestive heart failure. Cardiovascular medications were used less frequently in patients with CKD. Unadjusted survival was poorer in patients with CKD stages > or =II. In adjusted analyses, for those with CrCl < or =91, each 10 ml/min increase in CrCl was associated with a significantly decreased risk of mortality (hazards ratio 0.897, 95% confidence interval 0.815-0.986) (P = 0.024). The interaction between use of angiotensin-converting enzyme (ACE) inhibitors and CrCl was significantly associated with outcomes; the benefit of drug therapy was greater among patients with CKD. CONCLUSIONS: CKD is an independent predictor of risk among ACS patients, and is associated with less frequent use of proven medical therapies. More aggressive use of conventional cardiovascular therapies in patients with CKD and ACS may be warranted.

Early statin initiation and outcomes in patients with acute coronary syndromes.

CONTEXT: The secondary prevention benefit of therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been clearly demonstrated; however, the role of early initiation of statins after acute coronary syndromes (ACSs) is unknown. OBJECTIVE: To evaluate the association of early statin initiation (< or = 7 days) after ACS with 90-day and 1-year outcomes. DESIGN: Observational cohort from databases of 2 randomized clinical trials, SYMPHONY and 2nd SYMPHONY. SETTING: Nine hundred thirty-one clinical centers in 37 countries. PATIENTS: A total of 12,365 ACS patients randomized from August 1997 to August 1999 who were not taking statins prior to the index ACS and who either started statin therapy early (median, 2.0 [interquartile range, 1.0-3.1] days after ACS; n = 3952) or survived more than 5 days after ACS and never received statin therapy (n = 8413). MAIN OUTCOME MEASURES: Ninety-day incidence of death; death or myocardial infarction (MI); and death, MI, or severe recurrent ischemia; as well as 1-year incidence of death. RESULTS: Ninety-day and 1-year unadjusted mortality comparison suggested early statin benefit (1.2% for early statins vs 2.1% for no statins; hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.42-0.81 for 90-day comparisons and 2.3% for early statins vs 4.4% for no statins; HR, 0.52; 95% CI, 0.40-0.68 for 1-year comparison). However, no benefit was evident for 90-day death or MI (6.5% vs 6.9%; HR, 0.95; 95% CI, 0.82-1.11) or death, MI, or severe recurrent ischemia (9.2% vs 8.9%; HR, 1.04; 95% CI, 0.92-1.18). After propensity and covariate adjustment, there were no 90-day or 1-year differences between the early-statin group and the no-statin group. The 90-day adjusted HR for death was 1.08 (95% CI, 0.75-1.56); for death or MI, 1.08 (95% CI, 0.91-1.29); and for death, MI, or severe recurrent ischemia, 1.15 (95% CI, 0.99-1.34). One-year mortality-adjusted HR was 0.99 (95% CI, 0.73-1.33). Among 2711 patients with core laboratory lipid analysis, early statin was associated with higher adjusted risk for death or death or MI at cholesterol levels below treatment guidelines but was more favorable at higher levels. CONCLUSIONS: In this study, there was no relationship between early initiation of statin therapy and improved outcomes although our subset analysis suggests that outcomes after early statin initiation may vary with cholesterol levels. Confirmation of early treatment effects of statins on outcomes awaits the results of adequately powered randomized clinical trials.

An automated strategy for bedside aPTT determination and unfractionated heparin infusion adjustment in acute coronary syndromes: insights from PARAGON A.

BACKGROUND: Intravenous unfractionated heparin remains a cornerstone of anticoagulation therapy for patients with acute coronary syndromes, but regulation to a target aPTT is challenging. We assessed unfractionated heparin infusion regulation by bedside, whole-blood aPTT testing and computerized, algorithmic infusion adjustment, and further evaluated the relationship of achieving the target aPTT with clinical outcomes. METHODS AND RESULTS: We studied 1,275 patients randomized to unfractionated heparin in PARAGON-A, which tested lamifiban with or without unfractionated heparin versus unfractionated heparin. All patients had baseline and 6-hour blinded, bedside aPTTs, then aPTTs per algorithm. A central computer translated encrypted values to algorithmic dose-adjustment commands. We assessed the ability to achieve and maintain aPTTs of 50-70 seconds and associations of 6- and 12-hour aPTTs and time-to-target with 30-day outcomes.Overall, the median 6-hour aPTT was 50-70 seconds and remained so throughout infusion. Individually, only 33.6% of patients achieved 6-hour target-range aPTTs, and only 40% of all aPTTs were in-range. After achieving target, only 42% of subsequent measures were in-range. Thirty-day death or myocardial infarction (death/MI) increased non-significantly as time-to-target increased (p = 0.08). Thirty-day mortality was similar if target aPTT was reached, regardless of timing. Death/MI trended lower if target aPTT was reached by 8 hours (p = 0.10). The best clinical outcomes were associated with in-range aPTTs. CONCLUSIONS: This study represents the most systematic monitoring and regulation of unfractionated heparin anticoagulation to date. Although average anticoagulation achieved target range, wide inter- and intra-patient variability may have important implications for clinical outcomes.

Aspirin use post-acute coronary syndromes: intolerance, bleeding and discontinuation.

BACKGROUND: While aspirin's secondary prevention benefit is clear, prior reports indicate that 19-83% of eligible patients may not use aspirin chronically. METHODS: We investigated intolerance and bleeding while on aspirin and aspirin discontinuation using 5337 post-acute coronary syndrome patients considered appropriate for chronic antiplatelet therapy who were randomly assigned to aspirin in SYMPHONY and 2nd SYMPHONY and followed for 94 (64,157) days. Multivariable logistic regression models tested associations between baseline characteristics and aspirin discontinuation and bleeding. RESULTS: Nearly 18% of patients discontinued study aspirin; 48% subsequently used open-label aspirin and 5% other antiplatelet or anticoagulant therapy. Black race, recurrent ischemia, hypertension, chronic obstructive pulmonary disease, lighter weight, shorter time to treatment and use of non-steroidal anti-inflammatory agents, diuretics, and digitalis were independently associated with early discontinuation. Early discontinuation was less likely in Eastern Europe, Latin America and Asia. Although major or minor bleeding was common (12.6%), only 1.0% of aspirin-treated patients were reported to discontinue due to bleeding. Gastrointestinal (10.5%) and puncture site (7.6%) were the most common bleeding locations. Bleeding risk was associated with lower estimated creatinine clearance, shorter time to treatment, smoking, Killip class >II, higher systolic blood pressure, and use of aspirin or heparin prior to starting study aspirin. CONCLUSIONS: Despite early initiation and close follow-up, more than 9% of aspirin-treated patients discontinued therapy early and remained off treatment. Addressing the factors associated with both bleeding and discontinuation during chronic therapy is necessary to improve adherence to this inexpensive, life-saving therapy.